The magnetic resonance characteristics of sinonasal rhabdomyosarcoma in adults: analysis of 27 cases and comparison with pathological subtypes.

BACKGROUND: Sinonasal rhabdomyosarcoma (RMS) in adults is extremely rare, and early diagnosis and treatment are crucial to improve the patient's prognosis. The purpose of this study was to evaluate the magnetic resonance imaging (MRI) findings of sinonasal RMS in adults and analyze the correlations between the imaging features and pathological subtypes. METHODS: We reviewed 27 patients with pathologically proven RMS of the nasal cavity and paranasal sinuses, including embryonal RMS (ERMS) in 14 patients, alveolar RMS (ARMS) in seven patients, and mixed-type RMS in six patients. Conventional MRI was performed in all 27 patients, and high-resolution diffusion-weighted imaging was conducted in 25 patients. The tumor location, size, morphological features, signal intensity, texture, contrast enhancement characteristics, lymph node metastases, apparent diffusion coefficients (ADCs), and involvement of local soft tissues were independently assessed by two authors. RESULTS: On MR imaging, sinonasal RMS appeared isointense on T1-weighted imaging in 21 cases (77.8%) and heterogeneously hyperintense on T2-weighted imaging in 18 patients (66.7%). After enhancement, the tumors were heterogeneously enhanced in 24 cases (88.9%). Botryoid enhancement with multiple small rings resembling bunches of grapes was found in 15 cases (55.6%). Mucosal invasion of the maxillary sinus was identified in 51.9% patients. Skull and orbit involvement were found in 55.6% and 81.5% patients, respectively. Lymph node metastasis was seen in 18 cases (66.7%). There were significant differences in botryoid enhancement (P = 0.044) and skull involvement (P = 0.044) among different histological subtypes. The mean ADC value of RMS was 0.73 ± 0.082 × 10-3 mm2/s, and there was no significant difference among different histological subtypes. CONCLUSIONS: Some characteristic MRI findings such as botryoid enhancement in the ethmoid sinus, involvement of the orbit and skull, and a lower ADC value can provide important clues for preoperative diagnosis of sinonasal RMS in adults. Further, botryoid enhancement was more common in ERMS, while skull involvement was more common in ARMS.

Ocular Safety and Toxicokinetics of Bevacizumab-bvzr (Zirabev), a Bevacizumab Biosimilar, Administered to Cynomolgus Monkeys by Intravitreal Injection.

Purpose: Bevacizumab-bvzr (Zirabev®), a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor and a biosimilar to bevacizumab, is approved for intravenous administration for various indications worldwide. The objectives of this study were to evaluate the ocular toxicity, systemic tolerability, and toxicokinetics (TKs) of bevacizumab-bvzr following repeat intravitreal (IVT) injection to cynomolgus monkeys. Methods: Male monkeys were administered saline, vehicle, or bevacizumab-bvzr at 1.25 mg/eye/dose once every 2 weeks (3 doses total) for 1 month by bilateral IVT injection, followed by a 4-week recovery phase to evaluate the reversibility of any findings. Local and systemic safety was assessed. Ocular safety assessments included in-life ophthalmic examinations, tonometry (intraocular pressure, IOP), electroretinograms (ERGs), and histopathology. In addition, concentrations of bevacizumab-bvzr were measured in serum and in ocular tissues (vitreous humor, retina, and choroid/retinal pigment epithelium) and ocular concentration-time profiles and serum TKs were evaluated. Results: Bevacizumab-bvzr was tolerated locally and systemically, with an ocular safety profile comparable to the saline or vehicle control group. Bevacizumab-bvzr was observed in both serum and in the evaluated ocular tissues. There were no bevacizumab-bvzr-related microscopic changes or effects on IOP or ERGs. Bevacizumab-bvzr-related trace pigment or cells in vitreous humor (in 4 of 12 animals; commonly associated with IVT injection) and transient, nonadverse, mild ocular inflammation (in 1 of 12 animals) were noted upon ophthalmic examination and fully reversed during the recovery phase. Conclusions: Bevacizumab-bvzr was well tolerated via biweekly IVT administration in healthy monkeys, with an ocular safety profile comparable to saline or its vehicle control.

Middle Ear Teratoma: Clinical and Imaging Features.

BACKGROUND: Teratoma is a true neoplasm composed of a number of different types of tissue derived from the three germinal layers but rarely occurs in the middle ear (ME). The features of middle ear teratomas (MET) have not been well described. OBJECTIVE: The objective of this study is to explore the clinical and imaging features of MET, and report 2 rare cases of MET with ear malformation that have never been reported. MATERIALS AND METHODS: The clinical, CT and MRI data of 8 patients with a pathological diagnosis of MET were collected and retrospectively mined, and 14 patients with MET reported in previous literature were also reviewed. RESULTS: ① Female, left ear predominance in MET, and the most common symptoms were otorrhea and hearing loss. ② On CT and MRI, the MET presented as an irregular soft tissue mass that was heterogeneous, with fatty tissue and involved multiple sites, and the ET and tympanum were correspondingly expanded and locally destroyed. ③ Mictotia with MET in two patients was presented, which was the first report. CONCLUSION: MET has female sex and left ear predominance. CT and MRI can be used to diagnose MET and display its extent and its relationship to the carotid canal in detail. Complete surgical excision is the definitive treatment.

Behavioral, Histopathologic, and Molecular Biological Responses of Nanoparticle- and Solution-Based Formulations of Vincristine in Mice.

Clinical use of the chemotherapeutic agent vincristine (VCR) is limited by chemotherapy-induced peripheral neuropathy (CiPN). A new formulation of VCR encapsulated by nanoparticles has been proposed and developed to alleviate CiPN. We hypothesized in nonclinical animals that the nanoparticle drug would be less neurotoxic due to different absorption and distribution properties to the peripheral nerve from the unencapsulated free drug. Here, we assessed whether VCR encapsulation in nanoparticles alleviates CiPN using behavioral gait analysis (CatWalk), histopathologic and molecular biological (RT-qPCR) approaches. Adult male C57BL/6 mice were assigned to 3 groups (empty nanoparticle, nano-VCR, solution-based VCR, each n = 8). After 15 days of dosing, animals were euthanized for tissue collection. It was shown that intraperitoneal administration of nano-VCR (0.15 mg/kg, every other day) and the empty nanoparticle resulted in no changes in gait parameters; whereas, injection of solution-based VCR resulted in decreased run speed and increased step cycle and stance (P < 0.05). There were no differences in incidence and severity of degeneration in the sciatic nerves between the nano-VCR-dosed and solution-based VCR-dosed animals. Likewise, decreased levels of a nervous tissue-enriched microRNA-183 in circulating blood did not show a significant difference between the nano- and solution-based VCR groups (P > 0.05). Empty nanoparticle administration did not cause any behavioral, microRNA, or structural changes. In conclusion, this study suggests that the nano-VCR formulation may alleviate behavioral changes in CiPN, but it does not improve the structural changes of CiPN in peripheral nerve. Nanoparticle properties may need to be optimized to improve biological observations.

Intelligent fault diagnosis of planetary gearbox based on refined composite hierarchical fuzzy entropy and random forest.

This paper presents a novel signal processing scheme by combining refined composite hierarchical fuzzy entropy (RCHFE) and random forest (RF) for fault diagnosis of planetary gearboxes. In this scheme, we propose a refined composite hierarchical analysis based method to improve the feature extraction performance of existing MFE and HFE methods. First, RCHFE is applied to extract the fault-induced information from the vibration signals. Because a refined composite analysis is used in HFF, the feature extraction capability of HFF can be effectively enhanced. Then, the extracted features are fed into the RF for effective fault pattern identification. The superiority of the proposed RCHFE-RF method is validated using both simulated and experimental signals. Results show that the proposed method outperforms MFE-RF and HFE-RF in identifying fault types of planetary gearboxes.

Otoscopy and imaging features of spontaneous temporomandibular joint herniation into the external auditory canal.

OBJECTIVE: To explore the otoscopy, CT and MRI features of spontaneous temporomandibular joint(TMJ）herniation(STMJH) into the external auditory canal (EAC) through the persistent foramen of Huschke (PFH). METHODS: 15 cases diagnosed STMJH were collected. The otoscopy, CT data of 15 cases and MRI data of 6 cases were retrospectively reviewed. RESULTS: Otoscopy revealed a mass located in the anterior wall of the bony EAC that moved forwards and backwards during mouth opening and closing, respectively. CT showed a soft mass with bony defect in the anterior wall of the EAC, with no enhancement; the bony defect margin was well defined in all cases. The bone adjacent to the PFH was pressed and partially wrapped around the soft mass, as if "holding a ball," in seven cases. Pseudobone shell around the soft mass was observed in eight cases. Six cases included MRI scans, which showed TMJ soft tissue herniated into the EAC. CONCLUSION: STMJHs have unique otoscopic, CT and MRI features. The examination strategy recommended is dynamic otoscopy and conventional CT, MRI can be chosen when the herniation is complicated by infection or otitis externa or when the patient has TMJ dysfunction; conservative management and follow-up observations are the main treatment strategy recommended. ADVANCES IN KNOWLEDGE: Mechanical stress of TMJ on the EAC is thought to cause herniation and the special CT features, the location and size of the PFH, especially the location, are the major risk factors for TMJ herniation in patients with FH.

A Review of Early Fault Diagnosis Approaches and Their Applications in Rotating Machinery.

Rotating machinery is widely applied in various types of industrial applications. As a promising field for reliability of modern industrial systems, early fault diagnosis (EFD) techniques have attracted increasing attention from both academia and industry. EFD is critical to provide appropriate information for taking necessary maintenance actions and thereby prevent severe failures and reduce financial losses. A massive amounts of research work has been conducted in last two decades to develop EFD techniques. This paper reviews and summarizes the research works on EFD of gears, rotors, and bearings. The main purpose of this paper is to serve as a guidemap for researchers in the field of early fault diagnosis. After a brief introduction of early fault diagnosis techniques, the applications of EFD of rotating machine are reviewed in two aspects: fault frequency-based methods and artificial intelligence-based methods. Finally, a summary and some new research prospects are discussed.

Safety Assessment of Formulation Vehicles Following Intravitreal Administration in Rabbits.

PURPOSE: Evaluate 21 formulation vehicles administered to rabbits after intravitreal injection for tolerability and safety. METHODS: Forty-two Dutch Belted rabbits were anesthetized, and the eyes received a single intravitreal injection of the excipient formulation. Clinical signs and ocular irritation responses were recorded twice daily for 7 days and microscopic evaluation of the eyes, optic nerve, and eyelids was completed at 1-week post treatment. RESULTS: Saline (≥ 300 mOsm and ≤ 592 mOsm at pH 7.0 or 300 mOsm at pH 8.0) and 10 formulation excipients; (10% w/v PEG 3350 at pH 7.4, 1% polysorbate 21 at pH 7.4, PVA at pH 7.0, 0.2% polysorbate 80 at pH 7.2, 0.2% Pluronic F108® at pH 7.3, 2%, 100 mM sodium sulfate at pH 3.2, 2 mM sodium glycocholate at pH 7.4, and 275 mM D-mannitol pH 7.0 in sterile water, and 100 mM sodium phosphate in combination with 0.9% NaCl 300 mOsm and 0.01% or 0.05% polysorbate 80 at pH 7.4) considered as formulation vehicles for intravitreal injectables, were well-tolerated in rabbits. Clinical signs were transient and microscopic changes were not observed. CONCLUSIONS: Of the 21 formulation vehicles evaluated, 10 formulation vehicles were well-tolerated in rabbits and feasible candidates for future investigations.

A Novel Three-Dimensional Vector Analysis of Axial Globe Position in Thyroid Eye Disease.

Purpose. To define a three-dimensional (3D) vector method to describe the axial globe position in thyroid eye disease (TED). Methods. CT data from 59 patients with TED were collected and 3D images were reconstructed. A reference coordinate system was established, and the coordinates of the corneal apex and the eyeball center were calculated to obtain the globe vector [Formula: see text]. The measurement reliability was evaluated. The parameters of [Formula: see text] were analyzed and compared with the results of two-dimensional (2D) CT measurement, Hertel exophthalmometry, and strabismus tests. Results. The reliability of [Formula: see text] measurement was excellent. The difference between [Formula: see text] and 2D CT measurement was significant (p = 0.003), and [Formula: see text] was more consistent with Hertel exophthalmometry than with 2D CT measurement (p < 0.001). There was no significant difference between [Formula: see text] and Hirschberg test, and a strong correlation was found between [Formula: see text] and synoptophore test. When one eye had a larger deviation angle than its fellow, its corneal apex shifted in the corresponding direction, but the shift of the eyeball center was not significant. The parameters of [Formula: see text] were almost perfectly consistent with the geometrical equation. Conclusions. The establishment of a 3D globe vector is feasible and reliable, and it could provide more information in the axial globe position.

Assessment of Cochlea Endolymphatic Hydrops Using 3-D FLAIR and 3-D Real IR Sequence in Guinea Pigs via 3T MRI After Intratympanic Gadolinium: A Histopathological Comparison.

OBJECTIVE: We assessed whether the three-dimensional fluid-attenuated inversion-recovery (3-D FLAIR) and three-dimensional inversion-recovery with real reconstruction (3-D real IR) sequences can be used to detect cochlea endolymphatic hydrops (EHs) in guinea pigs using 3 Tesla magnetic resonance imaging (3T MRI). The results of 3-D real IR imaging were compared with histopathological outcomes. MATERIALS AND METHODS: Fourteen healthy men and women albino guinea pigs were used in this study. Their right ears received procedures that promoted EHs, and their left ears were used as untreated controls. High-resolution 3T MRI, combined with the intratympanic injection of gadolinium (Gd) in both ears, was performed 8 to 12 weeks after surgery. Both sides of the cochlea midmodiolar sections were observed under a light microscope and saved as the histopathological images. The signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) between the T2-weighted 3-D FLAIR and T2-weighted 3-D real IR sequences were compared. The appearance of EHs in the basal, second, third, and apical turns of the cochlea was further evaluated using 3-D FLAIR, 3-D real IR, and the histopathological images. Moreover, the maximum scala media area ratios (SMRs) on the histopathological sections were compared with the grading of the EHs on the 3-D real IR sequence with regard to each turn of the cochlea. RESULTS: Significant differences were found between the 3-D FLAIR and 3-D-real IR sequences with regard to the SNRs and CNRs (p < 0.05): the 3-D FLAIR sequence exhibited higher SNRs (SNRROI: 347.95 ±â€Š105.01; SNRB: 103.28 ±â€Š17.61) compared with the 3-D real IR sequence (SNRROI: 86.71 ±â€Š30.11; SNRB: 11.11 ±â€Š3.45), whereas the 3-D real IR sequence showed higher CNRs (2.78 ±â€Š0.58) compared with the 3-D FLAIR sequence (2.18 ±â€Š0.55). Various degrees of EHs were observed in each turn of the cochlea in the experimental ears on the basis of the histopathological images. Thirteen, 10, 4, and 0 EHs were observed in the basal, second, third, and apical turns of the cochlear using 3-D FLAIR images, respectively, whereas 14, 14, 14, and 13 EHs were found using 3-D real IR images, respectively. Significant differences were found between the two sequences when evaluating the second, third, and apical turns of the cochlear but not with regard to the basal turn (p < 0.05). The SMRs were proportional to the extent of the EHs on 3-D real IR imaging in each turn of the cochlea. CONCLUSIONS: 3-D real IR images are clearer than 3-D FLAIR images, and they can display cochlea EHs more precisely using 3T MRI in guinea pigs. The extent of the EHs on 3-D real IR imaging was more consistent with the histopathological observations in each turn of the cochlea.

Evaluation of miR-216a and miR-217 as Potential Biomarkers of Acute Exocrine Pancreatic Toxicity in Rats.

Detecting and monitoring exocrine pancreatic damage during nonclinical and clinical testing is challenging because classical biomarkers amylase and lipase have limited sensitivity and specificity. Novel biomarkers for drug-induced pancreatic injury are needed to improve safety assessment and reduce late-stage attrition rates. In a series of studies, miR-216a and miR-217 were evaluated as potential biomarkers of acute exocrine pancreatic toxicity in rats. Our results revealed that miR-216a and miR-217 were almost exclusively expressed in rat pancreas and that circulating miR-216a and miR-217 were significantly increased in rats following administration of established exocrine pancreatic toxicants caerulein (CL) and 1-cyano-2-hydroxy-3-butene (CHB) as well as in rats administered a proprietary molecule known to primarily affect the exocrine pancreas. Conversely, neither microRNA was increased in rats administered a proprietary molecule known to cause a lesion at the pancreatic endocrine-exocrine interface (EEI) or in rats administered an established renal toxicant. Compared with amylase and lipase, increases in miR-216a and miR-217 were of greater magnitude, persisted longer, and/or correlated better with microscopic findings within the exocrine pancreas. Our findings demonstrate that in rats, miR-216a and miR-217 are sensitive and specific biomarkers of acute exocrine pancreatic toxicity that may add value to the measurement of classical pancreatic biomarkers.

Identification and Evaluation of Novel MicroRNA Biomarkers in Plasma and Feces Associated with Drug-induced Intestinal Toxicity.

Gastrointestinal toxicity is dose limiting with many therapeutic and anticancer agents. Real-time, noninvasive detection of markers of toxicity in biofluids is advantageous. Ongoing research has revealed microRNAs as potential diagnostic and predictive biomarkers for the detection of select organ toxicities. To study the potential utility of microRNA biomarkers of intestinal injury in a preclinical toxicology species, we evaluated 3 rodent models of drug-induced intestinal toxicity, each with a distinct mechanism of toxicity. MiR-215 and miR-194 were identified as putative intestinal toxicity biomarkers. Both were evaluated in plasma and feces and compared to plasma citrulline, an established intestinal injury biomarker. Following intestinal toxicant dosing, microRNA changes in feces and plasma were detected noninvasively and correlated with histologic evidence of intestinal injury. Fecal miR-215 and miR-194 levels increased, and plasma miR-215 decreased in a dose- and time-dependent manner. Dose-dependent decreases in plasma miR-215 levels also preceded and correlated positively with plasma citrulline modulation, suggesting miR-215 is a more sensitive biomarker. Moreover, during the drug-free recovery phase, plasma miR-215 returned to predose levels, supporting a corresponding recovery of histologic lesions. Despite limitations, this study provides preliminary evidence that select microRNAs have the potential to act as noninvasive, sensitive, and quantitative biomarkers of intestinal injury.

Validation of Cross-Species Reactivity of the VEGF-A/PDGFRß Bifunctional Antibody PF-06653157.

PURPOSE: PF-06653157 is a bifunctional antagonist monoclonal antibody (mAb) that targets human VEGF-A ligand and PDGF-Rß. With the advent of PF-06653157 as an angiogenesis inhibitor and potential treatment for angiogenesis deregulation diseases, a relevant toxicology species is needed for toxicity and efficacy studies. Investigative studies were conducted to validate the mAb dual antagonist properties in a human system and determine its cross-reactive pharmacology in nonhuman cells. METHODS: Sequence alignment was used to determine percent sequence identity of VEGF and PDGF receptors and ligands; qualitative reverse transcription polymerase chain reaction (qRT-PCR) was used to determine the presence of PDGF-Rß on cells of interest. The functional activity of PF-06653157 antibody was assessed in human, dog, porcine, rabbit, rat, mouse, and cynomolgus monkey cells treated with VEGF and PDGF ligands through cell proliferation assays and western blot analysis of AKT and p44/p42 (ERK1/2) protein phosphorylation and enzyme-linked immunosorbent assay. RESULTS: PF-06653157 attenuated phosphorylation of AKT and p44/p42 proteins in human and cynomolgus monkey cells. The antibody did not attenuate AKT nor p44/p42 phosphorylation in any other species tested. PDGFR signaling could not be activated with human PDGF ligand in the porcine cells, so PF-06653157 activity in porcine remains inconclusive. CONCLUSION: The PF-06653157 mAb cross-reacts with cynomolgus monkey cells in a similar manner to human cells. Therefore, cynomolgus monkeys are considered the appropriate species for efficacy and regulatory toxicology studies in PF-06653157 development.

Editor's Highlight: Plasma miR-183/96/182 Cluster and miR-124 are Promising Biomarkers of Rat Retinal Toxicity.

Retinal toxicity is one of the leading causes of attrition in drug development, and drug-induced retinal toxicity remains an issue in both drug discovery and postmarketed drugs. Derisking strategies to help with early identification of retinal injury utilizing a predictive retinal miRNA biomarker would greatly benefit decision-making in drug discovery programs, ultimately reducing attrition due to retinal toxicity. Our previous work demonstrated elevation of circulating retina-enriched miRNAs in a retinal toxicity model. To further validate our previous observation, 2 additional rat retinal injury models were utilized in this study: NaIO3-induced retinal injury and laser-induced choroidal neovascularization (CNV) injury model. Following induction of retina tissue injuries, circulating miR-183/96/182 cluster (miR-183 cluster), and miR-124 was investigated, as well as evaluations using an electroretinogram (ERG) and histopathology analysis. Data revealed that circulating miR-183/96/182 cluster was significantly increased (2- to 15-fold) compared with baseline/control in both laser-induced CNV and NaIO3-induced retinal injury models. Moreover, the severity of the retinal injury evaluated by ERG and histopathology correlated highly with elevation of these retina-enriched miRNAs in plasma. MiR-124 was also significantly increased in comparison with baseline/control by ∼25-fold postrepeat-doses of 30 mg/kg NaIO3 treatment. Increased level of these plasma miRNA biomarkers appeared to be dose- and time-dependent upon NaIO3 or laser treatment. The results suggest that the retina-enriched miRNAs (miR-183/96/182 cluster and miR-124) could serve as convenient and predictive biomarkers of retinal toxicity in drug development.

Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats.

Retinal ocular toxicity is among the leading causes of drug development attrition in the pharmaceutical industry. Electroretinography (ERG) is a non-invasive functional assay used to assess neuro-retinal physiological integrity by measuring the electrical responses. To directly assess the utility of ERG, a series of studies was conducted following intravitreal and/or iv administration of pan-cyclin-dependent kinase inhibitors: AG-012,986 and AG-024,322 in rats. Both compounds have previously shown to induce retinal toxicity. Retinal injury was evaluated by ERG, histopathology and TUNEL staining. Intravitreal injection of AG-012,986 at ≥ 10 µg/eye resulted in decreases (60%) in ERG b-wave and microscopic changes of mild to moderate retinal degeneration, and at 30 µg/eye led to additional ophthalmic findings. Intravenous administration of AG-012,986 daily at ≥ 5 mg/kg resulted in dose-related decreases (25 to 40%) in b-wave and sporadic to intense positive TUNEL staining. Intravitreal injection of AG-024,322 at 30 µg/eye also resulted in decreases (50 to 60%) in b-wave, mild to marked retinal degeneration and mild vitreous debris. These experiments demonstrate that ERG can be used as a sensitive and reliable functional tool to evaluate retinal toxicity induced by test compounds in rats complementing other classical ocular safety measurements.

Toxicity of hydroxyurea in rats and dogs.

The toxicity of hydroxyurea, a treatment for specific neoplasms, sickle-cell disease, polycythemia, and thrombocytosis that kills cells in mitosis, was assessed in repeat-dose, oral gavage studies in rats and dogs and a cardiovascular study in telemetered dogs. Hydroxyurea produced hematopoietic, lymphoid, cardiovascular, and gastrointestinal toxicity with steep dose response curves. In rats dosed for 10 days, 50 mg/kg/day was tolerated; 500 mg/kg/day produced decreased body weight gain; decreased circulating leukocytes, erythrocytes, and platelets; decreased cellularity of thymus, lymph nodes, and bone marrow; and epithelial degeneration and/or dysplasia of the stomach and small intestine; 1,500 mg/kg/day resulted in deaths on day 5. In dogs, a single dose at ≥ 250 mg/kg caused prostration leading to unscheduled euthanasia. Dogs administered 50 mg/kg/day for 1 month had decreased circulating leukocytes, erythrocytes, and platelets; increased bone marrow cellularity with decreased maturing granulocytes; increased creatinine kinase activity; and increased iron pigment in bone marrow and hepatic sinusoidal cells. In telemetered dogs, doses ≥ 15 mg/kg decreased systolic blood pressure (BP); 50 mg/kg increased diastolic BP, heart rate, and change in blood pressure over time (+dP/dt), and decreased QT and PR intervals and maximum left ventricular systolic and end diastolic pressures with measures returning to control levels within 24 hr.

[Imaging evaluation of the cases with tympanicum and pulsatile tinnitus].

OBJECTIVE: To analyze the CT and MRI features of glomus tympanicum tumors accompanied with tympanitis and evaluate the diagnostic value of CT and MRI in order to improve the cognition for the disease. METHODS: The clinical materials and images of 8 patients with the symptoms of pulsatile tinnitus and hearing loss in whom glomus tympanicum tumors with tympanitis surgically and pathologically confirmed were retrospectively reviewed. The characteristics and diagnostic value of CT and MR imaging were summarized. RESULTS: By CT examination the lesions in middle ear and mastoid were preoperatively diagnosed as tympanitis in five cases and only in three cases the glomus tympanicum tumors were suspected. In six patients underwent MR examination the lesions were all preoperatively diagnosed as glomus tympanicum tumors accompanied with tympanitis. HRCT scanning of the temporal bone in all patients showed the soft tissue lesions in the tympanic cavity and mastoid, and the caritas tympanic were mostly (n = 3) or completely (n = 5) occupied by soft tissue lesions, but the auditory ossicles were all without destruction. Contrast-enhanced axial CT scanning performed in five cases showed less soft tissue mass on the cochlear promontory, and the size of mass was less than that observed in MR imaging. MR T(1)-weighted imaging showed the presence of isointense lesions in middle ear and isointense (n = 3) or hyperintense (n = 3) lesions in mastoid. On T(2)-weighted imaging the lesions with slight hyperintense were viewed in the middle ear and the lesions with hyperintense in mastoid. T(1)-weighted gadolinium-enhanced MRI showed the masses in tympanum were markedly increased enhancement, but the lesions in mastoid without enhancement. MRI and CT imaging revealed the masses in six cases of eight extending to the eustachian tube. CONCLUSION: When the glomus tympanicum tumor was accompanied with tympanitis the tumor could be misdiagnosed or missed only by CT examination. The patients with pulsatile tinnitus should be taken seriously. MRI with contrast-enhancement is superior to CT in the preoperative diagnosis and accurately evaluation for the glomus tympanicum tumors with tympanitis.

RTP801 gene expression is differentially upregulated in retinopathy and is silenced by PF-04523655, a 19-Mer siRNA directed against RTP801.

PURPOSE: The intraocular pharmacodynamics of PF-04523655, a small-interfering RNA (siRNA) directed against RTP801, was characterized using rat models of retinopathy. METHODS: Rat models of streptozotocin-induced diabetes and wet AMD were used to determine the onset, extent, and duration of siRNA inhibition of retinal RTP801 expression by PF-04523655, and this inhibition was characterized by pharmacokinetic/pharmacodynamic (PK/PD) modeling. A rat model of wet AMD was also used to examine PF-04523655 dose-dependent effects on the incidence of clinical grade 3 or 4 choroidal neovascularization lesions. Whole homogenate versus laser-capture microdissected (LCM) retinal samples were analyzed by quantitative PCR for RTP801 expression. RESULTS: RTP801 expression in RPE/choroid (RPE/C) increased in diabetic rats by up to 70% above nondiabetic rat levels. Inhibition of retinal RTP801 expression by PF-04523655 began 1 day after intravitreous injection and was observed through day 7 in the neurosensory retina and through day 14 or longer in RPE/C. PF-04523655 inhibition of RTP801 expression was maintained well after clearance of PF-04523655 from the eye and was best characterized by an effect compartment PK/PD model. Moreover, PF-04523655 administration decreased the incidence of clinical grade 3 or 4 lesions by approximately 60% (P = 0.053), and dose-dependently inhibited retinal RTP801 expression (P < 0.01). RTP801 expression was enriched in the outer nuclear layer in LCM samples. CONCLUSIONS: In rodent retinopathy models, administration of the siRNA, PF-04523655, reduced RTP801 expression in the retina, consistent with the RNA-induced silencing complex (RISC) mechanism of action. The pharmacodynamic profile from the animal models could be useful to elucidate dose and exposure dependency of RTP801 expression inhibition by siRNA.

Circulating microRNAs as biomarkers of retinal toxicity.

Despite of the attrition due to retinal toxicity during drug development there are no early reliable predictive biomarkers of retinal toxicity and this is increasingly becoming a concern. Thus far, in pharmacology and toxicology the technologies for assessing retinal side effects are limited to inconvenient visual behavioral tests, invasive electroretinograms or terminal histopathology. To address the lack of convenient early predictive retinal toxicity biomarkers, we explored a set of potential novel retinal enriched miRNAs in rats ex vivo and in vivo with known retinal toxicant pan-CDK inhibitors to assess circulating plasma miRNAs in rats and non-retinal toxicants as controls. Rats were administered a single intravitreal (IVT) injection and blood samples were collected pre-dose, various time points post-dose and then analyzed for five retinal enriched miRNAs (miR-96, miR-124a, miR181a, miR-182 and miR-183) by qRT-PCR. Ophthalmic exam, electroretinogram and histopathology were performed as confirmatory tests. All five miRNAs tested in retinal explants culture were highly expressed after pan-CDK inhibitor treatment. In vivo the pan-CDK inhibitors caused elevations of miR-96, miR-124a and miR-183 in blood. These results highly correlated with ocular exam, electroretinograms and microscopic findings. Comparatively, there were no changes in miRNA levels, electroretinograms, or histopathology in the negative control treatment groups. Although these miRNAs need additional confirmatory evaluation whether they truly predict retinal toxicity prior to clinical observations and histopathology, these results provide promise for further testing using additional retinal toxicants.

Role of magnetic resonance diffusion-weighted imaging in differentiating lacrimal masses.

PURPOSE: To evaluate the role of magnetic resonance (MR) diffusion-weighted imaging (DWI) in discriminating lacrimal masses, including neoplastic and nonneoplastic entities. MATERIALS AND METHODS: Forty-four patients with lacrimal masses underwent conventional MRI and DWI. The apparent diffusion coefficient (ADC) values of each mass and the ipsilateral temporal lobe were measured and the ratios of the lesion to temporal lobe ADC were calculated. RESULTS: Pleomorphic adenomas had significantly higher ADC values (1.37 ± 0.22 × 10(-3) mm(2) /sec) and ADC ratios (1.85 ± 0.34) than malignant tumors (1.03 ± 0.19 × 10(-3) mm(2) /sec, 1.37 ± 0.27) (P < 0.001), inflammatory pseudotumors (0.9 ± 0.08 × 10(-3) mm(2) /sec, 1.19 ± 0.07) (P < 0.01), reactive lymphoid hyperplasias (RLHs) (0.6 ± 0.06 × 10(-3) mm(2) /sec, 0.79 ± 0.07) (P < 0.001), and lymphomas (0.55 ± 0.06 × 10(-3) mm(2) /sec, 0.74 ± 0.08) (P < 0.001). RLHs and lymphomas had significantly lower ADC values and ADC ratios than malignant tumors (P < 0.05) and inflammatory pseudotumors (P < 0.05). An ADC value of less than 1.14 × 10(-3) mm(2) /sec and an ADC ratio of less than 1.6 were optimal for differentiating malignant tumors from benign tumors (sensitivity: 80 and 90%, specificity: 100 and 88.9%, respectively). An ADC value of less than 0.76 × 10(-3) mm(2) /sec and an ADC ratio of less than 1.0 were optimal for distinguishing lymphoproliferative disorders from inflammatory pseudotumors (sensitivity: 100%, specificity: 100% for both). CONCLUSION: DWI can help differentiate lacrimal masses and provides a potential clinical tool for noninvasive tissue characterization.