Salivary IL-6 mRNA is a Robust Biomarker in Oral Squamous Cell Carcinoma.

Salivary IL-6 mRNA was previously identified as a promising biomarker of oral squamous cell carcinoma (OSCC). We performed a multi-center investigation covering all geographic areas of Hungary. Saliva from 95 patients with OSCC and 80 controls, all Caucasian, were collected together with demographic and clinicopathological data. Salivary IL-6 mRNA was quantified by real-time quantitative PCR. Salivary IL-6 protein concentration was measured by enzyme-linked immune-sorbent assay. IL-6 protein expression in tumor samples was investigated by immunohistochemistry. Normalized salivary IL-6 mRNA expression values were significantly higher (p < 0.001) in patients with OSCC (mean ± SE: 3.301 ± 0.885) vs. controls (mean ± SE: 0.037 ± 0.012). Differences remained significant regardless of tumor stage and grade. AUC of the ROC curve was 0.9379 (p < 0.001; 95% confidence interval: 0.8973-0.9795; sensitivity: 0.945; specificity: 0.819). Salivary IL-6 protein levels were significantly higher (p < 0.001) in patients (mean ± SE: 70.98 ± 14.06 pg/mL), than in controls (mean ± SE: 12.45 ± 3.29). Specificity and sensitivity of IL-6 protein were less favorable than that of IL-6 mRNA. Salivary IL-6 mRNA expression was significantly associated with age and dental status. IL-6 manifestation was detected in tumor cells and tumor-infiltrating leukocytes, suggesting the presence of a paracrine loop of stimulation. Salivary IL-6 mRNA is one of the best performing and clinically relevant biomarkers of OSCC.

[Planning options of reconstructive and orthognathic operation by means of three-dimensional imaging]. / Arcrekonstrukciós és orthognath mutétek tervezési lehetoségei háromdimenziós képalkotói módszerekkel.

We summarize up-to-date planning technics of orthognathic and reconstructive surgery operation which appeared with three-dimensional imaging, using literature data and some clinical examples. In many cases, orthognathic and reconstructive operations mean the only treatment of facial deformity caused by tumour, traumatic injury or congenital anomaly. In this field, radiology plays an important role not only in the diagnosis but also in the planning of the treatment. With the appearance of cone-beam computed tomography (CBCT), the previously used two-dimensional cephalometric analysis on lateral cephalogram was changed for three-dimensional cephalometric measurements. The first step of the adaptation was the lateral and frontal x-ray images generated from the CBCT database and later the volume rendered surface and segmentation technics provided the moving of the facial bones in three dimensions which meant virtual surgical planning. With the development of CAD/CAM technic and the three-dimensional printing, many opportunities became available, such as preoperative bending splints and plates and printed surgical model for the tangible planning. The progress of imaging facilitated the individual, accurate, and reliable planning which significantly determines the success of the treatment. Orv Hetil. 2018; 159(39): 1584-1592.

Multiple microlithiasis in bilateral parotid glands as the initial clinical manifestation of primary Sjögren's syndrome.

We report a rare case of Sjögren's syndrome (SS) with multiple microliths in the bilateral parotid glands. A 41-year-old man presented to our department with mild pain in the region of the right parotid gland. The dental examination was negative except for the parotid regions. The right region was moderately swollen and the left mildly swollen. Plain radiography revealed multiple calculi in the bilateral parotid glands. Ultrasonography showed heterogenic parenchyma, with microliths and cystic lesions in the parotid glands and heterogenic echotexture in the submandibular glands. Immunologic tests and the Schirmer test confirmed the diagnosis of SS. As the patient had no classic symptoms of SS, the bilateral multiple microliths were the first sign, facilitating the final diagnosis. Early diagnosis of SS is highly relevant because the proper therapy can be initiated. Adequate follow-up and, especially, control of the disease activity by identifying the predictive factors, are the primary objectives of SS management, enabling personalized treatment of this malignant disease. This case is a good example of how detection of calcifications in the bilateral parotid glands by plain radiography can help diagnose SS at an early stage.

Landmark-based midsagittal plane analysis in patients with facial symmetry and asymmetry based on CBCT analysis tomography.

PURPOSE: Reconstruction of the facial midplane is relevant in anthropometry, orthodontics, maxillofacial surgery, and the accurate measurement of symmetry deviation is relevant in many fields of medicine especially when planning surgical treatment. In the literature, three different means of midplane generation have been published; however, there is currently no consensus regarding the approach to use. Morphometric methods are used to determine the true midsagittal plane (MSP), but its use in clinical practice is difficult. A regression plane based on N­ANS-PNS landmarks reportedly approximates the morphometric MSP. As these points are vulnerable, we investigated which combination of landmarks can be substituted in symmetric and asymmetric faces. PATIENTS AND METHODS: Thirty symmetric and 30 asymmetric faces were analyzed on cone-beam computed tomography scans. A total of 50 regression planes were generated based on three unpaired landmarks and 35 regression planes were generated based the midpoints of paired landmarks. The Na-ANS-PNS plane was used as reference plane, and the mean angle between it and each generated MSP was calculated. The differences from the reference plane were compared by t­test between the groups. RESULTS: In the symmetric group, 86% of angles deviated by <5° using unpaired points, whereby 74% of angles deviated by <5° for paired points. Between the two groups 50% of planes from midline points, and 77% of planes from paired points were significantly different. All planes deviated more in the asymmetric group. CONCLUSIONS: The N­ANS-PNS reference plane can be substituted with the following combinations: ANS-G-Ba, ANS-G-S, ANS-S-De, PNS-G-Ba, PNS-S-Ba, PNS-ANS-G, and PNS-N-Ba.

Lower face cephalometry based on quadrilateral analysis with cone-beam computed tomography: a clinical pilot study.

OBJECTIVE: As most orthognathic surgeries focus on the lower face, the aim of this study was to transfer previously developed two-dimensional cephalometry-which is useful for surgeons in the orthognathic surgery of the lower face-to three-dimensional (3D) cephalometry by using cone-beam computed tomography (CBCT). We selected the quadrilateral lower face analysis developed by the surgeon Di Paolo, who focused only for the lower face and mentioned that data in millimeters are more easy to use than angles for surgeons. Additionally, we wanted to create a 3D lower face analysis approach based on quadrilateral analysis and establish a reference table for surgical planning. STUDY DESIGN: Three investigators assigned 16 landmarks on CBCT images from 30 patients with normocclusion. Intra-class correlation coefficients (ICCs) and standard deviations (SDs) were calculated according to each landmark. The maxillary and mandibular lengths and widths and the anterior and posterior lower facial heights (ALFH and PLFH) are presented as means and SDs. The asymmetry of the face was calculated with paired t test, and the coherence of the lower face was assessed with correlation coefficients (r) and regression models. RESULTS: The ICCs were ≥0.90, and the SDs of the landmarks were lower than 1.00 mm, except for the J-point, which was located at the junction of the anterior border of the ramus and the corpus of the mandible. The SDs of linear measurements were 3.06-5.20 mm, and there was no significant facial asymmetry. The r among the structures was greater than 0.3 in 13 of 15 assessments. Based on these values, we could establish a floating norm of the lower face using the following five regressions: one linear regression for the mandibular length, two quadratic models for the ALFH and PLFH, and two multivariate regressions for the posterior widths of the maxillae and mandible. CONCLUSION: The adaptation of quadrilateral analysis can provide accurate 3D characterization of the morphology of the lower face and the floating norm based on millimeter values, which is practical for surgeons. As the 3D extension of quadrilateral analysis could provide references of the lower face, which might be an accurate 3D approach for presurgical planning, the further investigation in bigger sample would be relevant in the practice.

[Di Paolo's cephalometrical analysis of lower face by means of Cone-Beam CT]. / Az alsó archarmad Di Paolo-féle vizsgálata Cone-Beam CT adatállományon.

OBJECT: 3D cephalometry is often the only way to set up accurate diagnosis and treatment plan in the field of reconstructive surgery. In these cases complement exposures are needed beyond common cephalograms with higher accuracy than conventional Cone-Beam CT. Consequently the aim of our study was to perform a complex 3D cephalometry. As the first step of this approach, was the 3D adaptation of DiPaolo's Quadrilateral technique, and to determine norms of references in lower face by means of CBCT. METHOD: Thirty non-orthodontic CBCT scans were selected for the digitalization. The most important inclusion criteria was Class I occlusion. Locations of 55 landmarks were signed three times by three observers by means of Cranio Viewer software. RESULTS: However Quadrilateral analysis contains only millimetric values we also integrate angles in the 3D version to determine the width of maxilla and mandible. In the 2D examination--where landmarks were projected to the middle plane. The SDs of the lengths were between 2,66 mm and 5,20 mm. The ratios of normodivergent lower face were significant different from the one by DiPaolo. In 3D adaptation there were no significant differences between the measurements of the two sides (p ≥ 0.05). We found mostly strong and significant correlations between each anatomical structure except of angles. CONCLUSION: Creation of 3D Quadrilateral cephalometry by means of strong correlation and norms of Class I occlusion provide a practical, reliable method to measure also the transversal asymmetry of lower face which is necessary part of 3D cephalometry.

Long-term clinical and experimental/surface analytical studies of carbon/carbon maxillofacial implants.

BACKGROUND: Over the past 30-40 years, various carbon implant materials have become more interesting, because they are well accepted by the biological environment. The traditional carbon-based polymers give rise to many complications. The polymer complication may be eliminated through carbon fibres bound by pyrocarbon (carbon/carbon). The aim of this study is to present the long-term clinical results of carbon/carbon implants, and the results of the scanning electron microscope and energy dispersive spectrometer investigation of an implant retrieved from the human body after 8 years. METHODS: Mandibular reconstruction (8-10 years ago) was performed with pure (99.99 %) carbon implants in 16 patients (10 malignant tumours, 4 large cystic lesions and 2 augmentative processes). The long-term effect of the human body on the carbon/carbon implant was investigated by comparing the structure, the surface morphology and the composition of an implant retrieved after 8 years to a sterilized, but not implanted one. RESULTS: Of the 16 patients, the implants had to be removed earlier in 5 patients because of the defect that arose on the oral mucosa above the carbon plates. During the long-term follow-up, plate fracture, loosening of the screws, infection or inflammations around the carbon/carbon implants were not observed. The thickness of the carbon fibres constituting the implants did not change during the 8-year period, the surface of the implant retrieved was covered with a thin surface layer not present on the unimplanted implant. The composition of this layer is identical to the composition of the underlying carbon fibres. Residual soft tissue penetrating the bulk material between the carbon fibre bunches was found on the retrieved implant indicating the importance of the surface morphology in tissue growth and adhering implants. CONCLUSIONS: The surface morphology and the structure were not changed after 8 years. The two main components of the implant retrieved from the human body are still carbon and oxygen, but the amount of oxygen is 3-4 times higher than on the surface of the reference implant, which can be attributed to the oxidative effect of the human body, consequently in the integration and biocompatibility of the implant. The clinical conclusion is that if the soft part cover is appropriate, the carbon implants are cosmetically and functionally more suitable than titanium plates.

Evidence for Active Electrolyte Transport by Two-Dimensional Monolayers of Human Salivary Epithelial Cells.

Functional reconstruction of lost tissue by regenerative therapy of salivary glands would be of immense benefit following radiotherapy or in the treatment of Sjogren's syndrome. The purpose of this study was to develop primary cultures of human salivary gland cells as potential regenerative resources and to characterize their acinar/ductal phenotype using electrophysiological measurements of ion transport. Human salivary gland cultures were prepared either from adherent submandibular gland cells (huSMG) or from mixed adherent and nonadherent cells (PTHSG) and were cultivated in Hepato-STIM or minimum essential medium (MEM). Expression of key epithelial marker proteins was determined by quantitative reverse transcription polymerase chain reaction (RT-PCR). Transepithelial electrical resistance (TER) was monitored following seeding the cells on Transwell membranes. Transepithelial ion transport was estimated by short-circuit current (Isc) measurements in an Ussing chamber. Both huSMG and PTHSG cells showed epithelial characteristics when cultivated in Hepato-STIM, while fibroblast-like elements dominated in MEM. Compared to intact tissue, cultivation of the cells resulted in substantial decreases in AQP5 and NKCC1 expression and moderate increases in claudin-1 and ENaC expression. Both cultures achieved high TER and transepithelial electrolyte movement in Hepato-STIM, but not in MEM. The Isc was substantially reduced by basolateral Cl(-) and bicarbonate withdrawal, indicating the involvement of basolateral-to-apical anion transport, and by the blockade of apical ENaC by amiloride, indicating the involvement of apical-to-basolateral Na(+) transport. An almost complete inhibition was observed following simultaneous ENaC block and withdrawal of the two anions. Isc was enhanced by either apical adenosine triphosphate (ATP) or basolateral carbachol application, but not by forskolin, confirming the expected role of Ca(2+)-activated regulatory pathways in electrolyte secretion. Inhibition of basolateral NKCC1 by bumetanide reduced the response to ATP, indicating the active involvement of this transporter in Cl(-) secretion. In conclusion, we have demonstrated that both PTHSG and huSMG primary cultures cultivated in Hepato-STIM form two-dimensional monolayers in vitro on permeable supports and achieve active vectorial transepithelial electrolyte transport. The presence of both basolateral-to-apical anion fluxes and an apical-to-basolateral Na(+) flux indicates both acinar and ductal characteristics. With further refinement, this model should provide a firm basis for new interventions to correct salivary gland dysfunction.

[Calcifications in the maxillofacial area]. / Meszesedések a maxillofaciális régióban.

Among patients presenting for dental treatment we could reveal various calcifications on panoramic x-rays or on cone beam computed tomography (CBCT) Calcifications is more likely to occur in vessels, ligaments, glandular tissues and is usually associated with chronic inflammation or scarring. The purpose of this article is to describe the imaging characteristics of commonly observed calcifications of the maxillofacial area with presenting our own cases such as: tonsilloliths, calcified lymph nodes, elongeated styloid process (calcified stylohyoid chain), phleboliths, carotid atheromas, calcified laryngeal cartilage.

Measurements of orbital volume using cone-beam computed tomography in eye movement abnormalities.

PURPOSE: To measure the orbital volume in adult patients with unilateral eye movement abnormalities originating in childhood. METHODS: Cone-beam computed tomography was performed in 2 patients with eye movement abnormalities. A 28-year-old woman was treated because of right divergent squint originating at 8 years of age after penetrating corneal trauma. A 38-year-old man was examined because of abnormal head posture caused by left superior oblique underaction originating at 6 years of age. Orbital scans were analyzed with Cranioviewer 3D craniofacial cephalometric program. We measured bony orbital area in 6 slices (in ventro-dorsal direction per 4.8 mm) in every orbit on coronal scans. RESULTS: The volume was more in the orbit with unilateral divergent squint and less in the orbit with unilateral superior oblique underaction compared to the contralateral orbital volume measurements. CONCLUSION: Cranioviewer 3D craniofacial cephalometric program is suitable for volumetric analysis of the bony orbit on cone-beam computed tomography files. The development of the orbit can be influenced by extraocular muscle movements.

Measurement of orbital volume after enucleation and orbital implantation.

INTRODUCTION: This article reports experience relating to the measurement of orbital volume by means of cone beam computed tomography (CBCT) and Cranioviewer program software in patients who have undergone enucleation and orbital implantation. PATIENTS AND METHODS: CBCT scans were made in 30 cases, 10 of which were later excluded because of various technical problems. The study group therefore consisted of 20 patients (8 men and 12 women). The longest follow-up time was 7 years, and the shortest was 1 year. In all 20 cases, the orbital volume was measured with Cranioviewer orbital program software. Slices were made in the ventrodorsal direction at 4.8 mm intervals in the frontal plane, in both bony orbits (both that containing the orbital implant and the healthy one). Similar measurements were made in 20 patients with various dental problems. CBCT scans were recorded for the facial region of the skull, containing the orbital region. The Cranioviewer program can colour the area of the slices red, and it automatically measures the area in mm. RESULTS: In 5 of the 20 cases, the first 4 or all 5 slices revealed that the volume of the operated orbit was significantly smaller than that of the healthy orbit, in 12 cases only from 1 to 3 of the slices indicated such a significant difference, and in 3 cases no differences were observed between the orbits. In the control group of patients with various dental problems, there was no significant difference between the two healthy orbits. The accuracy of the volume measurements was assessed statistically by means of the paired samples t-test. SUMMARY: To date, no appropriate method is avaliable for exact measurement of the bony orbital volume, which would be of particular importance in orbital injury reconstruction. However, the use of CBCT scans and Cranioviewer orbital program software appears to offer a reliable method for the measurement of changes in orbital volume.

Porous Hydroxyapatite and Aluminium-Oxide Ceramic Orbital Implant Evaluation Using CBCT Scanning: A Method for In Vivo Porous Structure Evaluation and Monitoring.

Objective. This study aimed to define CBCT as a technique for postimplantation in vivo examination of porous hydroxyapatite and aluminium-oxide orbital implant shape, volume and density changes. Methods and Materials. CBCT was used to evaluate 30 enucleated patients treated with spherical polyglactin 910 wrapped hydroxyapatite and aluminum-oxide orbital implants. The mean duration of patient followup was 3.2 years or 1338 days with a range of 0.2 to 7.2 years or 79 to 2636 days in a population with an average age of 40.8 years. Results. The resolution of currently clinically used CBCT equipment allowed detailed structural observation of the orbital hydroxyapatite implants with some modifications. Volume and shape estimations were possible while density evaluation was more complicated compared to medical source computed tomography. The mean densities of the orbital implants were followed and a consistent gradual decrease identified from the beginning of implantation which was better defined after the applied correction procedure. Conclusion. CBCT with lower dosages of radiation exposure can be used to follow changes in implanted high-density porous structures. The density evaluation is possible with calibration modifications. Changes in orbital implant densities identified in this study may correspond to healing and maturation of soft tissues surrounding and penetrating the implants.

Cutaneous sinus tract of dental origin in children-a report of 28 new cases.

Little is known about the characteristics of cutaneous sinus tract (CST) of dental origin in children. 28 cases of CST of dental origin in children were evaluated. Age, sex, site of skin lesion, duration until diagnosis, teeth involved, etiology, treatment, and outcome were recorded. The last dental care visit was also recorded. The mean age was 10.25 years (range 4-16). The male to female ratio was 1:1.74. The mandibular-submandibular area was the most common site of skin lesions. The mandibular first molar was the most involved tooth, followed by the mandibular incisor. Caries was the most common etiology. The mean duration of lesions until correct diagnosis was 6.5 months (range 0.3-12 mos). The treatment was root canal therapy or extraction. After appropriate dental treatment, CSTs resolve rapidly. Surgical revision of the scars were indicated in eight (29%) patients, to provide better cosmetic results. In these patients, the duration of lesions were longer. Preventive dental care, as indicated by last dental care visit, was poor. CST in children is different from that in adults in terms of sites of skin lesions, duration of lesions, and involved tooth and similar to that in adults in terms of etiology and treatment modality. Early treatment of the dental infection may cause healing of the cutaneous lesion spontaneously, without a scar.

[Carbon/carbon implants in oral and maxillofacial surgery -- part 1]. / Karbon/karbon implantátumok az arc- és állcsontsebészetben - 1. rész.

UNLABELLED: Over the past 20-30 years various carbon implant materials have become more interesting, because they are well accepted by the biological environment. The traditional carbon-based polymers give rise to many complications. The polymer complication may be eliminated through carbon fibres bound by pyrocarbon (carbon/carbon). AIM: The aim of this study is to present the long-term results of carbon/carbon implants. METHODS: Mandibular reconstruction was performed with pure (99.99%) carbon implants in 16 patients. Predominantly tumorous cases were included (10 malignant tumors, 4 large cystic lesions and 2 augmentative processes). RESULTS: Because the interventions had been performed 6-8 years before the last follow-up visit, the authors report long-term results. Of the 16 patients, the implants had to be removed earlier in 5 patients because of the defect that arose on the oral mucosa above the carbon plates. The most probable cause of this complication was the strain in the oral mucosa and disturbances in its blood supply (previous surgery, irradiated tissue, etc.). During the long-term follow-up, plate fracture, loosening of screws, infection or inflammation around the carbon/carbon implants were not observed. After 8 years one carbon implant was substituted with an autogenous bone. CONCLUSIONS: The clinical conclusion is that if the soft part cover is appropriate, the carbon implants are cosmetically and functionally more suitable than titanium plates. The structural and chemical investigation of the removed implant will be published in the near future.

[Possibilities of clinical testing of osseointegration in oral implants]. / Fogászati implantátumok csontintegrációjának klinikai vizsgálatával szerzett tapasztalataink.

The osseointegration of oral implants is of utmost importance as far as the success of implant prosthetics is concerned. In clinical practice osseointegration can only be tested indirectly. The loading of implants is usually linked to osseointegration as a condition. Under some circumstances implants can be loaded before osseointegration is completed. The present study reviews the various methods of testing osseointegration and the conditions of immediate loading. In the present study the changes in the stability of 59 implants restored with screw-retained superstructures and partly immediately loaded, were observed over a period of several years, with the help of the Periotest method. Based on the statistical evaluation of the results, a significant correlation was found between implant insertion torque and primary stability. A difference was found between the stability of implants in the upper and lower jaws. A typical curve in the temporal changes of implant stability was described.

[A biomechanical study of Uniplant SP temporary dental implants: loading under laboratory conditions]. / Uniplant SP fogászati ideiglenes implantátumok laboratóriumi terheléses vizsgálata.

The mechanical strength parameters of Uniplant SP temporary implants were investigated. In clinical practice temporary implants are used to provide the patient with a fixed temporary restoration. Temporary implants are one-part implants small in diameter, and by design they have excellent primary stability. The temporary fixtures are usually placed simultaneously with the final implants. They positioned between the final implants. Due to their good stability they can immediately be loaded. They are usually expected to function till the final implants are ready for loading and when no longer needed, the temporary implants are removed. The abutment that carries the prosthetic components is manufactured in one piece with the implant, connected to it with a narrower neck portion. This neck part might easily fracture in the first instance when the abutment is bent to make abutments parallel in order to fabricate the temporary prosthetic device and in a second instance when temporary implants are removed. In the present study the mechanical properties of the cervical part were studied in a custom-designed device. Based on the results of the loading studies recommendations were made to modify the current shape of the implant. With minimal modification of the implant design and lengthening the implant neck risk of fracture can be significantly reduced.

Finite element analysis of the human mandible to assess the effect of removing an impacted third molar.

BACKGROUND AND AIM: Finite element analysis (FEA) was used to generate 3-dimensional models of a human mandible with impacted third molars. The aim was to analyze the effects of removing various amounts of bone around an impacted mandibular third molar and to predict the possibility of iatrogenic fracture. MATERIALS AND METHODS: Data were acquired from cone beam computed tomography (CBCT) scans of a patient using numerically calculated mechanical parameters. Virtual surgery was then performed on the mandibular models, and standardized chewing forces were applied to the resulting simulations. RESULTS: The modelling showed that the highest stress during normal clenching occurred if the surgical procedure involved the external oblique ridge. The peak stress occurred at the site of removal of the third molar, during contralateral loading of the mandible. DISCUSSION: Use of CBCT allowed production of high-quality models of an individual patient and simulation of various surgical scenarios. FEA identified the accumulation of stress and strain at specific parts of the mandible and predicted the responses of bone to mechanical activity. FEA could prove useful to dental practitioners in the future to predict the likelihood of iatrogenic fracture of the jaws after surgical removal of mandibular bone, such as occurs when the third molar is removed. This may allow dentists to change their approach to tooth removal in certain cases.

Finite element analysis of the human mandible at 3 different stages of life.

OBJECTIVE: This study analyzed detailed models of human mandibles at 3 different stages of life with simulation of supra normal chewing forces at static conditions. METHODS AND MATERIALS: Finite element analysis (FEA) was used to generate models from cone-beam computerized tomograms (CBCT) of 3 patients aged 12, 20, and 67 years, using numerically calculated material parameters. Estimated chewing forces were then applied to the simulations. RESULTS: The results reflect higher elasticity in younger models in all regions of the mandible. The experimental models show that physiologic load stress and strain distributional changes of the mandible vary according to age. CONCLUSION: The CBCT-based model generation used in this study provided high-quality model definition of the 3 individual patients of different ages. FEA has great potential to predict bone responses to paradigms of mechanical activity. Future applications of FEA will include surgical planning, surgical hardware testing, and the design of scaffolds and tissue-engineered constructs.

[Report of a rare case of tongue cancer in childhood]. / Nyelvkarcinóma ritka esete gyermekkorban.

The occurrence of tongue cancer is fairly rare in childhood, thus, clinicians may not include this possibility in differential diagnosis while observing a tongue lesion in this age. For this reason, adequate therapy and surgical removal can be performed only with great delay and it can lead to worse prognosis and outcome. The authors present a case of tongue cancer in a 15 year old child, with a review of the literature to alert the clinician to this entity and the importance of its diagnosis.