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Background Iron oxide nanoparticles are an alternative contrast agent for MRI. Gadolinium deposition has raised safety concerns, but it is unknown whether ferumoxytol administration also deposits in the brain. Purpose To investigate whether there are signal intensity changes in the brain at multiecho gradient imaging following ferumoxytol exposure in children and young adults. Materials and Methods This retrospective case-control study included children and young adults, matched for age and sex, with brain arteriovenous malformations who received at least one dose of ferumoxytol from January 2014 to January 2018. In participants who underwent at least two brain MRI examinations (subgroup), the first and last available examinations were analyzed. Regions of interests were placed around deep gray structures on quantitative susceptibility mapping and R2* images. Mean susceptibility and R2* values of regions of interests were recorded. Measurements were assessed by linear regression analyses: a between-group comparison of ferumoxytol-exposed and unexposed participants and a within-group (subgroup) comparison before and after exposure. Results Seventeen participants (mean age ± standard deviation, 13 years ± 5; nine male) were in the ferumoxytol-exposed (case) group, 21 (mean age, 14 years ± 5; 11 male) were in the control group, and nine (mean age, 12 years ± 6; four male) were in the subgroup. The mean number of ferumoxytol administrations was 2 ± 1 (range, one to four). Mean susceptibility (in parts per million [ppm]) and R2* (in inverse seconds [sec-1]) values of the dentate (case participants: 0.06 ppm ± 0.04 and 23.87 sec-1 ± 4.13; control participants: 0.02 ppm ± 0.03 and 21.7 sec-1 ± 5.26), substantia nigrae (case participants: 0.08 ppm ± 0.06 and 27.46 sec-1 ± 5.58; control participants: 0.04 ppm ± 0.05 and 24.96 sec-1 ± 5.3), globus pallidi (case participants: 0.14 ppm ± 0.05 and 30.75 sec-1 ± 5.14; control participants: 0.08 ppm ± 0.07 and 28.82 sec-1 ± 6.62), putamina (case participants: 0.03 ppm ± 0.02 and 20.63 sec-1 ± 2.44; control participants: 0.02 ppm ± 0.02 and 19.65 sec-1 ± 3.6), caudate (case participants: -0.1 ppm ± 0.04 and 18.21 sec-1 ± 3.1; control participants: -0.06 ppm ± 0.05 and 18.83 sec-1 ± 3.32), and thalami (case participants: 0 ppm ± 0.03 and 16.49 sec-1 ± 3.6; control participants: 0.02 ppm ± 0.02 and 18.38 sec-1 ± 2.09) did not differ between groups (susceptibility, P = .21; R2*, P = .24). For the subgroup, the mean interval between the first and last ferumoxytol administration was 14 months ± 8 (range, 1-25 months). Mean susceptibility and R2* values of the dentate (first MRI: 0.06 ppm ± 0.05 and 25.78 sec-1 ± 5.9; last MRI: 0.06 ppm ± 0.02 and 25.55 sec-1 ± 4.71), substantia nigrae (first MRI: 0.06 ppm ± 0.06 and 28.26 sec-1 ± 9.56; last MRI: 0.07 ppm ± 0.06 and 25.65 sec-1 ± 6.37), globus pallidi (first MRI: 0.13 ppm ± 0.07 and 27.53 sec-1 ± 8.88; last MRI: 0.14 ppm ± 0.06 and 29.78 sec-1 ± 6.54), putamina (first MRI: 0.03 ppm ± 0.03 and 19.78 sec-1 ± 3.51; last MRI: 0.03 ppm ± 0.02 and 19.73 sec-1 ± 3.01), caudate (first MRI: -0.09 ppm ± 0.05 and 21.38 sec-1 ± 4.72; last MRI: -0.1 ppm ± 0.05 and 18.75 sec-1 ± 2.68), and thalami (first MRI: 0.01 ppm ± 0.02 and 17.65 sec-1 ± 5.16; last MRI: 0 ppm ± 0.02 and 15.32 sec-1 ± 2.49) did not differ between the first and last MRI examinations (susceptibility, P = .95; R2*, P = .54). Conclusion No overall significant differences were found in susceptibility and R2* values of deep gray structures to suggest retained iron in the brain between ferumoxytol-exposed and unexposed children and young adults with arteriovenous malformations and in those exposed to ferumoxytol over time. © RSNA, 2020.
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Malformações Arteriovenosas/diagnóstico por imagem , Encéfalo/metabolismo , Meios de Contraste/administração & dosagem , Óxido Ferroso-Férrico/administração & dosagem , Ferro/metabolismo , Imageamento por Ressonância Magnética/métodos , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Estudos Retrospectivos , Adulto JovemAssuntos
Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Doença da Artéria Coronariana/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Pirrolidinas/efeitos adversos , Quinoxalinas/efeitos adversos , Rabdomiólise/induzido quimicamente , Sinvastatina/efeitos adversos , Sulfonamidas/efeitos adversos , Biópsia , Doença da Artéria Coronariana/complicações , Combinação de Medicamentos , Interações Medicamentosas , Hepatite C Crônica/complicações , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Mialgia/induzido quimicamente , Rabdomiólise/patologiaRESUMO
The calcified chondroid mesenchymal neoplasm (CCMN) represents a recently recognized tumor type with only 50 well-documented cases in the English-language literature. Herein we report an additional case of CCMN presenting as a large mass in the temporomandibular joint region of a 41-year-old female. A review of previously reported cases and the current case of CCMN shows the following features: 1) average age 52 years (range 14-87 years) and an approximately even sex distribution; 2) most frequently involved sites: distal extremities (including foot, hand, wrist, forearm) (n=41) and temporomandibular joint/temporal/parotid region (n=9); 3) multilobular soft tissue tumor with chondroid to cartilaginous matrix, often grungy or lace-like calcifications, and variable cytologic atypia; 4) frequently detected FN1 rearrangement (n=15), including FN1 fusion with FGFR2 (n=7) or other receptor tyrosine kinases; 5) 2 reported local recurrences (after incomplete excision); 6) no reports of malignant biologic behavior.
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Calcinose , Neoplasias , Adulto , Feminino , Humanos , Calcinose/patologia , Calcinose/diagnóstico por imagem , Calcinose/cirurgia , Diagnóstico Diferencial , Transtornos da Articulação Temporomandibular/patologia , Transtornos da Articulação Temporomandibular/diagnóstico por imagem , Transtornos da Articulação Temporomandibular/cirurgia , Neoplasias/diagnóstico , Neoplasias/patologia , Neoplasias/terapiaRESUMO
Pulmonary sarcoidosis is typically recognized as an interstitial lung disease with an infrequent occurrence of alveolar filling or acinar pattern. This rare form of alveolar sarcoidosis is known to have a rapid progression. Several case reports showed the development/worsening of sarcoidosis after COVID-19 infection. We present a case of a 60-year-old male with chronic hypoxic respiratory failure since having COVID-19 disease followed by gradual progression in symptoms, who had atypical sarcoid-like alveolar opacities on radiography, two prior negative bronchoscopies, transbronchial biopsy and BAL, and third bronchoscopic transbronchial biopsy suggestive of findings of poorly formed granulomas with high suspicion of alveolar sarcoidosis after ruling out other comparative possibilities, and later having a drastic improvement with sarcoidosis management. Our patient's worsening symptoms after COVID-19 infection suggest impaired immunoregulation role of the infection in developing the disease process.
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Immune-mediated necrotizing myopathy (IMNM) is a subtype of inflammatory myopathy that is characterized by proximal muscle weakness, markedly elevated serum creatine kinase, myopathic electromyographic findings, and muscle biopsies revealing necrosis or regeneration with sparse inflammatory infiltrate. IMNM tends to be idiopathic but has been associated with certain medications. This supports the possibility for other pharmacotherapies to induce IMNM-particularly leflunomide. Leflunomide is used in the treatment for rheumatoid arthritis and has been shown to induce autoimmune diseases-including autoimmune hepatitis and polymyositis. After an extensive review of history and workup of muscle weakness, we conclude that leflunomide induced an IMNM in our patient. As this is the first case of leflunomide-induced IMNM, it is important for clinicians to suspect an inflammatory myopathy in the setting of myositis while on leflunomide.
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Artrite Reumatoide , Doenças Autoimunes , Miosite , Humanos , Leflunomida/efeitos adversos , Músculo Esquelético/patologia , Miosite/induzido quimicamente , Miosite/complicações , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/complicações , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Debilidade MuscularRESUMO
CONTEXT.: Stanford Pathology began stepwise subspecialty implementation of whole slide imaging (WSI) in 2018 soon after the first US Food and Drug Administration approval. In 2020, during the COVID-19 pandemic, the Centers for Medicare & Medicaid Services waived the requirement for pathologists to perform diagnostic tests in Clinical Laboratory Improvement Amendments (CLIA)-licensed facilities. This encouraged rapid implementation of WSI across all surgical pathology subspecialties. OBJECTIVE.: To present our experience with validation and implementation of WSI at a large academic medical center encompassing a caseload of more than 50 000 cases per year. DESIGN.: Validation was performed independently for 3 subspecialty services with a diagnostic concordance threshold above 95%. Analysis of user experience, staffing, infrastructure, and information technology was performed after department-wide expansion. RESULTS.: Diagnostic concordance was achieved in 96% of neuropathology cases, 100% of gynecologic pathology cases, and 98% of immunohistochemistry cases. After full implementation, 8 high-capacity scanners were operational, with whole slide images generated on greater than 2000 slides per weekday, accounting for approximately 80% of histologic slides at Stanford Medicine. Multiple modifications in workflow and information technology were needed to improve performance. Within months of full implementation, most attending pathologists and trainees had adopted WSI for primary diagnosis. CONCLUSIONS.: WSI across all surgical subspecialities is achievable at scale at an academic medical center; however, adoption required flexibility to adjust workflows and develop tailored solutions. WSI at scale supported the health and safety of medical staff while facilitating high-quality patient care and education during COVID-19 restrictions.
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COVID-19 , Patologia Cirúrgica , Idoso , Estados Unidos , Humanos , Feminino , Patologia Cirúrgica/métodos , Interpretação de Imagem Assistida por Computador/métodos , Pandemias/prevenção & controle , Microscopia/métodos , Medicare , Teste para COVID-19RESUMO
Cerebral amyloid angiopathy (CAA) is a common untreatable cause of lobar hemorrhages and cognitive decline in the older population. Subset of patients present with its inflammatory subtype with rapid decline in cognitive functions and neurological deficits. Most commonly the underlying pathophysiology of this disease is deposition of insoluble amyloid protein into blood vessel walls which results in vessel fragility leading to local neurotoxicity which may eventually leads to lobar hemorrhages and cognitive decline. The term "Amyloid Spell" encompasses transient focal neurological deficits which is commonly misdiagnosed as seizures or transient ischemic attack in the emergency department. Radiologic findings in these patients may reveal microbleeds, cortical superficial siderosis, white matter hyperintensities, and cerebral edema which support the clinical diagnosis which could be otherwise challenging. CAA diagnostic criteria require CT (Edinburgh Criteria) or MRI imaging, or neuropathology. The diagnosis can be suspected without imaging or neuropathology but cannot be confirmed. This review article provides a critical outlook on different types of presentations, updated diagnostic criteria and management of CAA patients illustrating underlying mechanisms associated with neuronal injury secondary to amyloid deposition.
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BACKGROUND: Plasmablastic myeloma is an aggressive subtype of multiple myeloma with overall poor prognosis. Spinal cord compression and hyperammonemic encephalopathy are two grave complications of multiple myeloma with significantly poor survival outcomes. CASE REPORT: A 49-year-old male presented with a 5-day history of worsening abdominal distention with inability to walk, urinate or defecate. Imaging findings of innumerable spinal osteolytic lesions with paraspinal masses coupled with a bone marrow biopsy of ≥70% plasmablasts confirmed the diagnosis of plasmablastic myeloma. Despite spinal decompression surgery, the patient remained paraplegic. Three myeloma-directed chemotherapies failed, eventually leading to him developing hyperammonemic encephalopathy culminating in his death. CONCLUSION: Plasmablastic myeloma is a rare entity which poses therapeutic challenges especially in patients with negative prognosticators, including high-risk cytogenetic markers, extraosseous involvement with cord compression and hyperammonemic encephalopathy. Early aggressive management with consideration of novel therapeutic alternatives, especially in treatment refractory disease, can be worthwhile.
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Encefalopatias/etiologia , Hiperamonemia/etiologia , Mieloma Múltiplo/complicações , Compressão da Medula Espinal/etiologia , Antineoplásicos/uso terapêutico , Encefalopatias/diagnóstico , Descompressão Cirúrgica , Progressão da Doença , Evolução Fatal , Humanos , Hiperamonemia/diagnóstico , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Compressão da Medula Espinal/diagnóstico por imagem , Compressão da Medula Espinal/cirurgia , Falha de TratamentoRESUMO
BACKGROUND: Paragangliomas (PGLs) are rare neuroendocrine tumors that can arise from any autonomic ganglion of the body. Most PGLs do not metastasize. Here, we present a rare case of metastatic PGL of the spine in a patient with a germline pathogenic succinate dehydrogenase subunit B (SDHB) mutation. METHODS: In addition to a case report we provide a literature review of metastatic spinal PGL to highlight the importance of genetic testing and long-term surveillance of these patients. RESULTS: A 45-year-old woman with history of spinal nerve root PGL, 17 years prior, presented with back pain of several months' duration. Imaging revealed multilevel lytic lesions throughout the cervical, thoracic, and lumbar spine as well as involvement of the right mandibular condyle and clavicle. Percutaneous biopsy of the L1 spinal lesion confirmed metastatic PGL and the patient underwent posterior tumor resection and instrumented fusion of T7-T11. Postoperatively the patient was found to have a pathogenic SDHB deletion. CONCLUSIONS: Patients with SDHx mutation, particularly SDHB, have increased risk of developing metastatic PGLs. Consequently, these individuals require long-term surveillance given the risk for developing new tumors or disease recurrence, even years to decades after primary tumor resection. Surgical management of spinal metastatic PGL involves correcting spinal instability, minimizing tumor burden, and alleviating epidural cord compression. In patients with metastatic PGL of the spine, genetic testing should be considered.
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Recent evidence of gadolinium deposition in the brain has raised safety concerns. Iron oxide nanoparticles are re-emerging as promising alternative MR contrast agents, because the iron core can be metabolized. However, long-term follow up studies of the brain after intravenous iron oxide administration have not been reported thus far. In this study, we investigated, if intravenously administered ferumoxytol nanoparticles are deposited in porcine brains. Methods: In an animal care and use committee-approved prospective case-control study, ten Göttingen minipigs received either intravenous ferumoxytol injections at a dose of 5 mg Fe/kg (n=4) or remained untreated (n=6). Nine to twelve months later, pigs were sacrificed and the brains of all pigs underwent ex vivo MRI at 7T with T2 and T2*-weighted sequences. MRI scans were evaluated by measuring R2* values (R2*=1000/T2*) of the bilateral caudate nucleus, lentiform nucleus, thalamus, dentate nucleus, and choroid plexus. Pig brains were sectioned and stained with Prussian blue and evaluated for iron deposition using a semiquantitative scoring system. Data of ferumoxytol exposed and unexposed groups were compared with an unpaired t-test and a Mann-Whitney U test. Results: T2 and T2* signal of the different brain regions was not visually different between ferumoxytol exposed and unexposed controls. There were no significant differences in R2* values of the different brain regions in the ferumoxytol exposed group compared to controls (p>0.05). Prussian blue stains of the same brain regions, scored according to a semiquantitative score, were not significantly different either between the ferumoxytol exposed group and unexposed controls (p>0.05). Conclusions: Our study shows that intravenous ferumoxytol doses of 5-10 mg Fe/kg do not lead to iron deposition in the brain of pigs. We suggest iron oxide nanoparticles as a promising alternative for gadolinium-enhanced MRI.
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Encéfalo , Meios de Contraste/farmacocinética , Óxido Ferroso-Férrico/farmacocinética , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita , Administração Intravenosa , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Química Encefálica , Estudos de Casos e Controles , Meios de Contraste/administração & dosagem , Meios de Contraste/química , Óxido Ferroso-Férrico/administração & dosagem , Óxido Ferroso-Férrico/química , Estudos Prospectivos , Suínos , Porco Miniatura , Distribuição TecidualRESUMO
PURPOSE: Preclinical studies have demonstrated that postirradiation tumor revascularization is dependent on a stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in patients with newly diagnosed glioblastoma. PATIENTS AND METHODS: We enrolled nine patients in the phase I study and an additional 20 patients in phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via a peripherally inserted central catheter (PICC) line for 4 consecutive weeks beginning at day 35 of conventional treatment with concurrent chemoradiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors. RESULTS: Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 µg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months [95% confidence interval (CI), 15.9-NA] with a progression-free survival of 14.5 months (95% CI, 11.9-NA). MRI and histopathology support the mechanism of action to inhibit postirradiation tumor revascularization. CONCLUSIONS: Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemoirradiation in patients with newly diagnosed GBM and improves local control of tumor recurrences.
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Neoplasias Encefálicas/terapia , Quimiorradioterapia/mortalidade , Glioblastoma/terapia , Compostos Heterocíclicos/uso terapêutico , Macrófagos , Receptores CXCR4/antagonistas & inibidores , Adolescente , Adulto , Idoso , Fármacos Anti-HIV , Benzilaminas , Neoplasias Encefálicas/patologia , Ciclamos , Feminino , Seguimentos , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
Pit-1 immunostaining is not routinely used in the characterization of pituitary adenomas, and its utility in distinguishing adenomas dedicated towards the lactotroph, somatotroph, and thyrotroph lineage from null cell adenomas warrants further evaluation. Pituitary adenomas that were negative for expression of a basic panel of hormonal markers (ACTH, prolactin, and growth hormone) were further evaluated for TSH, SF-1, and Pit-1 expression using a tissue microarray. Among the 147 identified pituitary adenomas that were negative for ACTH, prolactin, growth hormone, and TSH, expression of SF-1 was present in 68 cases (46%). Of the remaining 72 cases with sufficient tissue for further analysis, four were Pit-1 positive (6% of the adenomas negative for ACTH, prolactin, growth hormone, TSH, and SF-1); the remaining 68 were potentially null cell adenomas. Two of the Pit-1-positive adenomas displayed a paranuclear CAM 5.2 staining pattern suggestive of a sparsely granulated somatotroph adenoma; however, only one case contained fibrous bodies within a majority of the adenoma cells. Our data suggests that Pit-1 can be utilized as a second tier immunostain in cases of clinically non-functioning adenomas that are immunonegative for ACTH, prolactin, growth hormone, TSH, and SF-1 in order to further segregate rare cases of Pit-1-positive adenomas from null cell adenomas. Pit-1 immunostaining can recognize rare cases of sparsely granulated somatotroph adenomas that appear immunonegative for growth hormone, as well as rare cases of other Pit-1-positive adenomas that are negative for Pit-1 lineage hormones. Overall, pituitary adenomas of the Pit-1 lineage that do not produce prolactin, growth hormone, or TSH are rare, with only four cases identified in the current study.
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Adenoma/patologia , Biomarcadores Tumorais/análise , Neoplasias Hipofisárias/patologia , Fator de Transcrição Pit-1/biossíntese , Adenoma/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Hipofisárias/metabolismo , Fator de Transcrição Pit-1/análiseRESUMO
Pokeweed antiviral protein (PAP) belongs to the family of type I ribosomeinactivating proteins (RIPs): Ribotoxins, which function by depurinating the sarcinricin loop of ribosomal RNA. In addition to its antibacterial and antifungal properties, PAP has shown promise in antiviral and targeted tumor therapy owing to its ability to depurinate viral RNA and eukaryotic rRNA. Several PAP genes are differentially expressed across pokeweed tissues, with natively isolated seed forms of PAP exhibiting the greatest cytotoxicity. To help elucidate the molecular basis of increased cytotoxicity of PAP isoenzymes from seeds, the present study used protein sequencing, mass spectroscopy and X-ray crystallography to determine the complete covalent structure and 1.7 Å Xray crystal structure of PAPS1aci isolated from seeds of Asian pokeweed (Phytolacca acinosa). PAPS1aci shares ~95% sequence identity with PAPS1 from P. americana and contains the signature catalytic residues of the RIP superfamily, corresponding to Tyr72, Tyr122, Glu175 and Arg178 in PAPS1aci. A rare proline substitution (Pro174) was identified in the active site of PAPS1aci, which has no effect on catalytic Glu175 positioning or overall activesite topology, yet appears to come at the expense of strained mainchain geometry at the preproline residue Val173. Notably, a rare type of Nglycosylation was detected consisting of NacetylDglucosamine monosaccharide residues linked to Asn10, Asn44 and Asn255 of PAPS1aci. Of note, our modeling studies suggested that the ribosome depurination activity of seed PAPs would be adversely affected by the Nglycosylation of Asn44 and Asn255 with larger and more typical oligosaccharide chains, as they would shield the rRNAbinding sites on the protein. These results, coupled with evidence gathered from the literature, suggest that this type of minimal Nglycosylation in seed PAPs and other type I seed RIPs may serve to enhance cytotoxicity by exploiting receptormediated uptake pathways of seed predators while preserving ribosome affinity and rRNA recognition.