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OBJECTIVES: This study evaluates the prognostic impact of the new grading system for lung adenocarcinoma, stratified by lymphadenectomy extent. MATERIALS AND METHODS: We analyzed 1258 lung adenocarcinoma patients who underwent curative resections between 2006 and 2017. We analyzed overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) across tumor grades and lymphadenectomy extent, categorized as IASLC-R0 (complete resection) or R(un) (uncertain resection). RESULTS: The median age of cohort was 63 and 41.9 % were male. The majority had undergone lobectomy. The distribution of tumors was 274 grade 1, 558 grade 2, and 426 grade 3 cases. After a median follow-up time of 102 months, the 10-year OS/CSS/RFS rates worsened significantly across grade 1-3: 92.4/99.3/92.3 %, 77.8/87.5/71.7 %, and 63.6/70.2/52.0 %, respectively (p < 0.001). Multivariate Cox regression analysis identified grade 3, R(un) lymphadenectomy, higher Charlson Comorbidity Index, smoking history, thoracotomy, higher pathology stage, and angiolymphatic invasion as independent prognostic factors for lower OS, CSS, and RFS. Furthermore, grade 3 patients benefited significantly from IASLC-R0 lymphadenectomy, showing significantly better OS and RFS than those who underwent R(un) lymphadenectomy (p = 0.007 for OS, p = 0.001 for RFS, post-propensity score matching). Among grade 3 tumors underwent R0 or R(un) resections found the incidence rates of local, distant, and simultaneous local and distant recurrence were 8.5 % vs 13.7 %, 11.0 % vs 12.2 %, and 11.0 % vs 20.6 %, respectively. CONCLUSION: Surgical outcomes for lung adenocarcinoma have declined across grades 1-3. IASLC-R(un) treatment worsens OS and RFS in grade 3. Intensive monitoring and adjuvant therapy should be considered when patients with grade 3 lung adenocarcinoma undergo R(un) lymphadenectomy.
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Here, we report the first cytology findings of the newly characterized entity, palisading adenocarcinoma of the salivary gland, diagnosed in the sublingual gland of a 61-year-old female. The liquid-based cytology showed a moderately cellular aspirate containing three-dimensional clusters and trabeculae of tumor cells of various sizes. The cells had dark ovoid nuclei, finely granular chromatin, inconspicuous to punctate nucleoli, and ample cyanophilic cytoplasm with indistinct cell borders. In conventional smears, the cells displayed frequent crush artifacts and anisonucleosis resembling endocrine-type atypia. The background was clean, devoid of secretions, and contained singly dispersed tumor cells with stripped nuclei. Interestingly, concentrically laminated globules of extracellular matrix surrounded by the tumor cells were identified. Mitotic figures and tumor necrotic debris were absent. The cytologic findings correlated with the histologic findings of the excision specimen. The cytologic differential diagnosis and tumor grading of palisading adenocarcinoma were briefly discussed.
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Multifocal papillary thyroid carcinomas (PTCs) are common and the majority of the tumors harbor mutual BRAF p.V600E mutation. This study aimed to investigate a contemporary series of multifocal PTCs with discordant molecular drivers. Consecutive thyroidectomies diagnosed with multifocal PTCs ≥0.5 cm between 2019 and 2023 were reviewed. Immunohistochemistry (IHC) for BRAF VE1 was performed for all tumors. Cases with discordant BRAF IHC results or morphologic discrepancy were identified, and BRAF IHC-negative tumors were subjected to RAS Q61R IHC and/or targeted RNA next-generation sequencing. A total of 770 patients with a main PTC ≥0.5 cm were identified; 255 (33.1%) had multifocal disease, and 142 (18.4%) had at least another PTC ≥0.5 cm. Among them, 13 cases (9.2%, 13/142) had discordant molecular drivers. Twelve cases had one or more BRAF-positive PTCs accompanied by a BRAF-negative PTC (3 with CCDC6::RET fusion, 1 with NCOA4::RET fusion, 1 with ACBD5::RET fusion, 2 with ETV6::NTRK3 fusion, 1 with TG::FGFR1 fusion, 1 with LMTK2::BRAF fusion, 1 with AGK::BRAF fusion and RAS p.Q61R mutation, 1 with RAS p.Q61R mutation, and 1 without detectable molecular drivers). The last case had tumors with discordant fusion drivers (VIM::NTRK3 and TNS1::BRAF). Most cases showed tumors that were morphologically distinct (92.3%, 12/13) and occurred in the contralateral lobes (76.9%, 10/13). Notably, we identified 4 cases (30.8%) that presented as collision tumors and 6 cases (46.2%) that showed lymph node metastases, including 2 with simultaneous involvement by tumors with discordant molecular drivers, as novel findings. In summary, a subset (9.2%) of multifocal PTCs had discordant molecular drivers and 84.6% of them were a combination of BRAF-positive and kinase gene fusion-associated PTCs, most with distinct morphologies. Almost half of the cases had nodal metastasis and a third of them showed simultaneous involvement by tumors with discordant molecular drivers. The results highlight the clinical importance of identifying such cases, given the potentially different treatments.
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BACKGROUND: Interstitial lung disease (ILD) treatment is a critical unmet need. Selenium is an essential trace element for human life and an antioxidant that activates glutathione, but the gap between its necessity and its toxicity is small and requires special attention. Whether selenium can be used in the treatment of ILD remains unclear. METHODS: We investigated the prophylactic and therapeutic effects of selenite, a selenium derivative, in ILD using a murine model of bleomycin-induced idiopathic pulmonary fibrosis (IPF). We further elucidated the underlying mechanism using in vitro cell models and examined their relevance in human tissue specimens. The therapeutic effect of selenite in bleomycin-administered mice was assessed by respiratory function and histochemical changes. Selenite-induced apoptosis and reactive oxygen species (ROS) production in murine lung fibroblasts were measured. RESULTS: Selenite, administered 1 day (inflammation phase) or 8 days (fibrotic phase) after bleomycin, prevented and treated deterioration of lung function and pulmonary fibrosis in mice. Mechanistically, selenite inhibited the proliferation and induced apoptosis of murine lung fibroblasts after bleomycin treatment both in vitro and in vivo. In addition, selenite upregulated glutathione reductase (GR) and thioredoxin reductase (TrxR) in murine lung fibroblasts, but not in lung epithelial cells, upon bleomycin treatment. GR and TrxR inhibition eliminates the therapeutic effects of selenite. Furthermore, we found that GR and TrxR were upregulated in the human lung fibroblasts of IPF patient samples. CONCLUSIONS: Selenite induces ROS production and apoptosis in murine lung fibroblasts through GR and TrxR upregulation, thereby providing a therapeutic effect in bleomycin-induced IPF.
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Apoptose , Bleomicina , Fibroblastos , Espécies Reativas de Oxigênio , Ácido Selenioso , Bleomicina/efeitos adversos , Animais , Camundongos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Ácido Selenioso/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Modelos Animais de Doenças , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Masculino , Proliferação de Células/efeitos dos fármacosRESUMO
Determining the exact type of epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutation in lung cancer has become important. We found that not all ex20ins mutations reported by cobas EGFR test v2 could be validated by Sanger sequencing even using surgical specimens with high tumor contents. This study aimed to validate the ex20ins results reported by the cobas test and to determine whether there were clinicopathological factors associated with aberrant cobas ex20ins report. In total, 123 cobas-reported cases with ex20ins were retrospectively collected and validated by Sanger sequencing and Idylla assay. Clinicopathological features between ex20ins cobas+/Sanger+ group (n = 71) and cobas+/Sanger- group (n = 52) were compared. The Idylla assay detected ex20ins in 82.6% of cobas+/Sanger+ cases but only in 4.9% of cobas+/Sanger- cases. The cobas+/Sanger- group was significantly associated with higher tumor contents, poorly differentiated patterns, tumor necrosis, and a lower internal control cycle threshold value reported by the Idylla which suggesting the presence of increased EGFR gene copy numbers. EGFR fluorescence in situ hybridization (FISH) revealed the majority of cobas+/Sanger- group had EGFR high copy number gain (16%) or amplification (76%) according to the Colorado criteria. Among cases reported to have concomitant classic EGFR and ex20ins mutations by the cobas, the classic EGFR mutations were all detected by Sanger sequencing and Idylla, while the ex20ins mutations were undetected by Sanger sequencing (0%) or rarely reported by Idylla assay (3%). FISH revealed high EGFR copy number gain (17.9%) and amplification (79.5%) in cases reported having concomitant classic EGFR and ex20ins mutations by the cobas. This study demonstrated an unusually high frequency of EGFR amplification in cases with aberrant cobas ex20ins report which could not be validated by Sanger sequencing or Idylla assay. Ex20ins reported by the cobas test should be validated using other methods especially those reported having concomitant ex20ins and classic EGFR mutations.
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Receptores ErbB , Éxons , Neoplasias Pulmonares , Humanos , Receptores ErbB/genética , Masculino , Feminino , Pessoa de Meia-Idade , Éxons/genética , Idoso , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnóstico , Estudos Retrospectivos , Mutagênese Insercional , Amplificação de Genes , Adulto , Mutação , Idoso de 80 Anos ou mais , Análise Mutacional de DNA/métodosRESUMO
BACKGROUND: Real-world vaccine effectiveness following the third dose of vaccination against SARS-CoV-2 remains less investigated among people with HIV (PWH). METHODS: PWH receiving the third dose of BNT162b2 and mRNA-1273 (either 50- or 100-µg) were enrolled. Participants were followed for 180 days until the fourth dose of COVID-19 vaccination, SARS-CoV-2 infection, seroconversion of anti-nucleocapsid IgG, death, or loss to follow-up. Anti-spike IgG was determined every 1-3 months. RESULTS: Of 1427 participants undergoing the third-dose COVID-19 vaccination, 632 (44.3%) received 100-µg mRNA-1273, 467 (32.8%) 50-µg mRNA-1273, and 328 (23.0%) BNT162b2 vaccine and the respective rate of SARS-CoV-2 infection or seroconversion of anti-nucleocapsid IgG was 246.1, 280.8 and 245.2 per 1000 person-months of follow-up (log-rank test, p = 0.28). Factors associated with achieving anti-S IgG titers >1047 BAU/mL included CD4 count <200 cells/mm3 (adjusted odds ratio [aOR], 0.11; 95% CI, 0.04-0.31), plasma HIV RNA >200 copies/mL (aOR, 0.27; 95% CI, 0.09-0.80), having achieved anti-spike IgG >141 BAU/mL within 3 months after primary vaccination (aOR, 3.69; 95% CI, 2.68-5.07), receiving BNT162b2 vaccine as the third dose (aOR, 0.20; 95% CI, 0.10-0.41; reference, 100-µg mRNA-1273), and having previously received two doses of mRNA vaccine in primary vaccination (aOR, 2.46; 95% CI, 1,75-3.45; reference, no exposure to mRNA vaccine). CONCLUSIONS: PWH receiving different types of the third dose of COVID-19 vaccine showed similar vaccine effectiveness against SARS-CoV-2 infection. An additional dose with 100-µg mRNA-1273 could generate a higher antibody response than with 50-µg mRNA-1273 and BNT162b2 vaccine.
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Vacina de mRNA-1273 contra 2019-nCoV , Anticorpos Antivirais , Vacina BNT162 , Vacinas contra COVID-19 , COVID-19 , Infecções por HIV , Imunoglobulina G , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , Masculino , Feminino , COVID-19/prevenção & controle , COVID-19/imunologia , Anticorpos Antivirais/sangue , Pessoa de Meia-Idade , Infecções por HIV/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacina BNT162/administração & dosagem , Vacina BNT162/imunologia , SARS-CoV-2/imunologia , Imunoglobulina G/sangue , Adulto , Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Vacina de mRNA-1273 contra 2019-nCoV/administração & dosagem , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Vacinação/métodos , Eficácia de Vacinas , SoroconversãoRESUMO
BACKGROUND: The RECOVERY trial demonstrated that the use of dexamethasone is associated with a 36% lower 28-day mortality in hospitalized patients with COVID-19 on invasive mechanical ventilation. Nevertheless, the optimal timing to start dexamethasone remains uncertain. METHODS: We conducted a quasi-experimental study at National Taiwan University Hospital (Taipei, Taiwan) using propensity score matching to simulate a randomized controlled trial to receive or not to receive early dexamethasone (6 mg/day) during the first 7 days following the onset of symptoms. Treatment was standard protocol-based, except for the timing to start dexamethasone, which was left to physicians' decision. The primary outcome is 28-day mortality. Secondary outcomes include secondary infection within 60 days and fulfilling the criteria of de-isolation within 20 days. RESULTS: A total of 377 patients with COVID-19 were enrolled. Early dexamethasone did not decrease 28-day mortality in all patients (adjusted odds ratio [aOR], 1.03; 95% confidence interval [CI], 0.97-1.10) or in patients who required O2 for severe/critical disease at admission (aOR, 1.05; 95%CI, 0.94-1.18); but is associated with a 24% increase in superinfection in all patients (aOR, 1.24; 95% CI, 1.12-1.37) and a 23% increase in superinfection in patients of O2 for several/critical disease at admission (aOR, 1.23; 95% CI, 1.02-1.47). Moreover, early dexamethasone is associated with a 42% increase in likelihood of delayed clearance of SARS-CoV-2 virus (adjusted hazard ratio, 1.42; 95% CI, 1.01-1.98). CONCLUSION: An early start of dexamethasone (within 7 days after the onset of symptoms) could be harmful to hospitalized patients with COVID-19.
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Tratamento Farmacológico da COVID-19 , COVID-19 , Dexametasona , Pontuação de Propensão , SARS-CoV-2 , Humanos , Dexametasona/uso terapêutico , Dexametasona/administração & dosagem , Masculino , Feminino , COVID-19/mortalidade , Pessoa de Meia-Idade , Taiwan/epidemiologia , Idoso , SARS-CoV-2/efeitos dos fármacos , Resultado do Tratamento , Respiração Artificial/estatística & dados numéricos , Idoso de 80 Anos ou mais , Hospitalização/estatística & dados numéricos , AdultoRESUMO
OBJECTIVES: Molecular subtyping of small cell lung cancer (SCLC) tumors based on the expression of four transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) using immunohistochemical (IHC) staining has recently emerged as a proposed approach. This study was aimed to examine this subtyping method in Asian patients with SCLC and investigate its correlation with treatment efficacy. MATERIALS AND METHODS: Seventy-two tumor samples from patients with SCLC, including de novo cases and those transformed from EGFR-mutant tumors, were analyzed. IHC staining was used to measure the expression of the four transcription factors and conventional SCLC markers. Subtypes were defined based on relative expression levels. The treatment response and outcome of patients receiving immune checkpoint inhibitors and chemotherapy were also reviewed. RESULTS: ASCL1 was the most common subtype, observed in 55.2 % of the samples, followed by NEUROD1 (26.9 %) and POU2F3 (9 %). No tumor exhibited predominant YAP1 positivity, while 41.8 % of the samples demonstrated positivity for two subtype markers. Approximately 50 % of the patients experienced a subtype switch after disease progression. Patients with the ASCL1/NEUROD1 (SCLC-A/N) subtype had similar progression-free survival (PFS) compared to non-SCLC-A/N patients after treatment with immune checkpoint inhibitors plus chemotherapy. Transformed SCLC patients had significantly worse PFS than de novo SCLC patients after chemoimmunotherapy. (2.1 vs. 5.4 months, P = 0.023) CONCLUSIONS: This study revealed the challenges associated with using IHC alone for molecular subtyping, highlighting the frequent co-expression of subtypes and temporal changes following treatment. Further research is warranted to explore the prognostic and therapeutic implications of IHC subtyping in patients with SCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fatores de Transcrição/metabolismoRESUMO
Introduction: Cohen's kappa is often used to quantify the agreement between two pathologists. Nevertheless, a high prevalence of the feature of interest can lead to seemingly paradoxical results, such as low Cohen's kappa values despite high "observed agreement." Here, we investigate Cohen's kappa using data from histologic subtyping assessment of lung adenocarcinomas and introduce alternative measures that can overcome this "kappa paradox." Methods: A total of 50 frozen sections from stage I lung adenocarcinomas less than or equal to 3 cm in size were independently reviewed by two pathologists to determine the absence or presence of five histologic patterns (lepidic, papillary, acinar, micropapillary, solid). For each pattern, observed agreement (proportion of cases with concordant "absent" or "present" ratings) and Cohen's kappa were calculated, along with Gwet's AC1. Results: The prevalence of any amount of the histologic patterns ranged from 42% (solid) to 97% (acinar). On the basis of Cohen's kappa, there was substantial agreement for four of the five patterns (lepidic, 0.65; papillary, 0.67; micropapillary, 0.64; solid, 0.61). Acinar had the lowest Cohen's kappa (0.43, moderate agreement), despite having the highest observed agreement (88%). In contrast, Gwet's AC1 values were close to or higher than Cohen's kappa across patterns (lepidic, 0.64; papillary, 0.69; micropapillary, 0.71; solid, 0.73; acinar, 0.85). The proportion of positive versus negative agreement was 93% versus 50% for acinar. Conclusions: Given the dependence of Cohen's kappa on feature prevalence, interrater agreement studies should include complementary indices such as Gwet's AC1 and proportions of specific agreement, especially in settings with a high prevalence of the feature of interest.
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Sclerosing pneumocytoma is a rare and distinct lung neoplasm whose histogenesis and molecular alterations are the subject of ongoing research. Our recent study revealed that AKT1 internal tandem duplications (ITD), point mutations, and short indels were present in almost all tested sclerosing pneumocytomas, suggesting that AKT1 mutations are a major driving oncogenic event in this tumor. Although the pathogenic role of AKT1 point mutations is well established, the significance of AKT1 ITD in oncogenesis remains largely unexplored. We conducted comprehensive genomic and transcriptomic analyses of sclerosing pneumocytoma to address this knowledge gap. RNA-sequencing data from 23 tumors and whole-exome sequencing data from 44 tumors were used to obtain insights into their genetic and transcriptomic profiles. Our analysis revealed a high degree of genetic and transcriptomic similarity between tumors carrying AKT1 ITD and those with AKT1 point mutations. Mutational signature analysis revealed COSMIC signatures 1 and 5 as the prevailing signatures of sclerosing pneumocytoma, associated with the spontaneous deamination of 5-methylcytosine and an unknown etiology, respectively. RNA-sequencing data analysis revealed that the sclerosing pneumocytoma gene expression profile is characterized by activation of the PI3K/AKT/mTOR pathway, which exhibits significant similarity between tumors harboring AKT1 ITD and those with AKT1 point mutations. Notably, an upregulation of SOX9, a transcription factor known for its involvement in fetal lung development, was observed in sclerosing pneumocytoma. Specifically, SOX9 expression was prominent in the round cell component, whereas it was relatively lower in the surface cell component of the tumor. To the best of our knowledge, this is the first comprehensive investigation of the genomic and transcriptomic characteristics of sclerosing pneumocytoma. Results of the present study provide insights into the molecular attributes of sclerosing pneumocytoma and a basis for future studies of this enigmatic tumor.
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Fosfatidilinositol 3-Quinases , Hemangioma Esclerosante Pulmonar , Humanos , Fosfatidilinositol 3-Quinases/genética , Hemangioma Esclerosante Pulmonar/genética , Hemangioma Esclerosante Pulmonar/patologia , Genômica , Perfilação da Expressão Gênica , RNARESUMO
BACKGROUND: The standard treatment for pathological N2 (pN2) non-small-cell lung cancer (NSCLC) patients is definitive chemoradiation. Surgery might be beneficial for resectable pN2 disease, so we investigated the recurrence-free interval of upfront surgery for selected patients with resectable pN2 disease. METHODS: The clinicopathologic characteristics of patients with pN2 NSCLC who underwent upfront anatomical resection at Taipei Veterans General Hospital from 2011 January to 2019 December were retrospectively reviewed. A Cox regression model was used to identify prognostic factors of recurrence-free survival (RFS). RESULTS: In total, 84 patients after curative lung anatomic resection were analyzed, with a 44-month median survival. The 1-, 3-, and 5-year RFS rates were 63.1%, 31.3%, and 19.9%, respectively, with a median RFS of 18.9 months. Multivariable cox regression analysis identified that the significant predictor for RFS was a tumor size of more than 3 cm (hazard ratio [HR] = 1.74, 95% CI, 1.07-2.83, p = 0.027). Visceral pleural invasion, LN harvest number, tumor stage, and N2 status including single zone (N2a) or multiple zones (N2b) were not prognostic factors in this study. CONCLUSION: Upfront surgery for resectable N2 disease achieved favorable outcomes in selected patients, especially better recurrence control with limited tumor size. Therapeutic advances might encourage surgeons to aggressive intervention.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Prognóstico , Estudos Retrospectivos , Estadiamento de Neoplasias , PneumonectomiaRESUMO
PURPOSE: Epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) are associated with poor prognosis and resistance to traditional therapies in patients with non-small cell lung cancer (NSCLC). We aimed to elucidate the characteristics and treatment patterns to improve outcomes among this population in Taiwan. METHODS: Patients with advanced or recurrent NSCLC harboring EGFR ex20ins from 2011 to 2021 were reviewed. The treatment groups were classified as platinum-based chemotherapy (PtC), EGFR tyrosine kinase inhibitor (TKI), and others. The response to therapy, objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and factors associated with survival were analyzed. RESULTS: Among the 71 patients, most were never-smoking males with stage IVB adenocarcinoma. The most common first-line (1L) regimen was PtC, followed by TKI. The most common second-line (2L) regimen was TKI. The median PFS of 1L treatment was 5.03 months, and the median OS was 18.43 months. Compared with that of TKI, 1L PtC use was associated with a higher ORR (26.3% vs. 9.1%) and DCR (60.5% vs. 18.2%) and a longer PFS (5.37 vs. 3.13 months, p = 0.044). PFS was also significantly longer in the 2L PtC group than in the 2L TKI group (4.73 vs. 2.25 months, p = 0.047). No patients receiving an immune checkpoint inhibitor-based regimen exhibited a therapeutic response. CONCLUSION: This study demonstrated the heterogeneous clinical characteristics and treatment pattern of NSCLC patients with EGFR ex20ins, underscoring the need for more effective therapies for this distinct molecular subtype.
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Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Humanos , Masculino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Éxons/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Platina/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Estudos RetrospectivosRESUMO
BACKGROUND: Cell-free tumor DNA (ctDNA) obtained through liquid biopsy is useful for the molecular analysis of advanced non-small-cell lung cancer (NSCLC). Few studies have directly compared analysis platforms in terms of their diagnostic performance in analyzing ctDNA obtained from the cerebrospinal fluid (CSF) of patients with leptomeningeal metastasis (LM). METHODS: We prospectively analyzed patients with epidermal growth factor receptor (EGFR)-mutant NSCLC who were subjected to CSF analysis for suspected LM. To detect EGFR mutations, CSF ctDNA was analyzed using the cobas EGFR Mutation Test and droplet digital polymerase chain reaction (ddPCR). CSF samples from osimertinib-refractory patients with LM were also subjected to next-generation sequencing (NGS). RESULTS: Significantly higher rates of valid results (95.1% vs. 78%, respectively, p = 0.04) and EGFR common mutation detection (94.3% vs. 77.1%, respectively, p = 0.047) were obtained through ddPCR than through the cobas EGFR Mutation Test. The sensitivities of ddPCR and cobas were 94.3% and 75.6%, respectively. The concordance rate for EGFR mutation detection through ddPCR and the cobas EGFR Mutation Test was 75.6% and that for EGFR mutation detection in CSF and plasma ctDNA was 28.1%. In osimertinib-resistant CSF samples, all original EGFR mutations were detected through NGS. MET amplification and CCDC6-RET fusion were demonstrated in one patient each (9.1%). CONCLUSIONS: The cobas EGFR Mutation Test, ddPCR, and NGS appear to be feasible methods for analyzing CSF ctDNA in patients with NSCLC and LM. In addition, NGS may provide comprehensive information regarding the mechanisms underlying osimertinib resistance.
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Carcinoma Pulmonar de Células não Pequenas , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias Pulmonares , Carcinomatose Meníngea , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Ácidos Nucleicos Livres/genética , Mutação , DNA Tumoral Circulante/genética , Receptores ErbB/genética , Carcinomatose Meníngea/tratamento farmacológico , Carcinomatose Meníngea/genéticaRESUMO
Immunotherapy in combination with chemotherapy is the current treatment of choice for frontline programmed cell death ligand 1 (PD-L1)-positive gastric cancer. However, the best treatment strategy remains an unmet medical need for elderly or fragile patients with gastric cancer. Previous studies have revealed that PD-L1 expression, Epstein-Barr virus association, and microsatellite instability-high (MSI-H) are the potential predictive biomarkers for immunotherapy use in gastric cancer. In this study, we showed that PD-L1 expression, tumor mutation burden, and the proportion of MSI-H were significantly elevated in elderly patients with gastric cancer who were older than 70 years compared with patients younger than 70 years from analysis of The Cancer Genome Atlas gastric adenocarcinoma cohort [≥70/<70: MSI-H: 26.8%/15.0%, P =0.003; tumor mutation burden: 6.7/5.1 Mut/Mb, P =0.0004; PD-L1 mRNA: 5.6/3.9 counts per million mapped reads, P =0.005]. In our real-world study, 416 gastric cancer patients were analyzed and showed similar results (≥70/<70: MSI-H: 12.5%/6.6%, P =0.041; combined positive score ≥1: 38.1%/21.5%, P <0.001). We also evaluated 16 elderly patients with gastric cancer treated with immunotherapy and revealed an objective response of 43.8%, a median overall survival of 14.8 months, and a median progression-free survival of 7.0 months. Our research showed that a durable clinical response could be expected when treating elderly patients with gastric cancer with immunotherapy, and this approach is worth further study.
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Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Humanos , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Herpesvirus Humano 4 , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Instabilidade de Microssatélites , Biomarcadores Tumorais/genéticaRESUMO
Micronodular thymoma with lymphoid stroma is a rare thymic neoplasm characterized by discrete nodules of epithelial tumor cells separated by abundant lymphoid stroma. The genetic features of micronodular thymoma with lymphoid stroma remain largely unexplored. Owing to the interference of abundant intratumoral, nonneoplastic lymphoid cells, a highly sensitive approach is necessary to study genetic changes in these tumors. In this study, we used a highly sensitive next-generation sequencing assay using the molecular barcoding Ion AmpliSeq HD technology to study the most commonly mutated genes in thymomas, including GTF2I, HRAS, NRAS, KRAS, and TP53. A total of 12 cases of micronodular thymomas with lymphoid stroma were tested, and 2 cases also had areas of type A thymoma in their tumor bed. Two micronodular thymic carcinomas with lymphoid stroma, a histological mimic of micronodular thymoma, were also included for comparison. Recurrent p.L424H mutations in GTF2I were found in all the cases of micronodular thymoma with lymphoid stroma but not in the cases of micronodular thymic carcinomas. In addition, 3 cases of micronodular thymoma with lymphoid stroma also had concomitant HRAS and/or KRAS mutations. Our study showed that p.L424H mutations in GTF2I is a constant genetic feature of micronodular thymoma with lymphoid stroma. This finding strongly suggests that micronodular thymoma with lymphoid stroma is closely related to type A and AB thymomas because they all share p.L424H mutations in GTF2I.
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Timoma , Neoplasias do Timo , Fatores de Transcrição TFIII , Fatores de Transcrição TFII , Humanos , Timoma/genética , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias do Timo/genética , Mutação , Fatores de Transcrição TFII/genéticaRESUMO
BACKGROUND: Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study was to investigate the potential roles of DUSPs in ankylosing spondylitis (AS). METHODS: Sixty AS patients and 45 healthy controls were enrolled in this study. Associations of gene expression of 23 DUSPs in peripheral T cells with inflammatory cytokine gene expression and disease activity of AS were analyzed. Finally, we investigated whether the characteristics of AS are developed in DUSP-knockout mice. RESULTS: The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in peripheral T cells were significantly higher in AS group than those of healthy controls (all p < 0.05), while DUSP22 (also named JKAP) mRNA levels were significantly lower in AS group than healthy controls (p < 0.001). The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in T cells were positively correlated with mRNA levels of tumor necrosis factor-α (TNF-α), whereas DUSP22 was inversely correlated (all p < 0.05). In addition, inverse correlations of DUSP22 gene expression in peripheral T cells with C-reactive protein, erythrocyte sedimentation rate, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were observed (all p < 0.05). More importantly, aged DUSP22 knockout mice spontaneously developed syndesmophyte formation, which was accompanied by an increase of TNF-α+, interleukin-17A+, and interferon-γ+ CD3+ T cells. CONCLUSIONS: DUSP22 may play a crucial role in the pathogenesis and regulation of disease activity of AS.
Assuntos
Espondilite Anquilosante , Linfócitos T , Animais , Camundongos , Fosfatases de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/metabolismo , Camundongos Knockout , RNA Mensageiro , Espondilite Anquilosante/genética , Fator de Necrose Tumoral alfaRESUMO
The distinction between different separate primary lung cancers (SPLCs) and intrapulmonary metastases (IPMs) is a challenging but clinically significant issue. Histopathology-based classification is the current practice; however, it is subjective and affected by interobserver variability. Recently, next-generation sequencing (NGS) panels have been used in lung cancer diagnostics. This study aimed to investigate the value of large-scale NGS panels for distinguishing between SPLCs and IPMs. A total of 32 patients with 69 lung adenocarcinomas were included. Comprehensive histopathologic assessments of multiple pulmonary adenocarcinomas were performed independently by 3 pathologists. The consensus of histopathologic classification was determined by a majority vote. Genomic analysis was performed using an amplicon-based large-scale NGS panel, targeting single-nucleotide variants and short insertions and deletions in 409 genes. Tumor pairs were classified as SPLCs or IPMs according to a predefined molecular classification algorithm. Using NGS and our molecular classification algorithm, 97.6% of the tumor pairs can be unambiguously classified as SPLCs or IPMs. The molecular classification was predictive of postoperative clinical outcomes in terms of overall survival (P = .015) and recurrence-free interval (P = .0012). There was a moderate interobserver agreement regarding histopathologic classification (κ = 0.524 at the tumor pair level). The concordance between histopathologic and molecular classification was 100% in cases where pathologists reached a complete agreement but only 53.3% where they did not. This study showed that large-scale NGS panels are a powerful modality that can help distinguish SPLCs from IPMs in patients with multiple lung adenocarcinomas and objectively provide accurate risk stratification.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/genética , Genômica , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Signaling driven by nucleic acid sensors participates in interferonopathy-mediated autoimmune diseases. NLRP12, a pyrin-containing NLR protein, is a negative regulator of innate immune activation and type I interferon (IFN-I) production. Peripheral blood mononuclear cells (PBMCs) derived from systemic lupus erythematosus (SLE) patients expressed lower levels of NLRP12, with an inverse correlation with IFNA expression and high disease activity. NLRP12 expression was transcriptionally suppressed by runt-related transcription factor 1-dependent (RUNX1-dependent) epigenetic regulation under IFN-I treatment, which enhanced a negative feedback loop between low NLRP12 expression and IFN-I production. Reduced NLRP12 protein levels in SLE monocytes was linked to spontaneous activation of innate immune signaling and hyperresponsiveness to nucleic acid stimulations. Pristane-treated Nlrp12-/- mice exhibited augmented inflammation and immune responses; and substantial lymphoid hypertrophy was characterized in NLRP12-deficient lupus-prone mice. NLRP12 deficiency mediated the increase of autoantibody production, intensive glomerular IgG deposition, monocyte recruitment, and the deterioration of kidney function. These were bound in an IFN-I signature-dependent manner in the mouse models. Collectively, we reveal a remarkable link between low NLRP12 expression and lupus progression, which suggests the impact of NLRP12 on homeostasis and immune resilience.