Diagnosis of skull-base invasion by nasopharyngeal tumors on CT with a deep-learning approach.

PURPOSE: To develop a convolutional neural network (CNN) model to diagnose skull-base invasion by nasopharyngeal malignancies in CT images and evaluate the model's diagnostic performance. MATERIALS AND METHODS: We divided 100 malignant nasopharyngeal tumor lesions into a training (n = 70) and a test (n = 30) dataset. Two head/neck radiologists reviewed CT and MRI images and determined the positive/negative skull-base invasion status of each case (training dataset: 29 invasion-positive and 41 invasion-negative; test dataset: 13 invasion-positive and 17 invasion-negative). Preprocessing involved extracting continuous slices of the nasopharynx and clivus. The preprocessed training dataset was used for transfer learning with Residual Neural Networks 50 to create a diagnostic CNN model, which was then tested on the preprocessed test dataset to determine the invasion status and model performance. Original CT images from the test dataset were reviewed by a radiologist with extensive head/neck imaging experience (senior reader: SR) and another less-experienced radiologist (junior reader: JR). Gradient-weighted class activation maps (Grad-CAMs) were created to visualize the explainability of the invasion status classification. RESULTS: The CNN model's diagnostic accuracy was 0.973, significantly higher than those of the two radiologists (SR: 0.838; JR: 0.595). Receiver operating characteristic curve analysis gave an area under the curve of 0.953 for the CNN model (versus 0.832 and 0.617 for SR and JR; both p < 0.05). The Grad-CAMs suggested that the invasion-negative cases were present predominantly in bone marrow, while the invasion-positive cases exhibited osteosclerosis and nasopharyngeal masses. CONCLUSIONS: This CNN technique would be useful for CT-based diagnosis of skull-base invasion by nasopharyngeal malignancies.

Blockage of CSF Outflow in Rats after Deep Cervical Lymph Node Ligation Observed Using Gd-based MR Imaging.

PURPOSE: To investigate whether deep cervical lymph node (DCLN) ligation alters intracranial cerebrospinal fluid (CSF) tracer dynamics and outflow using a rat model with intrathecal dynamic contrast-enhanced (DCE) MRI. METHODS: Six bilateral DCLN-ligated and six sham-operated rats were subjected to DCE MRI with Gd-BTDO3A, and dynamic T1-weighted images were acquired. ROIs were collected from the CSF at the C1 level (CSF_C1), CSF between the olfactory bulbs (CSF_OB), CSF at the pituitary recess (CSF_PitR), and CSF at the pineal recess (CSF_PinR), upper nasal turbinate (UNT), olfactory bulbs, cerebrum, and the jugular region. Time-intensity curves were evaluated, and the maximum slope, peak timing, peak signal ratio, and elimination half-life for the four CSF ROIs and UNT were calculated and compared. RESULTS: Delayed tracer arrival in the rostral CSF space and the nasal cavity with tracer retention in the ventral CSF space were observed in the ligation group. The maximum slopes were smaller in the ligation group at UNT (sham: 0.075 ± 0.0061, ligation: 0.044 ± 0.0086/min, P = 0.011). A significant difference was not detected in peak timings. The peak signal ratio values were lower in the ligation group at UNT (sham: 2.12 ± 0.19, ligation: 1.72 ± 0.11, P = 0.011). The elimination half-life was delayed in the ligation group at CSF_C1 (sham: 30.5 ± 2.70, ligation: 44.4 ± 12.6 min, P = 0.043), CSF_OB (sham: 30.2 ± 2.67, ligation: 44.8 ± 7.47 min, P = 0.021), and CSF_PitR (sham: 30.2 ± 2.49, ligation: 41.3 ± 7.57 min, P = 0.021). CONCLUSION: The DCLN ligation in rats blocked CSF outflow into the nasal cavity and caused CSF retention.

Objective Evaluation of Oral and Pharyngeal Areas in Autopsy Cases of Obstructive Sleep Apnea Syndrome via Postmortem CT.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) can cause sudden death during sleep. Previous findings have suggested that OSAS development is related to maxillofacial morphology. Evaluation of facial morphology can determine the risk of developing the disease, and establishing an objective method to assess the underlying etiology of OSAS-related death would be advantageous. OBJECTIVE: The objective of this study is to determine the key features of obstructive sleep apnea syndrome (OSAS) using postmortem oral and pharyngeal computed tomography (CT). METHODS: We retrospectively assessed autopsy cases of patients with (n=25) and without (n=25) OSAS-related death. We used oral and pharyngeal CT images to compare the oral and pharyngeal cavity volume (OPCV), oral and pharyngeal soft tissue volume (OPSV), oral and pharyngeal air space volume (OPAV), and OPAV to OPCV ratio (%air). Receiver operating curve (ROC) analysis was used to determine the accuracy of OSAS prediction. We assessed participants with body mass index (BMI) values within the normal range. RESULTS: Among the 50 subjects, we observed significant between-group differences in OPSV, OPAV, and % air, whereas there were significant between-group differences in OPSV and %air among 28 subjects with normal BMI values. Both comparisons suggested that OSAS-related death was associated with low %air and high OPSV values. CONCLUSION: The %air and OPSV are useful for assessing postmortem oropharyngeal CT images. OSAS-related sudden death is likely when %air and OPSV values are ≤20.1% and ≥127.2 ml, respectively. Among those with normal BMI values, % air and OPSV values of ≤22.8% and ≥111.5 ml, respectively, predict OSAS-related sudden death.

Non-Gaussian model-based diffusion-weighted imaging of oral squamous cell carcinoma: associations with Ki-67 proliferation status.

OBJECTIVES: To investigate possible associations between diffusion-weighted imaging (DWI) parameters derived from a non-Gaussian model fitting and Ki-67 status in patients with oral squamous cell carcinoma (OSCC). METHODS: Twenty-four patients with newly diagnosed OSCC were prospectively recruited. DWI was performed using six b-values (0-2500). The diffusion-related parameters of kurtosis value (K), kurtosis-corrected diffusion coefficient (DK), diffusion heterogeneity (α), distributed diffusion coefficient (DDC), slow diffusion coefficient (Dslow), and apparent diffusion coefficient (ADC) were calculated from four diffusion fitting models. Ki-67 status was categorized as low (Ki-67 percentage score < 20%), middle (20-50%), or high (> 50%). Kruskal-Wallis tests were performed between each non-Gaussian diffusion model parameters and Ki-67 grade. RESULTS: The Kruskal-Wallis tests revealed that multiple parameters (K, ADC, Dk, DDC and Dslow) showed statistically significant differences between the three levels of Ki-67 status (K: p = 0.020, ADC: p = 0.012, Dk: p = 0.027, DDC: p = 0.007 and Dslow: p = 0.026). CONCLUSIONS: Several non-Gaussian diffusion model parameters and ADC values were significantly associated with Ki-67 status and have potential as promising prognostic biomarkers in patients with OSCC.

Utility of the deep learning technique for the diagnosis of orbital invasion on CT in patients with a nasal or sinonasal tumor.

BACKGROUND: In nasal or sinonasal tumors, orbital invasion beyond periorbita by the tumor is one of the important criteria in the selection of the surgical procedure. We investigated the usefulness of the convolutional neural network (CNN)-based deep learning technique for the diagnosis of orbital invasion, using computed tomography (CT) images. METHODS: A total of 168 lesions with malignant nasal or sinonasal tumors were divided into a training dataset (n = 119) and a test dataset (n = 49). The final diagnosis (invasion-positive or -negative) was determined by experienced radiologists who carefully reviewed all of the CT images. In a CNN-based deep learning analysis, a slice of the square target region that included the orbital bone wall was extracted and fed into a deep-learning training session to create a diagnostic model using transfer learning with the Visual Geometry Group 16 (VGG16) model. The test dataset was subsequently tested in CNN-based diagnostic models and by two other radiologists who were not specialized in head and neck radiology. At approx. 2 months after the first reading session, two radiologists again reviewed all of the images in the test dataset, referring to the diagnoses provided by the trained CNN-based diagnostic model. RESULTS: The diagnostic accuracy was 0.92 by the CNN-based diagnostic models, whereas the diagnostic accuracies by the two radiologists at the first reading session were 0.49 and 0.45, respectively. In the second reading session by two radiologists (diagnosing with the assistance by the CNN-based diagnostic model), marked elevations of the diagnostic accuracy were observed (0.94 and 1.00, respectively). CONCLUSION: The CNN-based deep learning technique can be a useful support tool in assessing the presence of orbital invasion on CT images, especially for non-specialized radiologists.

Evaluation of oral air space volume in obstructive sleep apnea syndrome using clinical and postmortem CT imaging.

OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) induces upper airway occlusion and may cause sudden death during sleep. This study sought to clarify the relationship between oral air space volume and OSAS onset, which is influenced by multiple factors, such as jawbone, dentition morphology, and oral soft-tissue volume. METHODS: (1) 50 subjects from deceased cases were divided into two groups: OSAS (25 subjects) and controls (25 subjects). (2) 28 subjects from clinical cases were divided into two groups: OSAS (9 subjects) and controls (19 subjects). In all cases, the Computed Tomography (CT) images of the facial region were obtained, and four parameters of oral area volume were analyzed in deceased and clinical cases, and comparisons and analyses were performed between OSAS and control cases. In addition, the efficiency of measurement of these parameters was evaluated using Receiver Operating Characteristic (ROC) curves in OSAS. RESULTS: (1) In deceased cases, oral soft-tissue volume (OSV), oral air-space volume (OAV), and the ratio of OAV to OSV (%air) showed a significant correlation. (2) In clinical cases, OAV and %air showed a significant correlation. In both postmortem and clinical images, a small %air value indicates a high risk of developing OSAS and a high probability of OSAS-related sudden death. CONCLUSIONS: It was shown that the %air is an index to evaluate OSAS by CT imaging of the oral region. OSAS may be indicated when the %air value is ≦ 16.0% in deceased cases and ≦ 6.6% in clinical cases.

Quantification of Joint Space Width Difference on Radiography Via Phase-Only Correlation (POC) Analysis: a Phantom Study Comparing with Various Tomographical Modalities Using Conventional Margin-Contouring.

Several visual scoring methods are currently used to assess progression of rheumatoid arthritis (RA) on radiography. However, they are limited by its subjectivity and insufficient sensitivity. We have developed an original measurement system which uses a technique called phase-only correlation (POC). The purpose of this study is to validate the system by using a phantom simulating the joint of RA patients.A micrometer measurement apparatus that can adjust arbitrary joint space width (JSW) in a phantom joint was developed to define true JSW. The phantom was scanned with radiography, 320 multi detector CT (MDCT), high-resolution peripheral quantitative CT (HR-pQCT), cone beam CT (CBCT), and tomosynthesis. The width was adjusted to the average size of a women's metacarpophalangeal joint, from 1.2 to 2.2 mm with increments of 0.1 mm and 0.01 mm. Radiographical images were analyzed by the POC-based system and manual method, and images from various tomographical modalities were measured via the automatic margin detection method. Correlation coefficients between true JSW difference and measured JSW difference were all strong at 0.1 mm intervals with radiography (POC-based system and manual method), CBCT, 320MDCT, HR-pQCT, and tomosynthesis. At 0.01 mm intervals, radiography (POC-based system), 320MDCT, and HR-pQCT had strong correlations, while radiography (manual method) and CBCT had low correlations, and tomosynthesis had no statistically significant correlation. The smallest detectable changes for radiography (POC-based system), radiography (manual method), 320MDCT, HR-pQCT, CBCT, and tomosynthesis were 0.020 mm, 0.041 mm, 0.076 mm, 0.077 mm, 0.057 mm, and 0.087 mm, respectively. We conclude that radiography analyzed with the POC-based system might sensitively detect minute joint space changes of the finger joint.

Enhanced oncolytic activity of E4orf6-deficient adenovirus by facilitating nuclear export of HuR.

An AU-rich element (ARE) is RNA element that enhances the rapid decay of mRNA. The RNA binding protein HuR stabilizes ARE-mRNA by exporting it to the cytoplasm. In most of cancer cells, HuR is exported to the cytoplasm and ARE-mRNA is stabilized. In addition, the viral gene product E4orf6 exports HuR to stabilize ARE-mRNA in adenovirus-infected cells and the stabilization is required for full virus replication. Previously we showed the oncolytic activity of E4orf6-deleted adenovirus dl355, which can replicate in cancer cells where ARE-mRNA is stabilized. In this study, we examined whether the further enhancement of HuR export can stimulate the replication and the oncolytic activity of dl355. We found that ethanol treatment promoted the cytoplasmic relocalization of HuR in cancer cells. In addition, the replication efficiency of dl355 increased in ethanol-treated cells, and in response, the cytolytic activity of the virus also increased in vitro and in vivo. Upregulation of a cleaved-PARP level in infected cells mediated by ethanol is suggesting that ethanol activated the apoptosis induced by dl355. IVa2 mRNA, the only ARE-mRNA among transcripts of adenovirus was augmented by ethanol treatment. These data indicate that the enhancement of ARE-mRNA stabilization as a result of ethanol treatment upregulates the oncolytic activity of dl355 and suggests that the combined use of an oncolytic adenovirus and ethanol treatment may be a good strategy for cancer therapy.

Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment.

BACKGROUND: Tumor endothelial cells (TECs) perform tumor angiogenesis, which is essential for tumor growth and metastasis. Tumor cells produce large amounts of lactic acid from glycolysis; however, the mechanism underlying the survival of TECs to enable tumor angiogenesis under high lactic acid conditions in tumors remains poorly understood. METHODOLOGY: The metabolomes of TECs and normal endothelial cells (NECs) were analyzed by capillary electrophoresis time-of-flight mass spectrometry. The expressions of pH regulators in TECs and NECs were determined by quantitative reverse transcription-PCR. Cell proliferation was measured by the MTS assay. Western blotting and ELISA were used to validate monocarboxylate transporter 1 and carbonic anhydrase 2 (CAII) protein expression within the cells, respectively. Human tumor xenograft models were used to access the effect of CA inhibition on tumor angiogenesis. Immunohistochemical staining was used to observe CAII expression, quantify tumor microvasculature, microvessel pericyte coverage, and hypoxia. RESULTS: The present study shows that, unlike NECs, TECs proliferate in lactic acidic. TECs showed an upregulated CAII expression both in vitro and in vivo. CAII knockdown decreased TEC survival under lactic acidosis and nutrient-replete conditions. Vascular endothelial growth factor A and vascular endothelial growth factor receptor signaling induced CAII expression in NECs. CAII inhibition with acetazolamide minimally reduced tumor angiogenesis in vivo. However, matured blood vessel number increased after acetazolamide treatment, similar to bevacizumab treatment. Additionally, acetazolamide-treated mice showed decreased lung metastasis. CONCLUSION: These findings suggest that due to their effect on blood vessel maturity, pH regulators like CAII are promising targets of antiangiogenic therapy. Video Abstract.

Oncolytic potential of an E4-deficient adenovirus that can recognize the stabilization of AU-rich element containing mRNA in cancer cells.

AU-rich elements (AREs) are RNA elements that enhance the rapid decay of mRNA. The fate of ARE-mRNA is controlled by ARE-binding proteins. HuR, a member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, is involved in the export and stabilization of ARE-mRNA. In the vast majority of cancer cells, HuR constitutively relocates to the cytoplasm, resulting in the stabilization of ARE-mRNA. Previously, we described that the adenovirus gene product, E4orf6, which is necessary for virus replication, participates in ARE-mRNA export and stabilization. In the present study, we showed the oncolytic potential of E4orf6-deleted adenovirus dl355, which is expected to be replicated selectively in cancer cells. Virus production and cytolytic activity of dl355 were higher in cancer cells than in normal cells. HuR-depletion downregulated dl355 replication, demonstrating that ARE-mRNA stabilization is required for the production of this virus. Tumor growth was inhibited in nude mice by an intratumoral injection of dl355. Furthermore, dl355 had a stronger oncolytic effect than E1B55k-deleted adenovirus. These results indicate that dl355 has potential as an oncolytic adenovirus for a large number of cancers where ARE-mRNA is stabilized.

Adenovirus infection induces HuR relocalization to facilitate virus replication.

HuR is an RNA-binding protein of the embryonic lethal abnormal vision (ELAV) family, which binds to the AU-rich element (ARE) in the 3'-untranslated region (UTR) of certain mRNAs and is involved in the nucleo-cytoplasmic export and stabilization of ARE-mRNAs. The cytoplasmic relocalization of ARE-mRNAs with several proteins such as HuR and pp32 increases in cells transformed by the adenovirus oncogene product E4orf6. Additionally, these ARE-mRNAs were stabilized and acquired the potential to transform cells. Although, the relocalization of HuR and the stabilization of ARE-mRNAs are crucial for cell transformation, evidence regarding the relationship of HuR and ARE-mRNAs with adenovirus replication is lacking. In this report, we demonstrate that adenovirus infection induces the relocation of HuR to the cytoplasm of host cells. Analysis using the luciferase-ARE fusion gene and the tetracycline (tet)-off system revealed that the process of stabilizing ARE-mRNAs is activated in adenovirus-infected cells. Heat shock treatment or knockdown-mediated depletion of HuR reduced adenovirus production. Furthermore, expression of ARE-including viral IVa2 mRNA, decreased in HuR-depleted infected cells. These results indicate that HuR plays an important role in adenovirus replication, at least in part, by up-regulating IVa2 mRNA expression and that ARE-mRNA stabilization is required for both transformation and virus replication.

ROS enhance angiogenic properties via regulation of NRF2 in tumor endothelial cells.

Reactive oxygen species (ROS) are unstable molecules that activate oxidative stress. Because of the insufficient blood flow in tumors, the tumor microenvironment is often exposed to hypoxic condition and nutrient deprivation, which induces ROS accumulation. We isolated tumor endothelial cells (TECs) and found that they have various abnormalities, although the underlying mechanisms are not fully understood. Here we showed that ROS were accumulated in tumor blood vessels and ROS enhanced TEC migration with upregulation of several angiogenesis related gene expressions. It was also demonstrated that these genes were upregulated by regulation of Nuclear factor erythroid 2-related factor 2 (NRF2). Among these genes, we focused on Biglycan, a small leucine-rich proteoglycan. Inhibition of Toll-like receptors 2 and 4, known BIGLYCAN (BGN) receptors, cancelled the TEC motility stimulated by ROS. ROS inhibited NRF2 expression in TECs but not in NECs, and NRF2 inhibited phosphorylation of SMAD2/3, which activates transcription of BGN. These results indicated that ROS-induced BGN caused the pro-angiogenic phenotype in TECs via NRF2 dysregulation.

Magnetic displacement force and torque on dental keepers in the static magnetic field of an MR scanner.

PURPOSE: To evaluate the effect of the static magnetic field of magnetic resonance (MR) scanners on keepers (ie, ferromagnetic stainless steel plate adhered to the abutment tooth of dental magnetic attachments). MATERIALS AND METHODS: Magnetically induced displacement force and torque on keepers were measured using 1.5 Tesla (T) and 3.0 T MR scanners and a method outlined by American Society for Testing and Materials (ASTM). Changes in magnetic flux density before and after exposure to scanner static magnetic field were examined. RESULTS: The maximum magnetically induced displacement forces were calculated to be 10.3 × 10(-2) N at 1.5 T and 13.9 × 10(-2) N at 3.0 T on the cover surface. The maximum torques exerted on the keeper (4 mm in diameter) were 0.83 N × 4 mm at 1.5 T and 0.85 N × 4 mm at 3.0 T. These forces were considerably higher than the gravitational force (7.7 × 10(-4) N) of the keeper but considerably lower than the keeper-root cap proper adhesive force. The keepers' magnetic flux density remained less than that of the Earth. CONCLUSION: Magnetically induced displacement force and torque on the keeper in the MR scanner do not influence the keeper-root cap proper adhesive force.

The influence of tissue blood flow volume on energy metabolism in masseter muscles.

This study investigated the energy metabolism of masseter muscles by 31P-Magnetic Resonance Spectroscopy (MRS) during increased blood flow induced by hot pack application to clarify the influence of changes in blood flow on muscle fatigue. Twelve healthy subjects with no history of muscle pain in the masticatory system participated in this study. The 31P-MRS measurements were performed before and after hot pack application and the ratio of phosphocreatine (PCr) acting as the energy source to reproduce ATP to beta-ATP, the PCr/beta-ATP ratio, was analyzed. Results showed that PCr/beta-ATP ratios increased significantly by an average of 22.4% after the hot pack application. The results suggest that changes in blood flow volume influence the energy metabolism in masseter muscles and that blood flow increases due to the hot pack cause higher energy levels in masseter muscles and offer an advantageous condition for preventing and relieving muscle fatigue.

Impacted teeth in the maxilla: usefulness of 3D Dental-CT for preoperative evaluation.

OBJECTIVE: To compare the shapes of roots of impacted teeth shown in three-dimensional computed tomographic images (3D Dental-computed tomography (CT) images) and plain radiographs and to determine whether 3D Dental-CT images are useful for examination before performing an operation for extraction of a maxillary impacted tooth. METHODS AND PATIENTS: Images obtained from patients who had impacted teeth in the maxilla, including impacted mesial supernumerary teeth in 13 patients, impacted incisors in two patients, impacted canines in 11 patients, impacted premolars in four patients and impacted molars in three patients, were used in this study. In all patients, plain radiographs and 3D Dental-CT images were retrospectively reviewed by an oral radiologist for evidence of root dilaceration before operations to extract the impacted teeth were performed. The findings in the images were compared with intraoperative findings in all cases. RESULTS: The mean specificity and sensitivity of plain radiographs were 95 and 8%, respectively, while those of 3D Dental-CT images were 100 and 77%, respectively. There was a statistically significant (P<0.01) difference between the depiction capabilities of plain radiographs and 3D Dental-CT images with regard to dilacerations of roots of impacted teeth. DISCUSSION AND CONCLUSION: CT may enable radiologists to make a quick and accurate diagnosis of tooth impaction. 3D Dental-CT images are useful for determining the root shape of an impacted tooth in the maxilla.

Electromyographic activity of the jaw-closing muscles during jaw opening in patients with masseter muscle contracture.

Contracture of the jaw-closing muscles is one of the causes of limitation of jaw opening. This study examined whether there is any difference between the EMG activities of jaw-closing muscles during jaw opening in healthy people and in patients with masseter muscle contracture (MMC), who do not have a history of trauma or infection. The patient group consisted of eleven females, 18 to 62 years old with no history of trauma or infections, with limited mouth opening due to MMC. The control group included eleven healthy females, 23 to 50 years old. The EMG activity was recorded bilaterally in the central portion of masseter muscles (Mm), the anterior portion of temporal muscles (Tm), and the anterior belly of digastric muscles (Dm). Nine out of the patient group showed obvious EMG activity in Mm during jaw opening which was different from typical EMG patterns during jaw opening of up to 40 mm in the control group. Among the nine patients, eight showed antagonistic contraction in Tm as well as Mm. The mean integral value of Mm and Tm during jaw opening in the patient group was significantly higher than in the control group (P<0.01). These results suggest that EMG activity during jaw opening in MMC patients with no history of trauma or infections is different from that in healthy people.