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1.
Surg Radiol Anat ; 46(6): 725-731, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38530383

RESUMEN

PURPOSE: The tensor fasciae latae (TFL) muscle is supplied by the lateral femoral circumflex artery (LCFA), arising from the deep femoral artery. However, it has been noted that there is also a consistent vascular anastomotic network. The aim of this study was to describe the accessory vascularization of the TFL muscle through a descriptive anatomical study, in order to hypothesize the feasibility of harvesting a TFL flap in the event of an injury to the main pedicle. In addition, we illustrate this hypothesis with a successful clinical case of Scarpa freconstruction following ligature of the deep femoral artery. METHODS: The description of the accessory vascularization was obtained by injecting dye into seven lateral femoral circumflex arteries (LCFA), six superficial circumflex iliac arteries (SCIA), and three inferior gluteal arteries (IGA). RESULTS: The TFL muscle was vascularized primarily by the LCFA. A vascular anastomotic network with the SCIA and the IGA was observed. After selective injection to the SCIAs and IGAs, the subsequent injection to the LCFA showed a diffusion of the TFL skin paddle with a perforasome overlapping between the different vascular territories. CONCLUSION: The ascending branch of the lateral femoral circumflex plays a dominant role in the vascularization of the TFL muscle. As a result of a periarticular anastomotic network of the hip, this artery establishes several connections with the proximal arteries. Consequently, in cases where blood flow through the LCFA is interrupted, it should be equally possible to harvest the TFL flap through its accessory vascularization.


Asunto(s)
Arteria Femoral , Humanos , Arteria Femoral/anatomía & histología , Masculino , Femenino , Fascia Lata/irrigación sanguínea , Músculo Esquelético/irrigación sanguínea , Cadáver , Arteria Ilíaca/anatomía & histología , Arteria Ilíaca/anomalías , Variación Anatómica , Adulto , Persona de Mediana Edad , Colgajos Quirúrgicos/irrigación sanguínea
2.
Semin Neurol ; 42(6): 716-722, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36417990

RESUMEN

The diagnosis of neuromuscular disorders requires a thorough history including family history and examination, with the next steps broadened now beyond electromyography and neuropathology to include genetic testing. The challenge in diagnosis can often be putting all the information together. With advances in genetic testing, some diagnoses that adult patients may have received as children deserve a second look and may result in diagnoses better defined or alternative diagnoses made. Clearly defining or redefining a diagnosis can result in understanding of potential other systems involved, prognosis, or potential treatments. This article presents several cases and approach to diagnosis as well as potential treatment and prognostic concerns, including seipinopathy, congenital myasthenic syndrome, central core myopathy, and myotonic dystrophy type 2.


Asunto(s)
Distrofia Miotónica , Enfermedades Neuromusculares , Niño , Adulto , Humanos , Enfermedades Neuromusculares/diagnóstico , Enfermedades Neuromusculares/terapia , Enfermedades Neuromusculares/genética , Electromiografía , Pruebas Genéticas , Distrofia Miotónica/diagnóstico , Distrofia Miotónica/genética , Distrofia Miotónica/terapia
3.
AJR Am J Roentgenol ; 217(1): 186-197, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34010036

RESUMEN

OBJECTIVE. Tumefactive demyelination mimics primary brain neoplasms on imaging, often necessitating brain biopsy. This article reviews the literature for the clinical and radiologic findings of tumefactive demyelination in various disease processes to facilitate identification of tumefactive demyelination on imaging. CONCLUSION. Both clinical and radiologic findings must be integrated to distinguish tumefactive demyelinating lesions from similarly appearing lesions on imaging. Further research on the immunopathogenesis of tumefactive demyelination and associated conditions will elucidate their interrelationship.

4.
Mod Pathol ; 33(11): 2169-2185, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32467650

RESUMEN

Pathologists are responsible for rapidly providing a diagnosis on critical health issues. Challenging cases benefit from additional opinions of pathologist colleagues. In addition to on-site colleagues, there is an active worldwide community of pathologists on social media for complementary opinions. Such access to pathologists worldwide has the capacity to improve diagnostic accuracy and generate broader consensus on next steps in patient care. From Twitter we curate 13,626 images from 6,351 tweets from 25 pathologists from 13 countries. We supplement the Twitter data with 113,161 images from 1,074,484 PubMed articles. We develop machine learning and deep learning models to (i) accurately identify histopathology stains, (ii) discriminate between tissues, and (iii) differentiate disease states. Area Under Receiver Operating Characteristic (AUROC) is 0.805-0.996 for these tasks. We repurpose the disease classifier to search for similar disease states given an image and clinical covariates. We report precision@k = 1 = 0.7618 ± 0.0018 (chance 0.397 ± 0.004, mean ±stdev ). The classifiers find that texture and tissue are important clinico-visual features of disease. Deep features trained only on natural images (e.g., cats and dogs) substantially improved search performance, while pathology-specific deep features and cell nuclei features further improved search to a lesser extent. We implement a social media bot (@pathobot on Twitter) to use the trained classifiers to aid pathologists in obtaining real-time feedback on challenging cases. If a social media post containing pathology text and images mentions the bot, the bot generates quantitative predictions of disease state (normal/artifact/infection/injury/nontumor, preneoplastic/benign/low-grade-malignant-potential, or malignant) and lists similar cases across social media and PubMed. Our project has become a globally distributed expert system that facilitates pathological diagnosis and brings expertise to underserved regions or hospitals with less expertise in a particular disease. This is the first pan-tissue pan-disease (i.e., from infection to malignancy) method for prediction and search on social media, and the first pathology study prospectively tested in public on social media. We will share data through http://pathobotology.org . We expect our project to cultivate a more connected world of physicians and improve patient care worldwide.


Asunto(s)
Aprendizaje Profundo , Patología , Medios de Comunicación Sociales , Algoritmos , Humanos , Patólogos
5.
Microsurgery ; 40(1): 25-31, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30508290

RESUMEN

BACKGROUND: Extensive full thickness abdominopelvic defects pose a difficult challenge to surgeons. Autologous tissues are versatile and can provide a satisfying reconstructive option for this type of defects. The tensor fascia latae (TFL) and superficial circumflex iliac perforator (SCIP) flaps provide a large area of vascularized tissue and their use in reconstructive surgery is well-known. In this report, the authors present the experience of using combined TFL and propeller SCIP flaps for covering large abdominal and pelvic defects. METHODS: Four patients underwent reconstruction of soft-tissue abdominopelvic defects by combined TFL and SCIP flaps. Three were men and one woman, aged from 52 to 76 years. The etiologies of the defects were tissue loss after tumor resection in 3 cases and necrotizing fasciitis in the fourth case. Defect dimensions ranged from 32 × 20 cm to 45 × 17 cm. An acoustic handheld Doppler was utilized to detect perforator vessels, then TFL and SCIP flaps were elevated at the same time by 2 surgical teams. Donor sites of the flaps were closed primary except for one TFL flap donor site. The latter one was treated with negative pressure therapy and finally with a split-thick skin graft. RESULTS: The size of the TFL flaps ranged from 25-38 × 10-14 cm. Concerning the SCIP flaps, the dimensions ranged from 18-32 × 12-18 cm. The average flap dimensions were 30.25 × 11.75 cm for the TFL and 26.75 × 14 cm for the SCIP. Two TFL flaps presented a necrosis of the distal tip. All the other flaps survived entirely. Complete healing was achieved in all patients. Patients were followed for an average of 4 months postoperatively (ranging between 2 and 8 months). CONCLUSIONS: Combined TFL and SCIP flaps may represent an alternative reconstructive procedure for large abdominopelvic defects in well-selected cases.


Asunto(s)
Abdomen/cirugía , Fascia Lata , Arteria Ilíaca , Pelvis/cirugía , Colgajo Perforante/irrigación sanguínea , Procedimientos de Cirugía Plástica/métodos , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Anciano , Carcinoma Verrugoso/patología , Carcinoma Verrugoso/cirugía , Fascitis Necrotizante/patología , Fascitis Necrotizante/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/cirugía
6.
Sleep Breath ; 22(2): 547-554, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-28828549

RESUMEN

PURPOSE: Hypoxic insults occurring during the perinatal period remain the leading cause of permanent brain impairment. Severe cognitive and motor dysfunction, as seen in cerebral palsy, will occur in 4-10% of post-hypoxic newborns. Subtle cognitive impairment, apparent in disorders of minimal brain dysfunction will occur in > 3 million post-hypoxic newborns. Analyses of post-hypoxic rodent brains reveal reduced extracellular levels of dopamine, a key neurotransmitter of vigilance, execute function, and behavior. The purpose of this study was to assess whether synaptic levels of dopamine could be enhanced in post-hypoxic, hypodopaminergic rats. METHODS: Newborn male rats were exposed to subtle, repetitive hypoxic insults for 4-6 h per day, during postnatal days 7-11. During adolescence, we quantified dopamine content within the caudate nuclei. We then determined whether extracellular dopamine levels could be increased by injecting the psychostimulant d-amphetamine. We next assessed whether the post-hypoxic rat's response to d-amphetamine would differentially impact place preference behavior when compared with littermate controls. RESULTS: Total tissue content of dopamine was significantly higher in post-hypoxic rats. Injection of d-amphetamine liberated that dopamine which subsequently enhanced extracellular levels. Post-hypoxic rats acquired conditioned place preference for d-amphetamine during the training days. During the testing day, total time spent in the amphetamine-pairing box did not differ between post-hypoxic and control littermates. CONCLUSION: Postnatally occurring hypoxic insults promote remodeling of the dopaminergic system resulting in increased intracellular sequestering of this monoamine. That sequestered dopamine can be released using the psychostimulant d-amphetamine, which did not promote a conditioned place preference any greater than was observed in non-hypoxic littermate controls.


Asunto(s)
Dopamina/metabolismo , Hipoxia/metabolismo , Anfetamina/administración & dosificación , Anfetamina/farmacología , Animales , Animales Recién Nacidos , Masculino , Ratas , Ratas Sprague-Dawley
8.
J Neurooncol ; 135(3): 601-609, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28871469

RESUMEN

The 2016 World Health Organization Classification of Tumors of the Central Nervous System incorporates the use of molecular information into the classification of brain tumors, including grade II and III gliomas, providing new prognostic information that cannot be delineated based on histopathology alone. We hypothesized that these genomic subgroups may also have distinct imaging features. A retrospective single institution study was performed on 40 patients with pathologically proven infiltrating WHO grade II/III gliomas with a pre-treatment MRI and molecular data on IDH, chromosomes 1p/19q and ATRX status. Two blinded Neuroradiologists qualitatively assessed MR features. The relationship between each parameter and molecular subgroup (IDH-wildtype; IDH-mutant-1p/19q codeleted-ATRX intact; IDH-mutant-1p/19q intact-ATRX loss) was evaluated with Fisher's exact test. Progression free survival (PFS) was also analyzed. A border that could not be defined on FLAIR was most characteristic of IDH-wildtype tumors, whereas IDH-mutant tumors demonstrated either well-defined or slightly ill-defined borders (p = 0.019). Degree of contrast enhancement and presence of restricted diffusion did not distinguish molecular subgroups. Frontal lobe predominance was associated with IDH-mutant tumors (p = 0.006). The IDH-wildtype subgroup had significantly shorter PFS than the IDH-mutant groups (p < 0.001). No differences in PFS were present when separating by tumor grade. FLAIR border patterns and tumor location were associated with distinct molecular subgroups of grade II/III gliomas. These imaging features may provide fundamental prognostic and predictive information at time of initial diagnostic imaging.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Glioma/diagnóstico por imagen , Glioma/patología , Imagen por Resonancia Magnética , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Cromosomas Humanos Par 1 , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Glioma/genética , Glioma/metabolismo , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Organización Mundial de la Salud , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismo
9.
J Biol Chem ; 290(24): 14798-809, 2015 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-25837250

RESUMEN

Genomic heterogeneity is characteristic of glioblastoma (GBM). In many GBMs, the EGF receptor gene (EGFR) is amplified and may be truncated to generate a constitutively active form of the receptor called EGFRvIII. EGFR gene amplification and EGFRvIII are associated with GBM progression, even when only a small fraction of the tumor cells express EGFRvIII. In this study, we show that EGFRvIII-positive GBM cells express significantly increased levels of cellular urokinase receptor (uPAR) and release increased amounts of soluble uPAR (suPAR). When mice were xenografted with human EGFRvIII-expressing GBM cells, tumor-derived suPAR was detected in the plasma, and the level was significantly increased compared with that detected in plasma samples from control mice xenografted with EGFRvIII-negative GBM cells. suPAR also was increased in plasma from patients with EGFRvIII-positive GBMs. Purified suPAR was biologically active when added to cultures of EGFRvIII-negative GBM cells, activating cell signaling and promoting cell migration and invasion. suPAR did not significantly stimulate cell signaling or migration of EGFRvIII-positive cells, probably because cell signaling was already substantially activated in these cells. The activities of suPAR were replicated by conditioned medium (CM) from EGFRvIII-positive GBM cells. When the CM was preincubated with uPAR-neutralizing antibody or when uPAR gene expression was silenced in cells used to prepare CM, the activity of the CM was significantly attenuated. These results suggest that suPAR may function as an important paracrine signaling factor in EGFRvIII-positive GBMs, inducing an aggressive phenotype in tumor cells that are EGFRvIII-negative.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Animales , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Glioblastoma/patología , Xenoinjertos , Humanos , Ratones , Ratones SCID , Reacción en Cadena de la Polimerasa
10.
Pharmacogenomics J ; 14(6): 523-5, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24889923

RESUMEN

Psoriasis affects 2-3% of the population, causing significant morbidity and financial burden. Immunosuppressive drugs such as cyclosporine are first line systemic therapies for moderate-to-severe forms. However, patients exhibit heterogeneity in their response to therapy, possibly due to genetic factors. The aim of the present study was to assess the ABCB1 T-129C, G1199A, C1236T, G2677T and C3435T single-nucleotide polymorphisms (SNPs) as candidate predictive markers of response to cyclosporine treatment in 84 psoriasis patients. 62% of the patients were defined as responders and 38% as nonresponders. All SNPs complied with Hardy-Weinberg equilibrium. SNP and haplotype analyses were performed to access responsiveness to treatment. Association analysis revealed statistically significant association of SNP 3435 T with negative response (P=0.0075), a result that was further validated in haplotype analysis. This study is the first in the field of the pharmacogenetics of cyclosporine in psoriasis whose results merit further exploitation in larger independent cohorts.


Asunto(s)
Ciclosporina/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Psoriasis/tratamiento farmacológico , Psoriasis/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Femenino , Grecia , Humanos , Masculino , Psoriasis/metabolismo
11.
J Neurooncol ; 120(3): 539-46, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25135423

RESUMEN

A subset of patients with high-grade glioma and brain metastases who are treated with bevacizumab develop regions of marked and persistent restricted diffusion that do not reflect recurrent tumor. Here, we quantify the degree of restricted diffusion and the relative cerebral blood volume (rCBV) within these regions of bevacizumab-related imaging abnormality (BRIA) in order to facilitate differentiation of these lesions from recurrent tumor. Six patients with high-grade glioma and two patients with brain metastases who developed regions of restricted diffusion after initiation of bevacizumab were included. Six pre-treatment GBM controls were also included. Restriction spectrum imaging (RSI) was used to create diffusion maps which were co-registered with rCBV maps. Within regions of restricted diffusion, mean RSI values and mean rCBV values were calculated for patients with BRIA and for the GBM controls. These values were also calculated for normal-appearing white matter (NAWM). RSI values in regions of restricted diffusion were higher for both BRIA and tumor when compared to NAWM; furthermore RSI values in BRIA were slightly higher than in tumor. Conversely, rCBV values were very low in BRIA-lower than both tumor and NAWM. However, there was only a trend for rCBV values to be higher in tumor than in NAWM. When evaluating areas of restricted diffusion in patients with high-grade glioma or brain metastases treated with bevacizumab, RSI is better able to detect the presence of pathology whereas rCBV is better able to differentiate BRIA from tumor. Thus, combining these tools may help to differentiate necrotic tissue related to bevacizumab treatment from recurrent tumor.


Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Encefálicas/patología , Imagen de Difusión por Resonancia Magnética/métodos , Glioma/patología , Imagen de Perfusión/métodos , Adulto , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Bevacizumab , Volumen Sanguíneo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Encéfalo/efectos de la radiación , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/fisiopatología , Neoplasias Encefálicas/radioterapia , Circulación Cerebrovascular , Difusión , Femenino , Glioma/tratamiento farmacológico , Glioma/fisiopatología , Glioma/radioterapia , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/patología , Sustancia Blanca/fisiopatología , Sustancia Blanca/efectos de la radiación
12.
Neurosurg Focus ; 36(4): E23, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24812719

RESUMEN

Differentiating between low-grade gliomas (LGGs) of astrocytic and oligodendroglial origin remains a major challenge in neurooncology. Here the authors analyzed The Cancer Genome Atlas (TCGA) profiles of LGGs with the goal of identifying distinct molecular characteristics that would afford accurate and reliable discrimination of astrocytic and oligodendroglial tumors. They found that 1) oligodendrogliomas are more likely to exhibit the glioma-CpG island methylator phenotype (G-CIMP), relative to low-grade astrocytomas; 2) relative to oligodendrogliomas, low-grade astrocytomas exhibit a higher expression of genes related to mitosis, replication, and inflammation; and 3) low-grade astrocytic tumors harbor microRNA profiles similar to those previously described for glioblastoma tumors. Orthogonal intersection of these molecular characteristics with existing molecular markers, such as IDH1 mutation, TP53 mutation, and 1p19q status, should facilitate accurate and reliable pathological diagnosis of LGGs.


Asunto(s)
Neoplasias Encefálicas/genética , Glioma/genética , Mutación/genética , Proteína p53 Supresora de Tumor/genética , Islas de CpG , Metilación de ADN/genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Estudios de Asociación Genética , Glioma/diagnóstico , Humanos , Isocitrato Deshidrogenasa/genética , Masculino , MicroARNs/genética , Oligodendroglioma/diagnóstico , Oligodendroglioma/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/metabolismo
13.
Neurology ; 103(3): e209708, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-38991193

RESUMEN

The clinical assessment of patients with proximal muscle weakness represents a frequent yet intricate challenge. We present the case of a 60-year-old woman who experienced a progressive, symmetrical weakness in proximal limbs and bulbar muscles over 6 months. Notable clinical findings included bilateral ophthalmoparesis; widespread muscle atrophy; and pronounced weakness in craniobulbar, cervical, and proximal muscles, more severe than in distal ones. We elucidate a methodical diagnostic approach, focusing on constructing a comprehensive differential diagnosis and identifying potential causes of proximal muscle weakness. Special emphasis is placed on exploring the etiologies in cases presenting with both progressive muscle weakness and ophthalmoparesis. We further describe the role of muscle biopsy results and their integration with genetic testing outcomes.


Asunto(s)
Debilidad Muscular , Oftalmoplejía , Humanos , Femenino , Persona de Mediana Edad , Debilidad Muscular/etiología , Debilidad Muscular/diagnóstico , Oftalmoplejía/diagnóstico , Razonamiento Clínico , Diagnóstico Diferencial , Progresión de la Enfermedad
14.
Clin Cancer Res ; 30(2): 283-293, 2024 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-37773633

RESUMEN

PURPOSE: Pharmacologic ascorbate (P-AscH-) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans. PATIENTS AND METHODS: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. RESULTS: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7-26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. CONCLUSIONS: P-AscH- combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255.


Asunto(s)
Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Humanos , Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Biomarcadores , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/diagnóstico por imagen , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Imagen por Resonancia Magnética , Temozolomida/uso terapéutico
15.
EBioMedicine ; 99: 104894, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38086156

RESUMEN

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated. METHODS: Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed. FINDINGS: Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants. INTERPRETATION: Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study. FUNDING: Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).


Asunto(s)
Músculo Esquelético , Miopatías Estructurales Congénitas , Masculino , Lactante , Humanos , Músculo Esquelético/patología , Terapia Genética/efectos adversos , Terapia Genética/métodos , Debilidad Muscular , Fuerza Muscular , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/terapia , Miopatías Estructurales Congénitas/patología
16.
J Med Case Rep ; 17(1): 22, 2023 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-36683067

RESUMEN

BACKGROUND: Filar cysts are frequently found on neonatal ultrasound and are physiologically involuting structures with natural resolution. Hence, there has been no previous histologic correlation. Ventriculus terminalis is a focal central canal dilation in the conus medullaris and usually not clinically significant. Extra-axial cyst at the conus-filum junction connected to ventriculus terminalis is extremely rare, especially when associated with tethered lipomatous filum terminale and with progressive cyst enlargement. CASE PRESENTATION: A Caucasian female neonate with abnormal gluteal cleft had ventriculus terminalis cyst with an extra-axial cyst at the conus-filar junction and taut lipomatous filum on ultrasound examination and magnetic resonance imaging. This persisted at 6-month follow up imaging. In light of the nonresolving extra-axial mass and thick taut lipomatous filum, the child underwent L1-L3 osteoplastic laminectomies. The extra-axial cyst expanded after bony decompression and furthermore on dural opening; visualized on ultrasound. It communicated with the central canal and was documented with intraoperative photomicrographs. It was excised and filum sectioned. Histological immunostaining of the cyst wall showed neuroglial and axonal elements. The child did well without deficits at 4-year follow up with normal urodynamics. CONCLUSION: Progression dilation of ventriculus terminalis and extra-axial conofilar cyst with tethered lipomatous filum will likely progress to clinical significance and require surgical intervention. The embryologic basis for this pathology is discussed, with literature review.


Asunto(s)
Cauda Equina , Quistes , Niño , Recién Nacido , Animales , Humanos , Lactante , Femenino , Molleja de las Aves , Médula Espinal/patología , Quistes/diagnóstico por imagen , Quistes/cirugía , Dilatación Patológica/patología , Imagen por Resonancia Magnética
17.
Acta Neuropathol Commun ; 10(1): 17, 2022 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-35135626

RESUMEN

The descriptions of muscle pathology in dysferlinopathy patients have classically included an inflammatory infiltrate that can mimic inflammatory myopathies. Based on over 20 years of institutional experience in evaluating dystrophic and inflammatory myopathy muscle biopsies at the University of Iowa, we hypothesized the inflammatory histopathology of dysferlinopathy is more similar to limb-girdle pattern muscular dystrophies such as calpainopathy and Becker muscular dystrophy, and distinct from true inflammatory myopathies. Muscle biopsies from 32 dysferlinopathy, 30 calpainopathy, 30 Becker muscular dystrophy, and 30 inflammatory myopathies (15 each of dermatomyositis and inclusion body myositis) were analyzed through digital quantitation of CD3, CD4, CD8, CD20, and PU.1 immunostaining. The expression of MHC class I and deposition of complement C5b-9 was also evaluated. Dysferlinopathy, calpainopathy, and Becker muscular dystrophy muscle biopsies had similar numbers of inflammatory cell infiltrates and significantly fewer CD3+ T-lymphocytes than dermatomyositis (p = 0.05) and inclusion body myositis (p < 0.0001) biopsies. There was no statistically significant difference in the number of PU.1+ macrophages identified in any diagnostic group. MHC class I expression was significantly lower in the limb-girdle pattern muscular dystrophies compared to the inflammatory myopathies (p < 0.0001). In contrast, complement C5b-9 deposition was similar among dysferlinopathy, dermatomyositis, and inclusion body myositis biopsies but significantly greater than calpainopathy and Becker muscular dystrophy biopsies (p = 0.05). Compared to calpainopathy, Becker muscular dystrophy, and inflammatory myopathies, the unique profile of minimal inflammatory cell infiltrates, absent to focal MHC class I, and diffuse myofiber complement C5b-9 deposition is the pathologic signature of dysferlinopathy muscle biopsies.


Asunto(s)
Inflamación/patología , Distrofia Muscular de Cinturas/patología , Distrofia Muscular de Duchenne/patología , Miositis/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven
18.
Front Oncol ; 11: 668694, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34277415

RESUMEN

Gliomas are primary brain tumors that originate from glial cells. Classification and grading of these tumors is critical to prognosis and treatment planning. The current criteria for glioma classification in central nervous system (CNS) was introduced by World Health Organization (WHO) in 2016. This criteria for glioma classification requires the integration of histology with genomics. In 2017, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) was established to provide up-to-date recommendations for CNS tumor classification, which in turn the WHO is expected to adopt in its upcoming edition. In this work, we propose a novel glioma analytical method that, for the first time in the literature, integrates a cellularity feature derived from the digital analysis of brain histopathology images integrated with molecular features following the latest WHO criteria. We first propose a novel over-segmentation strategy for region-of-interest (ROI) selection in large histopathology whole slide images (WSIs). A Deep Neural Network (DNN)-based classification method then fuses molecular features with cellularity features to improve tumor classification performance. We evaluate the proposed method with 549 patient cases from The Cancer Genome Atlas (TCGA) dataset for evaluation. The cross validated classification accuracies are 93.81% for lower-grade glioma (LGG) and high-grade glioma (HGG) using a regular DNN, and 73.95% for LGG II and LGG III using a residual neural network (ResNet) DNN, respectively. Our experiments suggest that the type of deep learning has a significant impact on tumor subtype discrimination between LGG II vs. LGG III. These results outperform state-of-the-art methods in classifying LGG II vs. LGG III and offer competitive performance in distinguishing LGG vs. HGG in the literature. In addition, we also investigate molecular subtype classification using pathology images and cellularity information. Finally, for the first time in literature this work shows promise for cellularity quantification to predict brain tumor grading for LGGs with IDH mutations.

19.
Antioxidants (Basel) ; 10(12)2021 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-34943091

RESUMEN

Glioblastoma remains the deadliest form of brain cancer, largely because these tumors become resistant to standard of care treatment with radiation and chemotherapy. Intracellular production of reactive oxygen species (ROS) is necessary for chemo- and radiotherapy-induced cytotoxicity. Here, we assessed whether antioxidant catalase (CAT) affects glioma cell sensitivity to temozolomide and radiation. Using The Cancer Genome Atlas database, we found that CAT mRNA expression is upregulated in glioma tumor tissue compared with non-tumor tissue, and the level of expression negatively correlates with the overall survival of patients with high-grade glioma. In U251 glioma cells, CAT overexpression substantially decreased the basal level of hydrogen peroxide, enhanced anchorage-independent cell growth, and facilitated resistance to the chemotherapeutic drug temozolomide and ionizing radiation. Importantly, pharmacological inhibition of CAT activity reduced the proliferation of glioma cells isolated from patient biopsy samples. Moreover, U251 cells overexpressing CAT formed neurospheres in neurobasal medium, whereas control cells did not, suggesting that the radio- and chemoresistance conferred by CAT may be due in part to the enrichment of glioma stem cell populations. Finally, CAT overexpression significantly decreased survival in an orthotopic mouse model of glioma. These results demonstrate that CAT regulates chemo- and radioresistance in human glioma.

20.
Acad Pathol ; 8: 23742895211015337, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34046522

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic has had a major impact on education at all age levels, including professional schools and health professions programs. We describe the experience of adapting preclinical medical school courses within an integrated curriculum to virtual instruction. A major feature of two of the courses were pathology small groups adapted from pathology courses in the previous medical school curriculum. These small groups were designed to use facilitated groups of 8 to 10 students. With a sudden change to virtual learning, these small groups were shifted to large group virtual sessions. In general, the conversion went well, with ongoing optimization of the format of the large group sessions mainly occurring over the first several sessions. End-of-course student evaluations were generally positive, but with a preference toward returning to live sessions in the future. Scores on 5 multiple choice examinations in the spring 2020 course were essentially identical in mean, standard deviation, and distribution to examinations in the previous 2 years of the course that had similar layout and topic organization. We discuss the challenges and successes of the switch to virtual instruction and of teaching pathology content within an integrated medical school curriculum.

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