Chronic oxidative stress adaptation in head and neck cancer cells generates slow-cyclers with decreased tumour growth in vivo.

BACKGROUND: Reactive oxygen species (ROS) are implicated in cancer therapy and as drivers of microenvironmental tumour cell adaptations. Medical gas plasma is a multi-ROS generating technology that has been shown effective for palliative tumour control in head and neck cancer (HNC) patients before tumour cells adapted to the oxidative stress and growth regressed fatally. METHODS: In a bedside-to-bench approach, we sought to explore the oxidative stress adaptation in two human squamous cell carcinoma cell lines. Gas plasma was utilised as a putative therapeutic agent and chronic oxidative stress inducer. RESULTS: Cellular responses of single and multiple treated cells were compared regarding sensitivity, cellular senescence, redox state and cytokine release. Whole transcriptome analysis revealed a strong correlation of cancer cell adaption with increased interleukin 1 receptor type 2 (IL1R2) expression. Using magnetic resonance imaging, tumour growth and gas plasma treatment responses of wild-type (WT) and repeatedly exposed (RE) A431 cells were further investigated in a xenograft model in vivo. RE cells generated significantly smaller tumours with suppressed inflammatory secretion profiles and increased epidermal growth factor receptor (EGFR) activity showing significantly lower gas plasma sensitivity until day 8. CONCLUSIONS: Clinically, combination treatments together with cetuximab, an EGFR inhibitor, may overcome acquired oxidative stress resistance in HNC.

Decreased inflammatory profile in oral leukoplakia tissue exposed to cold physical plasma ex vivo.

BACKGROUND: Oral leukoplakia (OL) is an unfavorable oral disease often resistant to therapy. To this end, cold physical plasma technology was explored as a novel therapeutic agent in an experimental setup. METHODS: Biopsies with a diameter of 3 mm were obtained from non-diseased and OL tissues. Subsequently, cold atmospheric pressure plasma (CAP) exposure was performed ex vivo in the laboratory. After 20 h of incubation, biopsies were cryo-conserved, and tissue sections were quantified for lymphocyte infiltrates, discriminating between naïve and memory cytotoxic and T-helper cells. In addition, the secretion pattern related to inflammation was investigated in the tissue culture supernatants by quantifying 10 chemokines and cytokines. RESULTS: In CAP-treated OL tissue, significantly decreased overall lymphocyte numbers were observed. In addition, reduced levels were observed when discriminating for the T-cell subpopulations but did not reach statistical significance. Moreover, CAP treatment significantly reduced levels of C-X-C motif chemokine 10 (CXCL10) and granulocyte-macrophage colony-stimulating factor in the OL biopsies' supernatants. In idiopathically inflamed tissues, ex vivo CAP exposure reduced T-cells and CXCL10 as well but also led to markedly increased interleukin-1ß secretion. CONCLUSION: Our findings suggest CAP to have immuno-modulatory properties, which could be of therapeutic significance in the therapy of OL. Future studies should investigate the efficacy of CAP therapy in vivo in a larger cohort.

Impact of dental restorations and removable prostheses on potentially malignant oral mucosal disorders in the general population.

STATEMENT OF PROBLEM: Dental restorations and removable dental prostheses have been considered as risk factors for potentially malignant disorders of the oral mucosa. It remains unclear whether amalgam, composite resins, and prosthesis materials can induce potentially malignant disorders. PURPOSE: The purpose of this clinical study was to determine the relationship between the presence of amalgam and composite resin restorations, crowns and fixed partial dentures, and removable prostheses in potentially malignant disorders. MATERIAL AND METHODS: The data of 6041 participants in the population-based Studies of Health in Pomerania (SHIP) were accessed. Potentially malignant disorders had been clinically diagnosed by calibrated dentists and documented with photographs. Dental treatment was subdivided into restored and replaced teeth. Dental restorations were subclassified as buccal composite resin or amalgam restorations. Prosthetic treatment was subclassified into removable partial or complete prostheses and definitive restorations with crowns and fixed partial dentures. RESULTS: In the maxilla, participants with removable prostheses had a higher incidence of potentially malignant disorders than participants not undergoing treatment with removable prostheses (OR 2.12; 95% CI: 1.08-4.18), but not in the mandible (OR 1.30; 95% CI: 0.67-2.53). The surfaces with composite resin restorations were associated with a slightly higher risk of mucosal lesions than those without the restorations (OR 1.04; 95% CI: 1.01-1.07). No significant association was found between amalgam restorations and mucosal lesions. CONCLUSIONS: Participants with removable prostheses have a higher risk of potentially malignant disorders. Composite resin restorations are associated with a higher risk of mucosal lesions, whereas no significant association was found between amalgam restorations and mucosal lesions.

Effects of cold physical plasma on oral lichen planus: An in vitro study (Effects of CAP on OLP).

OBJECTIVES: In the search for more effective and safe treatment avenues, we investigated cold physical plasma as a new treatment modality for therapy of oral lichen planus (OLP). MATERIAL AND METHODS: Healthy and diseased human mucosal tissue samples with a size of 3 mm in diameter obtained from OLP patients were subjected to plasma treatment ex vivo or were left untreated. Tissue sections were quantified for immune-infiltration of CD4+ , CD8+ , CD45RA+ , and CD45R0+ T cells. Moreover, the tissues' inflammatory profile was assessed by analyzing 12 different cytokines in the surrounding media. RESULTS: A significantly increased infiltrate of CD8+ and CD45-R0+ T cells was detected in OLP tissue samples when compared to healthy tissue. A higher concentration of interleukin (IL) 1ß, IL6, IL8, and granulocyte macrophage-colony stimulating factor (GM-CMF) was detected in OLP samples compared to healthy mucosal tissue. For all cytokines and chemokines investigated, 23 out of 24 comparisons showed a decrease in tendency (significant for IL1ß, IL2, IL10, and GM-CSF) in response to plasma treatment. In ex vivo-treated tissue, a decrease of T-cell infiltrate in OLP lesions compared with healthy tissue was observed. CONCLUSION: Our findings suggest cold physical plasma can be a promising therapeutic option for OLP that requires further validation in vivo.

Physical plasma and leukocytes - immune or reactive?

Leukocytes are professionals in recognizing and removing pathogenic or unwanted material. They are present in virtually all tissues, and highly motile to enter or leave specific sites throughout the body. Less than a decade ago, physical plasmas entered the field of medicine to deliver their delicate mix of reactive species and other physical agents for mainly dermatological or oncological therapy. Plasma treatment thus affects leukocytes via direct or indirect means: immune cells are either present in tissues during treatment, or infiltrate or exfiltrate plasma-treated areas. The immune system is crucial for human health and resolution of many types of diseases. It is therefore vital to study the response of leukocytes after plasma treatment in vitro and in vivo. This review gathers together the major themes in the plasma treatment of innate and adaptive immune cells, and puts these into the context of wound healing and oncology, the two major topics in plasma medicine.

Third molars and periodontal damage of second molars in the general population.

AIM: The aim of this study was to clarify the association between impacted or erupted third molars and periodontal pathology, assessed by probing depth (PD) and clinical attachment levels (CAL), in adjacent second molars. MATERIALS AND METHODS: Data from the population-based Study of Health in Pomerania (SHIP) was used. This is the first project with whole-body magnetic resonance imaging (WB-MRI) application in a general population setting with dental issues. Calibrated and licensed dentists measured PD and CAL with a periodontal probe. RESULTS: In the mandible, individuals with erupted third molars had a 1.45-fold higher odds ratio (CI:1.03; 2.05; p = 0.031) and individuals with impacted third molars had a 2.37-fold higher odds ratio (CI:1.45; 3.85; p < 0.001) to have higher PD values in the adjacent distal site of second molar than individuals with missing third molars in the total population. These significant associations were even more pronounced in the population free of periodontitis disease. In participants with periodontitis in the maxilla, there was an association of erupted third molars with an increased PD of adjacent molars. CONCLUSION: In particular, in the mandible, those findings could guide dental practitioners more in the direction to remove the third molars after having evaluated the periodontium of the adjacent teeth.

Triterpenes for Well-Balanced Scar Formation in Superficial Wounds.

Triterpenes are demonstrably effective for accelerating re-epithelialisation of wounds and known to improve scar formation for superficial lesions. Among the variety of triterpenes, betuline is of particular medical interest. Topical betuline gel (TBG) received drug approval in 2016 from the European Commission as the first topical therapeutic agent with the proven clinical benefit of accelerating wound healing. Two self-conducted randomized intra-individual comparison clinical studies with a total of 220 patients involved in TBG treatment of skin graft surgical wounds have been screened for data concerning the aesthetic aspect of wound healing. Three months after surgery wound treatment with TBG resulted in about 30% of cases with more discreet scars, and standard of care in about 10%. Patients themselves appreciate the results of TBG after 3 months even more (about 50%) compared to standard of care (about 10%). One year after surgery, the superiority of TBG counts for about 25% in comparison with about 10%, and from the patients' point of view, for 25% compared to 4% under standard of care. In the majority of wound treatment cases, there is no difference visible between TBG treatment and standard of care after 1 year of scar formation. However, in comparison, TBG still offers a better chance for discreet scars and therefore happens to be superior in good care of wounds.

MRI-guided percutaneous transhepatic cholangiodrainage: feasibility study in a porcine model.

BACKGROUND AND STUDY AIMS: MRI-guided procedures combine high-quality imaging with lack of radiation. Percutaneous transhepatic cholangiodrainage under real-time MRI guidance (MRI-PTCD) seems promising, allowing targeted puncture and avoiding multiple blind passes and use of contrast, which are associated with standard PTCD's heaviest complications. PATIENTS AND METHODS: Aim of this study was to investigate the feasibility of MRI-PTCD in three outbred piglets. Obstructive cholestasis was induced by common bile duct ligation. Two days later, MRI-PTCD was performed (open MRI, 1.0 Tesla) with prototype MRI-compatible accessories. Visualization was achieved with a balanced steady-state free precession real-time sequence (bSSFP: 0.75 frames/s, TR/TE [ms]: 7.2/3.6; flip angle: 45°; 200 × 200 matrix size; resolution: 1.3 × 1.3 mm(2), slice thickness: 7 mm). Cannulation of the bile ducts was followed by placement of Yamakawa drainages. RESULTS: Twelve punctures were performed (four per animal, 10/12 successful); in 2/10 the bile ducts could not be cannulated. Animal survival was 100% and no significant complications occurred. CONCLUSIONS: Initial data show that MRI-PTCD can be successfully performed. This may lead to establishment of a new optimized PTCD technique compared to the standard approach under fluoroscopy.

Synergistic effect of cold gas plasma and experimental drug exposure exhibits skin cancer toxicity in vitro and in vivo.

INTRODUCTION: Skin cancer is often fatal, which motivates new therapy avenues. Recent advances in cancer treatment are indicative of the importance of combination treatments in oncology. Previous studies have identified small molecule-based therapies and redox-based technologies, including photodynamic therapy or medical gas plasma, as promising candidates to target skin cancer. OBJECTIVE: We aimed to identify effective combinations of experimental small molecules with cold gas plasma for therapy in dermato-oncology. METHODS: Promising drug candidates were identified after screening an in-house 155-compound library using 3D skin cancer spheroids and high content imaging. Combination effects of selected drugs and cold gas plasma were investigated with respect to oxidative stress, invasion, and viability. Drugs that had combined well with cold gas plasma were further investigated in vascularized tumor organoids in ovo and a xenograft mouse melanoma model in vivo. RESULTS: The two chromone derivatives Sm837 and IS112 enhanced cold gas plasma-induced oxidative stress, including histone 2A.X phosphorylation, and further reduced proliferation and skin cancer cell viability. Combination treatments of tumor organoids grown in ovo confirmed the principal anti-cancer effect of the selected drugs. While one of the two compounds exerted severe toxicity in vivo, the other (Sm837) resulted in a significant synergistic anti-tumor toxicity at good tolerability. Principal component analysis of protein phosphorylation profiles confirmed profound combination treatment effects in contrast to the monotherapies. CONCLUSION: We identified a novel compound that, combined with topical cold gas plasma-induced oxidative stress, represents a novel and promising treatment approach to target skin cancer.

Ankle laxity: stress investigation under MRI control.

OBJECTIVE: The purpose of this study was to examine the advantages of MRI-guided ankle stress examinations in the detection of chronic ankle instability. SUBJECTS AND METHODS: An MRI-compatible stress device was developed and tested for MRI safety. Bilateral MRI stress examinations were performed on 50 volunteers with and without clinically evident subjective instability of the ankle joints (72 subjective stable ankle joints in 37 subjects, 28 ankles in 15 subjects with chronic ankle instability). Both the inversion test and the anterior drawer test were performed under axial, coronal, 45° paraxial, and sagittal T2-weighted fast spin-echo image control. MR images were assessed for talar tilt, subtalar tilt, anterior talus translation, anterior calcaneus translation, medial talocalcaneal translation, and the diameters of the lateral ankle ligaments (anterior talofibular ligament, calcaneofibular ligament, and posterior talofibular ligament). RESULTS: The MRI stress device was found suitable and safe for use in the MRI environment. The talocrural and subtalar joints could be assessed simultaneously. Significant differences between groups A and B (p≤0.05) were found in talar tilt, subtalar tilt, anterior talus translation, anterior calcaneus translation, medial talocalcaneal translation, and decrease in diameters of calcaneofibular and posterior talofibular ligaments. Also found were sex differences in talar tilt, subtalar tilt, anterior talus translation, and diameters of the anterior talofibular, calcaneofibular, and posterior talofibular ligaments. Significant relations were found between talar tilt and anterior talus translation, subtalar tilt and anterior calcaneus translation, subtalar tilt and medial talocalcaneal translation, and between anterior calcaneus translation and medial talocalcaneal translation in groups A and B. CONCLUSION: Stress examination under MRI control has advantages in the assessment of mechanical ankle instability. Additional diagnostic and clinically relevant information is obtained through direct imaging of the ligaments and assessment of additional parameters of ankle laxity (subtalar tilt, anterior calcaneus translation, medial talocalcaneal translation). The main advantages are objective imaging and measurement of abnormal looseness of the lower ankle joint and its direct simultaneous comparison with the upper ankle joint.

Pulmonary Metastasising Aneurysmal Fibrous Histiocytoma: A Case Report, Literature Review and Proposal of Standardised Diagnostic Criteria.

An aneurysmal fibrous histiocytoma is a rare cutaneous soft-tissue tumour which accounts for approximately 0.06% of all dermatopathologies. Metastasis is exceedingly uncommon, to the point that there have only been eight reported cases in the scientific literature. We present the case of a 25-year-old male with a primary aneurysmal fibrous histiocytoma located in the nuchal region which exhibited rapid growth and abrupt ulceration over a short time span and showed signs of locoregional aggressive infiltration. A subsequent histopathological analysis confirmed the presence of diffuse solid and cystic pulmonary metastases. Further genetic sequencing verified LAMTOR1-PRKCD fusion. This case report seeks to review the existing literature on aneurysmal fibrous histiocytoma, discuss the challenges of differential diagnosis and propose standardised diagnostic criteria.

Evaluation of a MR-quadrupole imaging coil for spinal interventions in a vertical 1.0 T MRI.

The in vivo pain treatment was successfully performed with the patient in a prone position. The PD-weighted TSE with echo time = 10 ms rendered contrast-to-noise-ratio values of 27 ± 10 for needle/fat, 1.6 ± 5 for needle/muscle, and 4 ± 4.7 for needle/nerve tissue. The mean diameter of the needle artifact was 1.2 ± 0.2 mm. In the T(1)-weighted gradient echo, the needle's artifact diameter was 6 ± 2 mm; the needle's contrast-to-noise ratio relative to muscle tissue was 4 ± 2, 7.6 ± 1.5 for needle/fat, and 5 ± 1 for needle/nerve tissue. With the PD-weighted TSE (echo time = 10 ms) and the T(1)-weighted gradient echo, the needle was imaged reliably throughout the intervention. The butterfly surface coil is feasible for the guidance of spinal interventions in a prone patient.

Laparoscopic radiofrequency ablation of liver tumors: comparison of MR guidance versus conventional laparoscopic ultrasound for needle positioning in a phantom model.

Laparoscopic radiofrequency ablation (LapRFA) is an established procedure for liver tumors in patients who are unsuitable for resection. A novel technique of magnetic resonance (MR) guided needle positioning during LapRFA was developed and compared to conventional ultrasound (US) guidance in a phantom model. MR-guided procedures were conducted in a 1.0 tesla high field open MR using an MR compatible endoscope and camera. The ultrasound-guided procedure was performed with a clinically established laparoscopy setup and a 2D laparoscopic US probe. During both techniques an identical monopolar non-ferromagnetic RFA needle and a silicon-based phantom model were applied. Finally needle positioning was performed by two surgeons and one interventionalist. Time to needle placement and number of trials were recorded and statistically analyzed. MR-guided needle positioning under laparoscopic control was technically feasible. Average time to correct needle placement was 2' 6″ in the LapUS group and 1' 54″ in the MR group. The number of trials was 3.2 in the LapUS group and 2.6 in the MR group. Image quality was assessed by all participants. MR images showed a better tissue to tumor contrast and allowed an improved orientation due to multiplanar visualization. MR-guided laparoscopic RFA is a promising technique offering multiplanar needle positioning with high soft tissue contrast with immediate therapy control. In a phantom model it showed comparable results regarding needle positioning to the established technique of laparoscopic US guidance.

Prevalence and risk factors of potentially malignant disorders of the mucosa in the general population: Mucosa lesions a general health problem?

AIM: Oral cancer mostly develops from oral mucosa regions with morphological alterations transforming malignant. These visible precancerous mucosa lesions are named potentially malignant disorders (PMD). We aimed to analyze the prevalence of PMD and its risk factors for PMD in a population-based sample in Northern Germany. MATERIAL AND METHODS: Data of 6078 individuals from the population-based Study of Health in Pomerania (SHIP) was used. PMD were photographically documented and periodontal health was assessed in a standardized procedure. RESULTS: PMD were observed in 54 individuals (0.9%). The most prevalent PMD was homogenous leukoplakia (n = 37) followed by Lichen ruber (n = 9). Smoking (Odds Ratio (OR) 2.70; 95% confidence interval (CI): 1.24-5.87), male sex (OR 3.32; 95%-CI: 1.77-6.21), type 2 diabetes mellitus (OR 2.07; 95%-CI: 1.08-3.98) and body mass index (OR 1.09; CI 1.04-1.14) were significantly associated with PMD, with the corresponding area under the curve (AUC) being 0.696 (CI: 0.655; 0.737). CONCLUSION: Our results suggest a clinically relevant prevalence of PMD in the population. We identified male sex, type 2 diabetes mellitus, current smoking, and obesity as risk factors. We recommend photographic documentation and intensified training of medical and dental staff to detect and monitor PMD.

Development of a signal-inducing bone cement for magnetic resonance imaging.

PURPOSE: To develop a signal-inducing bone cement for musculoskeletal procedures in magnetic resonance imaging (MRI). MATERIALS AND METHODS: Acrylic resins were mixed with contrast agents (CAs) and water. We determined the ideal concentration of the components and assessed feasibility in cadaveric bones in an open high-field MR scanner. The contrast-to-noise ratio (CNR) in air and bone was evaluated and mechanical tests were achieved. We determined the amount of water that was not incorporated and measured the amount of CA released with photometric analysis. The cement was analyzed microscopically. RESULTS: Preparation and application of the CA-water-cement compound was feasible and its differentiation in MRI was clear. The maximal CNR(air) had a value of 157.5 (SD 18.3) in an interventional fast T1W turbo-spin echo (TSE) sequence. The compressive strength decreased with the amount of water added. Although nearly 50% of the water added was not incorporated in the cement, the CNR was sufficient for cement detection. The threshold for systemic toxicity of delivered CA was not reached and the microscopic analysis showed water bubbles in the cement. CONCLUSION: A signal-inducing bone cement is feasible for the use in MRI.

Initial results of MR-guided liver resection in a high-field open MRI.

BACKGROUND: The goal of this study was to evaluate high-field open magnetic resonance imaging (MRI) for intraoperative real-time imaging during hand-assisted laparoscopic liver resection. MR guidance has several advantages compared to ultrasound and may represent a future technique for abdominal surgery. Various MRI-safe and -compatible instruments were developed, tested, and applied to realize minimally invasive liver surgery under MR guidance. As proof of the concept, liver resection was performed in a porcine model. METHODS: All procedures were conducted in a 1.0-T open MRI unit. Imaging quality and surgical results were documented during three cadaveric and two live animal procedures. A nonferromagnetic hand port was used for manual access and the liver tissue was dissected using a Nd:YAG laser. RESULTS: The intervention time ranged from 126 to 145 min, with a dissection time from 11 to 15 min. Both live animals survived the intervention with a blood loss of 250 and 170 ml and a specimen weight of 138 and 177 g. A dynamic T2W fast spin-echo sequence allowed real-time imaging (1.5 s/image) with good delineation of major and small hepatic vessels. The newly developed MR-compatible instruments and camera system caused only minor interferences and artifacts of the MR image. CONCLUSION: MR-guided liver resection is feasible and provides additional image information to the surgeon. We conclude that MR-guided laparoscopic liver resection improves the anatomical orientation and may increase the safety of future minimally invasive liver surgery.

Passive navigation principle for orthopedic interventions with MR fluoroscopy.

INTRODUCTION: Of late, computer-assisted surgery has become a novel challenge for orthopedic surgeons. However, for orthopedic interventions magnetic resonance (MR) fluoroscopy is in its early stages of development. The authors have developed an innovative passive navigation concept, which is potentially applicable for many magnetic resonance image (MRI)-guided musculoskeletal interventions. With this method, no switching between different planes is required, since the cross-sectional modality of the MRI is used as a new navigation approach. MATERIALS AND METHODS: This method was mainly evaluated in retrograde drilling of artificial osteochondral lesions of the talus as an example of difficult navigation in drill placement due to poor visualization with X-ray and complex anatomy. To accomplish this objective, a passive navigation device was constructed and evaluated in nine cadaveric ankle joint specimens. Feasibility and accuracy of navigated drillings were evaluated. RESULTS: The interactive high-field MR fluoroscopy and the passive aiming device allow precise drilling of osteochondral lesions of the talus, despite the complex anatomy of the ankle. Drillings could be performed with an accuracy of 1.6 mm. The drilling guide was safe and easy to handle. CONCLUSION: The MR-assisted retrograde drilling of osteochondral lesions may enable precise and safe treatment without radiation exposure. This passive navigation technique for MR fluoroscopy is potentially applicable for many orthopedic interventions and may present an alternative to other navigation methods. Especially, the treatment of pediatric and adolescent patients may benefit from the typical MRI properties.

Molecular Mechanisms of the Efficacy of Cold Atmospheric Pressure Plasma (CAP) in Cancer Treatment.

Recently, the potential use of cold atmospheric pressure plasma (CAP) in cancer treatment has gained increasing interest. Especially the enhanced selective killing of tumor cells compared to normal cells has prompted researchers to elucidate the molecular mechanisms for the efficacy of CAP in cancer treatment. This review summarizes the current understanding of how CAP triggers intracellular pathways that induce growth inhibition or cell death. We discuss what factors may contribute to the potential selectivity of CAP towards cancer cells compared to their non-malignant counterparts. Furthermore, the potential of CAP to trigger an immune response is briefly discussed. Finally, this overview demonstrates how these concepts bear first fruits in clinical applications applying CAP treatment in head and neck squamous cell cancer as well as actinic keratosis. Although significant progress towards understanding the underlying mechanisms regarding the efficacy of CAP in cancer treatment has been made, much still needs to be done with respect to different treatment conditions and comparison of malignant and non-malignant cells of the same cell type and same donor. Furthermore, clinical pilot studies and the assessment of systemic effects will be of tremendous importance towards bringing this innovative technology into clinical practice.

Osteochondral lesions of the talus: retrograde drilling with high-field-strength MR guidance.

The institutional review board approved the use of cadaveric specimens, and informed consent was obtained from all volunteers. The authors performed and assessed a magnetic resonance (MR)-assisted navigation method for minimally invasive retrograde drilling of talar osteochondral lesions. For this method, a single imaging plane is sufficient for navigation during intervention. To accomplish this objective, a passive MR navigation device was used to evaluate 16 cadaveric ankle joints. Use of this interactive MR-assisted navigation method in combination with a passive aiming device allowed precise and rapid retrograde drilling of talar osteochondral lesions.

Tibia fracture following removal of the ETN (Expert Tibia Nail): a case report.

We report on a patient who sustained a fracture of the tibial shaft during the removal of the newest type of an intramedullary nail (Expert Tibia Nail, Synthes. In this case report, we discuss the causes of this complication and possible ways to prevent this.