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1.
Mod Pathol ; 37(3): 100420, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38185249

RESUMO

9p21 deletions involving MTAP/CDKN2A genes are detected in diffuse pleural mesotheliomas (DPM) but are absent in benign mesothelial proliferations. Loss of MTAP expression by immunohistochemistry (IHC) is well accepted as a surrogate for 9p21 deletion to support a diagnosis of DPM. Accurate interpretation can be critical in the diagnosis of DPM, but variations in antibody performance may impact interpretation. The objectives of this study were to compare the performance of MTAP monoclonal antibodies (mAbs) EPR6893 and 1813 and to compare MTAP expression by IHC with 9p21 copy number status in DPM. Cytoplasmic expression of MTAP IHC with mAbs EPR6893 (ab126770; Abcam) and 1813 (NBP2-75730, Novus Biologicals) was evaluated in 56 DPM (47 epithelioid, 7 biphasic, and 2 sarcomatoid) profiled by targeted next-generation sequencing. 9p21 Copy number status was assessed by Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) analysis and also by CDKN2A fluorescence in situ hybridization in discrepant cases when material was available. MTAP mAb 1813 showed stronger immunoreactivity, more specific staining, and no equivocal interpretations compared to mAb EPR6893 which showed equivocal staining in 19 (34%) of cases due to weak or heterogenous immunoreactivity, lack of definitive internal positive control, and/or nonspecific background staining. MTAP expression with mAb 1813 showed near perfect agreement with 9p21 copy number by combined FACETS/fluorescence in situ hybridization calls (κ = 0.85; 95% CI, 0.71-0.99; P < .001). MTAP IHC with mAb 1813 was 96% sensitive, 86% specific, and 93% accurate for 9p21 homozygous deletion. The findings of this study suggest that interpretation of MTAP IHC is improved with mAb 1813 because mAb EPR6893 was often limited by equivocal interpretations. We show that MTAP IHC and molecular assays are complementary in detecting 9p21 homozygous deletion. MTAP IHC may be particularly useful for low tumor purity samples and in low-resource settings.


Assuntos
Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Humanos , Biomarcadores Tumorais/análise , Inibidor p16 de Quinase Dependente de Ciclina/genética , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Mesotelioma/diagnóstico , Mesotelioma/genética , Mesotelioma/patologia , Mesotelioma Maligno/genética , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Deleção de Sequência , Ubiquitina Tiolesterase/genética
2.
Mod Pathol ; 36(3): 100030, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36788094

RESUMO

Neurofibromatosis type 2 (NF2) loss occurs in approximately 30% to 50% of diffuse pleural mesothelioma (DPM) with accumulation of yes-associated protein (YAP) 1 and transcriptional coactivator with PDZ-binding motif (TAZ) in tumor nuclei. NF2 and YAP/TAZ represent potential therapeutic targets. We investigated the performance of NF2-YAP/TAZ dual immunohistochemistry (IHC) in identifying DPM that harbors NF2 alterations and in distinguishing DPM from benign mesothelial proliferations. NF2-YAP/TAZ IHC was subsequently performed in a Discovery cohort of DPMs with (n = 10) or without (n = 10) NF2 alterations detected by next-generation sequencing (NGS) and 9 benign cases. The cutoff values for loss of NF2 expression and YAP/TAZ overexpression using IHC were determined in the Discovery cohort. The performance characteristics of NF2-YAP/TAZ IHC were investigated in a Validation cohort (20 DPMs and 10 benign cases). In the Discovery cohort, all DPMs with NF2 alterations using NGS showed NF2 IHC scores of <2, whereas all NF2-wild-type DPMs showed scores of ≥2. NF2-altered DPMs had significantly higher YAP/TAZ H-scores (P < .001) than NF2-wild-type DPM and benign pleura (median H-scores: 237.5 [range, 185-275], 130.0 [range, 40-225], and 10.0 [range, 0-75], respectively). NF2-YAP/TAZ IHC demonstrated 95.2% sensitivity, 100% specificity, 100% positive predictive value, and 95% negative predictive value for detecting NF2 alterations in DPM (n = 40) with NGS as the gold standard and 87.5% sensitivity and 100% specificity for distinguishing DPM (n = 40) from benign mesothelial proliferations (n = 19). NF2-YAP/TAZ IHC has a high sensitivity and specificity for detecting NF2 alterations in DPM and a high specificity for malignancy, highlighting potential utility for guiding NF2-targeted therapies and distinguishing DPM from benign mimics.


Assuntos
Mesotelioma Maligno , Mesotelioma , Neurofibromatose 2 , Humanos , Proteínas de Sinalização YAP , Neurofibromina 2/genética , Imuno-Histoquímica , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Mesotelioma/diagnóstico
3.
JCO Precis Oncol ; 8: e2400241, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39259915

RESUMO

PURPOSE: MDM2, a negative regulator of the TP53 tumor suppressor, is oncogenic when amplified. MDM2 amplification (MDM2amp) is mutually exclusive with TP53 mutation and is seen in 6% of patients with lung adenocarcinoma (LUAD), with significant enrichment in subsets with receptor tyrosine kinase (RTK) driver alterations. Recent studies have shown synergistic activity of MDM2 and MEK inhibition in patient-derived LUAD models with MDM2amp and RTK driver alterations. However, the combination of MDM2 and RTK inhibitors in LUAD has not been studied. METHODS: We evaluated the combination of MDM2 and RTK inhibition in patient-derived models of LUAD. RESULTS: In a RET-fusion LUAD patient-derived model with MDM2amp, MDM2 inhibition with either milademetan or AMG232 combined with selpercatinib resulted in long-term in vivo tumor control markedly superior to either agent alone. Similarly, in an EGFR-mutated model with MDM2amp, combining either milademetan or AMG232 with osimertinib resulted in long-term in vivo tumor control, which was strikingly superior to either agent alone. CONCLUSION: These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-mdm2 , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Camundongos , Amplificação de Genes
4.
Cancer Cytopathol ; 131(8): 495-506, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37127928

RESUMO

BACKGROUND: The World Health Organization incorporates morphologic features with prognostic significance in the 2021 classification of epithelioid diffuse pleural mesothelioma (E-DPM). Although cytology specimens are often the first and occasionally the only specimen available for patients with DPM, these features have not yet been investigated in cytology. METHODS: Nuclear atypia, pleomorphic features, necrosis, and architectural patterns were retrospectively assessed in 35 paired cytology and concurrent/consecutive surgical pathology specimens of E-DPM. Agreement between pairs was determined via unweighted κ scores. Discordant cases were re-reviewed to determine the reasons for disagreement. RESULTS: Interpretation of nuclear atypia in cytology was concordant with histology in all cases (κ = 1.000; p < .001). The presence of pleomorphic features and necrosis was concordant in 97.1% (κ = 0.842; p < .001) and 85.7% (κ = 0.481; p = .001) of paired cases, respectively. Assessment of architectural patterns in cytology showed only slight agreement with histology (κ = 0.127; p = .037). In cytology cases (n = 23) with cell block material available, assessment of nuclear atypia and the presence of pleomorphic features showed perfect agreement (κ = 1.000; p < .001, each), the presence of necrosis showed moderate agreement (κ = 0.465; p = .008), and assessment of architectural patterns showed slight agreement (κ = 0.162; p = .15) in paired specimens. Most disagreements were due to sampling differences between cytology and histology specimens. CONCLUSIONS: Although complete nuclear grading of E-DPM is not possible given the unreliability of mitotic counts in cytology, assessment of nuclear atypia in cytology specimens is shown to be reliable. Identification of pleomorphic features and necrosis is also reliable despite occasional sampling issues. Assessment of architectural patterns is more limited in cytology.


Assuntos
Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Humanos , Prognóstico , Mesotelioma/diagnóstico , Mesotelioma/patologia , Estudos Retrospectivos , Reprodutibilidade dos Testes , Necrose , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/patologia
5.
JTO Clin Res Rep ; 4(1): 100440, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36590015

RESUMO

Introduction: Single-agent monoclonal antibody therapy against programmed death-ligand 1 (PD-L1) has modest effects in malignant pleural mesothelioma. Radiation therapy can enhance the antitumor effects of immunotherapy. Nevertheless, the safety of combining anti-PD-L1 therapy with stereotactic body radiation therapy (SBRT) is unknown. We present the results of a phase 1 trial to evaluate the safety of the anti-PD-L1 antibody avelumab plus SBRT in patients with malignant pleural mesothelioma. Methods: This was a single-arm, investigator-initiated trial in patients who progressed on prior chemotherapy. Avelumab was delivered every other week, and SBRT was delivered to one lesion in three to five fractions (minimum of 30 Gy) followed by continuation of avelumab up to 24 months or until disease progression. The primary end point of the study was safety on the basis of grade 3+ nonhematologic adverse events (AEs) within 3 months of SBRT. Results: Thirteen assessable patients received a median of seven cycles (range: 2-26 cycles) of avelumab. There were 27 grade 1, 17 grade 2, four grade 3, and no grade 4 or 5 avelumab-related AEs. The most common were infusion-related allergic reactions (n = 6), anorexia or weight loss (n = 6), fatigue (n = 6), thyroid disorders (n = 5), diarrhea (n = 3), and myalgia or arthralgias (n = 3). There were 10 grade 1, four grade 2, one grade 3, and no grade 4 or 5 SBRT-related AEs. The most common were diarrhea (n = 3), chest pain/myalgia (n = 2), fatigue (n = 2), cough (n = 2), dyspnea (n = 2), and nausea/vomiting (n = 2). Conclusions: Combination avelumab plus SBRT seems tolerable on the basis of the prespecified toxicity end points of the first stage of this Simon two-stage design phase 1 study.

6.
J Surg Res ; 170(2): 325-31, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21571320

RESUMO

BACKGROUND: Following severe trauma, there is a profound elevation of catecholamine that is associated with a persistent anemic state. We have previously shown that ß-blockade (ßB) prevents erythroid growth suppression and decreases hematopoietic progenitor cell (HPC) mobilization following injury. Under normal conditions, granulocyte colony stimulating factor (G-CSF) triggers the activation of matrix metalloprotease-9 (MMP-9), leading to the egress of progenitor cells from the bone marrow (BM). When sustained, this depletion of BM cellularity may contribute to BM failure. This study seeks to determine if G-CSF plays a role in the ßB protection of BM following trauma. METHODS: Male Sprague-Dawley rats were subjected to either unilateral lung contusion (LC) ± ßB, hemorrhagic shock (HS) ± ßB, or both LC/HS ± ßB. Propranolol (ßB) was given immediately following resuscitation. Animals were sacrificed at 3 and 24 h and HPC mobilization was assessed by evaluating BM cellularity and flow cytometric analysis of peripheral blood for HPCs. The concentration of G-CSF and MMP-9 was measured in plasma by ELISA. RESULTS: BM cellularity is decreased at 3 h following LC, HS, and LC/HS. HS and LC/HS resulted in significant HPC mobilization in the peripheral blood. The addition of ßB restored BM cellularity and reduced HPC mobilization. Three h following HS and LC/HS, plasma G-CSF levels more than double, however LC alone showed no change in G-CSF. ßB significantly decreased G-CSF in both HS and LC/HS. Similarly, MMP-9 is elevated following LC/HS, and ßB prevents this elevation (390 ± 100 pg/mL versus 275 ± 80 pg/mL). CONCLUSION: ßB protection of the BM following shock and injury may be due to reduced HPC mobilization and maintenance of BM cellularity. Following shock, there is an increase in plasma G-CSF and MMP-9, which is abrogated by ßB and suggests a possible mechanism how ßB decreases HPC mobilization thus preserving BM cellularity. In contrast, ßB protection of BM following LC is not mediated by G-CSF. Therefore, the mechanism of progenitor cell mobilization from the BM is dependent on the type of injury.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Anemia/tratamento farmacológico , Medula Óssea/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/fisiologia , Propranolol/farmacologia , Ferimentos e Lesões/complicações , Anemia/etiologia , Animais , Medula Óssea/fisiologia , Catecolaminas/metabolismo , Contusões/complicações , Fator Estimulador de Colônias de Granulócitos/sangue , Mobilização de Células-Tronco Hematopoéticas , Masculino , Metaloproteinase 9 da Matriz/sangue , Ratos , Ratos Sprague-Dawley , Choque Hemorrágico/complicações
7.
J Trauma ; 70(5): 1043-9; discussion 1049-50, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21610422

RESUMO

BACKGROUND: Trauma-induced hypercatecholaminemia negatively impacts bone marrow (BM) function by suppressing BM hematopoietic progenitor cell (HPC) growth and increasing HPC egress to injured tissue. Beta blockade (BB) given before tissue injury alone has been shown to reduce both HPC mobilization and restore HPC colony growth within the BM. In a clinically relevant model, this study examines the effect of BB given after both tissue injury and hemorrhagic shock (HS). METHODS: Male Sprague-Dawley rats underwent lung contusion (LC) with a blast wave percussion. HS was achieved after LC by maintaining the mean arterial blood pressure 30 mm Hg to 35 mm Hg for 45 minutes. Propranolol (10 mg/kg) was given once the mean arterial blood pressure>80 mm Hg and subsequent doses were given daily (LC/HS/BB). One-day and 7-day postinjury, analysis of BM and lung tissue for the growth of HPCs, hematologic parameters, and histology of lung injury were performed. RESULTS: LC/HS significantly worsens BM CFU-E growth suppression (15±8 vs. 35±2) and increases CFU-E growth in injured tissue when compared with LC at 1 day and 7 days (33±5 vs. 22±9). The use of BB after LC/HS ameliorated BM suppression, the degree of anemia and HPC growth in the injured lung at 1 day and 7 days postinjury. Lung injury score shows that there was no worsening of lung healing with BB (LC/HS/BB 3.2±2 vs. LC/HS 3.8±0.8). CONCLUSION: In an injury and shock model, administration of propranolol immediately after resuscitation significantly reduced BM suppression, and the protective effect is maintained at 7 days with daily BB. Although BB appears to improve BM function by decreasing HPC mobilization to injured tissue, there was no worsening of lung healing. Therefore, the use of propranolol after trauma and resuscitation may minimize long-term BM suppression after injury with no adverse impact on healing.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Doenças da Medula Óssea/metabolismo , Medula Óssea/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Lesão Pulmonar/complicações , Choque Hemorrágico/metabolismo , Animais , Medula Óssea/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células-Tronco Hematopoéticas/metabolismo , Lesão Pulmonar/metabolismo , Lesão Pulmonar/fisiopatologia , Masculino , Propranolol/uso terapêutico , Ratos , Ratos Sprague-Dawley , Choque Hemorrágico/etiologia , Choque Hemorrágico/fisiopatologia , Ferimentos não Penetrantes/metabolismo
9.
Radiother Oncol ; 144: 101-104, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31786421

RESUMO

Durvalumab after concurrent chemoradiation has significantly improved survival in stage III non-small cell lung cancer (NSCLC). However, there is limited data evaluating the utilization and challenges to deliver durvalumab consolidation in the real world. We assessed the use of consolidative durvalumab at a large academic center to examine clinical limitations to delivery of this practice-changing regimen. We found that despite incorporating consolidative durvalumab into standard practice for stage III unresectable NSCLC, 27% patients did not initiate this treatment, largely due to disease progression or toxicity from chemoradiation.


Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias
10.
Cancer Med ; 9(13): 4622-4631, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32372571

RESUMO

INTRODUCTION: Durvalumab after concurrent chemoradiation (cCRT) is now standard of care for unresected stage III non-small cell lung cancer (NSCLC). However, there is limited data on radiation pneumonitis (RP) with this regimen. Therefore, we assessed RP and evaluated previously validated toxicity models in predicting for RP in patients treated with cCRT and durvalumab. METHODS: Patients treated with cCRT and ≥ 1 dose of durvalumab were evaluated to identify cases of ≥ grade 2 RP. The validity of previously published RP models was assessed in this cohort as well a reference cohort treated with cCRT alone. The timing and incidence of RP was compared between cohorts. RESULTS: In total, 11 (18%) of the 62 patients who received cCRT and durvalumab developed ≥ grade 2 RP a median of 3.4 months after cCRT. The onset of RP among patients treated with cCRT and durvalumab was significantly longer vs the reference cohort (3.4 vs 2.1 months; P = .01). Numerically more patients treated with cCRT and durvalumab developed RP than patients in the reference cohort (18% vs 9%, P = .09). Among patients treated with cCRT and durvalumab, 82% (n = 9) were responsive to treatment with high-dose glucocorticoids. Previously published RP models widely underestimated the rate of RP in patients treated with cCRT and durvalumab [AUC ~ 0.50; p(Hosmer-Lemeshow): 0.98-1.00]. CONCLUSIONS: Our data suggest a delayed onset of RP in patients treated with cCRT and durvalumab vs cCRT alone, and for RP to develop in a greater number of patients treated with cCRT and durvalumab. Previously published RP models significantly underestimate the rate of symptomatic RP among patients treated with cCRT and durvalumab.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia/efeitos adversos , Neoplasias Pulmonares/terapia , Pneumonite por Radiação/etiologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Quimiorradioterapia/métodos , Estudos de Coortes , Feminino , Glucocorticoides/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonite por Radiação/tratamento farmacológico , Pneumonite por Radiação/patologia
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