RESUMEN
Pulmonary arteriovenous malformations (PAVMs) are rare and most often identified in patients with hereditary hemorrhagic telangiectasia (HHT). We describe a patient with severe hypoxemia and orthodeoxia with imaging findings consistent with PAVMs. Resected lung pathologic findings confirmed the presence of numerous microscopic vascular abnormalities within the right lower lobe that was consistent with diffuse pulmonary arteriovenous shunts. Family history was negative for HHT but was positive for pulmonary arterial hypertension (PAH) in two second-degree relatives. A vascular malformation gene panel was negative for genes that commonly are associated with HHT but identified a pathogenic variant in the gene encoding bone morphogenetic protein receptor-2 (BMPR2 p.Cys123∗). Pathogenic variants in BMPR2 are a well-known cause of hereditary PAH; there have been several reports to date of patients with PAVMs and PAH. However, this is the first patient to be reported with a pathogenic variant in BMPR2 to have PAVMs in isolation.
Asunto(s)
Fístula Arteriovenosa , Malformaciones Arteriovenosas , Hipertensión Arterial Pulmonar , Venas Pulmonares , Telangiectasia Hemorrágica Hereditaria , Humanos , Malformaciones Arteriovenosas/diagnóstico , Malformaciones Arteriovenosas/genética , Malformaciones Arteriovenosas/cirugía , Telangiectasia Hemorrágica Hereditaria/complicaciones , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Telangiectasia Hemorrágica Hereditaria/genética , Pulmón , Fístula Arteriovenosa/complicaciones , Venas Pulmonares/cirugía , Venas Pulmonares/anomalías , Arteria Pulmonar/anomalías , Hipertensión Pulmonar Primaria Familiar/complicaciones , Hipertensión Arterial Pulmonar/complicacionesRESUMEN
Early lung cancer lesions develop within a unique microenvironment that undergoes constant cyclic stretch from respiration. While tumor stiffening is an established driver of tumor progression, the contribution of stress and strain to lung cancer is unknown. We developed tissue scale finite element models of lung tissue to test how early lesions alter respiration-induced strain. We found that an early tumor, represented as alveolar filling, amplified the strain experienced in the adjacent alveolar walls. Tumor stiffening further increased the amplitude of the strain in the adjacent alveolar walls and extended the strain amplification deeper into the normal lung. In contrast, the strain experienced in the tumor proper was less than the applied strain, although regions of amplification appeared at the tumor edge. Measurements of the alveolar wall thickness in clinical and mouse model samples of lung adenocarcinoma (LUAD) showed wall thickening adjacent to the tumors, consistent with cellular response to strain. Modeling alveolar wall thickening by encircling the tumor with thickened walls moved the strain amplification radially outward, to the next adjacent alveolus. Simulating iterative thickening in response to amplified strain produced tracks of thickened walls. We observed such tracks in early-stage clinical samples. The tracks were populated with invading tumor cells, suggesting that strain amplification in very early lung lesions could guide pro-invasive remodeling of the tumor microenvironment. The simulation results and tumor measurements suggest that cells at the edge of a lung tumor and in surrounding alveolar walls experience increased strain during respiration that could promote tumor progression.
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Neoplasias Pulmonares , Alveolos Pulmonares , Ratones , Animales , Análisis de Elementos Finitos , Alveolos Pulmonares/patología , Alveolos Pulmonares/fisiología , Pulmón , Neoplasias Pulmonares/patología , Carcinogénesis , Microambiente TumoralRESUMEN
PURPOSE: Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the von Hippel-Lindau tumor suppressor, resulting in activation of HIF-1α and HIF-2α. The current paradigm, established using mechanistic cell-based studies, supports a tumor promoting role for HIF-2α, and a tumor suppressor role for HIF-1α. However, few studies have comprehensively examined the clinical relevance of this paradigm. Furthermore, the hypoxia-associated factor (HAF), which regulates the HIFs, has not been comprehensively evaluated in ccRCC. EXPERIMENTAL DESIGN: To assess the involvement of HAF/HIFs in ccRCC, we analyzed their relationship to tumor grade/stage/outcome using tissue from 380 patients, and validated these associations using tissue from 72 additional patients and a further 57 patients treated with antiangiogenic therapy for associations with response. Further characterization was performed using single-cell mRNA sequencing (scRNA-seq), RNA-in situ hybridization (RNA-ISH), and IHC. RESULTS: HIF-1α was primarily expressed in tumor-associated macrophages (TAMs), whereas HIF-2α and HAF were expressed primarily in tumor cells. TAM-associated HIF-1α was significantly associated with high tumor grade and increased metastasis and was independently associated with decreased overall survival. Furthermore, elevated TAM HIF-1α was significantly associated with resistance to antiangiogenic therapy. In contrast, high HAF or HIF-2α were associated with low grade, decreased metastasis, and increased overall survival. scRNA-seq, RNA-ISH, and Western blotting confirmed the expression of HIF-1α in M2-polarized CD163-expressing TAMs. CONCLUSIONS: These findings highlight a potential role of TAM HIF-1α in ccRCC progression and support the reevaluation of HIF-1α as a therapeutic target and marker of disease progression.
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Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/mortalidad , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Renales/mortalidad , Macrófagos Asociados a Tumores/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/análisis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Biomarcadores de Tumor/análisis , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/terapia , Línea Celular Tumoral , Quimioterapia Adyuvante , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/análisis , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Neoplasias Renales/terapia , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Nefrectomía , Pronóstico , RNA-Seq , Estudios Retrospectivos , Análisis de la Célula Individual , Análisis de Supervivencia , Macrófagos Asociados a Tumores/inmunologíaRESUMEN
Structural variation (SV) is typically defined as variation within the human genome that exceeds 50 base pairs (bp). SV may be copy number neutral or it may involve duplications, deletions, and complex rearrangements. Recent studies have shown SV to be associated with many human diseases. However, studies of SV have been challenging due to technological constraints. With the advent of third generation (long-read) sequencing technology, exploration of longer stretches of DNA not easily examined previously has been made possible. In the present study, we utilized third generation (long-read) sequencing techniques to examine SV in the EGFR landscape of four haplotypes derived from two human samples. We analyzed the EGFR gene and its landscape (+/- 500,000 base pairs) using this approach and were able to identify a region of non-coding DNA with over 90% similarity to the most common activating EGFR mutation in non-small cell lung cancer. Based on previously published Alu-element genome instability algorithms, we propose a molecular mechanism to explain how this non-coding region of DNA may be interacting with and impacting the stability of the EGFR gene and potentially generating this cancer-driver gene. By these techniques, we were also able to identify previously hidden structural variation in the four haplotypes and in the human reference genome (hg38). We applied previously published algorithms to compare the relative stabilities of these five different EGFR gene landscape haplotypes to estimate their relative potentials to generate the EGFR exon 19, 15 bp canonical deletion. To our knowledge, the present study is the first to use the differences in genomic architecture between targeted cancer-linked phased haplotypes to estimate their relative potentials to form a common cancer-linked driver mutation.
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Genes erbB-1/genética , Variación Genética , Genoma Humano/genética , Inestabilidad Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Carcinoma de Pulmón de Células no Pequeñas/genética , Simulación por Computador , Haplotipos , Humanos , Neoplasias Pulmonares/genética , Análisis de Secuencia de ADNRESUMEN
Cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) is usually an inherited malignancy and may be a presenting indicator of familial adenomatous polyposis syndrome although it may occasionally be sporadic. Known CMVPTC mutations include adenomatous polyposis coli ( APC) and ß-catenin ( CTNNB1) genes. Despite its malignant classification, CMVPTC is considered to be a well-differentiated thyroid tumor with a generally good behavior. In contrast, poorly differentiated thyroid carcinoma is an aggressive tumor. We report a case of CMVPTC with poorly differentiated features in a young female without phenotypic features of familial adenomatous polyposis but with known germline alterations of the APC gene. High throughput sequencing showed germline chromosome 5q deletion encompassing the APC gene in all components with additional unique genetic alterations in the somatic components. A single nucleotide substitution (c.1548+1G>A, NM_000038.5) located one base pair downstream of exon 12 of the APC gene was identified in the CMVPTC component, and a pathogenic frameshift deletion in exon 14 of APC (c.3642del, p.Ser1214Argfs*51, NM_000038.5) was identified in the poorly differentiated thyroid carcinoma component. No other cancer-associated genes were identified by our techniques. Our case represents a rare phenomenon of poorly differentiated features in association with CMVPTC. To our knowledge, ours is the only such report of poorly differentiated features arising in association with an inherited CMVPTC.
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Adenocarcinoma Papilar/patología , Proteína de la Poliposis Adenomatosa del Colon/genética , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología , Adenocarcinoma Papilar/genética , Adulto , Diferenciación Celular , Análisis Mutacional de ADN , Femenino , Mutación del Sistema de Lectura , Humanos , Inmunohistoquímica , Mutación , Polimorfismo de Nucleótido Simple , Cáncer Papilar Tiroideo/genética , Glándula Tiroides/patología , Neoplasias de la Tiroides/genética , beta Catenina/genéticaRESUMEN
Jugular foramen cavernous hemangiomas are extremely rare vascular malformations, and, to the best of the authors' knowledge, their occurrence as multifocal lesions involving both intra- and extracranial compartments has never been reported before. Here, the authors describe the case of a 60-year-old woman with a complex multifocal jugular foramen cavernous hemangioma. The patient presented with signs and symptoms concerning for jugular foramen syndrome, as well as a right neck mass. Surgical extirpation of the lesion was achieved by a multidisciplinary team via a right infratemporal fossa approach (Fisch type A) with concurrent high neck dissection and a closure buttressed with an autologous fat graft and a temporoparietal fascial flap. Although rare, cavernous hemangiomas should be included in the differential diagnosis of jugular foramen masses.
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Mycobacterial spindle cell pseudotumor (MSP) is a rare benign spindle cell lesion containing acid-fact mycobacteria. These lesions are most commonly identified in the lymph nodes, skin, spleen, or bone marrow of immunocompromised patients and only rarely involve the lungs. We report 3 cases of pulmonary MSP, which include 2 patients who are known to be HIV-positive. The histopathological diagnosis of MSP in the lung lends itself to many challenges due to its rare incidence and its spindled tumor-like appearance. The differential diagnosis is broad and includes both benign and malignant entities. We highlight the importance of the clinical context in which these lesions typically present and the morphologic spectrum of features seen, and we offer a practical approach to the workup of pulmonary mycobacterial pseudotumor. Appropriate recognition of this entity should lead to an accurate diagnosis of a treatable benign condition despite the clinical presentation often favoring malignancy.
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Infección por Mycobacterium avium-intracellulare/diagnóstico , Infección por Mycobacterium avium-intracellulare/patología , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/patología , Adulto , Anciano , Femenino , Infecciones por VIH/complicaciones , Humanos , Huésped Inmunocomprometido , Masculino , Persona de Mediana Edad , Infección por Mycobacterium avium-intracellulare/inmunología , Infecciones del Sistema Respiratorio/microbiologíaRESUMEN
BACKGROUND: Eosinophilic granulomatosis with polyangiitis is a rare, necrotizing systemic vasculitis associated with asthma and hypereosinophilia. Its cause and pathophysiology are still being elucidated. CASE PRESENTATION: We report a case of eosinophilic granulomatosis with polyangiitis in a 50-year-old Caucasian woman who presented with chest pain, dyspnea at rest, fever, and periorbital swelling. She was found to have significant hypereosinophilia and cardiac tamponade physiology. A biopsy confirmed extensive infiltration of both lungs and pericardium by eosinophils. She did not have any anti-neutrophil cytoplasmic antibodies. CONCLUSIONS: Eosinophilic granulomatosis with polyangiitis diagnosis does not require the presence of anti-neutrophil cytoplasmic antibodies. Anti-neutrophil cytoplasmic antibody-positive and anti-neutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis may present with different clinical phenotypes, perhaps suggesting two distinct disease etiologies and distinct pathophysiology.
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Taponamiento Cardíaco/etiología , Síndrome de Churg-Strauss/complicaciones , Edema/etiología , Eosinofilia/complicaciones , Pulmón/patología , Órbita , Pericardio/patología , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Biopsia , Síndrome de Churg-Strauss/inmunología , Disnea/etiología , Eosinofilia/patología , Femenino , Fiebre/etiología , Humanos , Persona de Mediana EdadRESUMEN
Neovascular age-related macular degeneration (AMD) is treated with anti-VEGF intravitreal injections, which can cause geographic atrophy, infection, and retinal fibrosis. To minimize these toxicities, we developed a nanoparticle delivery system for recombinant Flt23k intraceptor plasmid (RGD.Flt23k.NP) to suppress VEGF intracellularly within choroidal neovascular (CNV) lesions in a laser-induced CNV mouse model through intravenous administration. In the current study, we examined the efficacy and safety of RGD.Flt23k.NP in mice. The effect of various doses was determined using fluorescein angiography and optical coherence tomography to evaluate CNV leakage and volume. Efficacy was determined by the rate of inhibition of CNV volume at 2 weeks post-treatment. RGD.Flt23k.NP had peak efficacy at a dose range of 30-60 µg pFlt23k/mouse. Using the lower dose (30 µg pFlt23k/mouse), RGD.Flt23k.NP safety was determined both in single-dose groups and in repeat-dose (three times) groups by measuring body weight, organ weight, hemoglobin levels, complement C3 levels, and histological changes in vital organs. Neither toxicity nor inflammation from RGD.Flt23k.NP was detected. No side effect was detected on visual function. Thus, systemic RGD.Flt23k.NP may be an alternative to standard intravitreal anti-VEGF therapy for the treatment of neovascular AMD.
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Inhibidores de la Angiogénesis/administración & dosificación , Neovascularización Coroidal/terapia , Portadores de Fármacos , Degeneración Macular/terapia , Plásmidos/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/química , Animales , Coroides/irrigación sanguínea , Coroides/metabolismo , Coroides/patología , Neovascularización Coroidal/genética , Neovascularización Coroidal/metabolismo , Neovascularización Coroidal/patología , Complemento C3/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Regulación de la Expresión Génica , Hemoglobinas/metabolismo , Humanos , Inyecciones Intravenosas , Inyecciones Intravítreas , Rayos Láser , Degeneración Macular/genética , Degeneración Macular/metabolismo , Degeneración Macular/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Nanopartículas/administración & dosificación , Nanopartículas/química , Plásmidos/química , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Amyloidosis involves extravascular deposition of fibrillar proteins within tissues and organs. Primary light chain amyloidosis represents the most common form of systemic amyloidosis involving deposition of monoclonal immunoglobulin light chains. Although pulmonary amyloid deposition is common in primary amyloidosis, clinically significant pulmonary amyloidosis is uncommon, and elevated pulmonary artery pressures are rarely observed in the absence of other underlying etiologies for pulmonary hypertension, such as elevated filling pressures secondary to cardiac amyloid. In this case report, we present a patient with primary light chain amyloidosis and pulmonary arterial hypertension in the setting of pulmonary vascular and right ventricular myocardial amyloid deposition.
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Neuroendocrine tumors (NETs) comprise a broad family of tumors that may or may not be associated with symptoms attributable to hormonal hypersecretion. The NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine Tumors discuss the diagnosis and management of both sporadic and hereditary NETs. This selection from the guidelines focuses on sporadic NETs of the pancreas, gastrointestinal tract, lung, and thymus.
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Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/terapia , Manejo de la Enfermedad , HumanosRESUMEN
BACKGROUND & AIMS: Eosinophilic esophagitis is usually triggered by foods, by unclear mechanisms. We evaluated the roles of IgE and IgG4 in the development of eosinophilic esophagitis. METHODS: We performed a prospective, randomized, double-blind, placebo-controlled trial of adults with eosinophilic esophagitis given an antibody against IgE (omalizumab, n = 16) or placebo (n = 14) every 2-4 weeks for 16 weeks, based on weight and serum level of IgE. Endoscopy was performed, esophageal biopsy specimens were collected, and symptoms were assessed at baseline and at 16 weeks. Maximum numbers of eosinophils/high-power field were determined. Homogenates of esophageal biopsy specimens from 11 subjects with eosinophilic esophagitis and 8 without (controls) were assessed for IgM, IgA, and IgG subclasses. In a retrospective analysis, we performed immunofluorescence analysis of IgG4 in fixed esophageal tissues from 2 patients with eosinophilic esophagitis who underwent esophagectomy and 47 consecutive autopsies (controls). We also performed immunofluorescence analysis of IgG4 in esophageal mucosal biopsy specimens from 24 subjects with eosinophilic esophagitis and 9 without (controls). Finally, sera were collected from 15 subjects with eosinophilic esophagitis and from 41 without (controls), and assayed for total and food-reactive IgG4. RESULTS: Omalizumab did not alter symptoms of eosinophilic esophagitis or eosinophil counts in biopsy samples compared with placebo. Homogenates of esophageal tissues from patients with eosinophilic esophagitis had a 45-fold increase in IgG4 compared with controls (P < 3 × 10(-5)), but no significant increases in other IgG subclasses, IgM, or IgA. Sparse stromal deposits resembling immune complexes were found in 2 of 5 eosinophilic esophagitis biopsy specimens based on ultrastructural analysis. Esophagectomy samples from 2 patients with eosinophilic esophagitis contained 180 and 300 IgG4 plasma cells/maximal high-power field, mainly in the deep lamina propria; these levels were greater than in tissues from controls. Fibrosis essentially was exclusive to the lamina propria. Granular extracellular IgG4 was detected in biopsy specimens from 21 of 24 patients with eosinophilic esophagitis, but in none of the specimens from 9 controls (P = 6 × 10(-6)). The total serum level of IgG4 increased only slightly in patients with eosinophilic esophagitis, compared with controls. Subjects with eosinophilic esophagitis had increased serum levels of IgG4 that reacted with milk, wheat, egg, and nuts-the 4 foods that most commonly trigger this condition (P ≤ 3 × 10(-4) for each food). CONCLUSIONS: In a prospective trial, omalizumab did not reduce symptoms of eosinophilic esophagitis or tissue eosinophil counts compared with placebo. This finding, along with observed granular deposits of IgG4, abundant IgG4-containing plasma cells, and serum levels of IgG4 reactive to specific foods, indicate that, in adults, eosinophilic esophagitis is IgG4-associated, and not an IgE-induced allergy. ClinicalTrials.gov number: NCT 00123630.
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Esofagitis Eosinofílica/inmunología , Esófago/inmunología , Hipersensibilidad a los Alimentos/inmunología , Inmunoglobulina E/metabolismo , Inmunoglobulina G/metabolismo , Adulto , Anciano , Antialérgicos/uso terapéutico , Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores/sangre , Biomarcadores/metabolismo , Biopsia , Método Doble Ciego , Esofagitis Eosinofílica/sangre , Esofagitis Eosinofílica/diagnóstico , Esofagitis Eosinofílica/tratamiento farmacológico , Esofagoscopía , Esófago/efectos de los fármacos , Hipersensibilidad a los Alimentos/sangre , Hipersensibilidad a los Alimentos/diagnóstico , Hipersensibilidad a los Alimentos/tratamiento farmacológico , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Omalizumab , Estudios Prospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , UtahRESUMEN
Monthly intraocular injections are widely used to deliver protein-based drugs that cannot cross the blood-retina barrier for the treatment of leading blinding diseases such as age-related macular degeneration (AMD). This invasive treatment carries significant risks, including bleeding, pain, infection, and retinal detachment. Further, current therapies are associated with a rate of retinal fibrosis and geographic atrophy significantly higher than that which occurs in the described natural history of AMD. A novel therapeutic strategy which improves outcomes in a less invasive manner, reduces risk, and provides long-term inhibition of angiogenesis and fibrosis is a felt medical need. Here we show that a single intravenous injection of targeted, biodegradable nanoparticles delivering a recombinant Flt23k intraceptor plasmid homes to neovascular lesions in the retina and regresses CNV in primate and murine AMD models. Moreover, this treatment suppressed subretinal fibrosis, which is currently not addressed by clinical therapies. Murine vision, as tested by OptoMotry, significantly improved with nearly 40% restoration of visual loss induced by CNV. We found no evidence of ocular or systemic toxicity from nanoparticle treatment. These findings offer a nanoparticle-based platform for targeted, vitreous-sparing, extended-release, nonviral gene therapy.
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ADN/administración & dosificación , Terapia Genética/métodos , Degeneración Macular/terapia , Nanocápsulas/administración & dosificación , Neovascularización Patológica/terapia , Retina/patología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Animales , ADN/genética , Fibrosis , Haplorrinos , Ratones , Resultado del TratamientoRESUMEN
OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of 5%. There is an urgent need for early detection while the tumors are small and surgically resectable. We assessed serum osteopontin (OPN) and tissue inhibitor of metalloproteinase 1 (TIMP-1) as possible diagnostic and prognostic biomarkers in a novel cohort of patients with pancreatic cancer. METHODS: Osteopontin and TIMP-1 levels were determined in sera from 86 patients with PDAC, 86 healthy control subjects, and 48 patients with chronic pancreatitis. Regression models were used to relate OPN and TIMP-1 to sex, age, stage, class, and treatment. Survival analyses were performed using univariate and multivariate Cox models. RESULTS: The serum levels of both OPN and TIMP-1 distinguished PDAC from chronic pancreatitis (P ≤ 0.0001) and healthy control subjects (P < 0.0001). The serum levels of both OPN and TIMP-1 also distinguished early-stage resectable PDAC cases from chronic pancreatitis (P < 0.04) and healthy control subjects (P < 0.01). High serum levels of OPN were significantly correlated with reduced patient survival. CONCLUSIONS: Serum OPN and TIMP-1 have use as diagnostic biomarkers in PDAC. Our data suggest a potential benefit of using OPN, TIMP-1, and CA 19-9 in a panel to improve diagnostic accuracy in PDAC.
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Biomarcadores de Tumor/sangre , Carcinoma Ductal Pancreático/sangre , Osteopontina/sangre , Neoplasias Pancreáticas/sangre , Inhibidor Tisular de Metaloproteinasa-1/sangre , Adulto , Anciano , Anciano de 80 o más Años , Antígeno CA-19-9/sangre , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/terapia , Estudios de Casos y Controles , Diagnóstico Diferencial , Detección Precoz del Cáncer , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Estimación de Kaplan-Meier , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Pancreatitis Crónica/sangre , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
PURPOSE: The process whereby liver inflammation develops in non-alcoholic steatohepatitis (NASH) is not fully understood. While modification of the inflammatory milieu is an attractive target to prevent the development of hepatocellular injury, most antiinflammatory agents have proven ineffective in this setting. Tetraethylthiuram disulfide (TDSF) is able to induce S-glutathionylation of NF-κB along with critical signaling proteins involved with inflammation, especially when complexed with a heavy metal. For this reason, we hypothesized that administration of TDSF would function to ameliorate necroinflammatory activity in a mouse model of NASH. METHODS: Mice were divided into five groups and received control chow versus a methionine-choline-deficient diet. After 6 weeks of TDSF versus sham gavage, animals were necropsied. Using conventional H&E staining, livers were examined using the Brunt scoring system by a hepatopathologist blinded to treatment groups. Validated mouse primer sets were used for quantitative real-time PCR to evaluate changes in mRNA expression. RESULTS: Livers treated with TDSF demonstrated a qualitative reduction in lobular inflammation, lipogranuloma formation, and Kupffer cell accumulation, but not steatosis. Significant reductions in inflammatory transcripts for α-1-collagen, TGF-ß, Mmp2, MCP-1, and TNF-1α were also observed. CONCLUSIONS: Animals treated with TDSF exhibit a reduction in lobular inflammation that is independent of lipid accumulation when administered MCD diet. Similar reductions are seen in several inflammatory transcripts associated with NASH. Additional work in this area may reveal a therapeutic role for TDSF or similar agents in curtailing inflammatory signaling within the liver.
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Endobronchial papilloma is a rare entity that is in the differential for solitary pulmonary nodule. It almost always follows a benign course, with only rare malignant transformation being reported in the squamous variant. No malignant transformation of the glandular variant has been reported to the best of our knowledge, and therefore endobronchial papilloma must be distinguished from more aggressive neoplasms. This distinction is particularly important when one encounters this neoplasm in a peripheral location at frozen section. We report a case of a 65-year-old female with an incidentally discovered solitary peripheral pulmonary nodule identified during a commercial whole-body screening computed tomography (CT) scan. Interval scans revealed a concerning doubling time, and she presented to the surgical service for removal of the mass. Intraoperative frozen section evaluation revealed histologic characteristics favoring a benign neoplasm. Permanent histologic section revealed a glandular papilloma. Over 7 years of follow-up revealed a benign clinical course.
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Errores Diagnósticos/prevención & control , Neoplasias Pulmonares/diagnóstico , Papiloma/diagnóstico , Anciano , Diagnóstico Diferencial , Femenino , Secciones por Congelación , Humanos , Hallazgos Incidentales , Neoplasias Pulmonares/cirugía , Papiloma/cirugía , Nódulo Pulmonar Solitario/diagnóstico , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Imagen de Cuerpo EnteroRESUMEN
Neuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgical management of neuroendocrine tumors of the pancreas.
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Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/terapia , Humanos , Estadificación de Neoplasias , Tumores Neuroendocrinos/clasificaciónRESUMEN
KIT mutations are known to occur in ~15% of chronic sun damaged cutaneous, mucosal, and acral melanomas. Melanomas with demonstrated activating mutations in KIT or platelet-derived growth factor receptor A (PDGFRA) may benefit from treatment with tyrosine kinase inhibitors. Currently, the limited data regarding KIT mutational status in ocular melanoma suggest that activating mutations are extremely rare. PDGFRA mutational status in ocular melanoma has not been determined. Seventy-five ocular melanomas (53 choroidal, 6 iris, 11 ciliary body, and 5 conjuctival) were selected from the files of the Department of Ophthalmology. High-resolution melting curve analysis and sequencing were performed to detect mutations in KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18. Results of mutational analysis were correlated with anatomical site and KIT (CD117) immunohistochemistry. Eight of 75 (11%) ocular melanomas contained mutations in either the KIT or PDGFRA gene. Five of 53 (9%) choroidal melanomas were associated with mutations (KIT exon 11=3; KIT exon 17=1; PDGFRA intron 18=1). Two of six (33%) iris melanomas and a single (9%) ciliary body melanoma harbored KIT exon 11 mutations. No mutations were identified in conjunctival melanomas. The distribution of KIT and PDGFRA mutations by ocular melanoma anatomical site did not reach statistical significance (P=0.393) CD117 positivity was not predictive of KIT mutational status as only 6 of 58 (10%) CD177-positive tumors harbored KIT mutations. In addition, a KIT exon 17 mutation was identified in one CD117-negative tumor. KIT and PDGFRA mutations do occur in ocular melanomas at a frequency (11%) that is similar to acral and mucosal melanomas. Limited correlation of CD117 positivity with mutational status suggests that all ocular melanomas should undergo mutational analysis to determine if imatinib therapy is appropriate.
Asunto(s)
Neoplasias del Ojo/genética , Melanoma/genética , Mutación , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Factor de Células Madre/genética , Análisis Mutacional de ADN , Neoplasias del Ojo/metabolismo , Neoplasias del Ojo/patología , Humanos , Inmunohistoquímica , Melanoma/metabolismo , Melanoma/patología , Microdisección , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas c-kit/metabolismoRESUMEN
Nonadherence in kidney transplant recipients was evaluated in this report using a questionnaire with five binary questions and one question on a continuous scale. Study participants at the University of Utah Transplant Program (n = 199) were 43.0 ± 14.2 years old; 67% were males, and 81% were White. Two questions that produced heterogeneous outcome were analyzed: 'Do you ever forget to take your medication?' (79% no, 21% yes) and 'Have you ever taken your medications late?' (67% no, 33% yes). Responses to these questions correlated (χ² 65.2, p < 0.001; correlation coefficient 0.57, p < 0.001). We performed a logistic regression analysis to identify factors associated with the combined outcome of forgetting/not taking medications altogether or taking medications off schedule. Higher comorbidity index [odds ratio (OR) 2.19, p < 0.001], living (compared to deceased) donor (OR 2.81, p = 0.005) and full-time employment were associated with forgetting medications or taking them late (OR 3.12, p = 0.01). Recipient age tended to be associated with lower risk of nonadherence, but did not reach statistical significance (OR 0.98 per year of age, p = 0.13). Education level, smoking status, recipient race, dialysis modality, number of medications and the time since first kidney transplantation were not associated with the outcome. In conclusion, renal transplant recipients with greater comorbidity, receiving kidney from a living donor and with full-time employment reported lower levels of medication adherence.