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1.
Histochem Cell Biol ; 160(2): 113-125, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37284845

RESUMO

Mismatch repair (MMR) testing on all new cases of colorectal cancer (CRC) has customarily been preferably performed on surgical specimens, as more tissue is available; however, new clinical trials for the use of immune checkpoint inhibitors in the neoadjuvant setting require MMR testing on biopsy samples. This study aims at identifying advantages, disadvantages and any potential pitfalls in MMR evaluation on biopsy tissue and how to cope with them. The study is prospective-retrospective, recruiting 141 biopsies (86 proficient (p)MMR and 55 deficient (d)MMR) and 97 paired surgical specimens (48 pMMR; 49 dMMR). In biopsy specimens, a high number of indeterminate stains was observed, in particular for MLH1 (31 cases, 56.4%). The main reasons were a punctate nuclear expression of MLH1, relatively weak MLH1 nuclear expression compared to internal controls, or both (making MLH1 loss difficult to interpret), which was solved by reducing primary incubation times for MLH1. A mean of  ≥ 5 biopsies had adequate immunostains, compared to ≤ 3 biopsies in inadequate cases. Conversely, surgical specimens rarely suffered from indeterminate reactions, while weaker staining intensity (p < 0.007) for MLH1 and PMS2 and increased patchiness grade (p < 0.0001) were seen. Central artefacts were almost exclusive to surgical specimens. MMR status classification was possible in 92/97 matched biopsy/resection specimen cases, and all of these were concordant (47 pMMR and 45 dMMR). Evaluation of MMR status on CRC biopsy samples is feasible, if pitfalls in interpretation are known, making laboratory-specific appropriate staining protocols fundamental for high-quality diagnoses.


Assuntos
Neoplasias Colorretais , Humanos , Estudos Retrospectivos , Estudos Prospectivos , Neoplasias Colorretais/genética , Biópsia
2.
Tech Coloproctol ; 26(9): 713-723, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35648263

RESUMO

BACKGROUND: Assessment of mucosal healing is important for the management of patients with inflammatory bowel disease (IBD), but endoscopy can miss microscopic disease areas that may relapse. Histological assessment is informative, but no single scoring system is widely adopted. We previously proposed an eight-item histological scheme for the easy, fast reporting of disease activity in the intestine. The aim of the present study was to evaluate the performance of our Simplified Histologic Mucosal Healing Scheme (SHMHS). METHODS: Between April and May 2021 pathologists and gastroenterologists in Italy were invited to contribute to this multicenter study by providing data on single endoscopic-histological examinations for their IBD patients undergoing treatment. Disease activity was expressed using SHMHS (maximum score, 8) and either Simple Endoscopic Score for Crohn's Disease (categorized into grades 0-3) or Mayo Endoscopic Subscore (range 0-3). RESULTS: Thirty hospitals provided data on 597 patients (291 Crohn's disease; 306 ulcerative colitis). The mean SHMHS score was 2.96 (SD = 2.42) and 66.8% of cases had active disease (score ≥ 2). The mean endoscopic score was 1.23 (SD = 1.05), with 67.8% having active disease (score ≥ 1). Histologic and endoscopic scores correlated (Spearman's ρ = 0.76), and scores for individual SHMHS items associated directly with endoscopic scores (chi-square p < 0.001, all comparisons). Between IBD types, scores for SHMHS items reflected differences in presentation, with cryptitis more common and erosions/ulcerations less common in Crohn's disease, and the distal colon more affected in ulcerative colitis. CONCLUSIONS: SHMHS captures the main histological features of IBD. Routine adoption may simplify pathologist workload while ensuring accurate reporting for clinical decision making.


Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Doença Crônica , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/patologia , Endoscopia Gastrointestinal , Humanos , Mucosa Intestinal/patologia , Índice de Gravidade de Doença
3.
Ann Oncol ; 29(12): 2356-2362, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30481267

RESUMO

Background: Following neoadjuvant chemotherapy for operable gastroesophageal cancer, lymph node metastasis is the only validated prognostic variable; however, within lymph node groups there is still heterogeneity with risk of relapse. We hypothesized that gene profiles from neoadjuvant chemotherapy treated resection specimens from gastroesophageal cancer patients can be used to define prognostic risk groups to identify patients at risk for relapse. Patients and methods: The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial (n = 202 with high quality RNA) samples treated with perioperative chemotherapy were profiled for a custom gastric cancer gene panel using the NanoString platform. Genes associated with overall survival (OS) were identified using penalized and standard Cox regression, followed by generation of risk scores and development of a NanoString biomarker assay to stratify patients into risk groups associated with OS. An independent dataset served as a validation cohort. Results: Regression and clustering analysis of MAGIC patients defined a seven-Gene Signature and two risk groups with different OS [hazard ratio (HR) 5.1; P < 0.0001]. The median OS of high- and low-risk groups were 10.2 [95% confidence interval (CI) of 6.5 and 13.2 months] and 80.9 months (CI: 43.0 months and not assessable), respectively. Risk groups were independently prognostic of lymph node metastasis by multivariate analysis (HR 3.6 in node positive group, P = 0.02; HR 3.6 in high-risk group, P = 0.0002), and not prognostic in surgery only patients (n = 118; log rank P = 0.2). A validation cohort independently confirmed these findings. Conclusions: These results suggest that gene-based risk groups can independently predict prognosis in gastroesophageal cancer patients treated with neoadjuvant chemotherapy. This signature and associated assay may help risk stratify these patients for post-surgery chemotherapy in future perioperative chemotherapy-based clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Esofágicas/terapia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Gástricas/terapia , Transcriptoma/genética , Adulto , Idoso , Quimioterapia Adjuvante/métodos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Esofagectomia , Esôfago/patologia , Esôfago/cirurgia , Feminino , Gastrectomia , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Prospectivos , Medição de Risco/métodos , Estômago/patologia , Estômago/cirurgia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Resultado do Tratamento
5.
Ann Oncol ; 28(6): 1243-1249, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28327965

RESUMO

Background: Patients often ask oncologists how long a cancer has been present before causing symptoms or spreading to other organs. The evolutionary trajectory of cancers can be defined using phylogenetic approaches but lack of chronological references makes dating the exact onset of tumours very challenging. Patients and methods: Here, we describe the case of a colorectal cancer (CRC) patient presenting with synchronous lung metastasis and metachronous thyroid, chest wall and urinary tract metastases over the course of 5 years. The chest wall metastasis was caused by needle tract seeding, implying a known time of onset. Using whole genome sequencing data from primary and metastatic sites we inferred the complete chronology of the cancer by exploiting the time of needle tract seeding as an in vivo 'stopwatch'. This approach allowed us to follow the progression of the disease back in time, dating each ancestral node of the phylogenetic tree in the past history of the tumour. We used a Bayesian phylogenomic approach, which accounts for possible dynamic changes in mutational rate, to reconstruct the phylogenetic tree and effectively 'carbon date' the malignant progression. Results: The primary colon cancer emerged between 5 and 8 years before the clinical diagnosis. The primary tumour metastasized to the lung and the thyroid within a year from its onset. The thyroid lesion presented as a tumour-to-tumour deposit within a benign Hurthle adenoma. Despite rapid metastatic progression from the primary tumour, the patient showed an indolent disease course. Primary cancer and metastases were microsatellite stable and displayed low chromosomal instability. Neo-antigen analysis suggested minimal immunogenicity. Conclusion: Our data provide the first in vivo experimental evidence documenting the timing of metastatic progression in CRC and suggest that genomic instability might be more important than the metastatic potential of the primary cancer in dictating CRC fate.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Progressão da Doença , Genoma , Humanos , Metástase Neoplásica
6.
Ann Oncol ; 27(1): 42-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26483050

RESUMO

BACKGROUND: The extranodal extension (ENE) of nodal metastasis (i.e. the extension of tumor cells through the nodal capsule into the perinodal adipose tissue) has recently emerged as an important prognostic factor in different types of malignancies. However, the tumor-node-metastasis (TNM) staging system for colorectal cancer does not consider it as a prognostic parameter. Therefore, we conducted a systematic review and meta-analysis to determine the prognostic role of ENE in patients with lymph node-positive colorectal cancer. MATERIALS AND METHODS: Two independent authors searched PubMed and SCOPUS until 7 January 2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with colorectal cancer, comparing participants with the presence of ENE (ENE+) versus only intranodal extension (ENE-) were eligible. Data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) together with 95% confidence intervals (CIs) for time-dependent risk related to ENE+, adjusted for potential confounders. RESULTS: Thirteen studies including 1336 patients were identified with a median follow-up of 4.7 years. ENE was associated with a higher T stage and tumor grading. In addition, ENE was associated with a significantly increased risk of all-cause mortality (RR = 1.75; 95% CI 1.42-2.16, P < 0.0001, I(2) = 60%; HR = 1.69, 95% CI 1.32-2.17, P < 0.0001, I(2) = 46%) and of recurrence of disease (RR = 2.07, 95% CI 1.65-2.61, P < 0.0001, I(2) = 47%; HR = 2.31, 95% CI 1.54-3.44, P < 0.0001, I(2) = 48%). CONCLUSIONS: Based of these results, in colorectal cancer, ENE should be considered from the gross sampling to the pathology report, as well as in future oncologic staging systems.


Assuntos
Neoplasias Colorretais/patologia , Linfonodos/patologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/terapia , Humanos , Metástase Linfática , Recidiva Local de Neoplasia , Prognóstico , Modelos de Riscos Proporcionais , Análise de Regressão , Resultado do Tratamento
7.
Pharmacogenomics J ; 16(3): 266-71, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26054330

RESUMO

The occurrence of a second primary esophageal carcinoma (EC) in long-term cancer survivors may represent a late effect of previous radio-chemotherapeutic treatment. To identify the genetic factors that could increase this risk, we analyzed nine variants within ERCC1, XPD, XRCC1 and XRCC3 DNA repair pathway genes, and GSTP1, TP53 and MDM2 genes in 61 patients who received radio-chemotherapy for a prior lymphoma or breast cancer; 29 of them had a second primary EC. This cohort consists of 22 esophageal squamous cell carcinoma (ESCC) and 7 esophageal adenocarcinoma (EADC) patients. A validation cohort of 154 patients with sporadic EC was also included. The XPD Asp312Asn (rs1799793) was found to be associated with the risk of developing second primary ESCC (P=0.015). The resultant variant was also involved in the onset of sporadic ESCC (P=0.0018). To know in advance who among long-term cancer survivors have an increased risk of EC could lead to a more appropriate follow-up strategy.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/terapia , Carcinoma de Células Escamosas/genética , Quimiorradioterapia , Neoplasias Esofágicas/genética , Variação Genética , Linfoma/terapia , Segunda Neoplasia Primária/genética , Sobreviventes , Proteína Grupo D do Xeroderma Pigmentoso/genética , Adenocarcinoma/diagnóstico , Neoplasias da Mama/patologia , Carcinoma de Células Escamosas/diagnóstico , Estudos de Casos e Controles , Neoplasias Esofágicas/diagnóstico , Carcinoma de Células Escamosas do Esôfago , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Linfoma/diagnóstico , Masculino , Segunda Neoplasia Primária/diagnóstico , Fenótipo , Projetos Piloto , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
8.
Dis Esophagus ; 28(4): 394-403, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24708360

RESUMO

Human epidermal growth factor receptor 2 (HER2) is involved in the malignant progression of several human cancers, including esophageal adenocarcinoma (EAC). The purpose of this study was to evaluate HER2 overexpression and to explore the feasibility of confocal laser endomicroscopy for in vivo molecular imaging of HER2 status in an animal model of Barrett's-related EAC. Rats underwent esophagojejunostomy with gastric preservation. At 30 weeks post-surgery, the esophagus of 46 rats was studied; endoscopic and histological findings were correlated with HER2 immunofluorescence on excised biopsies and gross specimens. At this age, 23/46 rats developed Barrett's esophagus (BE), and 6/46 had cancer (four EAC and two squamous cell carcinomas). A significant overexpression of HER2 was observed in esophageal adenocarcinoma compared with normal squamous esophagus (9.4-fold) and BE (6.0-fold). AKT and its phosphorylated form were also overexpressed in cancer areas. Molecular imaging was performed at 80 weeks post-surgery in four rats after tail injection of fluorescent-labeled anti-HER2 antibody. At this age, 3/4 rats developed advance adenocarcinoma and showed in vivo overexpression of HER2 by molecular confocal laser endomicroscopy with heterogeneous distribution within cancer; no HER2 signal was observed in normal or Barrett's tissues. Therefore, HER2 overexpression is a typical feature of the surgical induced model of EAC that can be easily quantified in vivo using an innovative mini-invasive approach including confocal endomicroscopy; this approach may avoid limits of histological evaluation of HER2 status on 'blinded' biopsies.


Assuntos
Adenocarcinoma/metabolismo , Esôfago de Barrett/metabolismo , Neoplasias Esofágicas/metabolismo , Imagem Molecular/métodos , Adenocarcinoma/induzido quimicamente , Animais , Esôfago de Barrett/complicações , Biópsia , Carcinoma de Células Escamosas/metabolismo , Modelos Animais de Doenças , Endoscopia , Neoplasias Esofágicas/induzido quimicamente , Imunofluorescência , Microscopia Intravital/métodos , Microscopia Confocal/métodos , Ratos , Ratos Sprague-Dawley , Receptor ErbB-2 , Coloração e Rotulagem
9.
Br J Cancer ; 111(9): 1780-7, 2014 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-25137017

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human malignancies with an overall 5-year survival rate of <5%. Despite significant advances in treatment of the disease during the past decade, the median survival rate (∼6 months) has hardly improved, warranting the need to identify novel targets for therapeutic approaches. METHODS: Quantitative real time PCR, western blot analyses and immunohistochemical staining of tissue microarrays were used to analyse the expression of TTK gene in primary PDAC tissues and cell lines. To inhibit TTK kinase expression in a variety of pancreatic cancer cell lines, RNA interference was used. Functional roles of this kinase in the context of PDAC were studied using cell proliferation, viability and anchorage-independent growth assays. Western blotting, fluorescence-activated cell sorting analyses and fluorescence microscopy were used to gain mechanistic insight into the functional effects. CONCLUSIONS: We show that the dual specificity kinase TTK (also known as Mps1), is strongly overexpressed in human PDAC. Functionally, cell proliferation was significantly attenuated following TTK knockdown, whereas apoptosis and necrosis rates were significantly increased. In addition, anchorage-independent growth, a hallmark of malignant transformation and metastatic potential, was strongly impaired in the absence of TTK gene function. Interestingly, immortalised normal pancreatic hTERT-HPNE cells were not affected by loss of TTK function. Mechanistically, these effects in cancer cells were associated with increased formation of micronuclei, suggesting that loss of TTK function in pancreatic cancer cells results in chromosomal instability and mitotic catastrophe. Taken together, our data show that TTK function is critical for growth and proliferation of pancreatic cancer cells, thus establishing this kinase as an interesting new target for novel therapeutic approaches in combating this malignancy.


Assuntos
Adenocarcinoma/patologia , Apoptose , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/patologia , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Pâncreas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Adenocarcinoma/metabolismo , Western Blotting , Carcinoma Ductal Pancreático/metabolismo , Estudos de Casos e Controles , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pancreáticas/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de Tecidos , Células Tumorais Cultivadas
11.
Br J Cancer ; 107(8): 1286-94, 2012 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-22955853

RESUMO

BACKGROUND: Recently, we developed an apoptotic assay for expanding the monitoring capabilities of the circulating tumour cells (CTC) test during therapy. An automated platform for computing CTCs was integrated with a mAb (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 in early apoptosis; we showed that live CTCs were associated with progression, consistent with enhanced cell migration and invasion. The test was first applied here to mRCC. METHODS: Live/apoptotic CTCs changes were measured in mRCC patients receiving first-line Sunitinib and compared with circulating endothelial cell (CEC) levels. RESULTS: The presence of EpCAM-positive, live CTCs predicts progression in individual mRCC patient, being associated with distant metastasis under first-line Sunitinib. Synchronous detection of CTCs and CEC levels discloses for the first time an association between their dynamic changes and outcome: a rapid increase of the CEC number as early as the first cycle of therapy is associated with CTC decrease in non-progressed patients, whereas a delayed response of CECs is related to higher CTC values in the progressed group indicating treatment failure. CONCLUSION: We demonstrated that a delayed response to antiangiogenic treatment indicated by persistent detection of CECs correlates with persistent live CTCs and more aggressive disease.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Células Endoteliais/patologia , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Células Neoplásicas Circulantes/patologia , Pirróis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Biomarcadores Tumorais , Progressão da Doença , Feminino , Humanos , Queratina-18 , Neoplasias Renais/patologia , Neoplasias Renais/secundário , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sunitinibe , Falha de Tratamento
12.
Dis Esophagus ; 25(3): 263-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21883657

RESUMO

The programmed cell death 4 (PDCD4) tumor suppressor is down-regulated in several malignancies, and the (subcellular) expression of its protein product is modulated by both oncomiR miR-21 and protein kinase B (Akt). PDCD4 and activated Akt (phosphorylated Akt [pAkt]) expression were assessed immunohistochemically in 53 tissue samples obtained from 25 endoscopic esophageal mucosal resections performed for squamous intraepithelial neoplasia (IEN) or squamous intramucosal carcinoma (IM-SSC). In total, 33 IEN (low-grade = 15; high-grade = 15) and 20 IM-SSC specimens were considered; 50 additional tissue samples of histologically proven normal esophageal mucosa were considered as normal controls. To further validate the results achieved, miR-21 expression (as assessed by quantitative real-time polymerase chain reaction and in situ hybridization) was tested in another series of 15 normal esophageal tissue samples, 15 high-grade IEN, and 15 IM-SCCs. Normal suprabasal squamous epithelial layers consistently featured strong PDCD4 nuclear immunostaining, which was significantly lower (P < 0.001) in IEN (both low-and high-grade) and in IM-SSC. Conversely, pAkt and miR-21 expression was significantly up-regulated in the whole spectrum of preneoplastic/neoplastic lesions considered. PDCD4 down-regulation, as assessed by immunohistochemistry, is a reliable biomarker of early-stage squamous cell esophageal neoplasia, providing additional information in the histological assessment of these lesions.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma in Situ/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/metabolismo , Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/patologia , Núcleo Celular/metabolismo , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Regulação para Baixo , Neoplasias Esofágicas/patologia , Humanos , Imuno-Histoquímica , Estudos Retrospectivos , Estatísticas não Paramétricas
13.
Cytopathology ; 23(4): 213-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22805511

RESUMO

AThe emerging treatment revolution determined by the advent of new targeted therapies requires accurate tumour subtyping as a mandatory step in the clinical workup of patients with non-small cell lung carcinoma (NSCLC). As a result of advanced and inoperable disease or poor performance status, in many patients, minimally invasive procedures must be employed to obtain diagnostic material. Fine needle aspiration (FNA) is a valid and widely employed alternative to either tru-cut or open-sky biopsy. Indeed, cytological specimens are suitable for techniques such as immunocytochemistry, mutation and microRNA analysis, and may present advantages over small biopsies especially if cell blocks are prepared and attention is paid to cytomorphology and pre-analytic management of specimens at the time they are collected. These will allow the adequate stratification of patients into different diagnostic and prognostic classes.


Assuntos
Adenocarcinoma , Biópsia por Agulha Fina/métodos , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Análise Mutacional de DNA , Endossonografia , Humanos , Imuno-Histoquímica , MicroRNAs , Prognóstico
16.
Cytopathology ; 22(5): 306-12, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20738359

RESUMO

OBJECTIVE: To prospectively investigate the role of trans-thoracic fine needle aspiration cytology (FNA) and the value of rapid on-site evaluation (ROSE) in the clinical management of patients with pulmonary nodules/masses. Computed tomography (CT)-guided FNA is commonly employed for the diagnosis of lung lesions although its position in the diagnostic work-up is still a matter of debate. METHODS: We reviewed 311 patients (211 males and 100 females, mean age 69.5 years) admitted to the University of Padova from 2004 to 2008, correlating the results of cytology with the available histological findings obtained from biopsies, surgery or autopsy. RESULTS: Smears were adequate in 305 cases (98%) and inadequate in six (2%); a diagnosis of malignancy was achieved in 263 cases (86.2%); 39 cases (12.8%) were classified as non-malignant; and three cases (1%) were classified as suspect for malignancy. When correlated with histology, FNA with ROSE discriminated malignant versus non-malignant lesions (Cohen's kappa 0.78), with three false negatives (sensitivity 96.3%, specificity 100%). Moreover, a satisfactory overall agreement of 71.4% was achieved in differentiating the cancer histological types. Pneumothorax occurred in 13 cases, haemoptysis in four, and chest pain in three. A single aspiration was sufficient in 79.6% of patients; two aspirations were needed in 17.4% and three in 3%. The low complication rate was related to the limited number of aspirations needed due to ROSE. CONCLUSIONS: FNA with ROSE is a safe and useful tool in the diagnostic work-up of lung cancer patients, with no contraindications to its use as the first diagnostic procedure for all patients with peripheral lung lesions. FNA with ROSE should be reconsidered in the guidelines for diagnosing and managing lung cancer.


Assuntos
Biópsia por Agulha Fina/métodos , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autopsia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tomografia Computadorizada por Raios X
17.
ESMO Open ; 6(4): 100211, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34271310

RESUMO

BACKGROUND: Intratumor heterogeneity (ITH) is described as the presence of various clones within one tumor, each with their own unique features in terms of morphology, inflammation, genetics or transcriptomics. Heterogeneity provides the fuel for drug resistance; therefore, an accurate assessment of tumor heterogeneity is essential for the development of effective therapies. The purpose of this study was to dissect morphologic and molecular ITH in colorectal adenocarcinoma. MATERIALS AND METHODS: A series of 120 V600EBRAF-mutated (V600EBRAFmt) consecutive metastatic colorectal adenocarcinomas was assessed for morphologic heterogeneity. The two heterogeneous components of each specimen underwent a histopathological, immunohistochemical and molecular characterization to evaluate: histologic variant, grading, tumor-infiltrating lymphocytes (TILs), mismatch repair proteins' expression, KRAS/BRAF/NRAS mutations, microsatellite instability (MSI) status and consensus molecular subtype (CMS). RESULTS: Thirty-one out of 120 (25.8%) V600EBRAFmt primary colorectal adenocarcinomas presented a heterogeneous morphology. Among these, eight cases had adequate material for molecular profiling. Five out of the eight (62.5%) cases resulted instable at MSI testing. The majority (62.5%) of the samples showed a CMS4 phenotype based on gene expression profiling. Heterogeneity in CMS classification was observed in four out of eight cases. One out of eight cases presented significant heterogeneity in the number of TILs between the two components of the tumor. CONCLUSIONS: Although the distribution of the immune infiltrate appears relatively conserved among heterogeneous areas of the same tumor, changes in gene expression profile and CMS occur in 50% of V600EBRAFmt adenocarcinoma cases in our small series and might contribute to variability in response to anticancer therapy and clinical outcomes. Assessment of morphological and molecular ITH is needed to improve colorectal cancer classification and to tailor anticancer treatments and should be included in the pathology report.


Assuntos
Neoplasias Colorretais , Adenocarcinoma/genética , Neoplasias Colorretais/genética , Humanos , Instabilidade de Microssatélites , Proteínas Proto-Oncogênicas B-raf/genética , Transcriptoma/genética
18.
ESMO Open ; 6(3): 100164, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34091263

RESUMO

The term liquid biopsy (LB) refers to the use of various biological fluids as a surrogate for neoplastic tissue to achieve information for diagnostic, prognostic and predictive purposes. In the current clinical practice, LB is used for the identification of driver mutations in circulating tumor DNA derived from both tumor tissue and circulating neoplastic cells. As suggested by a growing body of evidence, however, there are several clinical settings where biological samples other than tissue could be used in the routine practice to identify potentially predictive biomarkers of either response or resistance to targeted treatments. New applications are emerging as useful clinical tools, and other blood derivatives, such as circulating tumor cells, circulating tumor RNA, microRNAs, platelets, extracellular vesicles, as well as other biofluids such as urine and cerebrospinal fluid, may be adopted in the near future. Despite the evident advantages compared with tissue biopsy, LB still presents some limitations due to both biological and technological issues. In this context, the absence of harmonized procedures corresponds to an unmet clinical need, ultimately affecting the rapid implementation of LB in clinical practice. In this position paper, based on experts' opinions, the AIOM-SIAPEC-IAP-SIBIOC-SIF Italian Scientific Societies critically discuss the most relevant technical issues of LB, the current and emerging evidences, with the aim to optimizing the applications of LB in the clinical setting.


Assuntos
Células Neoplásicas Circulantes , Sociedades Científicas , Biomarcadores Tumorais/genética , Humanos , Itália , Biópsia Líquida
19.
Virchows Arch ; 475(2): 245-249, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30852641

RESUMO

BACKGROUND: Rhabdoid colorectal carcinoma (RC) is a rare lesion localized to the proximal colon of patients with a mean age at diagnosis of around 70 years. This tumor shows an aggressive behavior with an overall survival period shorter than 12 months. The diagnostic hallmark is the presence of rhabdoid cells. Alterations in chromatin remodeling (SMARCB1) and in the centrosome structure (CROCC) are reported in RC usually BRAFmut and MSI-H. RKO intestinal neoplastic cells culture (BRAFmut, SMARCB1wt, MSI-H) with CROCC knockdown exhibit rhabdoid features and develop prominent projections from the edge of the cell. METHODS: Here, we investigated two cases of CROCCmutSMARCB1wt RC by scanning and transmission electron microscopy (SEM, TEM). RESULTS: TEM confirmed the diagnostic presence of intermediate cytoplasmic filaments and nucleolar margination. SEM showed cellular protrusions (lamellipodia) in the intercellular spaces not evident at light microscopy. CONCLUSIONS: These protrusions CROCC-related might represent the pathogenetic mechanism underlying the rhabdoid aggressive behavior, independently of tumor staging. To our knowledge, the SEM technique was applied in the study of this neoplasm for the first time.


Assuntos
Adenocarcinoma/ultraestrutura , Neoplasias Colorretais/ultraestrutura , Proteínas do Citoesqueleto/genética , Tumor Rabdoide/ultraestrutura , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Humanos , Microscopia Eletrônica , Pseudópodes/patologia , Pseudópodes/ultraestrutura , Tumor Rabdoide/genética , Tumor Rabdoide/patologia
20.
Eur J Cancer ; 101: 191-200, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30077124

RESUMO

INTRODUCTION: The prognosis of small-cell lung cancer (SCLC) is dismal and new effective therapies are needed. Immunotherapy looks promising, but no molecular predictive markers are currently available, and data on immune microenvironment are very limited. METHODS: We retrospectively analysed 104 SCLC cases. Immunohistochemistry evaluation of PD-L1 was performed both on tumour cells (TCs) and on tumour-infiltrating immune cells (TIICs) by using anti-PD-L1 22C3 antibody (DAKO) and categorised by using 1% as cut-off point. Tumour-infiltrating lymphocytes (TILs) were characterised by using anti-CD8 and anti-FOXP3 antibodies. Semi-quantitative score was used and categorised as positive versus negative/low. The relation of molecular markers with prognosis and with clinical variables was evaluated. RESULTS: The analysis included 66 stage I-III patients (48 surgically resected, 18 treated with radical-intent chemoradiotherapy) and 38 metastatic cases. In the overall study population, PD-L1 was expressed on TCs and TIICs in 25% and 40% of cases, respectively. The proportion of PD-L1-positive cases was significantly higher in stage I-III versus metastatic patients (32% versus 13%, p: 0.034 for TCs; 51.5% versus 21% for TIICs, p: 0.002). CD8- and FOXP3-positive TILs were present in 59% and 72% of samples, respectively. The presence of FOXP3-TILs was associated with improved prognosis among non-metastatic patients, with a hazard ratio for survival of 0.32 (95% confidence interval [CI]: 0.16-0.7, p: 0.006) for univariate analysis, and 0.37 (95% CI: 0.17-0.81, p: 0.013) for multivariate analysis. CONCLUSIONS: Immune contexture of SCLC may differ according to stage. The presence of FOXP3-positive TILs is a potential prognostic marker for stage I-III SCLCs and warrants further investigation.


Assuntos
Antígeno B7-H1/imunologia , Fatores de Transcrição Forkhead/imunologia , Neoplasias Pulmonares/imunologia , Carcinoma de Pequenas Células do Pulmão/imunologia , Microambiente Tumoral/imunologia , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/biossíntese , Feminino , Fatores de Transcrição Forkhead/biossíntese , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/terapia
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