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1.
J Am Coll Surg ; 236(1): 126-134, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36519916

RESUMO

INTRODUCTION: Infiltrating tumor border configuration (ITBC) portends a poor prognosis compared with pushing tumor border configuration (PTBC) in colorectal cancer. The tumor and its surrounding immune microenvironment of tumor border configuration is not well-characterized. We aim to elucidate the differences in expression of molecular markers between the 2 groups using tissue microarray (TMA). STUDY DESIGN: Immunohistochemistry was performed on TMAs of surgical pathology specimens obtained from colorectal cancer patients consecutively operated at our institution from 2004 to 2015. TMAs were stained for immune cells (CD8, FOXP3, LAG3, PU1, CD163, and PDL1); HLA II, beta 2 microglobulin, and HC10 on tumor cells; BRAFV600E mutation; and DNA mismatch repair proteins (MMR) status. Patients who received neoadjuvant therapy were excluded. RESULTS: There were 646 tumors with ITBC and 310 tumors with PTBC. There was a significantly lower expression (p < 0.05) of immune components, namely CD8, FOXP3, LAG3, PU1, PDL1 immune cells, and Beta-2 Microglobulin on tumor cells in the tumors with ITBC compared with PTBC, except CD163 immune cells, and HC10 and HLAII on tumor cells. Tumors with ITBC were less likely to be associated with BRAFV600E mutations and deficient MMR proteins (p < 0.001). On analyzing MMR-proficient tumors separately, we could not find any difference in the expression of any molecular marker (including BRAF), except a lower expression of PDL1 immune cells in tumors with ITBC (p < 0.001). CONCLUSIONS: Colorectal tumors with ITBC are associated with a generalized low immune microenvironment and low rates of BRAFV600E mutation compared with tumors with PTBC. However, the molecular expression of tumor border configuration seems confounded by the MMR molecular signature. MMR-proficient colorectal tumors with ITBC are associated with a lower expression of only PDL1 immune cells among all immune markers examined.


Assuntos
Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Microambiente Tumoral , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Fatores de Transcrição Forkhead/metabolismo , Imuno-Histoquímica , Mutação , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
2.
Histopathology ; 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36458877

RESUMO

INTRODUCTION: p53 is an independent risk stratification marker in Barrett's esophagus (BE), but no universally accepted definition exists for abnormal p53 staining. Herein, we assess p53 stains in two cohorts to: 1) define abnormal p53 staining in BE-related dysplasia (BERD), and 2) assess the specificity and sensitivity of this cut point for the diagnosis of dysplasia. METHODS: Cohort 1 (n= 313) included 1) dysplastic BE biopsies, 2) prior non-dysplastic BE (NDBE) biopsies from the same patients, and 3) NDBE biopsies from patients who never progressed to dysplasia. Cohort 2 (n=193) consisted of BE biopsies in which p53 staining aided in diagnosing dysplasia. Automated p53 staining quantification was performed on cohort 1. A semi-quantitative p53 analysis, performed on both cohorts, included: 1) number of strongly positive glands, 2) strong glandular surface staining, 3) percentage of strongly positive glands, and 4) null phenotype. RESULTS: NDBE biopsies from cohort 1 patients who progressed to dysplasia were more likely to show p53 positivity than non-progressors (16.9% vs 0.6%) (p=0.0001). The optimal quantitative cut point for distinguishing dysplastic from never-dysplasia biopsies was 10 strongly positive cells. By semiquantitative analysis, a single strongly p53-positive gland distinguished dysplastic from never-dysplasia BE (sensitivity 98.6%, specificity 99.4%). The semi-quantitative and quantitative analyses correlated (p=0.0001). In cohort 2, the sensitivity and specificity for BERD of ≥1 strongly positive p53 gland were 86.0 and 88.6%. CONCLUSIONS: A single strongly positive p53 gland is sensitive and specific for BERD. Automated p53 analysis may reduce subjectivity associated with the diagnosis of BERD.

3.
Nat Biomed Eng ; 2022 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-36581695

RESUMO

Predictive machine-learning systems often do not convey the degree of confidence in the correctness of their outputs. To prevent unsafe prediction failures from machine-learning models, the users of the systems should be aware of the general accuracy of the model and understand the degree of confidence in each individual prediction. In this Perspective, we convey the need of prediction-uncertainty metrics in healthcare applications, with a focus on radiology. We outline the sources of prediction uncertainty, discuss how to implement prediction-uncertainty metrics in applications that require zero tolerance to errors and in applications that are error-tolerant, and provide a concise framework for understanding prediction uncertainty in healthcare contexts. For machine-learning-enabled automation to substantially impact healthcare, machine-learning models with zero tolerance for false-positive or false-negative errors must be developed intentionally.

4.
J Clin Pathol ; 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36418114
5.
J Clin Pathol ; 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36288948

RESUMO

AIMS: Synovial sarcoma (SS) is an aggressive neoplasm but with varied clinical outcomes despite standard treatment protocols. Several clinicopathological features and immunohistochemical stains have been proposed as prognostic markers in SS. The aim of this study was to evaluate SS from a single institution for prognostically relevant clinicopathological and immunohistochemical factors. METHODS: We identified a single-institution cohort of SS with follow-up. Clinical and pathological factors examined included age, sex, tumour location, AJCC (American Joint Committee on Cancer) stage, tumour size, grade and status of surgical margins. Immunohistochemical staining for p16, p53, RB1, MYC, PTEN (phosphatase and tensin homologue), ß-catenin, MDM2 and Ki67 proliferative index was performed on tissue microarray. Cox proportional hazard model was used for multivariate assessment of overall survival (OS) and disease-free survival (DFS). RESULTS: 133 patients with SS met the inclusion criteria for our cohort, with 100 having complete dataset for all study covariates. On Cox regression multivariate analysis, location (axial vs extremity, p<0.001), AJCC stage (p<0.001), p16 expression (≥75%, p=0.021) were significantly associated with worse OS, whereas PTEN intensity (score 2, p<0.001) and p53 expression (null/≥75%, p=0.013) were correlated with improved OS. For DFS analysis, location (axial vs extremity, p=0.030), tumour size (≥5 cm, p=0.009) and MYC expression (≥33%, p=0.013) were associated with inferior outcome. Only PTEN intensity (score 2, p<0.001) correlated with improved DFS. CONCLUSIONS: In reviewing numerous clinicopathological and immunohistochemical markers, this study shows that location, AJCC stage, p16, p53 and PTEN expression were prognostically significant in multivariate analysis for OS in a uniformly treated SS cohort. Location, tumour size, MYC and PTEN expression were significantly associated with DFS.

6.
Nat Commun ; 13(1): 6386, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36302907

RESUMO

As the thickness of a three-dimensional (3D) topological insulator (TI) becomes comparable to the penetration depth of surface states, quantum tunneling between surfaces turns their gapless Dirac electronic structure into a gapped spectrum. Whether the surface hybridization gap can host topological edge states is still an open question. Herein, we provide transport evidence of 2D topological states in the quantum tunneling regime of a bulk insulating 3D TI BiSbTeSe2. Different from its trivial insulating phase, this 2D topological state exhibits a finite longitudinal conductance at ~2e2/h when the Fermi level is aligned within the surface gap, indicating an emergent quantum spin Hall (QSH) state. The transition from the QSH to quantum Hall (QH) state in a transverse magnetic field further supports the existence of this distinguished 2D topological phase. In addition, we demonstrate a second route to realize the 2D topological state via surface gap-closing and topological phase transition mechanism mediated by a transverse electric field. The experimental realization of the 2D topological phase in a 3D TI enriches its phase diagram and marks an important step toward functionalized topological quantum devices.

7.
Cancer ; 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36305090

RESUMO

BACKGROUND: Survival in patients who have Ewing sarcoma is correlated with postchemotherapy response (tumor necrosis). This treatment response has been categorized as the response rate, similar to what has been used in osteosarcoma. There is controversy regarding whether this is appropriate or whether it should be a dichotomy of complete versus incomplete response, given how important a complete response is for in overall survival of patients with Ewing sarcoma. The purpose of this study was to evaluate the impact that the amount of chemotherapy-induced necrosis has on (1) overall survival, (2) local recurrence-free survival, (3) metastasis-free survival, and (4) event-free survival in patients with Ewing sarcoma. METHODS: In total, 427 patients who had Ewing sarcoma or tumors in the Ewing sarcoma family and received treatment with preoperative chemotherapy and surgery at 10 international institutions were included. Multivariate Cox proportional-hazards analyses were used to assess the associations between tumor necrosis and all four outcomes while controlling for clinical factors identified in bivariate analysis, including age, tumor volume, location, surgical margins, metastatic disease at presentation, and preoperative radiotherapy. RESULTS: Patients who had a complete (100%) tumor response to chemotherapy had increased overall survival (hazard ratio [HR], 0.26; 95% CI, 0.14-0.48; p < .01), recurrence-free survival (HR, 0.40; 95% CI, 0.20-0.82; p = .01), metastasis-free survival (HR, 0.27; 95% CI, 0.15-0.46; p ≤ .01), and event-free survival (HR, 0.26; 95% CI, 0.16-0.41; p ≤ .01) compared with patients who had a partial (0%-99%) response. CONCLUSIONS: Complete tumor necrosis should be the index parameter to grade response to treatment as satisfactory in patients with Ewing sarcoma. Any viable tumor in these patients after neoadjuvant treatment should be of oncologic concern. These findings can affect the design of new clinical trials and the risk-stratified application of conventional or novel treatments.

8.
Clin Cancer Res ; 2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36190545

RESUMO

PURPOSE: Selective FGFR inhibitors are effective against cholangiocarcinomas with FGFR gene alterations. Clinical trials suggest that expression of wild-type FGFR mRNA can predict sensitivity to FGFR inhibitors, but this biomarker has not been well characterized in cholangiocarcinoma.This study explores the prevalence of FGFR mRNA overexpression in cholangiocarcinoma, its role in predicting sensitivity to FGFR inhibitors, and its association with immune markers. EXPERIMENTAL DESIGN: Tissue microarrays of intrahepatic (ICCs) and extrahepatic cholangiocarcinomas (ECCs) resected between 2004 and 2015 were used to evaluate expression levels of FGFR1-4 mRNA by RNA in situ hybridization.Expression levels of FGFR2 mRNA expression were correlated with FGFR2 fusion status and with patient outcomes.Expression of PD-L1, CD8, and CD163 were assessed by immunohistochemistry. Expression of CSF1 and CSF1R were examined by RNA in situ hybridization. RESULTS: Among 94 patients with resected cholangiocarcinoma, the majority had ICC (77%). FGFR2 fusions were identified in 23% of ICCs and 5% of ECCs.High levels of FGFR mRNA in FGFR2 fusion-negative ICC/ECC were seen for: FGFR1 (ICC/ECC:15%/0%), FGFR2 (ICC/ECC: 57%/0%), FGFR3 (ICC/ECC: 53%/18%), and FGFR4 (ICC/ECC: 32%/0%). Overall, 62% of fusion-negative cholangiocarcinomas showed high levels of FGFR mRNA. In patients with advanced FGFR2 fusion-positive ICC, high levels of FGFR2 mRNA expression did not correlate with clinical benefit from FGFR inhibitors.FGFR2 fusion-positive tumors showed a paucity of PD-L1 on tumor cells. CONCLUSIONS: FGFR mRNA overexpression occurs frequently in cholangiocarcinoma in the absence of genetic FGFR alterations. This study identifies a molecular subpopulation in cholangiocarcinoma for which further investigation of FGFR inhibitors is merited outside currently approved indications.

9.
Surgery ; 172(6): 1800-1806, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36192215

RESUMO

BACKGROUND: Nonfunctional pancreatic neuroendocrine tumors display a wide range of biological behavior, and nodal disease is associated with metastatic disease and poorer survival. The aim of this study was to develop a tool to predict nodal disease in patients with small (≤2 cm) nonfunctional pancreatic neuroendocrine tumors. METHODS: A multicenter retrospective study was performed on patients undergoing resection for small nonfunctional pancreatic neuroendocrine tumors. Patients with genetic syndromes, metastatic disease at diagnosis, neoadjuvant therapy, or positive resection margin were excluded. Factors associated with nodal disease were identified to develop a predictive model. Internal validation was performed using bootstrap with 1,000 resamples. RESULTS: Nodal disease was observed in 39 (11.1%) of the 353 patients included. Presence of nodal disease was significantly associated with lower 5-year disease-free survival (71.6% vs 96.2%, P < .001). Two predictors were strongly associated with nodal disease: G2 grade (odds ratio: 3.51, 95% confidence interval: 1.71-7.22, P = .001) and tumor size (per mm increase, odds ratio: 1.14, 95% confidence interval: 1.03-1.25, P = .009). Adequate discrimination was observed with an area under the curve of 0.71 (95% confidence interval: 0.63-0.80). Based on risk distribution, 3 risk groups of nodal disease were identified; low (<5%), intermediate (≥5% to <20%), and high (≥20%) risk. The observed mean risk of nodal disease was 3.7% in the low-risk patients, 9.6% in the intermediate-risk patients, and 30.4% in the high-risk patients (P < .001). The 10-year disease-free survival in the low, intermediate, and high-risk groups was 100%, 88.8%, and 50.1%, respectively. CONCLUSION: Our model using tumor grade and size can predict nodal disease in small nonfunctional pancreatic neuroendocrine tumors. Integration of this tool into clinical practice could help guide management of these patients.


Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Tumores Neuroendócrinos/cirurgia , Tumores Neuroendócrinos/diagnóstico , Estudos Retrospectivos , Metástase Linfática , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/diagnóstico , Margens de Excisão
10.
Arch Pathol Lab Med ; 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36136300

RESUMO

CONTEXT.­: The pancreatobiliary tract exhibits a spectrum of heterogeneous fibroinflammatory conditions that may be the result of a primary immune-mediated mechanism, or a reaction to neoplasm. This often results in significant overlap regarding clinical presentation, symptoms, radiographic findings, serology, and histopathology between inflammatory and neoplastic lesions of the pancreas, which can lead to inadvertent surgical intervention. Among the multitude of primary fibroinflammatory pancreatic diseases, autoimmune pancreatitis, to include type 1 and type 2 autoimmune pancreatitis, and immunoglobulin G4-related sclerosing cholangitis (IgG4-RSC) are particularly challenging and require a multidisciplinary perspective to reliably make a diagnosis. This is of particular significance because these diseases typically have a favorable prognosis and readily respond to steroid therapy. OBJECTIVE.­: To present a multimodal approach to highlight distinctive and overlapping qualities that will aid in the diagnosis of these entities. DATA SOURCES.­: The review and analysis of literature describing autoimmune pancreatitis types 1 and 2 and IgG4-RSC. CONCLUSIONS.­: Diagnosis of autoimmune pancreatitis types 1 and 2, and IgG4-RSC requires a multimodal approach that relies on clinical, radiographic, serologic, histopathologic, and immunohistochemical correlation.

11.
Biophys J ; 121(22): 4394-4404, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36004781

RESUMO

Cell-cell interaction dictates cell morphology and organization, which play a crucial role in the micro-architecture of tissues that guides their biological and mechanical functioning. Here, we investigate the effect of cell density on the responses of cells seeded on flat substrates using a novel statistical thermodynamics framework. The framework recognizes the existence of nonthermal fluctuations in cellular response and thereby naturally captures entropic interactions between cells in monolayers. In line with observations, the model predicts that cell area and elongation decrease with increasing cell seeding density-both are a direct outcome of the fluctuating nature of the cellular response that gives rise to enhanced cell-cell interactions with increasing cell crowding. The modeling framework also predicts the increase in cell alignment with increasing cell density: this cellular ordering is also due to enhanced entropic interactions and is akin to nematic ordering in liquid crystals. Our simulations provide physical insights that suggest that entropic cell-cell interactions play a crucial role in governing the responses of cell monolayers.


Assuntos
Cristais Líquidos , Entropia , Termodinâmica , Cristais Líquidos/química
12.
Ann Surg Oncol ; 29(12): 7372-7382, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35917013

RESUMO

BACKGROUND: Extramural vascular invasion (EMVI) is a known poor prognostic factor in colorectal carcinoma; however, its molecular basis has not been defined. This study aimed to assess the expression of molecular markers in EMVI positive colorectal carcinoma to understand their tumor microenvironment. METHODS: Immunohistochemistry was performed on tissue microarrays of surgically resected colorectal cancer specimens for immunological markers, and BRAFV600E mutation (and on the tissue blocks for mismatch repair proteins). Automated quantification was used for CD8, LAG3, FOXP3, PU1, and CD163, and manual quantification was used for PDL1, HLA I markers (beta-2 microglobulin, HC10), and HLA II. The Wilcoxon rank-sum test was used to compare EMVI positive and negative tumors. A logistic regression model was fitted to assess the predictive effect of biomarkers on EMVI. RESULTS: There were 340 EMVI positive and 678 EMVI negative chemo naïve tumors. PDL1 was barely expressed on tumor cells (median 0) in the entire cohort. We found a significantly lower expression of CD8, LAG3, FOXP3, PU1 cells, PDL1 positive macrophages, and beta-2 microglobulin on tumor cells in the EMVI positive subset (p ≤ 0.001). There was no association of BRAFV600E or deficient mismatch repair proteins (dMMR) with EMVI. PU1 (OR 0.8, 0.7-0.9) and low PDL1 (OR 1.6, 1.1-2.3) independently predicted EMVI on multivariate logistic regression among all biomarkers examined. CONCLUSION: There is a generalized blunting of immune response in EMVI positive colorectal carcinoma, which may contribute to a worse prognosis. Tumor-associated macrophages seem to play the most significant role in determining EMVI.


Assuntos
Neoplasias Colorretais , Neoplasias Retais , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Fatores de Transcrição Forkhead , Humanos , Imuno-Histoquímica , Invasividade Neoplásica/patologia , Prognóstico , Neoplasias Retais/patologia , Microambiente Tumoral
13.
Nano Lett ; 22(17): 7166-7172, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-35994426

RESUMO

We demonstrate advantages of samples made by mechanical stacking of exfoliated van der Waals materials for controlling the topological surface state of a three-dimensional topological insulator (TI) via interaction with an adjacent magnet layer. We assemble bilayers with pristine interfaces using exfoliated flakes of the TI BiSbTeSe2 and the magnet Cr2Ge2Te6, thereby avoiding problems caused by interdiffusion that can affect interfaces made by top-down deposition methods. The samples exhibit an anomalous Hall effect (AHE) with abrupt hysteretic switching. For the first time in samples composed of a TI and a separate ferromagnetic layer, we demonstrate that the amplitude of the AHE can be tuned via gate voltage with a strong peak near the Dirac point. This is the signature expected for the AHE due to Berry curvature associated with an exchange gap induced by interaction between the topological surface state and an out-of-plane-oriented magnet.

15.
Cell Stem Cell ; 29(8): 1246-1261.e6, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35931033

RESUMO

Lgr5+ intestinal stem cells (ISCs) depend on niche factors for their proper function. However, the source of these ISC niche factors and how they support ISCs in vivo remain controversial. Here, we report that ISCs depend on lymphatic endothelial cells (LECs) and RSPO3+GREM1+ fibroblasts (RGFs). In the intestine and colon, LECs are surrounded by RGFs and are located near ISCs at the crypt base. Both LECs and RGFs provide the critical ISC niche factor RSPO3 to support ISCs, where RSPO3 loss in both cell types drastically compromises ISC numbers, villi length, and repair after injury. In response to injury, LEC and RGF numbers expand and produce greater amounts of RSPO3 and other growth/angiocrine factors to foster intestinal repair. We propose that LECs represent a novel niche component for ISCs, which together with RGFs serve as the major in vivo RSPO3 source for ISCs in homeostasis and injury-mediated regeneration.


Assuntos
Células Endoteliais , Células-Tronco , Fibroblastos , Homeostase , Mucosa Intestinal/metabolismo , Intestinos , Células-Tronco/metabolismo
16.
Histopathology ; 81(3): 380-388, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35789111

RESUMO

BACKGROUND: Serrated adenocarcinoma (SAC), a recognised WHO variant of colonic adenocarcinoma, is the purported end-product of serrated neoplasia. However, the diagnosis of SAC is infrequently rendered, and little is known about its prognosis, immune microenvironment and molecular alterations. MATERIALS AND METHODS: We assessed 903 consecutive colon carcinomas and recognised tumours with ≥ 5% (n = 77) serrated and ≥ 50% serrated patterns (n = 13). We assessed precursor polyps and synchronous polyps. We recorded demographic/clinical parameters, histological features and mismatch repair (MMR) status. We performed immunohistochemistry and quantification on tissue microarray for HLA class I/II proteins, B2MG, CD8, CD163, LAG3, FoxP3, PD-L1 and BRAF V600E. RESULTS: We identified ≥ 5% epithelial serration prevalence in 8.5% of cases and ≥ 50% epithelial serration prevalence in 1.4% of cases. Precursor lesions were present in 21.4% of cases; these were mostly tubular adenomas with two traditional serrated adenomas identified. SAC with ≥ 5% serrations exhibited lower numbers of CD8-positive lymphocytes (P = 0.002) and lower B2MG expression (P = 0.048), although neither value was significant at ≥ 50% serration threshold. There was no difference in HLA class I/II, or PD-L1 expression on tumour cells and no difference in PD-L1, LAG3, FoxP3 and CD163 expression on immune cells. There was no association with MMR status, or BRAFV600E relative to conventional adenocarcinoma. There was improved disease-specific survival on univariate (but not multivariate) analysis between carcinomas with serrated pattern and non-mucinous conventional colonic carcinomas at ≥ 5% epithelial serrations (P = 0.04). CONCLUSION: SAC category shows a limited impact on survival, and this phenotype may harbour a unique immunological milieu.


Assuntos
Adenocarcinoma , Adenoma , Carcinoma , Neoplasias do Colo , Pólipos do Colo , Neoplasias Colorretais , Adenocarcinoma/patologia , Adenoma/patologia , Antígeno B7-H1/genética , Biomarcadores Tumorais/análise , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Fatores de Transcrição Forkhead , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Microambiente Tumoral
17.
J Clin Invest ; 132(16)2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35708912

RESUMO

Aberrant expression of viral-like repeat elements is a common feature of epithelial cancers, and the substantial diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering independent of tissue origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer cell lines demonstrated that human satellite II (HSATII) satellite repeat expression was highly associated with epithelial-mesenchymal transition (EMT) and anticorrelated with IFN-response genes indicative of a more aggressive phenotype. SATII expression - and its correlation with EMT and anticorrelation with IFN-response genes - was also found in ovarian cancer RNA-Seq data and was associated with significantly shorter survival in a second independent cohort of patients with ovarian cancer. Repeat RNAs were enriched in tumor-derived extracellular vesicles capable of stimulating monocyte-derived macrophages, demonstrating a mechanism that alters the tumor microenvironment with these viral-like sequences. Targeting of HSATII with antisense locked nucleic acids stimulated IFN response and induced MHC I expression in ovarian cancer cell lines, highlighting a potential strategy of modulating the repeatome to reestablish antitumor cell immune surveillance.


Assuntos
Neoplasias Ovarianas , RNA Satélite , Carcinoma Epitelial do Ovário/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Ovarianas/genética , Fenótipo , RNA , Microambiente Tumoral/genética
18.
Arch Pathol Lab Med ; 146(10): 1184-1193, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35657750

RESUMO

CONTEXT.­: COVID-19 has been associated with liver injury, and a small subset of patients recovering from severe disease have shown persistent markedly elevated liver biochemistries for months after infection. OBJECTIVE.­: To characterize persistent biliary injury after COVID-19. DESIGN.­: A search of the pathology archives identified 7 post-COVID-19 patients with persistent biliary injury, and the clinical, radiologic, and pathologic features were assessed. RESULTS.­: All patients in this cohort presented with respiratory symptoms and had a complicated clinical course with acute elevation of liver biochemistries. Alkaline phosphatase (ALP) was markedly and persistently elevated after discharge (median peak ALP, 1498 IU/L, at a median of 84 days from diagnosis). Magnetic resonance cholangiopancreatography showed 3 patients with irregularity, stricturing, and dilatation of intrahepatic ducts; no radiographic abnormalities were identified in the remaining 4 patients. Liver biopsies showed mild portal changes with features of cholestatic injury in 4 patients (bile duct injury and canalicular cholestasis) and marked biliary obstruction in 2 patients (profound cholestasis, ductular reaction, and bile infarcts), but no SARS-CoV-2 RNA was identified on in situ hybridization. On follow-up, most patients had minimal intervention and showed marked improvement of liver biochemistries but with mild persistent elevation of ALP. CONCLUSIONS.­: A subset of critically ill COVID-19 patients demonstrates marked and persistent cholestatic injury, with radiographic and histologic evidence of secondary sclerosing cholangitis, suggesting that cholestatic liver disease and secondary sclerosing cholangitis may be long-term sequelae of COVID-19 acute illness as a longstanding manifestation of critical illness.


Assuntos
COVID-19 , Colangite Esclerosante , Colestase , Fosfatase Alcalina , COVID-19/complicações , Colangite Esclerosante/complicações , Colangite Esclerosante/diagnóstico , Colestase/complicações , Colestase/patologia , Humanos , RNA
19.
Mod Pathol ; 35(11): 1740-1748, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35773332

RESUMO

Programmed cell death ligand 1 (PD-L1) on tumor cells is a significant prognostic biomarker for a number of malignancies, although less is known about the significance of PD-L1 positive immune cells in colon carcinoma. The purpose of this study is to evaluate the role of PD-L1 in a large cohort of colon carcinomas to identify patterns of PD-L1 expression in the tumor microenvironment and its correlation with other key immune subsets to better understand the impact of these immune cells. We assessed 1218 colon carcinomas on representative tissue microarray sections, gathered relevant clinicopathologic information, and performed immunohistochemical staining for mismatch repair proteins, CD8, CD163, LAG3, PD-L1, FoxP3, and BRAF V600E. We then performed automated quantification; manual quantification was used for PD-L1 tumor cells and immune cells. Dual PD-L1/PU.1 immunostain was also performed. The majority of PD-L1 positive cells expressed PU.1 thus representing tumor-associated macrophages. Based on the median number of PD-L1 positive immune cells (7.6/mm2), we classified tumors into two classes: (1) PD-L1 immune cell low and (2) PD-L1 immune cell high. PD-L1 immune cell high colon carcinomas showed favorable prognostic pathologic features including less frequent extramural venous invasion (p = 0.0001) and lower AJCC stage (p = 0.0001); they were also more commonly associated with deficient mismatch repair (dMMR) (p = 0.0001) and BRAF V600E reactivity. PD-LI immune cell high tumors were associated with high CD8, CD163, and FoxP3 positive cells (p = 0.0001, respectively). PD-L1 immune cell high and LAG3 high colon carcinomas were associated with improved disease-specific survival (p = 0.0001 and 0.001, respectively). PD-L1 expression on tumor cells was not associated with disease-specific survival. On multivariate analysis of chemotherapy naïve stage 2 colon carcinomas, only extramural venous invasion (p = 0.002), perineural invasion (p = 0.001) and PD-L1 immune cell expression (p = 0.032) correlated with disease-specific survival. Resected colonic carcinomas with high expression of PD-L1 and LAG3 proteins on immune cells were associated with improved prognosis in colon carcinoma. The mechanism underlying the improved prognosis of colon carcinomas bearing high numbers of immunoregulatory cells needs further investigation.


Assuntos
Carcinoma , Neoplasias do Colo , Humanos , Antígeno B7-H1 , Proteínas Proto-Oncogênicas B-raf , Ligantes , Neoplasias do Colo/patologia , Prognóstico , Fatores de Transcrição Forkhead , Biomarcadores , Carcinoma/patologia , Linfócitos do Interstício Tumoral , Biomarcadores Tumorais/análise , Microambiente Tumoral
20.
Mod Pathol ; 35(11): 1723-1731, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35590108

RESUMO

Mucinous adenocarcinoma (MAD), the most common subtype of colonic adenocarcinoma (CA), requires >50% intratumoral mucin. There is limited data regarding the impact of MAD on key lymphocyte subsets and therapeutically critical immune elements. In this study we address: (1) the definition of MAD, (2) grading of MAD, and (3) the impact of MAD and extracellular mucin on intratumoral immune milieu. Estimation of the percentage of intratumoral mucin was performed by two pathologists. Tissue microarrays were stained for immune markers including CD8, CD163, PD-L1, FoxP3, ß2 microglobulin, HLA class I, and HLA class II. Immunohistochemistry for BRAF V600E was performed. MMR status was determined on immunohistochemistry for MSH2, MSH6, MLH1, PMS2. Manual and automated HALO platforms were used for quantification. The 903 CAs included 62 (6.9%) MAD and 841 CA with ≤ 50% mucin. We identified 225 CAs with mucinous differentiation, defined by ≥10% mucin. On univariate analysis neither cut point, 50% (p = 0.08) and 10% (p = 0.08) mucin, correlated with disease-specific survival (DSS). There were no differences in key clinical, histological and molecular features between MAD and CA with mucinous differentiation. On univariate analysis of patients with MAD, tumor grade correlated with DSS (p = 0.0001) while MMR status did not (p = 0.86). There was no statistically significant difference in CD8 (P = 0.17) and CD163 (P = 0.05) positive immune cells between MAD and conventional CA. However, deficient (d) MMR MADs showed fewer CD8 (P = 0.0001), CD163 (P = 0.0001) and PD-L1 (P = 0.003) positive immune cells compared to proficient (p)MMR MADs, a finding also seen with at 10% mucin cut point. Although MAD does not impact DSS, this study raises the possibility that the immune milieu of dMMR MADs and tumors with > =10% mucin may differ from pMMR MADs and tumors with <10% mucin, a finding that may impact immune-oncology based therapeutics.


Assuntos
Adenocarcinoma Mucinoso , Neoplasias do Colo , Neoplasias Colorretais , Humanos , Reparo de Erro de Pareamento de DNA , Antígeno B7-H1/genética , Proteína 2 Homóloga a MutS/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adenocarcinoma Mucinoso/genética , Neoplasias do Colo/patologia , Biomarcadores , Fatores de Transcrição Forkhead , Mucinas , Neoplasias Colorretais/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise
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