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Small cell lung cancer (SCLC) is the most lethal type of lung cancer. Paradoxically, this tumor displays an initial exquisite response to chemotherapy; however, at relapse, the tumor is highly resistant to subsequent available therapies. Here, we report that the expression of three prime repair exonuclease 1 (TREX1) is strongly induced in chemoresistant SCLCs. ATAC-seq and ChIP-seq revealed a significant increase in chromatin accessibility and transcriptional activity of TREX1 gene locus in chemoresistant SCLC. Analyses of human SCLC tumors and patient-derived xenografts (PDXs) also showed increase in TREX1 expression in post-chemotherapy samples. TREX1 depletion caused the activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway due to cytoplasmic accumulation of damage-associated double-stranded DNA, inducing immunogenicity and enhancing the sensitivity of drug resistant cells to chemotherapy. These findings suggest TREX1 upregulation may partially contribute to the survival of resistant cells, and its inhibition may represent a promising therapeutic strategy to enhance antitumor immunity and potentiate the efficacy of chemotherapy and/or immunotherapy in chemoresistant SCLCs.
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Diffuse mesotheliomas are characterized by recurrent genomic alterations involving tumor suppressors and epigenetic regulators such as BAP1, CDKN2A, MTAP, and NF2. Depending on the differential diagnosis as informed by histologic assessment, one can apply the appropriate immunohistochemical and/or molecular panels to reach the correct pathologic diagnosis, sometimes even in cases with limited tissues. Biomarkers aid in the diagnosis of mesothelioma in the following scenarios: 1) For a tumor that is overtly malignant, how can one distinguish mesothelioma from other tumors? 2) For a mesothelial proliferation, how can one distinguish mesothelioma from a reactive process? To distinguish mesotheliomas from carcinomas, at least two positive and two negative markers are currently recommended. To distinguish sarcomatoid mesothelioma from pleomorphic carcinoma, even more markers-and sometimes molecular testing-are needed. To distinguish mesothelioma from reactive mesothelial conditions, useful immunohistochemical biomarkers include BAP1, MTAP, and merlin, which serve as surrogates for the corresponding gene mutation status. In patients with unusual clinical history, for tumors with a peculiar microscopic appearance, and/or in cases with an equivocal immunophenotypic profile, molecular testing can help to exclude mimics and to confirm the pathologic diagnosis.
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Biomarcadores Tumorais , Mesotelioma , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mesotelioma/diagnóstico , Mesotelioma/genética , Mesotelioma/patologia , Mesotelioma/metabolismo , Diagnóstico Diferencial , Patologia Molecular/métodos , Imuno-Histoquímica , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismoRESUMO
PURPOSE: Histologic transformation to small cell lung cancer (SCLC) is a mechanism of treatment resistance in patients with advanced oncogene-driven lung adenocarcinoma (LUAD) that currently requires histologic review for diagnosis. Herein, we sought to develop an epigenomic cell-free (cf)DNA-based approach to non-invasively detect small cell transformation in patients with EGFR mutant (EGFRm) LUAD. EXPERIMENTAL DESIGN: To characterize the epigenomic landscape of transformed (t)SCLC relative to LUAD and de novo SCLC, we performed chromatin immunoprecipitation sequencing (ChIP-seq) to profile the histone modifications H3K27ac, H3K4me3, and H3K27me3, methylated DNA immunoprecipitation sequencing (MeDIP-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and RNA sequencing on 26 lung cancer patient-derived xenograft (PDX) tumors. We then generated and analyzed H3K27ac ChIP-seq, MeDIP-seq, and whole genome sequencing cfDNA data from 1 ml aliquots of plasma from patients with EGFRm LUAD with or without tSCLC. RESULTS: Analysis of 126 epigenomic libraries from the lung cancer PDXs revealed widespread epigenomic reprogramming between LUAD and tSCLC, with a large number of differential H3K27ac (n=24,424), DNA methylation (n=3,298), and chromatin accessibility (n=16,352) sites between the two histologies. Tumor-informed analysis of each of these three epigenomic features in cfDNA resulted in accurate non-invasive discrimination between patients with EGFRm LUAD versus tSCLC (AUROC=0.82-0.87). A multi-analyte cfDNA-based classifier integrating these three epigenomic features discriminated between EGFRm LUAD versus tSCLC with an AUROC of 0.94. CONCLUSIONS: These data demonstrate the feasibility of detecting small cell transformation in patients with EGFRm LUAD through epigenomic cfDNA profiling of 1 ml of patient plasma.
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The process of acetylation and deacetylation of histones within the nucleus operates within a dynamic equilibrium. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) collaboratively and precisely regulate normal gene transcription and expression. Any disorder in the activity of HATs/HDACs can lead to uncontrolled gene expression, consequently resulting in tumorigenesis. Histone deacetylase inhibitors (HDACIs) have the capacity to block the cell cycle, thereby restraining tumor cell proliferation and tumor growth. Also, HDACIs exhibit a significant capability to diminish the expression of apoptosis protein inhibitors such as Bcl-2 and B-cell lymphoma-extra-large (Bcl-xL), while concurrently up-regulating pro-apoptotic proteins such as Bax, Bad, and Bim. Also, HDACIs demonstrate the ability to inhibit tumor cell angiogenesis. Representing a new category of targeted anti-cancer therapeutics, HDACIs possess the capability to restore the expression of tumor suppressor genes, induce apoptosis, and stimulate cell differentiation. Additionally, they exert anti-cancer effects through diverse pathways both in vivo and in vitro, thereby presenting promising prospects in tumor therapy. This review delves into the involvement of HDACs in cancer pathology and the therapeutic potential of HDACIs as emerging drugs in cancer treatment.
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Inibidores de Histona Desacetilases , Neoplasias , Humanos , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Histona Desacetilases/metabolismo , Apoptose/efeitos dos fármacosRESUMO
Peritoneal inclusion cysts (PICs) are unilocular or multilocular cystic lesions lined by bland mesothelial cells. While most are small and localized, rare examples may be large or multifocal with diffuse peritoneal involvement, causing clinical and even pathologic concern for malignancy. We examined 20 PIC, including 8 large solitary and 12 multifocal lesions. Solitary PIC were found in 7 female and 1 male patients ranging from 19 to 55 (median: 37) years. Expanded collagenous (n=2) or edematous (n=1) areas were occasionally seen in the septae, and 1 had microscopic foci of myxoid stroma. Four had hobnail cells, and 1 had minor areas of papillary mesothelial hyperplasia. Multifocal PICs occurred in 9 female and 3 male patients ranging from 26 to 80 (median: 53) years. Three showed extensive associated fibrosis with entrapment of preexisting adipose tissue, 2 had areas resembling granulation tissue, and 3 had scattered foci of myxoid stroma. Hobnail cells were present in 9, papillary mesothelial hyperplasia in 2, entrapped single cells in 1, and 2 had areas resembling adenomatoid tumors. Two of the multifocal PICs had limited local recurrences at 18 and 21 months. No patients died of disease. Clonal alterations were not identified in any of the tested PICs (mutational and fusion analysis in 5, chromosomal microarray in 1). Despite limited local recurrences, we demonstrate that even large and multifocal PICs may lack identifiable genomic alterations and are associated with benign outcomes.
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Cistos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Cistos/patologia , Cistos/genética , Idoso , Adulto Jovem , Idoso de 80 Anos ou mais , Doenças Peritoneais/patologia , Doenças Peritoneais/genética , Recidiva , Imuno-HistoquímicaRESUMO
PURPOSE: To assess the potential of apparent diffusion coefficient (ADC) values derived from diffusion weighted (DW) MRI preoperatively to predict the predominant histologic component among biphasic pleural mesothelioma (PM) tumors. METHODS: ADC maps were generated from DW MRI scans. Histology and predominant component of biphasic PM were confirmed following surgical resection. Statistical analyses were done with R (R Foundation for Statistical Computing, Vienna, Austria). Average ADC values corresponding to epithelioid- and sarcomatoid-predominant tumors were compared. ADC thresholding was accomplished by recursive partitioning and confirmed with ROC analysis. RESULTS: Eighty-four patients with biphasic PM's, 69 (82 %) epithelioid-predominant (BE) and 15(18 %) sarcomatoid-predominant (BS) tumors were evaluated. Thirty-eight (45 %) patients underwent extrapleural pneumonectomy (EPP), 39 (46 %) had extended pleural decortication (ePDC) and 7 (8 %) had pleural decortication (PDC). ADC values ranged between 0.696 x 10-3 to 1.921 x 10-3 mm2/s. BE tumors demonstrated significantly higher ADC values than BS tumors (p = 0.026). ADC values above 0.94 x 10-3 mm2/s were associated with a significant increase of relative risk of being in group BE over group BS (relative risk: 1.47, 95 %CI: 1.05-2.06, p = 0.027) CONCLUSION: Average ADC values of BE tumors were higher than BS tumors and the two groups can be separated by a cut off value of 0.94 X 10-3 mm2/s.
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Imagem de Difusão por Ressonância Magnética , Mesotelioma , Neoplasias Pleurais , Humanos , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/patologia , Neoplasias Pleurais/cirurgia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Imagem de Difusão por Ressonância Magnética/métodos , Mesotelioma/diagnóstico por imagem , Mesotelioma/patologia , Mesotelioma/cirurgia , Adulto , Diagnóstico Diferencial , Idoso de 80 Anos ou mais , Sensibilidade e Especificidade , Reprodutibilidade dos Testes , Valor Preditivo dos Testes , Mesotelioma Maligno/diagnóstico por imagem , Mesotelioma Maligno/patologiaRESUMO
Myositis ossificans, a benign tumor composed of spindle cells and osteoblasts, can clinically and radiologically mimic osteosarcoma. While recognition and accurate diagnosis of myositis ossificans can be a challenge, this is critical as it may allow a conservative surgical approach to maximize functional outcomes. Herein, we present a patient with surface myositis ossificans confirmed genetically by the presence of COL1A1::USP6 gene fusion, along with a literature review. Due to the enhanced visualization of the bone matrix, computed tomography (CT) imaging may be a superior imaging modality to magnetic resonance (MR) imaging. Staged biopsies with samples obtained from the periphery and center of the lesions may allow pathologists to discern the zonal distribution histologically. Furthermore, immunohistochemistry fluorescence in situ hybridization and molecular testing can aid in the distinction of myositis ossificans from mimics. Because of their resemblance to other bone tumors, these cases of myositis ossificans highlight the importance of a multidisciplinary approach integrating clinical, radiologic, and pathologic analysis and involving serial imaging, sampling, and judicious use of ancillary immunohistochemical and molecular testing.
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Miosite Ossificante , Osteossarcoma , Humanos , Neoplasias Ósseas/patologia , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/diagnóstico por imagem , Colágeno Tipo I/genética , Colágeno Tipo I/análise , Cadeia alfa 1 do Colágeno Tipo I , Diagnóstico Diferencial , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Imageamento por Ressonância Magnética , Miosite Ossificante/diagnóstico , Miosite Ossificante/patologia , Miosite Ossificante/diagnóstico por imagem , Miosite Ossificante/genética , Osteossarcoma/diagnóstico , Osteossarcoma/patologia , Osteossarcoma/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Ubiquitina TiolesteraseRESUMO
CONTEXT.: Mesothelioma is an uncommon tumor that can be difficult to diagnose. OBJECTIVE.: To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma. DATA SOURCES.: Pathologists involved in the International Mesothelioma Interest Group and others with expertise in mesothelioma contributed to this update. Reference material includes peer-reviewed publications and textbooks. CONCLUSIONS.: There was consensus opinion regarding guidelines for (1) histomorphologic diagnosis of mesothelial tumors, including distinction of epithelioid, biphasic, and sarcomatoid mesothelioma; recognition of morphologic variants and patterns; and recognition of common morphologic pitfalls; (2) molecular pathogenesis of mesothelioma; (3) application of immunohistochemical markers to establish mesothelial lineage and distinguish mesothelioma from common morphologic differentials; (4) application of ancillary studies to distinguish benign from malignant mesothelial proliferations, including BAP1 and MTAP immunostains; novel immunomarkers such as Merlin and p53; fluorescence in situ hybridization (FISH) for homozygous deletion of CDKN2A; and novel molecular assays; (5) practical recommendations for routine reporting of mesothelioma, including grading epithelioid mesothelioma and other prognostic parameters; (6) diagnosis of mesothelioma in situ; (7) cytologic diagnosis of mesothelioma, including use of immunostains and molecular assays; and (8) features of nonmalignant peritoneal mesothelial lesions.
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AIM: To evaluate the motion amplitude of lung nodules in different locations during preoperative computed tomography (CT)-guided localization, and the influence of respiratory movement on CT-guided percutaneous lung puncture. MATERIALS AND METHODS: A consecutive cohort of 398 patients (123 men and 275 women with a mean age of 53.9 ± 10.7 years) who underwent preoperative CT-guided lung nodule localization from May 2021 to Apr 2022 were included in this retrospective study. The respiratory movement-related nodule amplitude in the cranial-caudal direction during the CT scan, characteristics of patients, lesions, and procedures were statistically analyzed. Univariate and multivariate logistic regression analyses were used to evaluate the influence of these factors on CT-guided localization. RESULTS: The nodule motion distribution showed a statistically significant correlation within the upper/middle (lingular) and lower lobes (p<0.001). Motion amplitude was an independent risk factor for CT scan times (p=0.011) and procedure duration (p=0.016), but not for the technical failure rates or the incidence of complications. Puncture depth was an independent risk factor for the CT scan times, procedure duration, technical failure rates, and complications (p<0.01). Female, prone, and supine (as opposed to lateral) positions were significant protective factors for pneumothorax, while the supine position was an independent risk factor for parenchymal hemorrhage (p=0.025). CONCLUSION: Respiratory-induced motion amplitude of nodules was greater in the lower lobes, resulting in more CT scan times/radiation dose and longer localization duration, but showed no statistically significant influence on the technical success rates or the incidence of complications during preoperative CT-guided localization.
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Neoplasias Pulmonares , Tomografia Computadorizada por Raios X , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos , Estudos Retrospectivos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Idoso , Nódulo Pulmonar Solitário/diagnóstico por imagem , Nódulo Pulmonar Solitário/cirurgia , Movimento , Cuidados Pré-Operatórios/métodos , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/cirurgia , Radiografia Intervencionista/métodos , RespiraçãoRESUMO
Objective: To examine the burden and trends of acute viral hepatitis in Guangdong Province from 1990 to 2019, and provide reference evidences for hepatitis prevention and control in the province. Methods: Data on acute viral hepatitis (hepatitis A, B, C, and E) in Guangdong from 1990 to 2019 were extracted from the Global Burden of Disease Study 2019 database. The incidence, prevalence, mortality, and disability-adjusted life years (DALY) data were analyzed by age and gender, and the estimated annual percentage change (EAPC) was calculated to describe the changing trends in disease burden. Results: From 1999 to 2019, the standardized incidence, prevalence, mortality, and DALY of acute viral hepatitis in Guangdong were higher than the national averages. In 2019, 51.43% (2 245 087/4 365 221) of acute viral hepatitis cases in Guangdong Province were mainly attributed to hepatitis B, and 77.18% (106/138) of deaths were due to acute hepatitis B. In different age groups, except for acute hepatitis B, which was more common in adults, the incidence rates of other types of viral hepatitis such as hepatitis A, B, and E showed an overall decreasing trend with age. The mortality rates of different types of acute viral hepatitis, except for the <5 age group, increased with age. The overall incidence and mortality rates of acute viral hepatitis were higher in men than in women. Conclusions: The overall burden of acute viral hepatitis in Guangdong declined in 2019, but remained higher than the national level. Further efforts are needed to strengthen hepatitis prevention and screening in different population in Guangdong Province, especially in children and the elderly.
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Hepatite A , Hepatite B , Adulto , Masculino , Criança , Humanos , Feminino , Idoso , Hepatite A/epidemiologia , Efeitos Psicossociais da Doença , Hepatite B/epidemiologia , Incidência , China/epidemiologia , Carga Global da Doença , Anos de Vida Ajustados por Qualidade de VidaRESUMO
Diagnosis of desmoid-type fibromatosis (DF) may be challenging on biopsy due to morphologic overlap with reactive fibrosis (scar) and other uniform spindle cell neoplasms. Evaluation of nuclear ß-catenin, a surrogate of Wnt pathway activation, is often difficult in DF due to weak nuclear expression and high background membranous/cytoplasmic staining. Lymphoid enhancer-factor 1 (LEF1) is a recently characterized effector partner of ß-catenin which activates the transcription of target genes. We investigated the performance of LEF1 and ß-catenin immunohistochemistry in a retrospective series of 156 soft tissue tumors, including 35 DF, 3 superficial fibromatosis, and 121 histologic mimics (19 soft tissue perineurioma, 8 colorectal perineurioma, 4 intraneural perineurioma, 26 scars, 23 nodular fasciitis, 6 low-grade fibromyxoid sarcomas, 6 angioleiomyomas, 5 neurofibromas, 5 dermatofibrosarcoma protuberans, 3 low-grade myofibroblastic sarcomas, 3 synovial sarcomas, 3 inflammatory myofibroblastic tumors, 2 schwannomas, and 1 each of Gardner-associated fibroma, radiation-associated spindle cell sarcoma, sclerotic fibroma, dermatofibroma, and glomus tumor). LEF1 expression was not only seen in 33/35 (94%) of DF but also observed in 19/23 (82%) nodular fasciitis, 7/19 (37%) soft tissue perineurioma, 2/3 (66%) synovial sarcoma, and 6/26 (23%) scar, as well as in 1 radiation-associated spindle cell sarcoma. The sensitivity and specificity of LEF1 IHC for diagnosis of DF were 94% and 70%, respectively. By comparison, ß-catenin offered similar sensitivity, 94%, but 88% specificity. Positivity for LEF1 and ß-catenin in combination showed sensitivity of 89%, lower than the sensitivity of ß-catenin alone (94%); however, the combination of both LEF1 and ß-catenin improved specificity (96%) compared to the specificity of ß-catenin alone (88%). Although LEF1 has imperfect specificity in isolation, this stain has diagnostic utility when used in combination with ß-catenin.
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Biomarcadores Tumorais , Fibromatose Agressiva , Imuno-Histoquímica , Fator 1 de Ligação ao Facilitador Linfoide , Neoplasias de Tecidos Moles , beta Catenina , Feminino , Humanos , Masculino , beta Catenina/análise , beta Catenina/metabolismo , Biomarcadores Tumorais/análise , Diagnóstico Diferencial , Fibromatose Agressiva/diagnóstico , Fibromatose Agressiva/patologia , Fator 1 de Ligação ao Facilitador Linfoide/análise , Estudos Retrospectivos , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologiaRESUMO
Thymic epithelial tumors (TETs) are rare tumors for which treatment options are limited. The ongoing need for improved systemic therapies reflects a limited understanding of tumor biology as well as the normal thymus. The essential role of the thymus in adaptive immunity is largely effected by its epithelial compartment, which directs thymocyte (T-cell) differentiation and immunologic self-tolerance. With aging, the thymus undergoes involution whereby epithelial tissue is replaced by adipose and other connective tissue, decreasing immature T-cell production. Against this natural drive toward involution, a fraction of thymuses will instead undergo oncologic transformation, leading to the formation of TETs, including thymoma and thymic carcinoma. The rarity of these tumors restricts investigation of the mechanisms of tumorigenesis and development of rational treatment options. To this end, the development of technologies which allow deep molecular profiling of individual tumor cells permits a new window through which to view normal thymic development and contrast the malignant changes that result in oncogenic transformation. In this review, we describe the findings of recent illuminating studies on the diversity of cell types within the epithelial compartment through thymic differentiation and aging. We contextualize these findings around important unanswered questions regarding the spectrum of known somatic tumor alterations, cell of origin, and tumor heterogeneity. The perspectives informed by single-cell molecular profiling offer new approaches to clinical and basic investigation of thymic epithelial tumors, with the potential to accelerate development of improved therapeutic strategies to address ongoing unmet needs in these rare tumors.
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Neoplasias Epiteliais e Glandulares , Timo , Neoplasias do Timo , Humanos , Neoplasias do Timo/patologia , Timo/patologia , Timo/imunologia , Neoplasias Epiteliais e Glandulares/patologia , Análise de Célula Única/métodos , Diferenciação CelularRESUMO
Objective: To explore the value of predicting shunt-dependent hydrocephalus (SDHC) in patients with aneurysmal subarachnoid hemorrhage (aSAH) based on whole brain CT perfusion(CTP) and clinical data within 24 hours at admission. Methods: The clinical and imaging data of aSAH patients who received interventional embolization in our hospital were retrospectively collected from March 2018 to August 2022. All patients underwent one-stop whole brain CT examination within 24 hours after symptom onset, and the qualitative and quantitative CTP parameters were obtained after post-processing. Follow-up was conducted once every 2 months by consulting electronic medical records or by telephone for 6 months. According to whether SDHC occurred or not, the patients were divided into SDHC group and non-SDHC group. The differences between the two groups were compared. Logistic regression model was used to analyze and determine the predictive factors of SDHC, and the SDHC predictive model was established. The effectiveness of the predictive model was evaluated by drawing the receiver operating characteristic (ROC) curve of the subjects. Results: A total of 414 patients were included, including 132 males and 282 females, aged (59±11) years. 17.6%(73/414) patients had SDHC. There were significant differences in the occurrence of acute hydrocephalus, the World Neurosurgical League Scale (WFNS), the Hunt-Hess scale, the modified Fisher score (mFS), and the qualitative and quantitative parameters of CTP between the two groups (both P<0.001). Multivariate logistic regression analysis showed that acute hydrocephalus (OR=8.621, 95%CI: 4.237-17.542),old age (OR=1.107, 95%CI: 1.068-1.148), high mFS and high Hunt-Hess classification (OR=3.740, 95%CI: 1.352-10.342) were the risk factors of SDHC in aSAH patients, and high mean cerebral blood flow (mCBF) (OR=0.931, 95%CI: 0.885-0.980) was a protective factor of SDHC.The area under ROC curve (AUC) of the prediction model constructed by these five variables was 0.923(95%CI: 0.89-0.95), with 84.5% sensitivity and 87.7% specificity. Conclusion: The mCBF and acute hydrocephalus, age, mFS and Hunt-Hess classification within 24 hours at admission can be used to predict SDHC for aSAH patients.
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Hidrocefalia , Hemorragia Subaracnóidea , Masculino , Feminino , Humanos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/diagnóstico , Hemorragia Subaracnóidea/cirurgia , Estudos Retrospectivos , Encéfalo , Perfusão/efeitos adversosRESUMO
Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a preclinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC. SIGNIFICANCE: SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC. This article is featured in Selected Articles from This Issue, p. 695.
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Resistencia a Medicamentos Antineoplásicos , Amplificação de Genes , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Camundongos , Animais , Proteínas Proto-Oncogênicas c-myc/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Phosphaturic mesenchymal tumor (PMT) is a rare tumor that causes tumor-induced osteomalacia. Patients present with non-specific symptoms secondary to renal phosphate wasting and decreased bone mineralization. We sought to assess: (1) What are the common presenting features, laboratory and imaging findings, histologic findings of phosphaturic mesenchymal tumors? (2) What are the available treatment strategies for phosphaturic mesenchymal tumors and their long-term outcomes in terms of local recurrence and symptom control after treatment? METHODS: We retrospectively identified patients with a histologic diagnosis of PMT located in the axial or appendicular skeleton, or surrounding soft tissues. A total of 10 patients were finally included in our study. RESULTS: Median tumor size was 1.9 cm (range, 1.1 to 6.1) and median time from symptom onset to diagnosis was 3 years (range, 0.5 to 15 years). All patients but one presented with hypophosphatemia (median 1.9 mg/dL, range 1.2 to 3.2). Pre-operative FGF-23 was elevated in all cases (median 423.5 RU/mL, range 235 to 8950). Six patients underwent surgical resection, three were treated percutaneously (radiofrequency ablation or cryoablation), and one refused treatment. Only one patient developed local recurrence and no patients developed metastatic disease. At last follow-up, nine patients showed no evidence of disease and one was alive with disease. CONCLUSION: Phosphaturic mesenchymal tumor is a rare tumor presenting with non-specific symptoms. Surgery is the standard treatment when negative margins can be achieved without significant morbidity. In patients with small tumors in surgically-inaccessible areas, radiofrequency ablation or cryoablation can be performed successfully.
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Osteomalacia , Humanos , Masculino , Feminino , Estudos Retrospectivos , Adulto , Osteomalacia/diagnóstico por imagem , Pessoa de Meia-Idade , Mesenquimoma/diagnóstico por imagem , Mesenquimoma/cirurgia , Adolescente , Resultado do Tratamento , Neoplasias de Tecido Conjuntivo/diagnóstico por imagem , Neoplasias de Tecido Conjuntivo/cirurgia , Síndromes Paraneoplásicas/diagnóstico por imagem , Fator de Crescimento de Fibroblastos 23 , Criança , Idoso , Hipofosfatemia/etiologia , Adulto Jovem , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Vacuum-assisted closure (VAC) temporization is a promising technique to achieve local control in aggressive soft tissue sarcomas. Despite its previously reported efficacy, adoption of VAC temporization remains limited, primarily due to the scarce literature on patient-reported outcomes (PROs) supporting its efficacy. This study compared the postoperative PROs after VAC temporization or single-stage (SS) excision and reconstruction for patients undergoing surgical resection for myxofibrosarcoma management. METHODS: A retrospective analysis of myxofibrosarcoma patients who underwent surgical resections at our institution from 2016 to 2022 was performed. Postoperative PROs collected prospectively for those treated with VAC temporization or SS excision/reconstruction were compared using a visual analog scale (VAS) for pain and three Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires: Global Health Short-Form Mental (SF Mental), Global Health Short-Form Physical (SF Physical), and Physical Function Short-Form 10a (SF 10a). Absolute and differential (postoperative minus preoperative) scores at the 1-month, 3-month, 6-month, 1-year, and 2-year time points were compared. RESULTS: The analysis included 79 patients (47 treated with VAC temporization and 32 treated with SS excision/reconstruction). All outcomes were similar between the groups except for physical function 1 year after surgery, in which the differential PROMIS SF 10a scores were higher in the SS group (p = 0.001). All the remaining absolute and differential PROMIS and VAS pain scores were similar between the groups at all time points. Postoperative complications did not differ between the groups. CONCLUSION: The PROs for physical and mental health, physical function, and pain were similar between the myxofibrosarcoma patients who had VAC temporization and those who had SS excision/reconstruction after surgical resection.
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Fibrossarcoma , Histiocitoma Fibroso Maligno , Tratamento de Ferimentos com Pressão Negativa , Adulto , Humanos , Tratamento de Ferimentos com Pressão Negativa/métodos , Estudos Retrospectivos , Complicações Pós-Operatórias , Fibrossarcoma/cirurgia , Medidas de Resultados Relatados pelo Paciente , Dor , Resultado do TratamentoRESUMO
Objective: To analyze the burden of cardiovascular disease (CVD) attributed to low physical activity (LPA) and its changing trends in China from 1990 to 2019. Methods: On the basis of the province results of the Study of Global Burden of Disease 2019 in China, we described the distribution of CVD death and disability-adjusted life year (DALY) attributed to LPA by sex, age and province. Joinpoint 4.9.1.0 was used to calculate the average annual percentage change. Results: In 2019, the number of CVD deaths and DALY attributed to LPA in people aged ≥25 years were 0.127 million and 1.863 million person-years in China, respectively, The age-standardized mortality rate (ASMR) and standardized DALY rate of CVD attributed to LPA were slightly higher in men than in women, and much higher in ischemic heart disease patients than in ischemic stroke patients. The ASMR (8.85/100 000) and the standardized DALY rate (112.34/100 000) of CVD attributed to LPA in China in 2019 showed no obvious change compared with 1990, while decreased in the last decade. The largest increases in the mortality rate and DALY rate were observed in people aged ≥75 years from 1990 to 2019 (26.89%, 15.61%), but the mortality rate and DALY rate in people aged 60-74 years showed a decreasing trend. The mortality rate and DALY rate in men aged 25- 44 years showed the largest increases (37.50%, 35.49%), while women aged ≥75 years had the largest increases (31.00%, 18.02%). In 2019, the highest ASMR and standardized DALY rate of CVD attributed to LPA were found in Jilin, Inner Mongolia and Hebei. The largest increases were found in Qinghai (182.41%, 154.70%), Gansu (181.29%, 152.77%), and Chongqing (132.01%, 102.79%) and the largest decreases were found in Beijing (59.11%, 62.09%), Macau (41.89%, 39.37%) and Guangdong (36.93%, 40.72%) from 1990 to 2019. Conclusion: The disease burden of CVD attributed to LPA in China was quite high and showed gender, age and area specific differences.
Assuntos
Doenças Cardiovasculares , Isquemia Miocárdica , Masculino , Humanos , Feminino , Doenças Cardiovasculares/epidemiologia , Anos de Vida Ajustados por Qualidade de Vida , China/epidemiologia , Pequim , Efeitos Psicossociais da DoençaRESUMO
CONTEXT.: Molecular testing has increasingly been utilized in the evaluation of mesothelioma. Diffuse mesothelioma comprises multiple distinct genetic subgroups. While most diffuse mesotheliomas lack oncogenic kinase mutations and instead harbor alterations involving tumor suppressors and chromatin regulators, a minor subset of tumors is characterized by uncommon alterations such as germline mutations, genomic near-haploidization, ALK rearrangement, ATF1 rearrangement, or EWSR1::YY1 fusion. OBJECTIVE.: To provide updates on the salient molecular features of diffuse mesothelioma, mesothelioma in situ, and other mesothelial lesions: well-differentiated papillary mesothelial tumor, adenomatoid tumor, peritoneal inclusion cyst, and others. We consider the diagnostic, prognostic, and predictive utility of molecular testing in mesothelial lesions. DATA SOURCES.: We performed a literature review of recently described genetic features, molecular approaches, and immunohistochemical tools, including BAP1, MTAP, and merlin in mesothelioma and other mesothelial lesions. CONCLUSIONS.: Our evolving understanding of the molecular diversity of diffuse mesothelioma and other mesothelial lesions has led to considerable changes in pathology diagnostic practice, including the application of immunohistochemical markers such as BAP1, MTAP, and merlin (NF2), which are surrogates of mutation status. In young patients and/or those without significant asbestos exposure, unusual mesothelioma genetics such as germline mutations, ALK rearrangement, and ATF1 rearrangement should be considered.
Assuntos
Biomarcadores Tumorais , Imuno-Histoquímica , Mesotelioma , Proteínas Supressoras de Tumor , Ubiquitina Tiolesterase , Humanos , Mesotelioma/diagnóstico , Mesotelioma/genética , Mesotelioma/metabolismo , Mesotelioma/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Neoplasias Mesoteliais/diagnóstico , Neoplasias Mesoteliais/genética , Neoplasias Mesoteliais/metabolismo , Neoplasias Mesoteliais/patologia , Mesotelioma Maligno/diagnóstico , Mesotelioma Maligno/genética , Mesotelioma Maligno/patologia , Mesotelioma Maligno/metabolismo , MutaçãoRESUMO
AIMS: Anastomosing haemangiomas are benign tumours with anastomosing vascular channels that may mimic angiosarcoma. While anastomosing haemangiomas have been described in diverse locations, particularly the abdominal/paraspinal region, data on anastomosing haemangiomas in the mediastinum remain limited. We report the clinicopathological, radiological and molecular characteristics of the largest single-institutional series of mediastinal anastomosing haemangiomas. METHODS AND RESULTS: In our pathology archives in 2011-23, we reviewed all vascular lesions involving the mediastinum and identified seven anastomosing haemangiomas. Clinical information was abstracted from medical charts; available radiological imaging was reviewed. Targeted DNA-based next-generation sequencing (447 genes, including GNAQ and GNA11) was performed on five cases. The seven patients included five women and two men, with an age range of 55-77 (median = 72) years. Of the six tumours with available radiology, two each were in the prevascular, visceral and paravertebral mediastinum, with lobulated peripheral enhancement in all tumours examined with contrast enhancement. Six patients underwent tumour resection; one patient received proton radiotherapy. Microscopically, each tumour was solitary and characterised by anastomosing capillary-sized vessels lined by hobnail endothelial cells. Fibrin microthrombi, hyaline globules and extramedullary haematopoiesis were common. In the five tumours analysed by next-generation sequencing, GNAQ p.Q209P was identified in one tumour; no additional reportable alterations were identified in the remaining cases. No recurrence was noted in the four patients with available follow-up of 3-58 (median = 9.5) months after resection. CONCLUSION: While mediastinal anastomosing haemangiomas can microscopically mimic angiosarcoma, awareness of this entity and radiological correlation may help to circumvent this diagnostic pitfall.
Assuntos
Hemangioma , Hemangiossarcoma , Radiologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Endoteliais/patologia , Hemangioma/diagnóstico por imagem , Hemangioma/genética , Hemangiossarcoma/patologia , Mediastino/patologiaRESUMO
The welfare and health of laying hens in the multitier system raise concern in public. The flock distributions during feeding time at 51 and 89 wk were studied in a multitier system. Furthermore, the ultra-high frequency radio frequency identification (UHF RFID) equipment was used to identify the transition between tiers and time spent in each tier of 48 focal hens (12 hens from each tier-group of the multitier system) at 92 wk of age. The body weight, tibia size (length and width), body damage (comb and rear part), and feather condition (neck, breast, back, tail, cloaca, and wings) of focal hens from different tier-groups were further compared. The results showed that the spatial distribution in flocks changed from top to bottom with increasing age. The hens at 51 wk of age were mainly distributed in the 4th tier (19.6 ± 5.0% in 1st tier, 9.6 ± 1.1% in 2nd tier, 23.6 ± 2.9% in 3rd tier and 47.3 ± 2.6% in 4th tier), and hens at 89 wk of age were mainly distributed in the lower tiers (33.5 ± 1.5% in 1st tier, 31.9 ± 5.1% in 2nd tier, 15.7 ± 3.4% in 3rd tier and 16.6 ± 3.1% in 4th tier). The spatial distribution of hens at 89 wk of age was more even than that at 51 wk of age. At 92 wk of age, the proportion of time spent in original tier of 4 tier-groups was 91.0 ± 5.7%, 51.9 ± 5.7%, 59.0 ± 7.0% and 63.0 ± 6.7%, respectively. Focal hens preferred to stay in the original tier and spent significantly less time in other tiers (P < 0.05). There was no significant difference in body weight, body damage score, tibia width and partial feather scores (neck, breast, tail, and cloaca) of focal hens among 4 tier-groups (P > 0.05). However, focal hens from 1st tier had worse feather scores on wings and back, and shorter tibia length compared to other tiers suggesting that there were more lower ranking birds that located in lower tier to avoid competition, but had equal access to resource, which is good for their welfare and health. In summary, the overcrowding situation was improved near the end of the laying cycle in the multitier system, thereby mitigating the potential negative effects to the lower ranking hens and maintain a satisfactory level of welfare and health for laying hens near the end of the laying cycle.