Virtual tumor mapping and margin control with 3-D planning and navigation.

Computer technology-based treatment approaches like intraoperative navigation and intensity-modulated radiation therapy have become important components of state of the art head and neck cancer treatment. Multidirectional exchange of virtual three-dimensional patient data via an interdisciplinary platform allows all medical specialists involved in the patients treatment to take full advantage of these technologies. This review article gives an overview of current technologies and future directions regarding treatment approaches that are based on a virtual, three-dimensional patient specific dataset: storage and exchange of spatial information acquired via intraoperative navigation allow for a highly precise frozen section procedure. In the postoperative setting, virtual reconstruction of the tumor resection surface provides the basis for improved radiation therapy planning and virtual reconstruction of the tumor with integration of molecular findings creates a valuable tool for postoperative treatment and follow-up. These refinements of established treatment components and novel approaches have the potential to make a major contribution to improving the outcome in head and neck cancer patients.

AI-Based Detection of Oral Squamous Cell Carcinoma with Raman Histology.

Stimulated Raman Histology (SRH) employs the stimulated Raman scattering (SRS) of photons at biomolecules in tissue samples to generate histological images. Subsequent pathological analysis allows for an intraoperative evaluation without the need for sectioning and staining. The objective of this study was to investigate a deep learning-based classification of oral squamous cell carcinoma (OSCC) and the sub-classification of non-malignant tissue types, as well as to compare the performances of the classifier between SRS and SRH images. Raman shifts were measured at wavenumbers k1 = 2845 cm-1 and k2 = 2930 cm-1. SRS images were transformed into SRH images resembling traditional H&E-stained frozen sections. The annotation of 6 tissue types was performed on images obtained from 80 tissue samples from eight OSCC patients. A VGG19-based convolutional neural network was then trained on 64 SRS images (and corresponding SRH images) and tested on 16. A balanced accuracy of 0.90 (0.87 for SRH images) and F1-scores of 0.91 (0.91 for SRH) for stroma, 0.98 (0.96 for SRH) for adipose tissue, 0.90 (0.87 for SRH) for squamous epithelium, 0.92 (0.76 for SRH) for muscle, 0.87 (0.90 for SRH) for glandular tissue, and 0.88 (0.87 for SRH) for tumor were achieved. The results of this study demonstrate the suitability of deep learning for the intraoperative identification of tissue types directly on SRS and SRH images.

A content-aware chatbot based on GPT 4 provides trustworthy recommendations for Cone-Beam CT guidelines in dental imaging.

OBJECTIVES: To develop a content-aware chatbot based on GPT-3.5-Turbo and GPT-4 with specialized knowledge on the German S2 Cone-Beam CT (CBCT) dental imaging guideline and to compare the performance against humans. METHODS: The LlamaIndex software library was used to integrate the guideline context into the chatbots. Based on the CBCT S2 guideline, 40 questions were posed to content-aware chatbots and early career and senior practitioners with different levels of experience served as reference. The chatbots' performance was compared in terms of recommendation accuracy and explanation quality. Chi-square test and one-tailed Wilcoxon signed rank test evaluated accuracy and explanation quality, respectively. RESULTS: The GPT-4 based chatbot provided 100% correct recommendations and superior explanation quality compared to the one based on GPT3.5-Turbo (87.5% vs. 57.5% for GPT-3.5-Turbo; P = .003). Moreover, it outperformed early career practitioners in correct answers (P = .002 and P = .032) and earned higher trust than the chatbot using GPT-3.5-Turbo (P = 0.006). CONCLUSIONS: A content-aware chatbot using GPT-4 reliably provided recommendations according to current consensus guidelines. The responses were deemed trustworthy and transparent, and therefore facilitate the integration of artificial intelligence into clinical decision-making.

Reconstruction of dental roots for implant planning purposes: a retrospective computational and radiographic assessment of single-implant cases.

PURPOSE: The aim of the study was to assess the deviation between clinical implant axes (CIA) determined by a surgeon during preoperative planning and reconstructed tooth axes (RTA) of missing teeth which were automatically computed by a previously introduced anatomical SSM. METHODS: For this purpose all available planning datasets of single-implant cases of our clinic, which were planned with coDiagnostix Version 9.9 between 2018 and 2021, were collected for retrospective investigation. Informed consent was obtained. First, the intraoral scans of implant patients were annotated and subsequently analyzed using the SSM. The RTA, computed by the SSM, was then projected into the preoperative planning dataset. The amount and direction of spatial deviation between RTA and CIA were then measured. RESULTS: Thirty-five patients were implemented. The mean distance between the occlusal entry point of anterior and posterior implants and the RTA was 0.99 mm ± 0.78 mm and 1.19 mm ± 0.55, respectively. The mean angular deviation between the CIA of anterior and posterior implants and the RTA was 12.4° ± 3.85° and 5.27° ± 2.97° respectively. The deviations in anterior implant cases were systematic and could be corrected by computing a modified RTA (mRTA) with decreased deviations (0.99 mm ± 0.84 and 4.62° ± 1.95°). The safety distances of implants set along the (m)RTA to neighboring teeth were maintained in 30 of 35 cases. CONCLUSION: The RTA estimated by the SSM revealed to be a viable implant axis for most of the posterior implant cases. As there are natural differences between the anatomical tooth axis and a desirable implant axis, modifications were necessary to correct the deviations which occurred in anterior implant cases. However, the presented approach is not applicable for clinical use and always requires manual optimization by the planning surgeon.

Automated detection of cephalometric landmarks using deep neural patchworks.

OBJECTIVES: This study evaluated the accuracy of deep neural patchworks (DNPs), a deep learning-based segmentation framework, for automated identification of 60 cephalometric landmarks (bone-, soft tissue- and tooth-landmarks) on CT scans. The aim was to determine whether DNP could be used for routine three-dimensional cephalometric analysis in diagnostics and treatment planning in orthognathic surgery and orthodontics. METHODS: Full skull CT scans of 30 adult patients (18 female, 12 male, mean age 35.6 years) were randomly divided into a training and test data set (each n = 15). Clinician A annotated 60 landmarks in all 30 CT scans. Clinician B annotated 60 landmarks in the test data set only. The DNP was trained using spherical segmentations of the adjacent tissue for each landmark. Automated landmark predictions in the separate test data set were created by calculating the center of mass of the predictions. The accuracy of the method was evaluated by comparing these annotations to the manual annotations. RESULTS: The DNP was successfully trained to identify all 60 landmarks. The mean error of our method was 1.94 mm (SD 1.45 mm) compared to a mean error of 1.32 mm (SD 1.08 mm) for manual annotations. The minimum error was found for landmarks ANS 1.11 mm, SN 1.2 mm, and CP_R 1.25 mm. CONCLUSION: The DNP-algorithm was able to accurately identify cephalometric landmarks with mean errors <2 mm. This method could improve the workflow of cephalometric analysis in orthodontics and orthognathic surgery. Low training requirements while still accomplishing high precision make this method particularly promising for clinical use.

Basic Principles of RNA Interference: Nucleic Acid Types and In Vitro Intracellular Delivery Methods.

Since its discovery in 1989, RNA interference (RNAi) has become a widely used tool for the in vitro downregulation of specific gene expression in molecular biological research. This basically involves a complementary RNA that binds a target sequence to affect its transcription or translation process. Currently, various small RNAs, such as small interfering RNA (siRNA), micro RNA (miRNA), small hairpin RNA (shRNA), and PIWI interacting RNA (piRNA), are available for application on in vitro cell culture, to regulate the cells' gene expression by mimicking the endogenous RNAi-machinery. In addition, several biochemical, physical, and viral methods have been established to deliver these RNAs into the cell or nucleus. Since each RNA and each delivery method entail different off-target effects, limitations, and compatibilities, it is crucial to understand their basic mode of action. This review is intended to provide an overview of different nucleic acids and delivery methods for planning, interpreting, and troubleshooting of RNAi experiments.

Stimulated Raman histology for histological evaluation of oral squamous cell carcinoma.

OBJECTIVES: To investigate whether in patients undergoing surgery for oral squamous cell carcinoma, stimulated Raman histology (SRH), in comparison with H&E-stained frozen sections, can provide accurate diagnoses regarding neoplastic tissue and sub-classification of non-neoplastic tissues. MATERIALS AND METHODS: SRH, a technology based on Raman scattering, was applied to generate digital histopathologic images of 80 tissue samples obtained from 8 oral squamous cell carcinoma (OSCC) patients. Conventional H&E-stained frozen sections were then obtained from all 80 samples. All images/sections (SRH and H&E) were analyzed for squamous cell carcinoma, normal mucosa, connective tissue, muscle tissue, adipose tissue, salivary gland tissue, lymphatic tissue, and inflammatory cells. Agreement between SRH and H&E was evaluated by calculating Cohen's kappa. Accuracy of SRH compared to H&E was quantified by calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) as well as area under the receiver operating characteristic curve (AUC). RESULTS: Thirty-six of 80 samples were classified as OSCC by H&E-based diagnosis. Regarding the differentiation between neoplastic and non-neoplastic tissue, high agreement between H&E and SRH (kappa: 0.880) and high accuracy of SRH (sensitivity: 100%; specificity: 90.91%; PPV: 90.00%, NPV: 100%; AUC: 0.954) were demonstrated. For sub-classification of non-neoplastic tissues, SRH performance was dependent on the type of tissue, with high agreement and accuracy for normal mucosa, muscle tissue, and salivary glands. CONCLUSION: SRH provides high accuracy in discriminating neoplastic and non-neoplastic tissues. Regarding sub-classification of non-neoplastic tissues in OSCC patients, accuracy varies depending on the type of tissue examined. CLINICAL RELEVANCE: This study demonstrates the potential of SRH for intraoperative imaging of fresh, unprocessed tissue specimens from OSCC patients without the need for sectioning or staining.

Donor site morbidity after computer assisted surgical reconstruction of the mandible using deep circumflex iliac artery grafts: a cross sectional study.

BACKGROUND: Computer Assisted Design and Computer Assisted Manufacturing (CAD/CAM) have revolutionized oncologic surgery of the head and neck. A multitude of benefits of this technique has been described, but there are only few reports of donor site comorbidity following CAD/CAM surgery. METHODS: This study investigated comorbidity of the hip following deep circumflex iliac artery (DCIA) graft raising using CAD/CAM techniques. A cross-sectional examination was performed to determine range of motion, muscle strength and nerve disturbances. Furthermore, correlations between graft volume and skin incision length with postoperative donor site morbidity were assessed using Spearman's rank correlation, linear regression and analysis of variance (ANOVA). RESULTS: Fifteen patients with a mean graft volume of 21.2 ± 5.7 cm3 and a mean incision length of 228.0 ± 30.0 mm were included. Patients reported of noticeable physical limitations in daily life activities (12.3 ± 11.9 weeks) and athletic activities (38.4 ± 40.0 weeks in mean) following surgery. Graft volume significantly correlated with the duration of the use of walking aids (R = 0.57; p = 0.033) and impairment in daily life activities (R = 0.65; p = 0.012). The length of the scar of the donor-site showed a statistically significant association with postoperative iliohypogastric nerve deficits (F = 4.4, p = 0.037). Patients with anaesthaesia of a peripheral cutaneous nerve had a larger mean scar length (280 ± 30.0 mm) than subjects with hypaesthesia (245 ± 10.1 mm) or no complaints (216 ± 27.7 mm). CONCLUSIONS: Despite sophisticated planning options in modern CAD/CAM surgery, comorbidity of the donor site following  iliac graft harvesting is still a problem. This study is the first to investigate comorbidity after DCIA graft raising in a patient group treated exclusively with CAD/CAM techniques. The results indicate that a minimal invasive approach in terms of small graft volumes and small skin incisions could help to reduce postoperative symptomatology. Trial registration Retrospectively registered at the German Clinical Trials Register (DRKS-ID: DRKS00029066); registration date: 23/05/2022.

Analysis of the accuracy of computer-assisted DCIA flap mandibular reconstruction applying a novel approach based on geometric morphometrics.

BACKGROUND: This study evaluated the accuracy of computer-assisted surgery (CAS)-driven DCIA (deep circumflex iliac artery) flap mandibular reconstruction by traditional morphometric methods and geometric morphometric methods (GMM). METHODS: Reconstruction accuracy was evaluated by measuring distances and angles between bilateral anatomical landmarks. Additionally, the average length of displacements vectors between landmarks was computed to evaluate factors assumed to influence reconstruction accuracy. Principal component analysis (PCA) was applied to unveil main modes of dislocation. RESULTS: High reconstruction accuracy could be demonstrated for a sample consisting of 26 patients. The effect of the number of segments and length of defect on reconstruction accuracy were close to the commonly used significance threshold (p = 0.062/0.060). PCA demonstrated displacement to result mainly from sagittal and transversal shifts. CONCLUSIONS: CAS is a viable approach to achieve high accuracy in mandibular reconstruction and GMM can facilitate the evaluation of factors influencing reconstruction accuracy and unveil main modes of dislocation in this context.

Impurities in commercial titanium dental implants - A mass and optical emission spectrometry elemental analysis.

OBJECTIVE: Titanium (Ti) is considered bioinert and is still regarded as the "gold standard" material for dental implants. However, even 'commercial pure' Ti will contain minor fractions of elemental impurities. Evidence demonstrating the release of Ti ions and particles from 'passive' implant surfaces is increasing and has been attributed to biocorrosion processes which may provoke immunological reactions. However, Ti observed in peri-implant tissues has been shown to be co-located with elements considered impurities in biomedical alloys. Accordingly, this study aimed to quantify the composition of impurities in commercial Ti dental implants. METHODS: Fifteen commercial titanium dental implant systems were analyzed using inductively coupled plasma-mass spectrometry (ICP-MS) and optical emission spectrometry (ICP-OES). RESULTS: The elemental composition of implants manufactured from commercially pure grades of Ti, Ti-6Al-4V, and the TiZr alloy (Roxolid) conformed to the respective ISO/ASTM standards or manufacturers´ data (TiZr/Roxolid). However, all implants investigated included exogenous metal contaminants including Ni, Cr, Sb, and Nb to a variable extent. Other contaminants detected in a fraction of implants included As and the radionuclides U-238 and Th-232. SIGNIFICANCE: Although all Ti implant studies conformed with their standard compositions, potentially allergenic, noxious metals and even radionuclides were detected. Since there are differences in the degree of contamination between the implant systems, a certain impurity fraction seems technically avoidable. The clinical relevance of these findings must be further investigated, and an adaptation of industry standards should be discussed.

Comparison of the 3D-Microstructure Between Alveolar and Iliac Bone for Enhanced Bioinspired Bone Graft Substitutes.

In oral- and maxillofacial bone augmentation surgery, non-vascularized grafts from the iliac crest demonstrate better clinical performance than alveolar bone grafts. The underlying mechanisms are not fully understood but are essential for the enhancement of bone regeneration scaffolds. Synchrotron Radiation µ-CT at a pixel size of 2.3 µm was used to characterize the gross morphology and the vascular and osteocyte lacuna porosity of patient-matched iliac crest/alveolar bone samples. The results suggest a difference in the spatial distribution of the vascular pore system. Fluid simulations reveal the permeability tensor to be more homogeneous in the iliac crest, indicating a more unidirectional fluid flow in alveolar bone. The average distance between bone mineral and the closest vessel pore boundary was found to be higher in alveolar bone. At the same time, osteocyte lacunae density is higher in alveolar bone, potentially compensating for the longer average distance between the bone mineral and vessel pores. The present study comprehensively quantified and compared the 3D microarchitecture of intraindividual human alveolar and iliac bone. The identified difference in pore network architecture may allow a bone graft from the iliac crest to exhibit higher regeneration potential due to an increased capacity to connect with the surrounding pore network of the residual bone. The results may contribute to understanding the difference in clinical performance when used as bone grafts and are essential for optimization of future scaffold materials.

Automated segmentation of head CT scans for computer-assisted craniomaxillofacial surgery applying a hierarchical patch-based stack of convolutional neural networks.

PURPOSE: Computer-assisted techniques play an important role in craniomaxillofacial surgery. As segmentation of three-dimensional medical imaging represents a cornerstone for these procedures, the present study was aiming at investigating a deep learning approach for automated segmentation of head CT scans. METHODS: The deep learning approach of this study was based on the patchwork toolbox, using a multiscale stack of 3D convolutional neural networks. The images were split into nested patches using a fixed 3D matrix size with decreasing physical size in a pyramid format of four scale depths. Manual segmentation of 18 craniomaxillofacial structures was performed in 20 CT scans, of which 15 were used for the training of the deep learning network and five were used for validation of the results of automated segmentation. Segmentation accuracy was evaluated by Dice similarity coefficient (DSC), surface DSC, 95% Hausdorff distance (95HD) and average symmetric surface distance (ASSD). RESULTS: Mean for DSC was 0.81 ± 0.13 (range: 0.61 [mental foramen] - 0.98 [mandible]). Mean Surface DSC was 0.94 ± 0.06 (range: 0.87 [mental foramen] - 0.99 [mandible]), with values > 0.9 for all structures but the mental foramen. Mean 95HD was 1.93 ± 2.05 mm (range: 1.00 [mandible] - 4.12 mm [maxillary sinus]) and for ASSD, a mean of 0.42 ± 0.44 mm (range: 0.09 [mandible] - 1.19 mm [mental foramen]) was found, with values < 1 mm for all structures but the mental foramen. CONCLUSION: In this study, high accuracy of automated segmentation of a variety of craniomaxillofacial structures could be demonstrated, suggesting this approach to be suitable for the incorporation into a computer-assisted craniomaxillofacial surgery workflow. The small amount of training data required and the flexibility of an open source-based network architecture enable a broad variety of clinical and research applications.

Computed Tomography-Based Investigation on the Effects of Intravenous Bisphosphonate Administration on Tooth Growth in a Minipig Animal Model.

Background and Objectives: The objective of this study was to evaluate the effects of bisphosphonate (BP) administration on tooth growth, using CT-data of a minipig animal model investigation. Materials and Methods: Tooth growth was evaluated in minipigs, with eight animals receiving weekly zoledronate (ZOL) and three animals serving as the control group. Tooth growth was evaluated at the right 2nd molar (M2) in the maxilla. A computed tomography-based measuring method was applied to evaluate tooth growth in the coronal-apical, buccal-oral and mesial-distal axis. Results: ZOL-administration was found to impact tooth growth in all evaluated measuring axes, with the highest effect observed in the coronal-apical axis. Conclusions: Detrimental effects of BP administration on growing teeth have been reported by a number of investigators. The results of this investigation demonstrate that intravenous ZOL affects the growth of the whole tooth within a short period of administration. With BPs being administered to a growing number of pediatric patients, further studies should be conducted to qualify and quantify the effects of BPs on developing teeth.

Increased Osteogenic Activity of Dynamic Cultured Composite Bone Scaffolds: Characterization and In Vitro Study.

PURPOSE: The purpose of this study was to develop and characterize beta-tricalcium phosphate (ß-TCP)/polycaprolactone (PCL) scaffolds, with 2 different ratios (50/50% and 65/35%), using 3-dimensionally (3D) printed dissolvable molds, and to evaluate cellular growth and osteogenic differentiation of both groups seeded with porcine bone marrow stem cells (pBMSCs) under dynamic culture in vitro. MATERIALS AND METHODS: Two different groups of scaffolds were produced: group 1 (n = 40) with a ratio (wt%) of 50/50% and group 2 (n = 40) with 65/35% of ß-TCP/PCL. Physicochemical, morphological, and mechanical characterization of the scaffolds were performed. Scaffolds were seeded with pBMSCs and differentiated osteogenically in dynamic culture. Cell density, distribution, and viability were assessed. Osteogenic differentiation was examined through alkaline phosphatase (ALP) staining, immunofluorescence, and photospectrometry. RESULTS: Osteogenic differentiated constructs showed homogenous and viable cell distribution. Cell density was significantly higher (P < .05) for 65/35% scaffolds at 10 days postseeding, whereas at 6 weeks, cell number equalized for both groups. ALP activity increased over time and was significantly higher (P < .05) for 65/35% scaffolds at 14 days postseeding. CONCLUSIONS: The mechanical properties of the developed 65/35% scaffolds were within the range of natural trabecular bone. Moreover, the 65/35% scaffolds showed biological advantages, such as higher cell growth and higher ALP activity.

Stimulated Raman histology in the neurosurgical workflow of a major European neurosurgical center - part A.

Histopathological diagnosis is the current standard for the classification of brain and spine tumors. Raman spectroscopy has been reported to allow fast and easy intraoperative tissue analysis. Here, we report data on the intraoperative implementation of a stimulated Raman histology (SRH) as an innovative strategy offering intraoperative near real-time histopathological analysis. A total of 429 SRH images from 108 patients were generated and analyzed by using a Raman imaging system (Invenio Imaging Inc.). We aimed at establishing a dedicated workflow for SRH serving as an intraoperative diagnostic, research, and quality control tool in the neurosurgical operating room (OR). First experiences with this novel imaging modality were reported and analyzed suggesting process optimization regarding tissue collection, preparation, and imaging. The Raman imaging system was rapidly integrated into the surgical workflow of a large neurosurgical center. Within a few minutes of connecting the device, the first high-quality images could be acquired in a "plug-and-play" manner. We did not encounter relevant obstacles and the learning curve was steep. However, certain prerequisites regarding quality and acquisition of tissue samples, data processing and interpretation, and high throughput adaptions must be considered. Intraoperative SRH can easily be integrated into the workflow of neurosurgical tumor resection. Considering few process optimizations that can be implemented rapidly, high-quality images can be obtained near real time. Hence, we propose SRH as a complementary tool for the diagnosis of tumor entity, analysis of tumor infiltration zones, online quality and safety control and as a research tool in the neurosurgical OR.

Neuropathological interpretation of stimulated Raman histology images of brain and spine tumors: part B.

Intraoperative histopathological examinations are routinely performed to provide neurosurgeons with information about the entity of tumor tissue. Here, we quantified the neuropathological interpretability of stimulated Raman histology (SRH) acquired using a Raman laser imaging system in a routine clinical setting without any specialized training or prior experience. Stimulated Raman scattering microscopy was performed on 117 samples of pathological tissue from 73 cases of brain and spine tumor surgeries. A board-certified neuropathologist - novice in the interpretation of SRH - assessed image quality by scoring subjective tumor infiltration and stated a diagnosis based on the SRH images. The diagnostic accuracy was determined by comparison to frozen hematoxylin-eosin (H&E)-stained sections and the ground truth defined as the definitive neuropathological diagnosis. The overall SRH imaging quality was rated high with the detection of tumor cells classified as inconclusive in only 4.2% of all images. The accuracy of neuropathological diagnosis based on SRH images was 87.7% and was non-inferior to the current standard of fast frozen H&E-stained sections (87.3 vs. 88.9%, p = 0.783). We found a substantial diagnostic correlation between SRH-based neuropathological diagnosis and H&E-stained frozen sections (κ = 0.8). The interpretability of intraoperative SRH imaging was demonstrated to be equivalent to the current standard method of H&E-stained frozen sections. Further research using this label-free innovative alternative vs. conventional staining is required to determine to which extent SRH-based intraoperative decision-making can be streamlined in order to facilitate the advancement of surgical neurooncology.

The Role of von Willebrand Factor in Microvascular Surgery in Severely Injured Patients.

Microvascular anastomosis has become a standard surgical technique for reconstruction because of increasing possibilities, indications, and clinical success regarding the survival of the flaps. However, the main dreaded complications exist in thrombosis. Leaving surgical complications aside, systemic problems like disorder of the coagulation-fibrinolysis system are a significant cause of graft loss usually being unrecognized. Reports exist describing a hypercoagulable state with clotting activation and inhibition of fibrinolysis after trauma and delayed surgery considering the secondary homeostasis. In this clinical case, a patient had a large soft tissue defect at the temporal side of the head after severe trauma. After some days of primary stabilization, reconstruction using a free microvascular latissimus dorsi flap was performed. Multiple revisions of the arterial and venous branches had to be performed intraoperatively due to insufficient flap perfusion. After 24 hours, definitive flap loss occurred due to multiple thrombosis in the arterial and venous branches. Postoperative comprehensive coagulation analysis revealed a distinct activation of primary hemostasis with massively increased von Willebrand factor parameters and factor VIII activity as well as acetylsalicylic acid resistance contributing to thrombotic occlusion. In severely injured patients, comprehensive preoperative determination of the coagulation status (especially those of the primary hemostasis) is indispensable before performing free flap reconstruction surgeries to reduce the risk of microvascular flap loss.

Evaluation of computed tomography settings in the context of visualization and discrimination of low dose injections of a novel liquid soft tissue fiducial marker in head and neck imaging.

BACKGROUND: Intraoperative incorporation of radiopaque fiducial markers at the tumor resection surface can provide useful assistance in identifying the tumor bed in postoperative imaging for RT planning and radiological follow-up. Besides titanium clips, iodine containing injectable liquid fiducial markers represent an option that has emerged more recently for this purpose. In this study, marking oral soft tissue resection surfaces, applying low dose injections of a novel Conformité Européenne (CE)-marked liquid fiducial marker based on sucrose acetoisobutyrate (SAIB) and iodinated SAIB (x-SAIB) was investigated. METHODS: Visibility and discriminability of low dose injections of SAIB/x-SAIB (10 µl, 20 µl, 30 µl) were systematically studied at different kV settings used in clinical routine in an ex-vivo porcine mandible model. Transferability of the preclinical results into the clinical setting and applicability of DE-CT were investigated in initial patients. RESULTS: Markers created by injection volumes as low as 10 µl were visible in CT imaging at all kV settings applied in clinical routine (70-120 kV). An injection volume of 30 µl allowed differentiation from an injection volume of 10 µl. In a total of 118 injections performed in two head and neck cancer patients, markers were clearly visible in 83% and 86% of injections. DE-CT allowed for differentiation between SAIB/x-SAIB markers and other hyperdense structures. CONCLUSIONS: Injection of low doses of SAIB/x-SAIB was found to be a feasible approach to mark oral soft tissue resection surfaces, with injection volumes as low as 10 µl found to be visible at all kV settings applied in clinical routine. With the application of SAIB/x-SAIB reported for tumors of different organs already, mostly applying relatively large volumes for IGRT, this study adds information on the applicability of low dose injections to facilitate identification of the tumor bed in postoperative CT and on performance of the marker at different kV settings used in clinical routine.

Intraoperative marking of the tumour resection surface for improved radiation therapy planning in head and neck cancer: preclinical evaluation of a novel liquid fiducial marker.

OBJECTIVE: To evaluate a novel liquid fiducial marker for intraoperative marking of the tumour resection surface in oral cancer patients to facilitate precise postoperative delineation of the interface between the tumour resection border and reconstructed tissue for intensity-modulated radiation therapy. METHODS: A total of 200 markers were created by injecting the volumes of 10 µl, 20 µl, 30 µl, 40 µl and 50 µl of a liquid marker composed of sucrose acetoisobutyrate (SAIB) and iodinated sucrose acetoisobutyrate (x-SAIB) into the soft tissue of porcine mandible segments. Visibility of the resulting markers was quantified by threshold-based segmentation of the marker volume in CT- and CBCT imaging and by a comparison of signal intensities in MRI. RESULTS: Even the lowest volume of SAIB-/x-SAIB investigated (10 µl) resulted in a higher visibility (CTSoft tissue: 88.18 ± 13.23 µl; CTBone: 49.55 ± 7.62 µl; CBCT: 54.65 ± 12.58 µl) than observed with the incorporation of titanium ligature clips (CTSoft tissue: 50.15 ± 7.50 mm3; CTBone: 23.90 ± 3.39 mm3; CBCT: 33.80 ± 9.20 mm3). Markers created by the injection of 10 µl and 20 µl could reliably be delineated from markers created by the injection of higher volumes. CONCLUSION: SAIB/x-SAIB, which has recently become available as a Conformité Européenne (CE)-marked fiducial marker, provides an option for fast and reliable production of markers with excellent visibility in imaging modalities used in oral cancer radiation therapy (RT) planning routine.

Concentration of Penicillin G in Jawbone Affected by Antiresorptive Agent-Related Osteonecrosis Following a Single Preoperative Dose.

The aim of this study was to evaluate the concentration of penicillin G in bone affected by antiresorptive agent-related osteonecrosis of the jaw (ARONJ) following a single preoperative dose of 10 million international units (6000 mg). ARONJ is a major concern in patients administered antiresorptive agents for conditions associated with pathologically increased bone resorption. Antibiotic therapy is a key component of most treatment approaches for ARONJ and penicillin based regimens, providing a cost effective therapy option with a favorable side effect profile, are administered most frequently. In this study, high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) was applied to evaluate penicillin G concentration in serum and bone samples of 19 patients suffering from ARONJ and undergoing surgical treatment under perioperative intravenous (IV) antibiotic therapy. Penicillin G bone concentrations were above the limit of detection (0.1 µg/g bone tissue) in 16 out of 19 samples, with a median concentration of 2.7 µg/g (range 0.1-8.8 µg/g). Penicillin G concentrations in intraoperative serum samples were above the limit of detection in all serum samples, with a median concentration of 116 µg/mL (range 1-232 µg/mL). Thus, considering bacteria frequently found in ARONJ lesions, penicillin G at levels providing adequate antimicrobial activity was detected in the serum and 16 out of 19 osteonecrotic lesions of patients suffering from ARONJ.