Influence of analytical procedures on miRNA expression analyses in saliva samples.

Aim of this study was to demonstrate the influence of different analytical procedures and techniques on the resulting miRNA expression profile in healthy control subjects and tumor patients using the oral squamous cell carcinoma (OSCC) model and to demonstrate the technical and biological reproducibility. Body fluids such as saliva are suitable for non-invasive miRNA analysis because ubiquitously circulating miRNA can be found in them. It was technically possible to distinguish between healthy and diseased samples based on the miRNA expression profile found. Regardless of the methodology used, good technical reproducibility of the results seems to be achievable. On the other hand, biological reproducibility was inadequate, which is why prompt sampling and sequencing is recommended. The data indicate that malignant lesions can be detected using miRNA signatures extracted from saliva. This could stimulate further research to establish standardized protocols and kits for sample collection, miRNA extraction, sequencing and interpretation of results.

Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial.

Antibodies targeting the immune checkpoint molecules PD-1, PD-L1 and CTLA-4, administered alone or in combination with chemotherapy, are the standard of care in most patients with metastatic non-small-cell lung cancers. When given before curative surgery, tumor responses and improved event-free survival are achieved. New antibody combinations may be more efficacious and tolerable. In an ongoing, open-label phase 2 study, 60 biomarker-unselected, treatment-naive patients with resectable non-small-cell lung cancer were randomized to receive two preoperative doses of nivolumab (anti-PD-1) with or without relatlimab (anti-LAG-3) antibody therapy. The primary study endpoint was the feasibility of surgery within 43 days, which was met by all patients. Curative resection was achieved in 95% of patients. Secondary endpoints included pathological and radiographic response rates, pathologically complete resection rates, disease-free and overall survival rates, and safety. Major pathological (≤10% viable tumor cells) and objective radiographic responses were achieved in 27% and 10% (nivolumab) and in 30% and 27% (nivolumab and relatlimab) of patients, respectively. In 100% (nivolumab) and 90% (nivolumab and relatlimab) of patients, tumors and lymph nodes were pathologically completely resected. With 12 months median duration of follow-up, disease-free survival and overall survival rates at 12 months were 89% and 93% (nivolumab), and 93% and 100% (nivolumab and relatlimab). Both treatments were safe with grade ≥3 treatment-emergent adverse events reported in 10% and 13% of patients per study arm. Exploratory analyses provided insights into biological processes triggered by preoperative immunotherapy. This study establishes the feasibility and safety of dual targeting of PD-1 and LAG-3 before lung cancer surgery.ClinicalTrials.gov Indentifier: NCT04205552 .

Extracranial Hypoglossal Schwannoma: Case Report and Literature Review.

BACKGROUND: Schwannomas are solitary neurogenic tumors originating from the myelin sheath of peripheral nerves. Extracranial hypoglossal schwannomas comprise <5% of all head and neck schwannomas and can mimic submandibular salivary gland tumors. CASE REPORT: We report the diagnostic imaging, surgical treatment, and histopathological findings of a rare case of extracranial schwannoma of the hypoglossal nerve in a 73-year-old female, presented with an asymptomatic swelling in the left submandibular region that had been persisted for approximately three years. CONCLUSION: Accurate diagnosis of this rare clinical entity requires comprehensive diagnostics. The optimal therapeutic strategy is nerve-sparing surgical excision, although it can be challenging.

Evaluation of Five-year Overall Survival Rates Among 18,331 Head and Neck Cancer Patients Exposed to Different Targeted Therapies Through Real-world Data in a Case-controlled Study.

BACKGROUND/AIM: Targeted therapy is an important and fast developing aspect of modern tumor therapy including therapy of head and neck cancer (HNC). Surgically treated patients often experience significant limitations to their ability to swallow, speak, or mimic expressions. In cases of recurrent tumors or palliative situations, targeted therapies such as immune checkpoint inhibitors (ICI) are frequently employed. This study compared different targeted therapies focusing on survival probability. PATIENTS AND METHODS: Data from patients with head and neck cancer treated with different therapy regimens from the TriNetX network were analyzed. Two groups were formed: Cohort I received one targeted therapy, whereas patients in cohort II received a different targeted therapy. Cohorts I and II were matched 1:1 with respect to certain confounders. After defining the primary outcome as "death", a Kaplan-Meier analysis was performed, and the risk ratio (RR), odds ratio (OR), and hazard ratio (HR) were calculated. RESULTS: A total of 18,331 patients with HNC treated with targeted therapy were analyzed. Patients treated with VEGF inhibitors had a significantly longer overall survival than patients treated with c-MET or EGFR inhibitors. Patients treated with PI3K inhibitors showed a significantly reduced survival probability compared to those treated with c-MET, mTOR, and RET inhibitors. CONCLUSION: EGFR inhibitors are one of the most frequently used targeted therapies in HNC. However, in the present analysis, a survival advantage of patients treated with c-MET inhibitors or VEGF inhibitors was observed compared to those treated with EGFR inhibitors.

Sex-specific Real-World 5-year Overall Survival Rates for (Radio)chemotherapy, Targeted Therapy, and Combinations in Patients With Head and Neck Cancer.

BACKGROUND/AIM: Sex-specific medicine, an emerging field in healthcare, has gained significant recognition and importance in recent years. To the best of our knowledge, there are currently no valid data on the influence of sex on 5-year overall survival of patients with head and neck cancer undergoing (radio)chemotherapy, targeted therapy, and combination treatments, using Real-World Data. We hypothesize that sex has a significant impact on 5-year overall survival across different therapy regimens for head and neck cancer. PATIENTS AND METHODS: Data from head and neck cancer patients treated with different regimens from the TriNetX network were analyzed. Two groups were formed: Cohort I (female) and cohort II (male), which were matched 1:1 with respect to certain confounders. After defining the primary outcome as "death", a Kaplan-Meier analysis was performed, and the risk ratio (RR), odds ratio (OR) and hazard ratio (HR) were calculated. RESULTS: A total of 16,529 patients with OSCC were analyzed. This retrospective case-matched analysis found a tendency for female patients to have a greater 5-year overall survival probability than male patients with respect to the various therapeutic regimens for OSCC. CONCLUSION: There is an urgent need for more personalized medicine in patients with head and neck cancer due to the limited data available. It is still questionable whether therapies are equally effective in men and women, although, according to the guidelines, the treatments are mostly the same for both sexes.

Ibuprofen Reduces 5-Year Overall Survival of Head and Neck Cancer Patients With Immunotherapy - A Retrospective Case-controlled Real-World Data Analysis of 10,000 Patients.

BACKGROUND/AIM: Resistance to immunotherapy can be explained by an abnormal microbiome of the gut. In Europe in particular, the use of ibuprofen, with or without proton-pump inhibitors to protect the gastric mucosa, is widespread. This study aimed to investigate the impact of ibuprofen use on the effectiveness of immunotherapy in patients with head and neck carcinoma. PATIENTS AND METHODS: Data from patients with head and neck carcinoma (ICD-10-Codes: C00-C14) receiving pembrolizumab, from the TriNetX network, were analyzed. Two groups were formed for the analyses: Cohort I received ibuprofen at least once within 6 months before and after immunotherapy, whereas patients in cohort II received ibuprofen with proton-pump inhibitors or no ibuprofen at all. Cohorts I and II were matched 1:1 with respect to age, sex, lymph node metastases, nicotine dependence, alcohol dependence, and body mass index (BMI). The primary outcome was death and a Kaplan-Meier analysis was performed, and the risk ratio (RR), odds ratio (OR), and hazard ratio (HR) were calculated. RESULTS: The analysis showed that 823 patients with ibuprofen and 724 patients without ibuprofen died within 5 years, showing a significant risk difference of 5.3% (p=0.001). The RR was 1.137 [95% confidence interval (CI)=1.053-1.227], OR was 1.245 (95% CI=1.093-1.418), and HR was 1.202 (95%CI=1.088-1.329). CONCLUSION: Ibuprofen significantly decreases the drug effectiveness of immunotherapy and may be related to changes in the human microbiome. However, further prospective, randomized, and double-blind studies are needed to validate our data and to adequately address confounders.

The Multifaceted Roles of Lamins in Lung Cancer and DNA Damage Response.

Emerging evidence suggests that lamin functions are not limited to maintaining the structural integrity of the nucleus in eukaryotic cells but that these functions affect many facets of cancer biology. An increasing number of reports suggest that adaptive changes in the lamin subtype composition within the nuclear lamina could affect essential features of cancer development and aggressiveness. These include regulation of cellular stiffness and mobility as well as epithelial-to-mesenchymal transition (EMT), all of which directly impact the metastatic properties of cancer cells. Additionally, insights from studies on the physiological functions of lamins suggest that cancer cells could hijack the ability of lamins to modify chromatin accessibility, cell cycle regulation, and DNA damage response. Here, we present a comprehensive overview of the role of lamins in lung cancer and DNA damage response, which is commonly evoked by lung cancer therapies. Collectively, this information should help better understand the sometimes-conflicting reports on lamin functions in lung cancer as well as in other cancer types.

Prosthetically guided oral implant surgery. A retrospective cohort study evaluating the 5-year surgical outcome.

Purpose: This study primarily evaluated the 5-year implant survival and success rate of prosthetically guided inserted implants. The secondary aim was to evaluate the impact of clinical variables on the development of mucositis, peri-implant bone resorption, peri-implantitis, as well as early and late implant failure. Materials and methods: An observational retrospective single-centre study was conducted on patients who were treated with dental implants in the department of oral and plastic maxillofacial surgery of the military hospital of Ulm University between 2008 and 2010. In all patients, computer-assisted 3D planning after wax-up of the prosthetic restoration and template-guided surgery with titanium implants were performed. Bone augmentation procedures were performed primarily if needed. Intraoperative and postoperative complications as well as technical and mechanical complications after prosthesis loading were evaluated. In a 5-year clinical and radiological follow-up, implant success and implant survival were assessed using descriptive statistics. A multivariable regression analysis evaluated the potential impact of augmentation procedures, wound healing complications, smoking, history of periodontitis, and preoperative API (approximal plaque index) and SBI (sulcus bleeding index) values on peri-implant mucositis, peri-implant bone resorption, peri-implantitis, as well as early and late implant failure. Results: In this study, 466 implants in 283 patients were considered for inclusion, and sufficient data were obtained for analysis from 368 (78.9%) implants in 229 (80.9%) patients. An overall implant survival rate of 98.1% (n=361/368) at the 5-year follow-up was revealed. According to the success criteria of the study, the 5-year success rate was 97.04% (n=263/271). An early implant failure of 1.07% (n=5/466) was recorded. 48.2% of the implants were affected by peri-implant mucositis (n=122/253), while peri-implant bone resorption was detected in 21.7% of the radiologically examined implants (n=59/271). Fifteen cases of peri-implantitis (5.5%) were detected. Peri-implant bone resorption increased significantly after bone augmentation procedures (p=0.028). Wound healing complications after implantation significantly increased the prevalence of late implant failure in the maxilla (p<0.001). Peri-implant bone resorption and peri-implantitis were significantly more prevalent in smokers (p=0.022/p=0.043). Implants in patients with API>20% presented significantly higher rates of peri-implant mucositis (p=0.042). Wound healing complications after augmentation, history of periodontitis, and SBI>20% had no significant impact on the study parameters. Conclusions: The study confirms the reliability of prosthetically guided implant surgery, showing a high implant survival and success rate in a 5-year follow-up. Intraoperative complications and technical or mechanical complications after prosthesis loading remain within acceptable clinical limits. The rate of peri-implant mucositis, peri-implant bone resorption, and peri-implantitis was within the current literature range. Optimizing periodontal health and reducing smoking would improve the outcome. Further studies need to clarify the clinical indications and investigate the long-term surgical outcome of this treatment concept.

Accuracy Analysis of Computer-Assisted and Guided Dental Implantology by Comparing 3D Planning Data and Actual Implant Placement in a Mandibular Training Model: A Monocentric Comparison between Dental Students and Trained Implantologists.

The aim of this study was to investigate how precisely implantation can be realized by participants on a phantom head according to preliminary planning. Of particular interest here was the influence of participants' previous knowledge and surgical experience on the precision of the implant placement. The placed implants were scanned using an intraoral scanner, saved as STL files, and superimposed with the 3D-planned implant placement. Deviations from the planning were indicated in millimeters and degrees. We were able to show that on average, the deviations from computer-assisted 3D planning were less than 1 mm for implantologists, and the students also did not deviate more than 1.78 mm on average from 3D planning. This study shows that guided implantology provides predictable and reproducible results in dental implantology. Incorrect positioning, injuries to anatomical structures, and implant positions that cannot be prosthetically restored can thus be avoided.

Surface Chemistry and Specific Surface Area Rule the Efficiency of Gold Nanoparticle Sensitizers in Proton Therapy.

Gold nanoparticles (AuNPs) are currently the most studied radiosensitizers in proton therapy (PT) applicable for the treatment of solid tumors, where they amplify production of reactive oxygen species (ROS). However, it is underexplored how this amplification is correlated with the AuNPs' surface chemistry. To clarify this issue, we fabricated ligand-free AuNPs of different mean diameters by laser ablation in liquids (LAL) and laser fragmentation in liquids (LFL) and irradiated them with clinically relevant proton fields by using water phantoms. ROS generation was monitored by the fluorescent dye 7-OH-coumarin. Our findings reveal an enhancement of ROS production driven by I) increased total particle surface area, II) utilization of ligand-free AuNPs avoiding sodium citrate as a radical quencher ligands, and III) a higher density of structural defects generated by LFL synthesis, indicated by surface charge density. Based on these findings it may be concluded that the surface chemistry is a major and underexplored contributor to ROS generation and sensitizing effects of AuNPs in PT. We further highlight the applicability of AuNPs in vitro in human medulloblastoma cells.

Nanopore Sequencing Techniques: A Comparison of the MinKNOW and the Alignator Sequencers.

Whole genome and transcriptome analyses represent powerful tools. Despite improvements in sequencing methodology, whole transcriptome analyses are still tedious, especially for methodologies producing long reads. Here, we compare the sequence data analysis software MinKNOW and our tool Alignator. Furthermore, we provide a walk-through from RNA isolation and preparation for MinION sequencing as well as insides in the processing of sequencing data using both tools.

Dental Root Injuries Caused by Osteosynthesis Screws in Orthognathic Surgery-Comparison of Conventional Osteosynthesis and Osteosynthesis by CAD/CAM Drill Guides and Patient-Specific Implants.

BACKGROUND/AIM: The primary aim was to evaluate the prevalence and localisation of dental injuries caused by osteosynthesis screws during orthognathic surgery, comparing two different CAD/CAM planning/surgical approaches through retrospective evaluation of post-operative computed tomography. MATERIAL AND METHODS: This study considered all patients who underwent orthognathic surgery from 2010-2019. The examination for dental root injuries between conventional osteosynthesis (Maxilla conventional cohort) and osteosynthesis with patient-specific implant (Maxilla PSI cohort) was performed by evaluating the post-operative CT scans. RESULTS: A total of 126 patients were included in the study. Among the 61 patients of the Maxilla conventional cohort, 10 dental root injuries in 8 patients (13.1%) were detected in the post-operative CT scan, representing 1.5% (n = 10/651) of the osteosynthesis screws inserted in proximity of the alveolar crest. No dental injury occurred following osteosynthesis in the 65 patients of the Maxillary PSI cohort (n = 0/773 screws) (p < 0.001). During a mean follow-up period of 13 months after primary surgery, none of the injured teeth showed evidence of periapical alterations and no endodontic treatments were necessary. CONCLUSIONS: Maxillary positioning using CAD/CAM-fabricated drill/osteotomy guide and osteosynthesis with PSI can significantly reduce the risk for dental injury compared to the conventional procedure. However, the clinical significance of the detected dental injuries was rather minor.

Comparison of Anatomical Preformed Titanium Implants and Patient-Specific CAD/CAM Implants in the Primary Reconstruction of Isolated Orbital Fractures-A Retrospective Study.

BACKGROUND/AIM: Reconstruction of the fractured orbit remains a challenge. The aim of this study was to compare anatomical preformed titanium orbital implants with patient-specific CAD/CAM implants for precision and intraoperative applicability. MATERIAL AND METHODS: A total of 75 orbital reconstructions from 2012 to 2022 were retrospectively assessed for their precision of implant position and intra- and postoperative revision rates. For this purpose, the implant position after digital orbital reconstruction was checked for deviations by mirroring the healthy orbit at 5 defined points, and the medical records of the patients were checked for revisions. RESULTS: The evaluation of the 45 anatomical preformed orbital implant cases showed significantly higher deviations and an implant inaccuracy of 66.6% than the 30 CAD/CAM cases with only 10% inaccuracy. In particular, the CAD/CAM implants were significantly more precise in medial and posterior positioning. In addition, the intraoperative revision rates of 26.6% vs. 11% after 3D intraoperative imaging and the postoperative revision rates of 13% vs. 0 for the anatomical preformed implants were significantly higher than for patient-specific implants. CONCLUSION: We conclude that patient-specific CAD/CAM orbital implants are highly suitable for primary orbital reconstruction. These seem to be preferable to anatomical preformed implants in terms of precision and revision rates.

Comparison of Laser-Sintered and Milled Patient-Specific Reconstruction Plates for Complications and Outcomes in Mandibular Defects-Comparative Analysis of a Single-Center Cohort.

CAD/CAM-manufactured implants are increasingly becoming the standard in current therapy. The question of whether the manufacturing-related rougher surface of selective laser fusion plates compared to milled, smoother reconstruction plates leads to increased postoperative complications such as infections, plate exposure, and fistulas has not yet been determined. A retrospective analysis of 98 patients who underwent surgical treatment with either a selective laser fusion plate or a milled reconstruction plate at our hospital was performed. The only significant predictors of the revision risk were the operation time and use of antiresorptive medication. In the KLS Martin® group, the risk of revision decreased by approximately 20% for each additional hour by which the operation time was increased (OR = 0.81). In the Depuy Synthes® group, the risk of revision increased by approximately 11% with each additional hour of operative time (OR = 0.81 × 1.37 = 1.11). Both groups showed no significant differences in the number of necessary revision surgeries as well as inpatient complications. In summary, we can say that the assumption that additively manufactured reconstruction plates have a rougher surface due to selective laser melting and thus make plaque accumulation and revisions more likely has not been confirmed. Overall, it seems imperative to select further studies regarding the clinical outcome depending on the selected plate system.

BRAF inhibitors in BRAF V600E-mutated ameloblastoma: systematic review of rare cases in the literature.

BACKGROUND: Ameloblastoma in 66% of the cases harbor a somatic mutation of the "mitogen-activated protein kinase" signaling pathway (BRAF V600E). In V600E mutations, BRAF is in the permanent "on" state and relays the growth-promoting signals independently of the EGFR pathway. Therefore, mutant BRAF represents a target for handful of new drugs. METHODS: We conducted a literature search, with the search terms "Vemurafenib, Dabrafenib, Ameloblastoma, and BRAF." These included seven case reports with nine patients who underwent monotherapy with Dabrafenib or Vemurafenib or combination therapy with Dabrafenib and Trametinib. RESULTS: The patients age ranges from 10 years up to 86 years. The distribution of women and men is 4:5. Patients with an initial diagnosis of ameloblastoma, as well as recurrences or metastasized ameloblastoma were treated. Indications cover neoadjuvant therapy up to the use in metastasized patients in an irresectable state. Results ranging from "only" tumor size reduction to restitutio ad integrum. CONCLUSION: We see the use of BRAF Inhibitors to reduce tumor size with consecutive surgical treatment as a reasonable option for therapy. However, we are aware that at present the data are based only on case reports with the longest follow-up of just 38 months. We encourage further clinical trials in the use of BRAF Inhibitors for selecting ameloblastoma patients in a multi-center setting.

MRONJ of the Mandible-From Decortication to a Complex Jaw Reconstruction Using a CAD/CAM-Guided Bilateral Scapula Flap.

Medication-related osteonecrosis of the jaw (MRONJ) has been an integral part of the maxillofacial patient population for some time. The therapeutic concept ranges from conservative approaches over less extended decortications to major jaw resections, which can result in a considerable loss of quality of life. Based on three case reports, this paper presents the long-term history of patients with MRONJ of the mandible, whose disease ultimately resulted in partial or total mandibular resection and subsequent multisegmental reconstruction using a microvascular anastomosed bone flap. Furthermore, a suitable alternative for complex mandibular reconstruction is demonstrated when using a free fibula flap is not possible. The options are limited, particularly when multisegmental restoration of mandibular continuity is required. One case presents a mandible reconstruction using a CAD/CAM-guided bilateral scapular free flap (CAD/CAM = Computer-Aided Design and Manufacturing), which has not been described for this purpose before. Due to the complexity, computer-assisted surgery and patient-specific implants seem reasonable, which is why a special focus was applied to this topic.

First-Hand Experience and Result with New Robot-Assisted Laser LeFort-I Osteotomy in Orthognathic Surgery: A Case Report.

BACKGROUND: We report the world's first developer-independent experience with robot-assisted laser Le Fort I osteotomy (LLFO) and drill-hole marking in orthognathic surgery. To overcome the geometric limitations of conventional rotating and piezosurgical instruments for performing osteotomies, we used the stand-alone robot-assisted laser system developed by Advanced Osteotomy Tools. The aim here was to evaluate the precision of this novel procedure in comparison to the standard procedure used in our clinic using a computer-aided design/computer-aided manufacturing (CAD/CAM) cutting guide and patient-specific implant. METHODS: A linear Le-Fort-I osteotomy was digitally planned and transferred to the robot. The linear portion of the Le-Fort I osteotomy was performed autonomously by the robot under direct visual control. Accuracy was analyzed by superimposing preoperative and postoperative computed tomography images, and verified intraoperatively using prefabricated patient-specific implant. RESULTS: The robot performed the linear osteotomy without any technical or safety issues. There was a maximum difference of 1.5 mm on average between the planned and the performed osteotomy. In the robot-assisted intraoperative drillhole marking of the maxilla, which was performed for the first time worldwide, were no measurable deviations between planning and actual positioning. CONCLUSION: Robotic-assisted orthognathic surgery could be a useful adjunct to conventional drills, burrs, and piezosurgical instruments for performing osteotomies. However, the time required for the actual osteotomy as well as isolated minor design aspects of the Dynamic Reference Frame (DRF), among other things, still need to be improved. Still further studies for final evaluation of safety and accuracy are also needed.

Student experiences of professionalism and role models in an oral and maxillofacial surgery internship: A qualitative study.

INTRODUCTION: Dental students have a clear concept of professionalism and the importance of role models. Our aim was to determine how dental students experience their first oral and maxillofacial surgery internship in terms of their concept of professionalism and their perception of role models. METHODS: From June to August 2020, semi-structured telephone interviews were conducted with 22 dental students in their eighth and ninth semesters at the Medical Faculty of the University of Ulm. The interviews were transcribed and evaluated by qualitative content analysis according to Mayring. RESULTS: The students' concept of dental professionalism was shaped by the elements of a good approach to patients, professional competence, and manual skills. This perception was not changed by the internship. Having a role model was seen as an important learning strategy, and role models were perceived in both positive and negative ways. Role models were perceived as positive if they corresponded to the student's concept of professionalism and as negative if they did not correspond to this concept, especially with regard to social interaction or the approach to patients. Students' reactions to discrepancies between their own moral values and the role models' behaviour were characterised by passivity and withdrawal. With regard to potential future careers, positive internship experiences supported student goals, whereas negative experiences raised doubts about them. CONCLUSION: Supervising dentists may still underestimate the considerable impact of internships, and their awareness of this impact needs to be increased. Students' reactions to conflicts between reality and their own values do not appear to be constructive. One approach to solving this problem may be to include discussions of professional development in curricula.