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1.
Head Neck Pathol ; 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350806

RESUMO

The lungs are a common site of metastasis of head and neck (H&N) squamous cell carcinomas (SCC). This study attempts to define p16 immunoexpression and presence of HPV in primary SCC of the lung and determine their usefulness in discriminating between primary lung SCC and metastasis from HPV-associated oropharyngeal primary. Pathology archives were searched for patients with SCC of the lung without SCC elsewhere. Tissue microarray was constructed and immunohistochemistry performed using anti-p40 and anti-p16 antibodies. All cases were tested for HPV viral proteins E6/E7 by RNA in situ hybridization (ISH) and available positive cases for HPV DNA by polymerase chain reaction (PCR). Eight of 25 (32%) showed cytoplasmic and nuclear expression of p16: 2 (8%) strong and 2 (8%) moderate in > 70% of tumor cells; 1 (4%) strong, 1 (4%) moderate, and 1 (4%) weak in 50-70% of tumor cells; 1 (4%) weak in < 50% of tumor cells. E6/E7 mRNA ISH was negative in all cases. Seven of 8 (87.5%) p16-expressing cases were available for testing by HPV PCR; all were negative for HPV DNA. A retrospective control group of 12 patients with possible SCC metastatic to lung was also identified; high-risk HPV DNA was present in 3, confirming metastasis. p16 expression in lung SCC is not uncommon and may not discriminate between primary pulmonary SCC and metastasis from HPV-associated oropharyngeal primary. Confirmatory HPV testing (high risk HPV DNA or E6/E7 mRNA) is recommended to differentiate metastasis from oropharyngeal primary from two separate primaries.

2.
Histopathology ; 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32333813

RESUMO

AIMS: Nuclear grade has been recently validated as a powerful prognostic tool in epithelioid malignant pleural mesothelioma (E-MPM). In other studies histological parameters including pleomorphic features and growth patterns were also shown to exert prognostic impact. The primary aims of our study are (i) externally validate the prognostic role of pleomorphic features in E-MPM and (ii) investigate if evaluating growth pattern in addition to 2-tier nuclear grade improves prognostication. METHODS AND RESULTS: 614 consecutive cases of E-MPM from our institution over a period of 15 years were retrospectively reviewed, of which 51 showed pleomorphic features. E-MPM with pleomorphic features showed significantly worse overall survival compared to those without (5.4 versus 14.7 months). Tumours with predominantly micropapillary pattern showed the worst survival (6.2 months) followed by solid (10.5 months), microcystic (15.3 months), discohesive (16.1 months), trabecular (17.6 months) and tubulo-papillary (18.6 months). Sub-classification of growth patterns into high grade (solid, micropapillary) and low grade (all others) led to good separation of overall survival (10.5 versus 18.0 months) but did not predict survival independent of 2-tier nuclear grade. A composite score comprised of growth pattern and 2-tier nuclear grade did not improve prognostication compared with nuclear grade alone. Intra-tumoural heterogeneity in growth patterns is ubiquitous. CONCLUSIONS: Our findings support the incorporation of E-MPM with pleomorphic features in the epithelioid subtype as a highly aggressive variant distinct from 2-tier nuclear grade. E-MPM demonstrates extensive heterogeneity in growth pattern but its evaluation does not offer additional prognostic utility to 2-tier nuclear grade.

3.
J Thorac Oncol ; 15(6): 1037-1053, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32165206

RESUMO

INTRODUCTION: Histologic subtypes of malignant pleural mesothelioma are a major prognostic indicator and decision denominator for all therapeutic strategies. In an ambiguous case, a rare transitional mesothelioma (TM) pattern may be diagnosed by pathologists either as epithelioid mesothelioma (EM), biphasic mesothelioma (BM), or sarcomatoid mesothelioma (SM). This study aimed to better characterize the TM subtype from a histological, immunohistochemical, and molecular standpoint. Deep learning of pathologic slides was applied to this cohort. METHODS: A random selection of 49 representative digitalized sections from surgical biopsies of TM was reviewed by 16 panelists. We evaluated BAP1 expression and CDKN2A (p16) homozygous deletion. We conducted a comprehensive, integrated, transcriptomic analysis. An unsupervised deep learning algorithm was trained to classify tumors. RESULTS: The 16 panelists recorded 784 diagnoses on the 49 cases. Even though a Kappa value of 0.42 is moderate, the presence of a TM component was diagnosed in 51%. In 49% of the histological evaluation, the reviewers classified the lesion as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 observed in 44% was less frequent in TM than in EM and BM. p16 homozygous deletion was higher in TM (73%), followed by BM (63%) and SM (46%). RNA sequencing unsupervised clustering analysis revealed that TM grouped together and were closer to SM than to EM. Deep learning analysis achieved 94% accuracy for TM identification. CONCLUSION: These results revealed that the TM pattern should be classified as non-EM or at minimum as a subgroup of the SM type.

4.
Surg Pathol Clin ; 13(1): 165-188, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32005430

RESUMO

Patients with connective tissue diseases may have pulmonary involvement, including interstitial lung disease. Various patterns of interstitial lung disease have been classically described in certain connective tissue diseases. It is now recognized that there is significant overlap between patterns of interstitial lung disease observed in the various connective tissue diseases. Differentiating idiopathic from connective tissue disease-related interstitial lung disease is challenging but of clinical importance. New concepts in the diagnosis of connective tissue disease related interstitial lung disease may prove useful in making the diagnosis.

5.
Biochim Biophys Acta Biomembr ; 1862(5): 183205, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32001212

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by an abnormal healing response to injury of the alveolar epithelium. Tight junctions provide a physical barrier at the apical intercellular space between epithelial cells and regulate paracellular flux. While tight junction alterations are known to contribute to barrier dysfunction in a number of disease states, the role of tight junction proteins in IPF is poorly defined. To determine a potential role for tight junction protein alterations in IPF, we performed immunohistochemical staining for tight junction proteins ZO-1, occludin, claudin-2, claudin-3, claudin-4, claudin-5, and claudin-18. Staining intensity and localization were compared between IPF and control lung tissues. IPF was associated with type II pneumocyte hyperplasia and altered tight junction protein expression. While there was no difference in the expression of ZO-1, claudin-3, or claudin-5, between IPF and normal control, there was an overall increase in claudin-2 expression in bronchiolar and alveolar epithelium and a decrease in claudin-4 expression in type II pneumocytes. There was also increased occludin and decreased claudin-18 expression in pneumocytes overlying fibroblastic foci. These findings suggest that epithelial barrier alterations may be important to the pathogenesis of IPF.

6.
Pediatr Pulmonol ; 55(3): E1-E4, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31944579

RESUMO

Pleuroparenchymal fibroelastosis (PPFE), which is primarily diagnosed in adults, is a progressive lung pathology associated with significant morbidity and mortality. PPFE is characterized by pleural and subpleural parenchymal disease causing dyspnea, cough, and recurrent pneumothoraces. PPFE can be precipitated by autoimmune disorders, recurrent respiratory infections, chemotherapy, and transplant. We describe the youngest recorded patient to develop PPFE, whose symptoms began several years after treatment for neuroblastoma. Her symptoms were initially mistaken for worsening asthma, and multiple comorbidities developed during the prolonged time to recognition of PPFE and she progressed to fatal lung disease before potentially curative lung transplantation could occur.

7.
Mod Pathol ; 33(2): 245-254, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31231127

RESUMO

Ancillary studies facilitate accurate diagnosis of morphologically challenging mesothelial proliferations. The current diagnostic algorithm proceeds from BAP1 immunohistochemistry to CDKN2A fluorescence in situ hybridization. While MTAP immunohistochemistry has recently shown promise as a surrogate for CDKN2A fluorescence in situ hybridization, it has been examined in only a few single-institution studies. Furthermore, there are no published reports on interobserver agreement or interlaboratory reproducibility for MTAP immunohistochemistry. We performed MTAP immunohistochemistry on 20 benign mesothelial lesions and 99 malignant mesotheliomas from five mesothelioma centers in four countries, and each MTAP stain was independently interpreted by four pathologists. CDKN2A fluorescence in situ hybridization data were available for a subset of cases, and a subset of cases was subjected in MTAP immunohistochemistry in multiple laboratories to assess interlaboratory reproducibility. Interobserver agreement in MTAP immunostain interpretation was excellent for all mesothelial lesions (kappa: 0.85) and for malignant mesothelioma cases only (kappa: 0.82). Interlaboratory reproducibility was also excellent (kappa values for paired protocols: 0.77-0.89). MTAP loss by immunohistochemistry was 78% sensitive and 96% specific for CDKN2A homozygous deletion. MTAP immunohistochemistry is a reliable surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant mesothelioma. Interobserver agreement is excellent for interpretation of MTAP staining, and protocols performed in different laboratories yield concordant MTAP staining results. Rare cases with immunohistochemical MTAP loss may retain normal CDKN2A copy number, and the MTAP staining results should be correlated with clinicopathologic findings and other ancillary studies.

8.
Pediatr Dev Pathol ; 23(2): 163-166, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31514577

RESUMO

We present a case of a neonate with tracheoesophageal fistula and esophageal atresia along with a suspicious lung mass who had a false-positive newborn screen for cystic fibrosis due to an elevated serum immunoreactive trypsinogen with an additionally elevated serum lipase. The infant's lung mass was found to contain heterotopic pancreatic tissue consisting of acini, ducts, and islet cells, without an associated gastrointestinal duplication cyst. This constellation of congenital abnormalities has not been described in previous literature. Also, this is the first reported case of a neonate with elevated serum pancreatic enzymes in which the underlying etiology was discovered to be heterotopic pancreas.

9.
Oncogenesis ; 8(9): 49, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484920

RESUMO

Squamous cell carcinoma (SCC) and malignant pleural mesothelioma (MPM) are thoracic malignancies with very poor prognosis and limited treatment options. It is an established fact that most of the solid tumors have overexpression of EPHA2 receptor tyrosine kinase. EPHA2 is known to exhibit opposing roles towards cancer progression. It functions in inhibiting cancer survival and migration via a ligand and tyrosine kinase dependent signaling (Y772). Whereas it is known to promote tumor progression and cell migration through a ligand-independent signaling (S897). We analyzed the expression profile and mutational status of the ephrin receptor A2 (EPHA2) in SCC and MPM cell lines and primary patient specimens. The EPHA2 receptor was found to be either overexpressed, mutated or amplified in SCC and MPM. In particular, the EPHA2 mutants A859D and T647M were interesting to explore, A859D Y772 dead mutant exhibited lower levels of phosphorylation at Y772 compared to T647M mutant. Molecular Dynamics simulations studies suggested that differential changes in conformation might form the structural basis for differences in the level of EPHA2 activation. Consequently, A859D mutant cells exhibited increased proliferation as well as cell migration compared to controls and T647M mutant. Kinomics analysis demonstrated that the STAT3 and PDGF pathways were upregulated whereas signaling through CBL was suppressed. Considered together, the present work has uncovered the oncogenic characteristics of EPHA2 mutations in SSC and MPM reinstating the dynamics of different roles of EPHA2 in cancer. This study also suggests that a combination of doxazosin and other EPHA2 inhibitors directed to inhibit the pertinent signaling components may be a novel therapeutic strategy for MPM and Non-small cell lung cancer patients who have either EPHA2 or CBL alterations.

10.
Hum Pathol ; 87: 11-17, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30794891

RESUMO

Malignant mesothelioma (MM) is an aggressive neoplasm with poor prognosis. The Dako PD-L1 22C3 and 28-8 pharmDx assays are approved by the US Food and Drug Administration (FDA) as companion and complementary diagnostics for the anti-PD-1 drugs pembrolizumab and nivolumab, respectively. Data from multiple clinical trials indicate that immunotherapy has antitumor activity in advanced malignant pleural (MPM) and peritoneal mesothelioma (MPeM). However, large studies of PD-L1 expression in MM using the FDA-approved anti-PD-L1 assays are lacking. We stained tissue microarray sections (N = 125; 112 MPM and 13 MPeM) using 2 FDA-approved clinical immunohistochemical makers for PD-L1 expression: Dako PD-L1 22C3 pharmDx and Dako PD-L1 28-8 pharmDx. Overall, 22% (27/125) of MMs were positive using the 22C3 assay, whereas 27% (32/117) were positive using the 28-8 assay, using a tumor proportion score cutoff of 1%. Tumor cell PD-L1 expression was strongly correlated with PD-L1 expression on tumor-associated immune cells. No significant difference in PD-L1 expression was observed by patient sex, age, treatment history, pathologic stage, or histologic subtype. However, the proportion of cases positive for PD-L1 expression was higher among MPeM compared to MPM (P = .007 for 22C3 assay; P = .04 for 28-8 assay). PD-L1 is expressed in a substantial proportion of MM cases, as measured by FDA-approved companion assays for widely used immunotherapeutic drugs. PD-L1 expression is particularly prevalent in MPeM. These findings support large clinical studies to further examine PD-L1 as a biomarker for a subset of MM patients that may benefit from immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Neoplasias Peritoneais/metabolismo , Neoplasias Pleurais/metabolismo , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/tratamento farmacológico , Mesotelioma/mortalidade , Mesotelioma/patologia , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/patologia , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , Prognóstico , Taxa de Sobrevida , Resultado do Tratamento
11.
Lung Cancer ; 127: 69-75, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30642555

RESUMO

The pathologist plays a central role in the diagnosis and management of malignant mesothelioma, including definitive tissue-based diagnosis in conjunction with clinical and radiographic data; diverse ancillary studies of diagnostic, prognostic, and predictive importance; and research efforts to better define the pathobiology of mesothelioma and develop novel clinical applications. The pivotal role of pathology in care of mesothelioma patients was on display at the recent meeting of the International Mesothelioma Interest Group (iMig) in Ottawa, Canada. This review summarizes the key findings of the "Molecular Pathways and Diagnosis in Malignant Mesothelioma" plenary session, including a large multi-institutional validation of a composite nuclear grading system for pleural mesothelioma, including incorporation of tumor necrosis as an additional independent prognostic factor; the correlation between nuclear grading in small biopsies and paired resection specimens in pleural mesothelioma; a multi-institutional study of important clinical and pathologic prognostic factors in peritoneal mesothelioma; the diagnostic role of HEG1 immunohistochemistry as a highly sensitive and specific marker of mesothelial lineage; the prevalence and diagnostic significance of MET protein overexpression in mesothelioma, as well as the correlation between MET protein overexpression and MET gene amplification; and the prognostic role of EZH2 protein overexpression in mesothelioma, together with data indicating an important pathogenic role for EZH2 in mesothelioma tumorigenesis. Special consideration is given to the convergence of diagnostic, prognostic, and predictive tools and their role in guiding highly personalized patient-centered management, and to the translation of novel research findings to practical techniques for routine pathologic practice.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/diagnóstico , Mesotelioma/diagnóstico , Neoplasias Peritoneais/diagnóstico , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/metabolismo , Canadá , Congressos como Assunto , Regulação Neoplásica da Expressão Gênica , Humanos , Cooperação Internacional , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Neoplasias Peritoneais/metabolismo , Prognóstico , Opinião Pública , Transdução de Sinais
12.
Echocardiography ; 36(2): 285-291, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30592782

RESUMO

BACKGROUND: Despite routine use of echocardiographic parameters to evaluate the severity of cardiac amyloidosis (CA), this methodology has not been well validated. We developed a histopathologic schema for quantifying CA burden and evaluated its relationship with clinical outcomes. Additionally, echocardiographic parameters were tested as potential noninvasive indices of CA burden. METHODS: We retrospectively studied 59 patients with CA (17 light chain, 42 transthyretin) who underwent endomyocardial biopsies. Light microscopy with staining was used to categorize CA burden as mild-to-moderate (<50%) or high (≥50%). Kaplan-Meier survival analysis was performed for the two groups. In 34 patients with good-quality echocardiograms, we measured left ventricular volumes, ejection fraction (EF), interventricular septal thickness (IVSt), posterior wall thickness (PWt), LV mass, lateral e'-velocity, and global longitudinal strain (GLS). These parameters were compared between the two groups. RESULTS: Thirty-five patients had mild-to-moderate and 24 severe amyloid burden. Kaplan-Meier curves demonstrated a trend toward worse mortality with high CA burden, which was more common and associated with higher mortality specifically in transthyretin-type patients. Echocardiography-derived IVSt, PWt, and LV mass were directly related to CA burden, while LV EF, e'-velocity, and GLS magnitude were inversely related to CA burden. CONCLUSIONS: Our findings provided a signal that CA burden is a clinically important entity with potentially valuable prognostic information. Echocardiographic parameters of LV anatomy and function correlate with histopathologic burden of CA, which is inversely related to survival. Further studies are needed to determine whether these parameters could be used as imaging biomarkers of treatment-related changes in CA burden.


Assuntos
Amiloidose/diagnóstico por imagem , Amiloidose/patologia , Ecocardiografia/métodos , Cardiopatias/diagnóstico por imagem , Cardiopatias/patologia , Idoso , Efeitos Psicossociais da Doença , Feminino , Humanos , Masculino , Estudos Retrospectivos , Análise de Sobrevida
13.
Int J Gynecol Pathol ; 38(4): 346-352, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29620587

RESUMO

Mucolipidosis type II, also known as I-cell disease, is an autosomal recessive inborn error of metabolism, resulting from loss-of-function mutations in GNPTAB. Affected infants exhibit multiple physical anomalies and developmental delay, and death from disease follows in early childhood. Here we present an instructive case of mucolipidosis type II affecting 1 fetus and placental disk in a dichorionic-diamnionic twin pregnancy delivered at 36-wk gestation. The second twin and placental disk showed no abnormality. On microscopic examination, the affected placenta displayed marked vacuolization of the syncytiotrophoblast and Hofbauer cells, which was confirmed on ultrastructural examination. To our knowledge, this is the first description of placental findings in a twin pregnancy, wherein only 1 twin is affected by an inborn error of metabolism. This provides an opportunity to highlight the placental abnormalities seen in this group of diseases, and to emphasize the role of pathologic examination in early detection of otherwise unsuspected inborn errors of metabolism.


Assuntos
Mucolipidoses/diagnóstico por imagem , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Adulto , Feminino , Feto , Humanos , Recém-Nascido , Masculino , Mucolipidoses/genética , Mucolipidoses/patologia , Placenta/anormalidades , Placenta/diagnóstico por imagem , Placenta/patologia , Gravidez , Gravidez de Gêmeos , Gêmeos
14.
Am J Respir Crit Care Med ; 199(6): 747-759, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30216085

RESUMO

RATIONALE: Mediastinal lymph node (MLN) enlargement on chest computed tomography (CT) is prevalent in patients with interstitial lung disease (ILD) and may reflect immunologic activation and subsequent cytokine-mediated immune cell trafficking. OBJECTIVES: We aimed to determine whether MLN enlargement on chest CT predicts clinical outcomes and circulating cytokine levels in ILD. METHODS: MLN measurements were obtained from chest CT scans of patients with ILD at baseline evaluation over a 10-year period. Patients with sarcoidosis and drug toxicity-related ILD were excluded. MLN diameter and location were assessed. Plasma cytokine levels were analyzed in a subset of patients. The primary outcome was transplant-free survival (TFS). Secondary outcomes included all-cause and respiratory hospitalizations, lung function, and plasma cytokine concentrations. Cox regression was used to assess mortality risk. Outcomes were assessed in three independent ILD cohorts. MEASUREMENTS AND MAIN RESULTS: Chest CT scans were assessed in 1,094 patients (mean age, 64 yr; 52% male). MLN enlargement (≥10 mm) was present in 66% (n = 726) and strongly predicted TFS (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.12-2.10; P = 0.008) and risk of all-cause and respiratory hospitalizations (internal rate of return [IRR], 1.52; 95% CI, 1.17-1.98; P = 0.002; and IRR, 1.71; 95% CI, 1.15-2.53; P = 0.008, respectively) when compared with subjects with MLN <10 mm. Patients with MLN enlargement had lower lung function and decreased plasma concentrations of soluble CD40L (376 pg/ml vs. 505 pg/ml, P = 0.001) compared with those without MLN enlargement. Plasma IL-10 concentration >45 pg/ml predicted mortality (HR, 4.21; 95% CI, 1.21-14.68; P = 0.024). Independent analysis of external datasets confirmed these findings. CONCLUSIONS: MLN enlargement predicts TFS and hospitalization risk in ILD and is associated with decreased levels of a key circulating cytokine, soluble CD40L. Incorporating MLN and cytokine findings into current prediction models might improve ILD prognostication.


Assuntos
Doenças Pulmonares Intersticiais/mortalidade , Linfonodos/diagnóstico por imagem , Mediastino/diagnóstico por imagem , Valor Preditivo dos Testes , Tomografia Computadorizada por Raios X/métodos , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Mod Pathol ; 32(3): 376-386, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30315275

RESUMO

Accurate distinction of benign mesothelial proliferations from malignant mesothelioma remains a diagnostic challenge. Sequential use of BAP1 immunohistochemistry and CDKN2A fluorescence in situ hybridization is specific for diagnosis of mesothelioma, but fluorescence in situ hybridization is both costly and time-consuming. Early data indicate that mesothelioma shows extensive loss of nuclear 5-hydroxymethylcytosine (5-hmC). We studied 49 cases of mesothelioma (17 epithelioid mesothelioma, 22 biphasic mesothelioma, and 10 sarcomatoid mesothelioma) and 23 benign mesothelial proliferations using a 5-hmC single immunohistochemical stain, CAM5.2/5-hmC double immunohistochemical stain, and BAP1 immunohistochemistry. Estimations of extent of 5-hmC loss were made using the 5-hmC single stain and CAM5.2/5-hmC double stain, and extent of nuclear 5-hmC loss was definitively quantitated in at least 1000 cells per case. Mean nuclear 5-hmC loss in mesothelioma (84%) was significantly greater than in benign mesothelial proliferations (4%) (p < 0.0001). Using 5-hmC loss in > 50% of tumor nuclei to define the diagnosis of mesothelioma, 5-hmC immunohistochemistry showed sensitivity of 92% and specificity of 100%. An immunopanel including 5-hmC and BAP1 immunohistochemistry achieved sensitivity of 98% and specificity of 100%. Extensive nuclear 5-hmC loss is sensitive and specific for mesothelioma in the differential diagnosis with benign mesothelial proliferations. In challenging mesothelial lesions, immunohistochemical studies showing either extensive 5-hmC loss or BAP1 loss indicate a diagnosis of mesothelioma, precluding the need for CDKN2A fluorescence in situ hybridization in a considerable number of cases.


Assuntos
Biomarcadores Tumorais/análise , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/diagnóstico , Mesotelioma/diagnóstico , Neoplasias Pleurais/diagnóstico , Tumor Fibroso Solitário Pleural/diagnóstico , Desoxicitidina/análise , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Sensibilidade e Especificidade , Proteínas Supressoras de Tumor/análise , Ubiquitina Tiolesterase/análise
16.
Cancer Discov ; 8(12): 1548-1565, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30322867

RESUMO

Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. SIGNIFICANCE: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Mutação , Neoplasias Pleurais/genética , Idoso , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Mesotelioma/patologia , Mesotelioma/terapia , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Neoplasias Pleurais/terapia , Prognóstico , Metiltransferases de Proteína/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética
17.
J Clin Oncol ; 36(28): 2863-2871, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30113886

RESUMO

PURPOSE: The aim of the current study was to determine the prevalence and clinical predictors of germline cancer susceptibility mutations in patients with malignant mesothelioma (MM). METHODS: We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM. RESULTS: Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54). CONCLUSION: A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.


Assuntos
Mutação em Linhagem Germinativa/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Eur Respir J ; 51(6)2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29724923

RESUMO

We studied whether African-American race is associated with younger age and decreased survival time at diagnosis of interstitial lung disease (ILD).We performed a multicentre, propensity score-matched analysis of patients with an ILD diagnosis followed at five US hospitals between 2006 and 2016. African-Americans were matched with patients of other races based on a time-dependent propensity score calculated from multiple patient, physiological, diagnostic and hospital characteristics. Multivariable logistic regression models were used. All-cause mortality and hospitalisations were compared between race-stratified patient cohorts with ILD, and sensitivity analyses were performed.The study included 1640 patients with ILD, 13% of whom were African-American, followed over 5041 person-years. When compared with patients of other races, African-Americans with ILD were younger at diagnosis (56 years versus 67 years), but in the propensity-matched analyses had greater survival (hazard ratio 0.46, 95% CI 0.28-0.77; p=0.003) despite similar risk of respiratory hospitalisations (relative risk 1.04, 95% CI 0.83-1.31; p=0.709), and similar GAP-ILD (gender-age-physiology-ILD) scores at study entry. Sensitivity analyses in a separate cohort of 9503 patients with code-based ILD diagnosis demonstrated a similar association of baseline demographic characteristics with all-cause mortality.We conclude that African-Americans demonstrate a unique phenotype associated with younger age at ILD diagnosis and perhaps longer survival time.


Assuntos
Afro-Americanos , Hospitalização/estatística & dados numéricos , Doenças Pulmonares Intersticiais/mortalidade , Adulto , Idoso , Causas de Morte , Feminino , Humanos , Modelos Logísticos , Doenças Pulmonares Intersticiais/etnologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pontuação de Propensão , Estudos Retrospectivos , Estados Unidos
19.
Innovations (Phila) ; 13(2): 140-143, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29688941

RESUMO

Coronary artery bypass surgery is most commonly performed using a hand-sewn technique with a continuous monofilament suture. The C-Port distal anastomotic device is a miniature stapler designed to create an arteriotomy and attach the graft to the coronary artery all in one step. It is the only distal coronary anastomotic device currently approved for clinical use and can be useful in facilitating less invasive coronary surgery. This report examines the histological attributes of such an anastomosis in a patient who underwent heart transplantation approximately 1 year after robotic totally endoscopic stapled coronary bypass using the C-Port anastomotic device. There have been no previous reports of histological examination of this type of bypass graft in humans in the literature. We found that the C-Port single-shot stapled coronary anastomotic device had a similar histological appearance to a traditional hand-sewn technique using monofilament suture. The amount of inflammation around the anastomosis using the two techniques was found to be comparable in this histological case study in an explanted human heart. There was no evidence of increased neointimal hyperplasia. These findings add to the already known equivalent clinical patency rates of the C-Port device in coronary bypass procedures.


Assuntos
Anastomose Cirúrgica/instrumentação , Ponte de Artéria Coronária/métodos , Doença da Artéria Coronariana/cirurgia , Vasos Coronários/cirurgia , Insuficiência Cardíaca/cirurgia , Técnicas de Sutura/estatística & dados numéricos , Anastomose Cirúrgica/métodos , Vasos Coronários/transplante , Endoscopia/métodos , Desenho de Equipamento , Transplante de Coração/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Robótica/métodos , Grampeadores Cirúrgicos/efeitos adversos , Resultado do Tratamento , Grau de Desobstrução Vascular
20.
AJR Am J Roentgenol ; 210(5): 1034-1041, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29547052

RESUMO

OBJECTIVE: The purpose of this study was to assess the diagnostic significance of CT patterns that cannot be classified according to current idiopathic pulmonary fibrosis (IPF) guidelines and of specific findings of the inconsistent with usual interstitial pneumonitis (UIP) pattern. MATERIALS AND METHODS: Subjects with a multidisciplinary diagnosis of interstitial lung disease who had undergone surgical lung biopsy and chest CT within 1 year of each other were included in the study. The predominant distribution and pattern of disease were scored. Cases were classified as UIP, possible UIP, or inconsistent with UIP at chest CT according to 2011 IPF guidelines. Cases that could not be confidently categorized with current guidelines were annotated as indeterminate. RESULTS: UIP, possible UIP, and inconsistent with UIP CT patterns were associated with pathologic UIP in 89.6%, 81.6%, and 60.0% of subjects. An indeterminate CT pattern (7.7% [20/259]) was associated with a UIP pathologic diagnosis in 55.0% of cases. This finding was not statistically different from the findings in the group with the inconsistent with UIP CT pattern (p = 0.677) but was different from the findings in the UIP (p < 0.001) and possible UIP (p = 0.031) groups. In regard to specific findings of the inconsistent with UIP CT category, ground-glass opacity, air-trapping, consolidation, and axial distribution were associated with a non-UIP pathologic diagnosis; however, there was no significant association with zonal distribution. CONCLUSION: A substantial minority of cases cannot be confidently categorized according to current guidelines for IPF and differ diagnostically from the possible UIP and UIP CT categories. The term "inconsistent with UIP" is misleading and should be renamed.


Assuntos
Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/patologia , Guias de Prática Clínica como Assunto , Tomografia Computadorizada por Raios X/métodos , Idoso , Biópsia , Feminino , Humanos , Fibrose Pulmonar Idiopática/cirurgia , Masculino , Pessoa de Meia-Idade
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