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CONTEXT.: The characteristic molecular signature for both atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma is amplified sequences derived from chromosome 12q13-15, including MDM2 proto-oncogene (MDM2). As the progression of atypical lipomatous tumor/well-differentiated liposarcoma to the more aggressive dedifferentiated liposarcoma has the potential to adversely affect patient outcomes, the extent of the latter component might be important to evaluate. OBJECTIVE.: To investigate the correlation between clinicopathologic characteristics, including tumor size, modified Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade, molecular data, and outcomes in 123 surgically resected MDM2-amplified liposarcomas. DESIGN.: Pathology reports and clinical records were reviewed. A log-rank test was used to compare the survival trends, and univariate logistic regression was performed to identify variables associated with adverse events (distant metastasis and/or death), from which the P value was derived to construct a multivariate regression model. RESULTS.: In univariate analysis, the largest single dimension of the dedifferentiated component, the percentage of cells with gain of chromosome 12, mitotic count, and the presence of modified FNCLLC grade 3 were associated with adverse events. In multivariate analysis, the largest single dimension of the dedifferentiated component (odds ratio: 1.169; 95% CI: 1.053, 1.299; P = .003), and a higher mitotic count (odds ratio: 1.133; 95% CI: 1.037, 1.237; P = .006) were correlated with adverse events. There was no statistically significant association between current local recurrence status, overall largest tumor dimension, overall tumor volume, MDM2 copy number, or MDM2 to chromosome 12 centromere probe ratio and adverse outcomes. CONCLUSIONS.: Staging dedifferentiated liposarcoma based on the size of the dedifferentiated component better predicts the outcome.
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Introduction. MYC overexpression is a known phenomenon in breast cancer. This study investigates the correlation of MYC gene copy number amplification and MYC protein overexpression with coexisting genetic abnormalities and associated clinicopathologic features in breast cancer patients. Methods. The study analyzed data from 81 patients with localized or metastatic breast cancers using targeted next-generation sequencing and MYC immunohistochemical studies, along with pathological and clinical data. Results. Applying the criteria of MYC/chromosome 8 ratio ≥5, MYC copy number amplified tumors (n = 11, 14%) were associated with invasive ductal carcinoma (91% vs 68%, P = .048), poorly differentiated (grade 3, 64% vs 30%, P = .032), mitotically active (Nottingham mitotic score 3, 71% vs 20%, P = .004), estrogen receptor (ER)-negative (45% vs 12%, P = .008), and triple-negative (56% vs 12%, P = .013) compared to MYC non-amplified tumors. Among MYC-amplified breast cancer patients, those with triple-negative status showed significantly shorter disease-free survival time than non-triple negative MYC-amplified patients (median survival month: 25.5 vs 127.6, P = .049). MYC amplification is significantly associated with TP53 mutation (P = .007). The majority (10 of 11; 91%) of MYC-amplified tumors showed positive c-MYC immunostaining. Conclusion. Breast cancers with MYC copy number amplication display distinct clinicopathologic characteristics indicative of more aggressive behavior.
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The published grant number was "OFJH2021008", while the correct should read "DFJH2021008". Reference: Yinghong Wu, Huiling Liu, Minghao Zhong, Xiyi Chen, Zhiqiong Ba, Guibin Qiao, Jiejie Feng, Xiuqun Zeng: Enhanced Patient Comfort and Satisfaction with Early Oral Feeding after Thoracoscopic Lung Cancer Resection. Med Sci Monit, 2023; 29: e941577. DOI: 10.12659/MSM.941577.
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BACKGROUND The study aimed to compare the patient-reported outcomes in patients who underwent early vs conventional feeding after thoracoscopic lung cancer resection. MATERIAL AND METHODS The study enrolled 211 patients who underwent thoracoscopic lung cancer resection at a tertiary hospital between July 2021 and July 2022. Patients were randomly assigned to the conventional group or the early feeding group. There were 106 patients in the early feeding group and 105 patients in the conventional group. The conventional group received water 4 h after extubation and liquid/semi-liquid food 6 h after extubation. In contrast, the early feeding group received water 1 h after extubation and liquid/semi-liquid food 2 h after extubation. The primary outcomes were the degree of hunger, thirst, nausea, and vomiting. The secondary outcomes were postoperative complications, duration of hospital stay, and chest tube drainage. RESULTS No differences were found between the 2 groups in the degrees of postoperative nausea, vomiting, or pain after extubation for 1, 2, 4, and 8 h. Postoperative complications, duration of chest tube drainage, and duration of hospital stay were also similar (P=0.567, P=0.783, P=0.696). However, the hunger and thirst scores after extubation for 2 h and 4 h decreased and were lower in the early feeding group (both P<0.001). No patients developed choking, postoperative aspiration, gastrointestinal obstruction, or other complications. CONCLUSIONS Early oral feeding after thoracoscopic lung cancer resection is safe and can increase patient comfort postoperatively.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/cirurgia , Conforto do Paciente , Satisfação do Paciente , Náusea e Vômito Pós-Operatórios/etiologia , Satisfação Pessoal , Água , Tempo de InternaçãoRESUMO
BACKGROUND: Retesting for Human epidermal growth factor receptor-2 (HER2) in post-neoadjuvant therapy resection is variable, and data is conflicting regarding the prognostic significance of changes in HER2 expression pre and post therapy. METHODS: We identified 104 patients with localized HER2 IHC 3+ breast cancer who received neoadjuvant trastuzumab(T)/pertuzumab(P) containing chemotherapy at Yale Cancer Center between 2012 and 2022. Patients were divided into 3 cohorts by response and HER2 IHC in the residual disease: Cohort 1 pathologic complete response (pCR), Cohort 2 pre-treatment IHC 3+/post treatment IHC 1+/2+, and Cohort 3 pre-treatment IHC 3+/post-treatment IHC 3+. Kaplan-Meier survival analysis was performed to assess recurrence free survival at 36 months. RESULTS: The overall pCR rate was 62.5% (65/104), while 37.5% (39/104) of patients had residual disease (RD). Among patients with RD, 58.9% (23/39) remained IHC 3+ and 41.1% (16/39) had reduced HER2 expression IHC1+ or 2+. In patients with HER2 IHC 3+ RD, 26% (6/23) developed local recurrence or distant metastasis while none of patients with post NAT HER2 IHC 1+ or 2+ RD had relapse (p = 0.0309). In patients with pCR, 6.15% (4/65) had recurrence. Kaplan-Meier survival analysis revealed superior disease-free survival in patients with reduced HER2 IHC expression compared to those with remained IHC 3+ (log rank p = 0.004). CONCLUSION: We conclude that reduced HER2 expression by IHC following neoadjuvant treatment was associated with lower recurrence rates in HER2 IHC 3+ breast cancer. If confirmed, RD HER2 IHC expression could be used as a prognostic biomarker to stratify patients in adjuvant trials and identify patients who may benefit from more intensive adjuvant therapy and post therapy surveillance.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Prognóstico , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/etiologia , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêuticoRESUMO
Despite the widespread implementation of pneumococcal vaccines, hypervirulent Streptococcus pneumoniae serotype 19A is endemic worldwide. It is still unclear whether specific genetic elements contribute to complex pathogenicity of serotype 19A isolates. We performed a large-scale pan-genome-wide association study (pan-GWAS) of 1,292 serotype 19A isolates sampled from patients with invasive disease and asymptomatic carriers. To address the underlying disease-associated genotypes, a comprehensive analysis using three methods (Scoary, a linear mixed model, and random forest) was performed to compare disease and carriage isolates to identify genes consistently associated with disease phenotype. By using three pan-GWAS methods, we found consensus on statistically significant associations between genotypes and disease phenotypes (disease or carriage), with a subset of 30 consistently significant disease-associated genes. The results of functional annotation revealed that these disease-associated genes had diverse predicted functions, including those that participated in mobile genetic elements, antibiotic resistance, virulence, and cellular metabolism. Our findings suggest the multifactorial pathogenicity nature of this hypervirulent serotype and provide important evidence for the design of novel protein-based vaccines to prevent and control pneumococcal disease. IMPORTANCE It is important to understand the genetic and pathogenic characteristics of S. pneumoniae serotype 19A, which may provide important information for the prevention and treatment of pneumococcal disease. This global large-sample pan-GWAS study has identified a subset of 30 consistently significant disease-associated genes that are involved in mobile genetic elements, antibiotic resistance, virulence, and cellular metabolism. These findings suggest the multifactorial pathogenicity nature of hypervirulent S. pneumoniae serotype 19A isolates and provide implications for the design of novel protein-based vaccines.
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Infecções Pneumocócicas , Streptococcus pneumoniae , Humanos , Sorogrupo , Estudo de Associação Genômica Ampla , Vacinas Pneumocócicas/genética , SorotipagemRESUMO
Purpose: O6-methylguanine DNA methyltransferase (MGMT)-silenced tumors reveal sensitivity to temozolomide (TMZ), which may be enhanced by PARP inhibitors. Approximately 40% of colorectal cancer has MGMT silencing and we aimed to measure antitumoral and immunomodulatory effects from TMZ and olaparib in colorectal cancer. Experimental Design: Patients with advanced colorectal cancer were screened for MGMT promoter hypermethylation using methylation-specific PCR of archival tumor. Eligible patients received TMZ 75 mg/m2 days 1-7 with olaparib 150 mg twice daily every 21 days. Pretreatment tumor biopsies were collected for whole-exome sequencing (WES), and multiplex quantitative immunofluorescence (QIF) of MGMT protein expression and immune markers. Results: MGMT promoter hypermethylation was detected in 18/51 (35%) patients, 9 received study treatment with no objective responses, 5/9 had stable disease (SD) and 4/9 had progressive disease as best response. Three patients had clinical benefit: carcinoembryonic antigen reduction, radiographic tumor regression, and prolonged SD. MGMT expression by multiplex QIF revealed prominent tumor MGMT protein from 6/9 patients without benefit, while MGMT protein was lower in 3/9 with benefit. Moreover, benefitting patients had higher baseline CD8+ tumor-infiltrating lymphocytes. WES revealed 8/9 patients with MAP kinase variants (7 KRAS and 1 ERBB2). Flow cytometry identified peripheral expansion of effector T cells. Conclusions: Our results indicate discordance between MGMT promoter hypermethylation and MGMT protein expression. Antitumor activity seen in patients with low MGMT protein expression, supports MGMT protein as a predictor of alkylator sensitivity. Increased CD8+ TILs and peripheral activated T cells, suggest a role for immunostimulatory combinations. Significance: TMZ and PARP inhibitors synergize in vitro and in vivo in tumors with MGMT silencing. Up to 40% of colorectal cancer is MGMT promoter hypermethylated, and we investigated whether TMZ and olaparib are effective in this population. We also measured MGMT by QIF and observed efficacy only in patients with low MGMT, suggesting quantitative MGMT biomarkers more accurately predict benefit to alkylator combinations.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Temozolomida/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Reparo do DNA , O(6)-Metilguanina-DNA Metiltransferase , Neoplasias Colorretais/tratamento farmacológico , AlquilantesRESUMO
OBJECTIVE: Diagnosis of inflammatory bowel disease (IBD)-associated dysplastic lesions can be challenging. This study aims to evaluate MYC immunohistochemistry (IHC) as a potential biomarker for IBD-associated dysplasia and compare its effectiveness with p53 IHC. METHODS: The study cohort included resections from 12 IBD patients with carcinoma and concurrent conventional low-grade dysplasia (LGD), as well as biopsies from 21 patients with visible conventional LGD, which were followed up for 2 years with subsequent endoscopic examination. MYC and p53 IHC and MYC-FISH analysis were performed. RESULTS: Sensitivity for LGD detection was 67% (8/12) and 50% (6/12) for MYC and p53, respectively, but the difference was not statistically significant (p = 0.2207). MYC and p53 overexpression were not always mutually exclusive, nor were they always present simultaneously. Patients who presented dysplasia in subsequent biopsies (7/21) were found to be more likely present with multiple LGD polyps and MYC-overexpressed LGD in the initial biopsies, compared to those without subsequent dysplasia (p < 0.05). These dysplastic lesions were commonly associated with chronic colitis (p = 0.0614). The distribution of LGD sites did not show a significant difference between patients with and without subsequent LGD. In MYC overexpressed cases, homogeneously strong nuclear expression was not identified in all dysplastic epithelial cells, and no MYC amplification was found in these cases by FISH. CONCLUSION: MYC IHC can complement p53 IHC as an adjunct biomarker for diagnosing IBD-associated conventional LGD and can be used for the prediction of subsequent LGD in the follow-up biopsies combined with endoscopic features.
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Genetic aberrations in the Estrogen Receptor 1 (ESR1) gene have been identified as an important mechanism of resistance to endocrine therapy in metastatic breast carcinoma. In this study, we aimed to correlate ESR1 genetic aberrations with the ER and PR status in paired metastatic and primary breast carcinomas. Patients with ER-positive breast cancer were divided into two groups: ESR1 genetic aberration (n = 26) and wild-type control (n = 29) based on genetic profiling of their metastatic tumors. Clinicopathological features and ER/PR status were analyzed in paired primary and metastatic tumors. Although there was no significant difference in ER expression between the ESR1 aberration and control groups in primary tumors, ER positivity rate in metastatic tumors was significantly higher in the ESR1 aberration group than in the control group (100% vs. 86%, P < .05). ESR1 aberrated cases were associated with more liver metastases than control tumors (46% vs. 10%, P < .01). The ER percentage and intensity slightly increased from primary to metastatic tumors in the ESR1 aberration group compared to a decrease in both in the wild-type group (percentage increase 2% vs. decrease 19%, P = .0594; intensity increase 0.04 vs. decrease 0.8, p < .05). Patients with ESR1 aberrated metastases were more likely than those with wild-type ESR1 metastases to have the following characteristics: 1) ER percentage ≥90% and intensity >2, as well as PR percentage ≥30% and intensity >1 in metastatic tumors; 2) ER percentage ≥90% and PR percentage ≥70% in primary tumors; and 3) slightly increase in ER percentage and intensity from primary to metastatic tumors. Based on the ER/PR parameters of paired primary and metastatic breast cancer, ESR1 aberration in metastasis may be predicted.
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Neoplasias da Mama , Receptores de Estrogênio , Humanos , Feminino , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genéticaRESUMO
CONTEXT.: Repeated surgery is necessary for 20% to 40% of breast conservation surgeries owing to the unavailability of any adjunctive, accurate, and objective tool in the surgeon's hand for real-time margin assessment to achieve the desired balance of oncologic and cosmetic outcomes. OBJECTIVE.: To assess the feasibility of using a multispectral autofluorescence imaging device for discriminating malignant neoplasm from normal breast tissue in pathology as a critical step in the development of a device for intraoperative use, and to demonstrate the device's utility for use in processing and prioritizing specimens during frozen section and in the pathology grossing room. DESIGN.: We performed a preliminary assessment of our device, called the TumorMAP system, on 172 fresh tissue blocks from 115 patients obtained from lumpectomy specimens at the time of initial gross examination and compared the device results with gold standard pathology evaluation. RESULTS.: The preliminary results demonstrate the potential of our device in detecting breast cancer in fresh tissue samples with a sensitivity of 82%, a specificity of 91%, a positive predictive value of 84%, and a negative predictive value of 89%. CONCLUSIONS.: Our results suggest that the TumorMAP system is suitable for the detection of malignant neoplasm in freshly excised breast specimens and has the potential to evaluate resection margins in real time.
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BACKGROUND: SMARCA4/BRG1-deficient tumors and those that have loss of SMARCA/BRG1 have been described as various aggressive carcinomas and sarcomas, including a subset of non-small cell lung carcinoma (NSCLC). Cytomorphologic features of NSCLCs are yet to be described. The objective of this study was to evaluate the cytomorphologic features, immunohistochemical profile, and molecular profile of SMARCA4/BRG1-deficient NSCLC (SMARCA4-dNSCLC). METHODS: The authors retrospectively searched for cases with SMARCA4/BRG1 functional loss alterations, which were identified in molecular studies and further confirmed by immunocytochemistry, and they reviewed the cytomorphologic features. Tumors with BRG1 loss were also stained with an extensive antibody panel. Molecular profiling and clinical information of the identified cases were scrutinized. RESULTS: In total, 12 cytopathology cases from different anatomic sites were included. All cases showed variable expression of cytokeratin irrespective of type. One-half of cases had glandular features, followed by squamoid features, and poorly differentiated features. The most common cytologic features included sheets or papillary architecture, round or oval cell shapes, nuclear enlargement, moderate-to-marked pleomorphism, and coarse chromatin. Two cases with poorly differentiated cytomorphology had a predominance of single cells, scant cytoplasm, and macronucleoli. Variable expression of epithelial markers was noted in all cases. TP53 was the most frequently co-mutated gene in SMARCA4-dNSLCs. CONCLUSIONS: This study demonstrates that SMARCA4-dNSCLCs can have a wide spectrum of cytomorphologic features, ranging from a relatively well differentiated adenocarcinoma to a poorly differentiated/undifferentiated carcinoma, with the majority of cases exhibiting some high-grade features, such as mitosis, apoptosis, necrosis, and marked pleomorphism.
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Carcinoma Pulmonar de Células não Pequenas , DNA Helicases , Neoplasias Pulmonares , Proteínas Nucleares , Fatores de Transcrição , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , DNA Helicases/genética , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Nucleares/genética , Estudos Retrospectivos , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Readout-segmented echo-planar diffusion-weighted imaging (RS-EPI) can improve image quality and signal-to-noise ratio, the resulting apparent diffusion coefficient (ADC) value acts as a more sensitive biomarker to characterize tumors. However, data regarding the differentiation of breast cancer (BC) receptor statuses using RS-EPI are limited. PURPOSE: To determine whether RS-EPI improves the differentiation of receptor statuses compared with conventional single-shot (SS) EPI in breast MRI. STUDY TYPE: Retrospective. POPULATION: A total of 151 BC women with the mean age of 50.6 years. FIELD STRENGTH/SEQUENCE: A 3 T/ RS-EPI and SS-EPI. ASSESSMENT: The ADCs of the lesion and normal background tissue from the two sequences were collected by two radiologists with 15 years of experience working of breast MRI (M.H.Z. and X.F.C.), and a normalized ADC was calculated by dividing the mean ADC value of the lesion by the mean ADC value of the normal background tissue. STATISTICAL TESTS: Agreement between the ADC measurements from the two sequences was assessed using the Pearson correlation coefficient and Bland-Altman plots. One-way analysis of variance, Kruskal-Wallis test, and median difference were used to compare the ADC measurements for all lesions and different receptor statuses. A P value less than 0.05 indicated a significant result. RESULTS: The ADC measurements of all lesions and normal background tissues were significantly higher on RS-EPI than on SS-EPI (1.82 ± 0.33 vs. 1.55 ± 0.30 and 0.83 ± 0.11 vs. 0.79 ± 0.10). The normalized ADC was lower on RS-EPI than on SS-EPI (0.47 ± 0.11 vs. 0.53 ± 0.12, a median difference of -0.04 [95% CI: -0.256 to 0.111]). For both diffusion methods, only the ADC measurement of RS-EPI was higher for human epidermal growth factor receptor-2 (HER-2)-positive tumors than for HER-2-negative tumors (0.87 ± 0.10 vs. 0.81 ± 0.11), and this measurement was associated with HER-2 positive status (adjusted odds ratio [OR] = 654.4); however, similar results were not observed for the ADC measurement of SS-EPI (0.80 ± 0.10 vs. 0.78 ± 0.11 with P = 0.199 and adjusted OR = 0.21 with P = 0.464, respectively). DATA CONCLUSION: RS-EPI can improve the distinction between HER-2-positive and HER-2-negative breast cancer, complementing the clinical application of diffusion imaging. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 1.
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Neoplasias da Mama , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Imagem Ecoplanar/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Razão Sinal-RuídoRESUMO
Automatic arrhythmia detection is very important for cardiovascular health. It is generally performed by measuring the electrocardiogram (ECG) signals of standard multiple leads. However, the correlations of multiple leads are often ignored. In addition, an extensive and complex feature extraction process is usually needed in most existing studies. Therefore, these challenges will not only lead to the loss of overall lead information, but also cause the detection performance to depend on the quality of features. To solve these challenges, a novel multi-lead arrhythmia detection model based on a heterogeneous graph attention network is proposed in this paper. We have modeled the multi-lead data as a heterogeneous graph to integrate diverse information and construct intra-lead and inter-lead correlations in multi-lead data, providing a reasonable and effective the data model. A heterogeneous graph network with a dual-level attention strategy has been utilized to capture the interactions among diverse information and information types. At the same time, our model does not require any feature extraction process for the ECG signals, which avoids out complex feature engineering. Extensive experimental results show that multi-lead information and complex correlations can be well captured, thus confirming that the proposed model results in significant improvements in multi-lead arrhythmia detection.
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Arritmias Cardíacas , Redes Neurais de Computação , Humanos , Arritmias Cardíacas/diagnóstico , Eletrocardiografia/métodos , AlgoritmosRESUMO
Introduction. As a tumor suppressor, germline and somatic inactivation of BRCA1 associated protein 1 gene (BAP1) is a common finding in mesothelioma, melanocytic tumors, clear cell renal cell carcinoma and several other epithelial, mesenchymal and neural tumors. Incidence of BAP1 genetic alterations and subsequent expression loss has not been well established in non-small cell lung carcinoma (NSCLC) by large-scale studies. Design. After IRB approval, a total of 356 NSCLC cases of our institution between July 2016 and June 2020 were reviewed. The study cohort consisted of 214 (60%) adenocarcinomas, 89 (25%) squamous cell carcinomas, and 53 (15%) diagnosed as "non-small cell lung carcinoma" without specified subtype. All tumors underwent comprehensive target cancer gene next generation sequencing (Oncomine Assay). The protein expression status of BAP1 was subsequently evaluated by immunohistochemistry. Results. BAP1 somatic mutations were detected in 8 NSCLC tumors (incidence: 2.2%). Tumors harboring BAP1 mutations were all diagnosed at advanced stage and carried at least one additional genetic alteration. Immunohistochemically, four tumors showed complete loss of BAP1 protein expression, including two adenocarcinomas which harbored different missense BAP1 mutations and another two with bioinformatically predicated deleterious frameshifting mutations. Conclusion. Compared with known BAP1 loss associated other malignancies, such as mesothelioma, inactivation of BAP1 by somatic mutation is a rare occurrence in NSCLC. BAP1 mutations and loss of expression in NSCLC are accompanied by other complex genetic alternations, suggesting BAP1 mutation maybe a late event NSCLC carcinogenesis.
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Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Mesotelioma Maligno , Proteínas Supressoras de Tumor , Ubiquitina Tiolesterase , Adenocarcinoma/genética , Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesotelioma Maligno/genética , Mesotelioma Maligno/patologia , Mutação , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genéticaRESUMO
CONTEXT.: Recent advances in comprehensive genomic profiling by next-generation sequencing have uncovered the genomic alterations at the molecular level for many types of tumors; as such, numerous small specific molecules that target these alterations have been developed and widely used in the management of these cancers. OBJECTIVE.: To provide a concise molecular genomic update in solid, bone and soft tissue tumors, hematopoietic as well as lymphoid malignancies; discuss its clinical applications; and familiarize practicing pathologists with the emerging cancer biomarkers and their diagnostic utilities. DATA SOURCES.: This review is based on the National Comprehensive Cancer Network guidelines and peer-reviewed English literature. CONCLUSIONS.: Tumor-specific biomarkers and molecular/genomic alterations, including pan-cancer markers, have been significantly expanded in the past decade thanks to large-scale high-throughput technologies and will continue to emerge in the future. These biomarkers can be of great value in diagnosis, prognosis, and/or targeted therapy/treatment. Familiarization with these emerging and ever-changing tumor biomarkers will undoubtedly aid pathologists in making accurate and state-of-the-art diagnoses and enable them to be more actively involved in the care of cancer patients.
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Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Genômica , Neoplasias Hematológicas/genética , Transtornos Linfoproliferativos/genética , Técnicas de Diagnóstico Molecular , Neoplasias de Tecidos Moles/genética , Neoplasias Ósseas/patologia , Perfilação da Expressão Gênica , Neoplasias Hematológicas/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Transtornos Linfoproliferativos/patologia , Valor Preditivo dos Testes , Neoplasias de Tecidos Moles/patologia , TranscriptomaRESUMO
Anaplastic lymphoma kinase (ALK) rearrangement-associated renal cell carcinoma (ALK-rearranged RCC) is a new provisional entity that has been included in the 2016 World Health Organization classification of RCCs. We report 2 cases of ALK-rearranged RCC, 1 with a vinculin-ALK (VCL-ALK) fusion and the other with an EML4-ALK fusion. The VCL-ALK RCC occurred in a 14-year-old girl with sickle cell trait and showed features similar to previously described VCL-ALK RCCs, including medullary epicenter, solid architecture, and polygonal cells with cytoplasmic vacuoles. The EML4-ALK RCC occurred in a 14-year-old boy with no evidence of sickle cell trait and had multiple less-specific growth patterns comprising tubular, solid, and tubulopapillary architectures in the desmoplastic stroma, reminiscent of collecting duct carcinoma. Both tumors demonstrated cytoplasmic and membranous ALK protein expression by immunohistochemistry. Fluorescence in situ hybridization confirmed the ALK gene rearrangements in both cases. On review in the literature, we found that solid architecture and cytoplasmic vacuoles were present significantly more frequently in VCL-ALK RCC than in non-VCL-ALK RCC, supporting the distinctive nature of the former.
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Quinase do Linfoma Anaplásico/genética , Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Proteínas de Fusão Oncogênica/genética , Vinculina/genética , Adolescente , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Feminino , Rearranjo Gênico , Humanos , Rim/patologia , Rim/cirurgia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , NefrectomiaRESUMO
Primary lung adenocarcinomas are rare in pediatric patients, and even rarer in patients without precedent malignancy or congenital malformation. Here we present the first reported case of primary lung cribriform adenocarcinoma with squamoid morules in a previously healthy adolescent female. Molecular testing identified CTNNB1 mutation in the tumor and excluded other common mutations in lung adenocarcinoma. Our case suggests molecular alterations to the same signaling pathway can lead to similar histomorphology regardless of the tissue of origin.
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Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Neoplasias Pulmonares/patologia , Pulmão/patologia , beta Catenina/genética , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Adolescente , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , MutaçãoRESUMO
Trophoblastic neoplasms involving the ovary are uncommon and include gestational tumors, which are either metastatic from the uterus or ectopic and nongestational tumors, which include those of germ cell type/origin and somatic tumors with trophoblastic differentiation; in all these types, most are pure choriocarcinoma. Intermediate trophoblastic tumors, which include placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT), are rare in the ovary, with most assumed to be gestational; this is the only category formally recognized in 2014 World Health Organization (WHO) classification, likely due to few well-documented nongestational examples. We report the clinicopathologic features of 6 ovarian intermediate trophoblastic tumors, including 3 PSTTs, 2 ETTs, and 1 ETT with choriocarcinomatous differentiation. DNA-based short tandem repeat genotyping identified 4 of these as nongestational (3 PSTTs and 1 ETT), as evidenced by sharing of alleles between tumor and normal tissue at all informative loci. Interestingly, all 3 of the nongestational PSTTs coexisted with mature cystic teratoma. The remaining 2 tumors (1 ETT and 1 ETT with some choriocarcinomatous differentiation) were gestational (likely ectopic due to lack of evidence of a uterine tumor), as evidenced by the presence of both maternal and novel/nonmaternal alleles at informative loci in tumor compared with normal tissue. It is important to recognize a distinct category of primary ovarian nongestational intermediate trophoblastic tumors of germ cell type/origin, including PSTT and ETT, in classification systems to guide clinical management, as gestational and nongestational tumors have different genetic origins and may require different therapy. Genotyping is useful for classification as nongestational versus gestational, particularly as traditional clinicopathologic findings cannot always predict the nature of a trophoblastic tumor.
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Biomarcadores Tumorais/genética , Coriocarcinoma não Gestacional/genética , Neoplasias Ovarianas/genética , Tumor Trofoblástico de Localização Placentária/genética , Adulto , Baltimore , Biomarcadores Tumorais/análise , Diferenciação Celular , Pré-Escolar , China , Coriocarcinoma não Gestacional/química , Coriocarcinoma não Gestacional/classificação , Coriocarcinoma não Gestacional/patologia , Células Epitelioides/patologia , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/química , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/patologia , Fenótipo , Gravidez , Terminologia como Assunto , Tumor Trofoblástico de Localização Placentária/química , Tumor Trofoblástico de Localização Placentária/classificação , Tumor Trofoblástico de Localização Placentária/patologiaRESUMO
Our previous studies have demonstrated that XIAP promotes bladder cancer metastasis through upregulating RhoGDIß/MMP-2 pathway. However, the molecular mechanisms leading to the XIAP upregulation was unclear. In current studies, we found that XIAP was overexpressed in human high grade BCs, high metastatic human BCs, and in mouse invasive BCs. Mechanistic studies indicated that XIAP overexpression in the highly metastatic T24T cells was due to increased mRNA stability of XIAP that was mediated by downregulated miR-200c. Moreover, the downregulated miR-200c was due to CREB inactivation, while miR-200c downregulation reduced its binding to the 3'-UTR region of XIAP mRNA. Collectively, our results demonstrate the molecular basis leading to XIAP overexpression and its crucial role in BC invasion.