Familial Paget's disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27).

INTRODUCTION: Paget's disease of bone (PDB) is a skeletal disorder characterized by disorganized bone remodeling due to abnormal osteoclasts. Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) gene encodes the receptor activator of nuclear factor kappa B (RANK), which has a critical role in osteoclast function. There are five types of rare PDB and related osteolytic disorders due to TNFRSF11A tandem duplication variants so far, including familial expansile osteolysis (84dup18), expansile skeletal hyperphosphatasia (84dup15), early-onset familial PDB (77dup27), juvenile PDB (87dup15), and panostotic expansile bone disease (90dup12). MATERIALS AND METHODS: We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant. RESULTS: This family had bone symptoms, hyperphosphatasia, hearing loss, tooth loss, and ocular manifestations such as angioid streaks or early-onset glaucoma. We identified a novel duplication variant of TNFRSF11A (72dup27). Angioid streaks were recognized in Juvenile Paget's disease due to loss-of-function variants in the gene TNFRSF11B, and thought to be specific for this disease. However, the novel recognition of angioid streaks in our family raised the possibility of occurrence even in bone disorders due to TNFRSF11A duplication variants and the association of RANKL-RANK signal pathway as the pathogenesis. Glaucoma has conversely not been reported in any case of Paget's disease. It is not certain whether glaucoma is coincidental or specific for PDB with 72dup27. CONCLUSION: Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.

Imaging of spinal chordoma and benign notochordal cell tumor (BNCT) with radiologic pathologic correlation.

Benign notochordal cell tumor (BNCT) and chordoma are neoplasms of notochordal differentiation. BNCT represents notochordal rests, commonly an incidental lesion present in the spine in 19% of cadaveric specimens. BNCTs are often radiographically occult. CT of BNCT frequently reveals patchy sclerosis between areas of maintained underlying trabeculae. BNCT demonstrates marrow replacement on T1-weighted MR images with high signal intensity on T2-weighting. BNCTs are frequently smaller than 35 mm and lack significant enhancement, bone destruction, cortical permeation, or soft tissue components. Biopsy or surgical resection of BNCT is usually not warranted, although imaging surveillance may be indicated. Chordoma is a rare low-grade locally aggressive malignancy representing 1-4% of primary malignant bone tumors. Chordoma is most frequent between the ages of 50-60 years with a male predilection. Clinical symptoms, while nonspecific and location dependent, include back pain, numbness, myelopathy, and bowel/bladder incontinence. Unfortunately, lesions are often large at presentation owing to diagnosis delay. Imaging of chordoma shows variable mixtures of bone destruction and sclerosis, calcification (50-70% at CT) and large soft tissue components. MR imaging of chordoma reveals multilobulated areas of marrow replacement on T1-weighting and high signal intensity on T2-weighting reflecting the myxoid component within the lesion and areas of hemorrhage seen histologically. Treatment of chordoma is primarily surgical with prognosis related to resection extent. Unfortunately, complete resection is often not possible (21-75%) resulting in high local recurrence incidence (19-75%) and a 5-year survival rate of 45-86%. This article reviews and illustrates the clinical characteristics, pathologic features, imaging appearance spectrum, treatment, and prognosis of BNCT and spinal chordoma.

Analysis of the Infiltrative Features of Chordoma: The Relationship Between Micro-Skip Metastasis and Postoperative Outcomes.

BACKGROUND: Chordomas are very rare primary malignant bone tumors that arise commonly from the sacrum (50-60%) and clivus (25-35%). Chordomas have a high rate of recurrence. The authors confirmed a unique histologic infiltration pattern of chordomas that resembles a skip-metastatic lesion in normal tissue around tumor, which they named "micro-skip metastasis." This study aimed to examine the correlations between the clinicopathologic features of chordomas, including micro-skip metastasis, and the clinical outcomes, including overall survival, local recurrence-free survival, and distant metastasis-free survival. METHODS: The study analyzed histopathologic and clinical data from patients with sacral chordomas who underwent en bloc resection from July 1991 through July 2014. Cases with a minimum follow-up period shorter than 20 months after resection were excluded. Kaplan-Meier survival analyses with log-rank tests were performed for overall survival, metastasis-free survival, and recurrence-free survival. RESULTS: The study retrospectively reviewed 40 patients. The mean follow-up period was 98.2 months (range 22-297 months). The local recurrence rate was 41.3%. Micro-skip metastases, observed in 17 patients (42.5%), were associated with a significantly increased risk of local recurrence (p = 0.023) but not with overall survival or distant metastasis-free survival. Poorer overall survival was associated with histologic vascular invasion (p = 0.030) and a greater maximum tumor diameter (p = 0.050). CONCLUSIONS: The presence of micro-skip metastasis was associated with a higher rate of local recurrence. The maximum tumor diameter and the presence of histologic vascular invasion were associated with poorer overall survival.

The potential of virtual reality-based training to enhance the functional autonomy of Alzheimer's disease patients in cooking activities: A single case study.

Impairments in performing activities of daily living occur early in the course of Alzheimer's disease (AD). There is a great need to develop non-pharmacological therapeutic interventions likely to reduce dependency in everyday activities in AD patients. This study investigated whether it was possible to increase autonomy in these patients in cooking activities using interventions based on errorless learning, vanishing-cue, and virtual reality techniques. We recruited a 79-year-old woman who met NINCDS-ADRDA criteria for probable AD. She was trained in four cooking tasks for four days per task, one hour per day, in virtual and in real conditions. Outcome measures included subjective data concerning the therapeutic intervention and the experience of virtual reality, repeated assessments of training activities, neuropsychological scores, and self-esteem and quality of life measures. The results indicated that our patient could relearn some cooking activities using virtual reality techniques. Transfer to real life was also observed. Improvement of the task performance remained stable over time. This case report supports the value of a non-immersive virtual kitchen to help people with AD to relearn cooking activities.

[Unruptured Arteriosclerotic Aneurysm in the Distal Middle Cerebral Artery:A Case Report].

We report a rare case of an unruptured cerebral aneurysm in the left distal middle cerebral artery(MCA). A 76-year-old woman was referred to our department for unruptured cerebral aneurysms detected incidentally by magnetic resonance angiography. A left carotid angiogram revealed a saccular aneurysm arising in an arterial trunk unrelated to the branching zone of the distal MCA. The patient underwent an operation for trapping and excision of the saccular aneurysm in the distal MCA followed by end-to-end anastomosis. Histological analysis revealed an aneurysmally-dilated artery exhibiting thickened fibrous intima with foci of calcification and fragmented internal elastic lamina. Neither dissection nor infection were observed. The histological findings suggested that the aneurysm in this case was associated with arteriosclerotic change. Considering the medical history of the patient, we conclude that aging and hypertension are factors of the development of the cerebral aneurysm in our case, although the aneurysm is located in the distal MCA in which it is considered to low hemodynamic stress. We report this extremely rare case with a literature review.

Melorheostosis with recurrent soft-tissue components: a histologically confirmed case.

Melorheostosis is a very rare disorder characterized by irregular cortical thickening seen on radiographs. In this paper, we present a case of melorheostosis with microscopically confirmed soft-tissue components. The patient was a 51-year-old man who complained of severe pain in the lateral aspect of his right knee. The excision of an ossified soft-tissue lesion relieved intractable pain that had lasted 20 years. Microscopically, the cortex of the affected fibula was composed of thick compact bone and the soft-tissue component consisted of dense compact bone without endochondral ossification. The presence of soft-tissue osseous nodules around the joints is one of the specific conditions for melorheostosis and should be differentiated from synovial chondromatosis. The ossified soft-tissue lesion in our patient is to our knowledge the first reported case of the histologically confirmed soft-tissue component of melorheostosis, which differs from that of synovial chondromatosis.

Detecting everyday action deficits in Alzheimer's disease using a nonimmersive virtual reality kitchen.

Alzheimer's disease (AD) causes impairments affecting instrumental activities of daily living (IADL). Transdisciplinary research in neuropsychology and virtual reality has fostered the development of ecologically valid virtual tools for the assessment of IADL, using simulations of real life activities. Few studies have examined the benefits of this approach in AD patients. Our aim was to examine the utility of a non-immersive virtual coffee task (NI-VCT) for assessment of IADL in these patients. We focus on the assessment results obtained from a group of 24 AD patients on a task designed to assess their ability to prepare a virtual cup of coffee, using a virtual coffee machine. We compared performance on the virtual task to an identical daily living task involving the actual preparation of a cup of coffee, as well as to global cognitive, executive, and caregiver-reported IADL functioning. Relative to 32 comparable, healthy elderly (HE) controls, AD patients performed worse than HE controls on all tasks. Correlation analyses revealed that NI-VCT measures were related to all other neuropsychological measures. Moreover, regression analyses demonstrated that performance on the NI-VCT predicted actual task performance and caregiver-reported IADL functioning. Our results provide initial support for the utility of our virtual kitchen for assessment of IADL in AD patients.

Preliminary validation of the Virtual Kitchen Challenge as an objective and sensitive measure of everyday function associated with cerebrovascular disease.

Preliminary validity of a computer-based test of everyday function (Virtual Kitchen Challenge [VKC]) was examined against brain-imaging markers of cerebrovascular disease and in contrast to conventional neuropsychological and self-report measures. Twenty community-dwelling older adults (n = 6 mild cognitive impairment) performed simulated breakfast and lunch tasks using a computer touchscreen (VKC). Automated measures (completion time, proportion time off screen, etc.) were computed during training and test conditions. White matter hyperintensity (WMH) volumes from brain magnetic resonance imaging and conventional measures of cognition and function also were obtained. VKC completion time and proportion time off screen improved significantly from training to test and were significantly associated with WMH volume (r > 0.573). VKC measures and WMH were not significantly correlated with conventional cognitive or self-report measures. The VKC holds promise as a valid measure of subtle functional difficulties in older adults that is sensitive to change and cerebrovascular pathology, highlighting its potential for clinical trials. Highlights: Virtual Kitchen Challenge (VKC) scores showed significant improvement from training to test conditions.VKC scores (completion time and proportion of time off screen) were associated with a neuroimaging biomarker of brain health (white matter hyperintensities).

Case Report: Extraskeletal osteosarcoma with preceding myositis ossificans.

Extraskeletal osteosarcoma (EO) is a soft tissue sarcoma characterized by the production of bone matrix by neoplastic cells. Benign osteoid in EO, leading to a diagnostic dilemma, is rarely encountered. Herein, for the first time, we present a case with cytogenetically confirmed EO combined with or preceding myositis ossificans (MO). A 21-year-old man had a mildly painful swelling in his left knee. Imaging studies demonstrated a 39-mm mass with peripheral mineralization and cystic change on the posterolateral side of the left fibular head. He was clinically suspected of having either MO or a malignancy, such that wide resection was performed. Macroscopically, the mass was grayish to brown. In the cut section, multiple cystic lesions in addition to solid components were noted. Histopathologically, the solid components demonstrated diffuse proliferation of pleomorphic tumor cells with osteoclast-like giant cells. The malignant tumor cells formed osteoid. In the periphery, the mass was benign, showing mature bone tissue and focally non-malignant woven bone with fibroblasts, compatible with zonation. Fluorescence in situ hybridization (FISH) demonstrated split signals of the USP6 gene. These findings suggested EO with preceding MO. Although the pathogenesis remains to be elucidated, the observed USP6 rearrangement might contribute to both the diagnosis of EO with preceding MO and an understanding of the underlying histopathology.

A Case of GATA3 Positive Pleomorphic Liposarcoma, Epithelioid Variant: A Diagnostic Pitfall.

Pleomorphic liposarcoma is a rare malignant adipocytic tumor showing undifferentiated pleomorphic sarcoma morphology with various degrees of epithelioid features. It is sometimes difficult to distinguish from carcinoma metastasis. Immunohistochemical panel is very important for differential diagnosis; however, there is a risk that unexpected staining could lead to misinterpretation. We report a pleomorphic liposarcoma, epithelioid variant, in an 88-year-old man, with tricky-positive staining for GATA3. Histological examination revealed a tumor with epithelioid morphology. The tumor consists of solid sheets of epithelioid tumor cells with focal aggregates of pleomorphic lipoblasts. Immunohistochemically, the adipocytic tumor cell areas were positive for S100 protein, and the epithelioid tumor cells showed CAM 5.2 positivity. GATA3 was diffusely positive. The combination of CAM 5.2 and GATA3 staining suggested the possibility of metastatic cancer, but systemic clinical examinations did not detect any presence of a primary tumor, including urinary bladder, breasts, and salivary glands. The pathological diagnosis of pleomorphic liposarcoma, epithelioid variant, was made because of the presence of malignant lipoblasts. Our report may contribute for differential diagnosis of pleomorphic liposarcoma, epithelioid variant, with unexpected positive immunoreaction for GATA3.

Pre-operative selective arterial embolization as a neoadjuvant therapy for proximal humerus giant cell tumor of bone: radiological and histological evaluation.

The management of giant cell tumor of the proximal humerus that extends to the joint is challenging. Here, we report a case of proximal humerus giant cell tumor with cortical bone destruction extending to the shoulder joint. Pre-operative selective arterial embolization induced peripheral tumor ossification. Subsequently, the lesion was removed by intralesional curettage, and the cavity was filled with cement. Macroscopically, the inner wall of the cavity was found to be lined with a thick fibrous membrane. Histologically, massive fibrosis and resultant remodeling of the destroyed cortical bone were induced, which was consistent with the peripheral ossification on the plain radiograph. We believe that selective arterial embolization can be an effective neoadjuvant therapy for giant cell tumors of the extremities, especially for tumors with large cortical defects or joint involvement.

An autopsy case of pulmonary arterial hypertension in an elderly patient with multimorbidity: a case report.

BACKGROUND: There is an increasing number of elderly patients with pulmonary arterial hypertension (PAH), and their characteristics differ from those of young or middle-aged patients with this condition. CASE SUMMARY: A 73-year-old woman with a history of myocardial infarction and cardiovascular risk factors was admitted to the hospital with 2-week exertional dyspnoea. Her initial diagnosis was heart failure with preserved ejection fraction, but the symptoms persisted despite receiving treatment with diuretics. Additional tests showed a significant decrease in diffusing capacity of carbon monoxide and findings suggestive of severe pulmonary hypertension (PH). Contrast-enhanced computed tomography of the chest, and pulmonary angiography, showed no narrowing or obstruction of the pulmonary arteries. Right heart catheterization revealed haemodynamic data implying pre-capillary PH. Her condition gradually deteriorated to World Health Organization functional class IV, and sequential combination therapy with tadalafil, macitentan, and selexipag was initiated with a PAH diagnosis; however, she died 1 month later. Pathological findings in autopsy were consistent with PAH, and some parts of the lungs revealed the presence of obstructive and interstitial lung disease. DISCUSSION: The majority of elderly patients with PAH might have multimorbidity. However, there is no specific treatment strategy. It is associated with diagnostic delay and worse prognosis; therefore, early suspicion and comprehensive tests, including right heart catheterization, are essential for better management.

Subchondral insufficiency fracture of the knee: review of current concepts and radiological differential diagnoses.

Subchondral insufficiency fracture of the knee (SIFK) is a common cause of knee joint pain in older adults. SIFK is a type of stress fracture that occurs when repetitive and excessive stress is applied to the subchondral bone. If the fracture does not heal, the lesion develops into osteonecrosis and results in osteochondral collapse, requiring surgical management. Because of these clinical features, SIFK was initially termed "spontaneous osteonecrosis of the knee (SONK)" in the pre-MRI era. SONK is now categorized as an advanced SIFK lesion in the spectrum of this disease, and some authors believe the term "SONK" is a misnomer. MRI plays a significant role in the early diagnosis of SIFK. A subchondral T2 hypointense line of the affected condyle with extended bone marrow edema-like signal intensity are characteristic findings on MRI. The large lesion size and the presence of osteochondral collapse on imaging are associated with an increased risk of osteoarthritis. However, bone marrow edema-like signal intensity and osteochondral collapse alone are not specific to SIFK, and other osteochondral lesions, including avascular necrosis, osteochondral dissecans, and osteoarthritis should be considered. Chondral lesions and meniscal abnormalities, including posterior root tears, are also found in many patients with SIFK, and they are considered to be related to the development of SIFK. We review the clinical and imaging findings, including the anatomy and terminology history of SIFK, as well as its differential diagnoses. Radiologists should be familiar with these imaging features and clinical presentations for appropriate management.

The route of metastatic vertebral tumors extending to the adjacent vertebral body: a histological study.

BACKGROUND: Each vertebra can be regarded as a compartment surrounded by several anatomically characterized barriers. However, in some cases tumors extend beyond these barriers. The route of vertical extension to the adjacent vertebrae is unclear. The extent of vertical extension of a metastatic spinal tumor is important in making the preoperative decision regarding the cranio-caudal surgical margin. The objective of this study was to investigate the route of vertical extension of metastatic vertebral tumors. METHODS: We examined 20 en bloc resected metastatic vertebral bodies in which the tumors had extended outside the vertebral body. Five to eight sagittal sections including the pedicle, and the lateral and central parts of the PLL were prepared from each resected specimen. The sections were stained with hematoxylin and eosin, and elastica van Gieson. Histological examination focused on the routes of the vertical extension of the tumor at each barrier tissue and the degree of tumor extension along each route. RESULTS: Vertical extension of the tumor was observed at the ALL in 6 cases, at the central part of the PLL in 14 cases, at the lateral part of the PLL in 20 cases, at the cartilaginous endplate in 3 cases, and at the periosteum on the lateral side of vertebral body in 7 cases. The tumor had extended the farthest at the lateral part of the PLL in 18 cases, at the lateral side of the vertebral body in 1 case, and through the disc in 1 case. CONCLUSIONS: Metastatic vertebral tumors most commonly extend vertically at the lateral part of the PLL. The lateral part of the PLL is raised by the tumor, which extends between the PLL and the posterior aspect of the disc.

A desmoplastic fibroblastoma that developed in the anterior mediastinum: a case report.

BACKGROUND: Desmoplastic fibroblastoma (also known as collagenous fibroma) is a benign, slowly growing soft-tissue tumor. Most desmoplastic fibroblastomas develop in the limbs, neck, or trunk. A mediastinal origin is quite rare. CASE PRESENTATION: A 32-year-old Asian female was referred to us for the diagnosis and treatment of an anterior mediastinal tumor. The tumor was 80 mm in the largest diameter and was located on the pericardium. No invasion was evident. She underwent resection of the tumor via video-assisted thoracoscopic resection. The tumor was totally encapsulated, and its pedicle was on the pericardium. The resected specimen was very rigid, making it difficult to remove from the intercostal space. Histologically, the tumor was composed of a paucicellular dense collagenous tissue. Mitosis was rarely observed, and cellular atypia was not evident, suggesting that the tumor was benign. We diagnosed the tumor as a desmoplastic fibroblastoma by morphology and immunohistochemistry. CONCLUSIONS: Desmoplastic fibroblastoma of the mediastinum is an extremely rare disease. Preoperative diagnosis is difficult. Early surgical resection is suitable for diagnosis and treatment planning.

Pregnancy complicated with Alport syndrome: a good obstetric outcome and failure to diagnose an infant born to a mother with Alport syndrome by umbilical cord immunofluorescence staining.

Alport syndrome is a familial progressive nephritis. The most frequent type is X-linked Alport syndrome, caused by genetic abnormalities in the alpha 5 chain of type IV collagen. Skin biopsy is a useful tool for diagnosing this disease. It is not well known how this syndrome affects pregnancy and how it is affected by pregnancy, or whether the umbilical cord may provide material for detecting this collagen abnormality. We report a primigravida with Alport syndrome with mild proteinuria who gave birth abdominally to a term male infant without deteriorating renal function during pregnancy. The umbilical cord from not only this infant but also from an Alport (-) control infant showed negative immunofluorescence staining for the alpha 5 chain of type IV collagen. Women with Alport syndrome without renal dysfunction may follow an uneventful obstetrical course until term. The cord may not be suitable for diagnosing Alport syndrome with immunofluorescence staining.

Androgen Receptor Predicts First and Multiple Recurrences in Non-Muscle Invasive Urothelial Carcinoma of the Bladder.

The aim of this study is to investigate the role of androgen receptor (AR) expression on clinicopathologic characteristics, first recurrence free survival (RFS), progression free survival (PFS) and multiple recurrences in non-muscle invasive bladder cancer (NMIBC). AR expression in 40 paraffin-embedded specimens of primarily diagnosed NMIBC after transurethral resection was examined by immunohistochemistry using a monoclonal AR antibody. Associations between AR expression and clinicopathologic features and prognosis were statistically assessed. Multivariate Cox proportional hazards model was applied for evaluating predictive factors on RFS and PFS. For multiple recurrences, we used the Andersen-Gill model. AR was positive in 20/40 (50%) cases. Twenty-three patients (57.5%) had no recurrence, 10 (25.0%) had one recurrence, and 7 (17.5%) experienced more than one recurrence. AR expression and clinicopathologic features were not significantly correlated (P >0.05). Univariate analyses showed that AR expression was significantly associated with RFS and PFS (P <0.05). Via multivariate analyses, positive AR expression was significantly associated with lower risk of first recurrence (hazard ratio (HR) = 0.265; 95% confidence interval (95% CI) = 0.084-0.829; P = 0.022). Multivariate analysis of PFS was not feasible in our cohort. Using the multivariate Andersen-Gill model, positive AR expression in the primary tumor was an independent factor predicting lower risk of multiple recurrences (HR = 0.387, 95% CI = 0.161-0.927, P = 0.033). Androgen receptor expression is associated with first and multiple recurrences in NMIBC.

The Virtual Kitchen Challenge: preliminary data from a novel virtual reality test of mild difficulties in everyday functioning.

Background: Efficient, objective measures of mild functional difficulties are lacking. Preliminary data from a novel, non-immersive virtual reality, performance-based task (Virtual Kitchen Challenge; VKC) were obtained to address this gap. Methods: 14 older and 21 younger adults completed cognitive tests and two everyday tasks (breakfast, lunch) in the VKC with virtual objects and a touch-screen and in the Real Kitchen with real objects (order counterbalanced). Automated performance measures were obtained from the VKC program and human coders scored VKC and Real Kitchen videos for errors. Results: Older adults made more errors than younger adults on the VKC and Real Kitchen, with similar error patterns across measures. VKC automated measures were significantly related to measures from human coders, performance on the Real Kitchen, and cognitive test scores. Conclusion: The VKC is a valid and highly efficient performance-based measure of subtle functional difficulties with great potential for future clinical and research applications.

Advantage of FISH analysis using FKHR probes for an adjunct to diagnosis of rhabdomyosarcomas.

Translocations can be detected using fluorescence in situ hybridization (FISH) in formalin-fixed paraffin-embedded tissues. Recently, a commercially available FKHR (13q14) dual-color, break-apart rearrangement probe has been developed. However, the advantages of using this probe have not been reported. This study demonstrated the usefulness of this probe for the clinical diagnosis of rhabdomyosarcomas (RMS). We studied 33 RMS (19 embryonal rhabdomyosarcomas [ERMS], including three sclerosing-type RMS, and 14 alveloar rhabdomyosarcomas [ARMS]). Fluorescence signals were detected for 18 of the 19 (94.7%) ERMS and 13 of the 14 (92.8%) ARMS. A split-signal pattern was detected in 12 of 13 (92.3%) ARMS but was not detected in any of the ERMS, including the three sclerosing-type RMS. Amplification and polyploidy were present in both the ERMS and the ARMS. Our FISH study highlighted the excellent performance of the presently reported commercial break-apart probe for the detection of FKHR gene rearrangements in RMS. Because amplification and polyploidy were detected in both the ERMS and the ARMS, sufficient care should be taken when counting the nuclear signals. No rearrangements of the FKHR gene were found in any of the three sclerosing-type RMS when examined using a FISH assay, supporting the hypothesis that sclerosing RMS can be included as an ERMS.