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1.
Cytopathology ; 35(4): 444-453, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38534091

RESUMO

Interobserver variability remains a major challenge for cytopathologists despite the development of standardized reporting and classification systems. Indeed, whereas moderate-to-good interobserver agreement is generally achievable when the differential diagnosis between benign and malignant entities is straightforward, high levels of variability make the diagnostic interpretation of atypical and suspicious samples not consistent. This review explores the landscape of interobserver agreement in cytopathology across different anatomical sites.


Assuntos
Citodiagnóstico , Variações Dependentes do Observador , Humanos , Citodiagnóstico/métodos , Diagnóstico Diferencial , Neoplasias/patologia , Neoplasias/diagnóstico , Citologia
2.
Cytopathology ; 35(3): 330-343, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38308401

RESUMO

Recently, significant advances in the molecular characterization of salivary gland neoplasms have facilitated the classification and diagnosis of specific diagnostic entities. In the highly challenging diagnostic scenario of salivary malignancies, molecular testing is increasingly being adopted in routine practice to refine the cytological diagnosis of salivary lesions. Here, we reviewed the most recent evidence in the field of salivary glands molecular cytopathology.


Assuntos
Neoplasias das Glândulas Salivares , Glândulas Salivares , Humanos , Biópsia por Agulha Fina , Glândulas Salivares/patologia , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/genética , Técnicas de Diagnóstico Molecular , Estudos Retrospectivos
3.
Cytopathology ; 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38979838

RESUMO

Fine-needle aspiration (FNA) guided by ultrasound (US) has emerged as a highly precise diagnostic method for managing thyroid nodules, significantly diminishing unnecessary surgeries. The effectiveness of US-guided FNA is high when a single specialist performs the FNA procedure and the microscopy. This paradigm has paved the way for the evolution of interventional cytopathology, a specialist with a pivotal role in the preoperative diagnostic process, encompassing patient history review, clinical examination, FNA execution under US guidance, preparation, and microscopic interpretation of cytological samples. As the landscape of precision medicine unfolds, molecular testing assumes greater importance in thyroid cytopathology, particularly in refining the risk of malignancy for indeterminate nodules. The updated Bethesda classification system underscores the clinical significance of molecular tests, emphasizing their role in refining diagnostic accuracy. With this evolving landscape, interventional cytopathologists must adapt by acquiring expertise in molecular technologies and addressing ongoing challenges in workflow harmonization and optimization. This paper delves into our decade-long experience as interventional cytopathologists, focusing on recent endeavours to ensure adequate samples not only for microscopic diagnosis but also for molecular testing. Additionally, here we review the challenges of integrating next-generation sequencing (NGS) technology into clinical practice, highlighting the importance of integrating clinically meaningful molecular data into comprehensive molecular cytology reports.

4.
Cytopathology ; 34(3): 198-203, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36658094

RESUMO

BACKGROUND: The management of cutaneous melanoma has changed dramatically in recent years thanks to the development of tyrosine kinase and immune-checkpoint inhibitors (ICIs). Thus, multiple biomarker testing is becoming ever more important for the identification of patients who are potentially eligible for these treatments. One reliable approach to the molecular evaluation of metastatic melanoma is fine needle cytology (FNC). To examine the utility of this approach for assessing PD-L1 expression levels, we evaluated the cellular adequacy of residual cell block (CB) material from metastatic melanomas that were previously tested for BRAF and NRAS mutations. METHODS: We retrieved from our internal archives a series of FNC samples of metastatic melanoma that had been subjected to molecular testing on residual CB material or a dedicated needle rinse between January 2016 and July 2022. Real-time polymerase chain reaction was used to assess BRAF and NRAS status, and an SP263 assay was employed to ascertain PD-L1 expression levels. RESULTS: Overall, n = 19 cases were selected. Of these, 11 (57.9%) cases revealed a BRAF exon 15 p.V600E mutation, one case (5.3%) revealed NRAS mutation, and seven cases (36.8%) showed no mutations. Regarding PD-L1 assessment, 16/19 (84.2%) cases were deemed adequate, meaning they contained at least 100 viable cells. CONCLUSIONS: We highlighted the feasibility of assessing PD-L1 expression levels in residual CB material from metastatic melanomas previously tested for BRAF and NRAS mutations. Moreover, we pointed out that FNC needle rinses may be an alternative source of nucleic acids for molecular testing, preserving CB material for immunocytochemistry evaluation.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/diagnóstico , Melanoma/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Antígeno B7-H1 , Proteínas Proto-Oncogênicas B-raf/genética , GTP Fosfo-Hidrolases/genética , Biomarcadores , Melanoma Maligno Cutâneo
5.
Cytopathology ; 34(1): 5-14, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36082410

RESUMO

Whole slide imaging (WSI) allows pathologists to view virtual versions of slides on computer monitors. With increasing adoption of digital pathology, laboratories have begun to validate their WSI systems for diagnostic purposes according to reference guidelines. Among these the College of American Pathologists (CAP) guideline includes three strong recommendations (SRs) and nine good practice statements (GPSs). To date, the application of WSI to cytopathology has been beyond the scope of the CAP guideline due to limited evidence. Herein we systematically reviewed the published literature on WSI validation studies in cytology. A systematic search was carried out in PubMed-MEDLINE and Embase databases up to November 2021 to identify all publications regarding validation of WSI in cytology. Each article was reviewed to determine if SRs and/or GPSs recommended by the CAP guideline were adequately satisfied. Of 3963 retrieved articles, 25 were included. Only 4/25 studies (16%) satisfied all three SRs, with only one publication (1/25, 4%) fulfilling all three SRs and nine GPSs. Lack of a suitable validation dataset was the main missing SR (16/25, 64%) and less than a third of the studies reported intra-observer variability data (7/25, 28%). Whilst the CAP guideline for WSI validation in clinical practice helped the widespread adoption of digital pathology, more evidence is required to routinely employ WSI for diagnostic purposes in cytopathology practice. More dedicated validation studies satisfying all SRs and/or GPSs recommended by the CAP are needed to help expedite the use of WSI for primary diagnosis in cytopathology.


Assuntos
Interpretação de Imagem Assistida por Computador , Microscopia , Humanos , Microscopia/métodos , Interpretação de Imagem Assistida por Computador/métodos , Variações Dependentes do Observador , Citodiagnóstico/métodos , Laboratórios
6.
Cytopathology ; 34(6): 581-589, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37530465

RESUMO

OBJECTIVE: Despite an increase in thyroid fine needle aspiration (FNA) and advances in whole slide imaging (WSI) adoption, digital pathology is still considered inadequate for primary diagnosis of these cases. Herein, we aim to validate the utility of WSI in thyroid FNAs employing the Delphi method strategy. METHODS: A panel of experts from seven reference cytology centres was recruited. The study consisted of two consecutive rounds: (1) an open-ended, free-response questionnaire generating a list of survey items; and (2) a consensus analysis of 80 selected shared WSIs from 80 cases by six investigators answering six morphological questions utilising a 1 to 5 Likert scale. RESULTS: High consensus was achieved for all parameters, with an overall average score of 4.27. The broad majority of items (84%) were ranked either 4 or 5 by each physician. Two badly scanned cases were responsible for more than half of the low-ranked (≤2) values (57%). Good to excellent (≥3) diagnostic confidence was reached in more than 95.2% of cases. For most cases (78%) WSI assessment was not limited by technical issues linked to the image acquisition process. CONCLUSION: This systematic Delphi study indicates broad consensus among participating physicians on the application of DP to thyroid cytopathology, supporting expert opinion that WSI is reliable and safe for primary diagnostic purposes.

7.
Int J Mol Sci ; 24(3)2023 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-36768889

RESUMO

Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are low-risk thyroid lesions most often characterised by RAS-type mutations. The histological diagnosis may be challenging, and even immunohistochemistry and molecular approaches have not yet provided conclusive solutions. This study characterises a set of NIFTPs by Matrix-Assisted Laser Desorption/Ionisation (MALDI)-Mass Spectrometry Imaging (MSI) to highlight the proteomic signatures capable of overcoming histological challenges. Archived formalin-fixed paraffin-embedded samples from 10 NIFTPs (n = 6 RAS-mutated and n = 4 RAS-wild type) were trypsin-digested and analysed by MALDI-MSI, comparing their profiles to normal tissue and synchronous benign nodules. This allowed the definition of a four-peptide signature able to distinguish RAS-mutant from wild-type cases, the latter showing proteomic similarities to hyperplastic nodules. Moreover, among the differentially expressed signals, Peptidylprolyl Isomerase A (PPIA, 1505.8 m/z), which has already demonstrated a role in the development of cancer, was found overexpressed in NIFTP RAS-mutated nodules compared to wild-type lesions. These results underlined that high-throughput proteomic approaches may add a further level of biological comprehension for NIFTPs. In the future, thanks to the powerful single-cell detail achieved by new instruments, the complementary NGS-MALDI imaging sequence might be the correct methodological approach to confirm that the current NIFTP definition encompasses heterogeneous lesions that must be further characterised.


Assuntos
Adenocarcinoma Folicular , Neoplasias da Glândula Tireoide , Humanos , Adenocarcinoma Folicular/patologia , Proteômica , Neoplasias da Glândula Tireoide/patologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
8.
Cytopathology ; 33(6): 668-677, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35986701

RESUMO

OBJECTIVE: Fine needle cytology (FNC) is widely used as a first-line procedure in the diagnostic algorithm of lymphadenopathies. In a metastatic setting, a first-line diagnostic approach identifies non-haematopoietic malignancy; however, cytopathologists could also provide a second diagnostic level, identifying the origin of the primary tumour. This paper outlines a comprehensive and practical approach to the cytological diagnosis of lymph node metastases. METHODS: Cytological diagnoses of lymph node metastases performed over a 10-year period were selected and divided into two groups. The first group, labelled "oncological," comprised patients with a previous history of malignancy; the second group, labelled "naïve," included patients with no relevant history. Pathology records were retrieved to record microscopic findings, namely, background appearance, group architecture, and specific cell features; data from cell block (CB) preparations were also collected. RESULTS: Overall, 982 cases were selected: 497 cases (50.61%) in the naïve group, and 485 (49.39%) in the oncological group. Overall, a second diagnostic level was achieved in 834/982 cases (84.92%); cases diagnosed as carcinoma not otherwise specified were more frequent in the naïve group than in the oncological group (17.51% vs. 8.04%, P < 0.01). Notably, although CB material was available in only 44.87% of the naïve cases, we were able to achieve a second diagnostic level thanks to the integration of clinical and cytomorphological findings, plus lymph node topography, in 82.49% of the cases. CONCLUSION: Our results confirmed that in a metastatic setting, FNC can reliably lead to the identification of the origin of the primary tumour.


Assuntos
Citodiagnóstico , Linfonodos , Biópsia por Agulha Fina/métodos , Humanos , Linfonodos/patologia , Metástase Linfática/diagnóstico , Metástase Linfática/patologia , Agulhas
9.
Int J Mol Sci ; 23(15)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35955681

RESUMO

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have increased and improved the treatment options for patients with non-oncogene-addicted advanced stage non-small cell lung cancer (NSCLC). However, the role of ICIs in oncogene-addicted advanced stage NSCLC patients is still debated. In this study, in an attempt to fill in the informational gap on the effect of ICIs on other driver mutations, we set out to provide a molecular landscape of clinically relevant oncogenic drivers in programmed death-ligand 1 (PD-L1) positive NSCLC patients. METHODS: We retrospectively reviewed data on 167 advanced stage NSCLC PD-L1 positive patients (≥1%) who were referred to our clinic for molecular evaluation of five driver oncogenes, namely, EGFR, KRAS, BRAF, ALK and ROS1. RESULTS: Interestingly, n = 93 (55.7%) patients showed at least one genomic alteration within the tested genes. Furthermore, analyzing a subset of patients with PD-L1 tumor proportion score (TPS) ≥ 50% and concomitant gene alterations (n = 8), we found that n = 3 (37.5%) of these patients feature clinical benefit with ICIs administration, despite the presence of a concomitant KRAS gene alteration. CONCLUSIONS: In this study, we provide a molecular landscape of clinically relevant biomarkers in NSCLC PD-L1 positive patients, along with data evidencing the clinical benefit of ICIs in patient NSCLC PD-L1 positive alterations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos
10.
Cytopathology ; 32(5): 596-603, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33955097

RESUMO

Over the past decade, immunotherapy has emerged as one of the most promising cancer treatments. Several monoclonal antibodies targeting the programmed death 1 (PD-1)/ programmed death ligand-1 (PD-L1) pathway have been integrated into standard-of-care treatments for a wide range of cancer types. Although all the available PD-L1 immunohistochemistry (IHC) assays have been developed on formalin-fixed histological specimens, a growing body of research has recently suggested the feasibility of PD-L1 testing on cytological samples. Although promising results have been reported, several important issues still need to be addressed. Among these are pre-analytical issues, cyto-hystological correlation, and inter-observer agreement. This review will briefly summarise the knowledge gaps and future directions of cytopathology in the immuno-oncology scenario.


Assuntos
Antígeno B7-H1/metabolismo , Citodiagnóstico/métodos , Imunoterapia/métodos , Oncologia/métodos , Anticorpos Monoclonais/metabolismo , Humanos , Imuno-Histoquímica/métodos
11.
Cytopathology ; 32(5): 588-595, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33792981

RESUMO

The application of next generation sequencing (NGS) technology to cytological samples has significantly modified molecular cytopathology practice. Cytological samples represent a valid source of high-quality DNA for NGS analysis, especially for predicting patients' response to targeted treatments and for refining the risk of malignancy in indeterminate cytological diagnoses. However, several pre-analytical factors may influence the reliability of NGS clinical analysis. Here, we briefly review the challenges of NGS in cytology practice, focusing on those pre-analytical factors that may negatively affect NGS success rates and routine diagnostic applications. Finally, we address the future directions of the field.


Assuntos
Citodiagnóstico/métodos , Técnicas Citológicas/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patologia
12.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375029

RESUMO

The transcription factor Forkhead box E1 (FOXE1) is a key player in thyroid development and function and has been identified by genome-wide association studies as a susceptibility gene for papillary thyroid cancer. Several cancer-associated polymorphisms fall into gene regulatory regions and are likely to affect FOXE1 expression levels. However, the possibility that changes in FOXE1 expression modulate thyroid cancer development has not been investigated. Here, we describe the effects of FOXE1 gene dosage reduction on cancer phenotype in vivo. Mice heterozygous for FOXE1 null allele (FOXE1+/-) were crossed with a BRAFV600E-inducible cancer model to develop thyroid cancer in either a FOXE1+/+ or FOXE1+/- genetic background. In FOXE1+/+ mice, cancer histological features are quite similar to that of human high-grade papillary thyroid carcinomas, while cancers developed with reduced FOXE1 gene dosage maintain morphological features resembling less malignant thyroid cancers, showing reduced proliferation index and increased apoptosis as well. Such cancers, however, appear severely undifferentiated, indicating that FOXE1 levels affect thyroid differentiation during neoplastic transformation. These results show that FOXE1 dosage exerts pleiotropic effects on thyroid cancer phenotype by affecting histology and regulating key markers of tumor differentiation and progression, thus suggesting the possibility that FOXE1 could behave as lineage-specific oncogene in follicular cell-derived thyroid cancer.


Assuntos
Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Câncer Papilífero da Tireoide/genética , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Animais , Apoptose/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Fatores de Transcrição Forkhead/metabolismo , Pleiotropia Genética , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo
13.
Epidemiol Prev ; 44(1): 56-63, 2020.
Artigo em Italiano | MEDLINE | ID: mdl-32374115

RESUMO

OBJECTIVES: to evaluate the implementation of an integrated care model for thyroid disease on thyroid surgery at the University Hospital "Federico II" of Naples (Campania Region, Southern Italy). DESIGN: quasi-experimental design employing an interrupted time series analysis. SETTING AND PARTICIPANTS: all subjects who were admitted to the University Hospital "Federico II" for thyroid surgery between January 2008 and December 2018. The integrated care model for thyroid disease was implemented starting from January 2016. MAIN OUTCOME MEASURES: rate of partial thyroidectomies over all thyroidectomies; rate of diagnosed thyroid cancers over all diagnosed thyroid tumours; length of stay (LOS). Differences pre- and post-interventions were assessed employing Poisson (for count outcomes) and linear (for continuous outcomes) regression models. Models were adjusted for age, gender, tumour diagnosis (none, benign, malignant), Charlson index, and discharge month. RESULTS: data on 4,233 thyroidectomies were included. There was no difference between pre- and post-intervention trends for the rate of partial thyroidectomies over all thyroidectomies (pre-intervention: IRR 1.00; 95%CI 0.99;1.00 - post-intervention: IRR 1.00; 95%CI 0.98;1.02) and for the rate of diagnosed thyroid cancers over all thyroid tumours (pre-intervention IRR 0.99; 95%CI 0.99;1.00 - post-intervention IRR 1.00; 95%CI 0.99;1.01). On the contrary, the LOS reduced from 4.5 (±4.3) days in 2008 to 3.2 (±3.2) days in 2018. The multivariate analysis confirmed this reduction, estimated to be 1.1 days on average in the pre-intervention eight-year period (pre-intervention coefficient -0.01; 95%CI -0.02;-0.01), followed by an even greater reduction in the post-intervention three-year period which was estimated to be 1.1 day (post-intervention: coefficient -0.03; 95%CI -0.05;-0.01). CONCLUSIONS: the implementation of an integrated care model for thyroid disease contributed to reduce the LOS for thyroidectomies, improving the efficiency in the management of thyroid disease. However, this intervention had no impact in reducing the rate of total thyroidectomies.


Assuntos
Doenças da Glândula Tireoide/epidemiologia , Prestação Integrada de Cuidados de Saúde , Feminino , Humanos , Análise de Séries Temporais Interrompida , Itália/epidemiologia , Tempo de Internação , Masculino , Alta do Paciente , Neoplasias da Glândula Tireoide
15.
Br J Cancer ; 116(6): 802-810, 2017 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-28170370

RESUMO

BACKGROUND: When tumour tissue is unavailable, cell-free DNA (cfDNA)can serve as a surrogate for genetic analyses. Because mutated alleles in cfDNA are usually below 1%, next-generation sequencing (NGS)must be narrowed to target only clinically relevant genes. In this proof-of-concept study, we developed a panel to use in ultra-deep sequencing to identify such mutations in cfDNA. METHODS: Our panel ('SiRe') covers 568 mutations in six genes (EGFR, KRAS, NRAS, BRAF, cKIT and PDGFRα)involved in non-small-cell lung cancer (NSCLC), gastrointestinal stromal tumour, colorectal carcinoma and melanoma. We evaluated the panel performance in three steps. First, we analysed its analytical sensitivity on cell line DNA and by using an artificial reference standard with multiple mutations in different genes. Second, we analysed cfDNA from cancer patients at presentation (n=42), treatment response (n=12) and tumour progression (n=11); all patients had paired tumour tissue and cfDNA previously genotyped with a Taqman-derived assay (TDA). Third, we tested blood samples prospectively collected from NSCLC patients (n=79) to assess the performance of SiRe in clinical practice. RESULTS: SiRe had a high analytical performance and a 0.01% lower limit of detection. In the retrospective series, SiRe detected 40 EGFR, 11 KRAS, 1 NRAS and 5 BRAF mutations (96.8% concordance with TDA). In the baseline samples, SiRe had 100% specificity and 79% sensitivity relative to tumour tissue. Finally, in the prospective series, SiRe detected 8.7% (4/46) of EGFR mutations at baseline and 42.9% (9/21) of EGFR p.T790M in patients at tumour progression. CONCLUSIONS: SiRe is a feasible NGS panel for cfDNA analysis in clinical practice.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Colorretais/genética , DNA de Neoplasias/genética , Tumores do Estroma Gastrointestinal/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Melanoma/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , DNA de Neoplasias/sangue , Feminino , Seguimentos , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/sangue , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Melanoma/sangue , Melanoma/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Curva ROC
16.
Mol Carcinog ; 55(5): 793-807, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-25917796

RESUMO

Colorectal cancer (CRC) is one of the most frequent and deadly malignancies worldwide. Despite the progresses made in diagnosis and treatment, the identification of tumor markers is still a strong clinical need, because current treatments are efficacious only in a subgroup of patients. UbcH10 represents a potential candidate biomarker, whose expression levels could be employed to predict response or resistance to chemotherapy or targeted agents. UbcH10 mRNA and protein expression levels have been evaluated in a large group of CRC patients and correlated with clinico-pathological characteristics, including KRAS mutations. Moreover, the endogenous levels of UbcH10 and its role on cell growth have been evaluated in CRC cells. Finally, to investigate the impact of UbcH10 protein expression on the response to irinotecan, its active metabolite SN-38 and cetuximab treatment, UbcH10 silencing experiments were carried-out on two colon carcinoma cell lines, Caco-2, and DLD1. Overexpression of UbcH10 mRNA and protein was observed in the vast majority of patients analyzed. UbcH10 suppression decreased CRC cell growth rate (at least in part through deregulation of Cyclin B and ERK1) and sensitized them to pharmacological treatments with irinotecan, SN-38 and cetuximab (at least in part through a down-regulation of AKT). Taken together, these findings indicate that UbcH10 expression regulates CRC growth and could play an important role in the personalization of the therapy of CRC patients.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/patologia , Expressão Gênica , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Células CACO-2 , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cetuximab/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HT29 , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Prognóstico
17.
Am J Physiol Renal Physiol ; 306(10): F1243-50, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24647711

RESUMO

Both experimental and clinical studies have suggested that any potential treatment of polycystic kidney disease (PKD) should start early and last for a long time to be effective, with unavoidable side reactions and considerable costs. The aim of the present study was to test how low doses of rapamycin (RAPA; 0.15 mg/kg ip for 4 days/wk), tolvaptan (TOLV; 0.005% in diet), or AEZ-131 (AEZ; a novel ERK inhibitor, 30 mg/kg for 3 days/wk by gavage), alone and in association, affect the progression of polycystic renal disease in PCK rats. Rats were treated for 8 wk starting at 4-6 wk of age. The efficacy of low doses of such drugs in inhibiting their respective targets was confirmed by immunoblot experiments. Compared with rats in the control (CON) group, RAPA treatment caused a significant reduction in cyst volume density (CVD; -19% vs. the CON group) and was numerically similar to that in TOLV-treated rats (-18%, not significiant), whereas AEZ treatment was not effective. RAPA + TOLV treatment resulted in a significantly lower CVD (-49% vs. the CON group) and was associated with a striking decrease in cAMP response element-binding protein phosphorylation, and similar data were detected in RAPA + AEZ-treated rats (-42%), whereas TOLV + AEZ treatment had virtually no effect. RAPA administration significantly lessened body weight gain, whereas TOLV administration resulted a mild increase in diuresis and a significant increase in cAMP urinary excretion. Histological data of tubular proliferation were in full agreement with CVD data. In conclusion, this study demonstrates that the association of low doses of RAPA, TOLV, and AEZ slows the progression of PKD with limited side effects, suggesting the use of combined therapies also in clinical trials.


Assuntos
Benzazepinas/uso terapêutico , Progressão da Doença , Inibidores Enzimáticos/uso terapêutico , Doenças Renais Policísticas/tratamento farmacológico , Sirolimo/uso terapêutico , Animais , Benzazepinas/farmacologia , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Inibidores Enzimáticos/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Doenças Renais Policísticas/metabolismo , Doenças Renais Policísticas/patologia , Ratos , Ratos Endogâmicos , Ratos Mutantes , Ratos Sprague-Dawley , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Tolvaptan , Resultado do Tratamento
18.
Acta Cytol ; 58(6): 589-94, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25428205

RESUMO

OBJECTIVES: In this study we reviewed our practice of lung cancer epidermal growth factor receptor (EGFR) mutational testing in an academic centralized laboratory setting, where direct smears and liquid-based cytology (LBC) slides represent the most frequent cytological specimens received. The aim was to assess the differences, if any, between these sample types in terms of DNA yield, adequacy rates and overall EGFR testing performance. STUDY DESIGN: A total of 362 cases were retrieved - received from January 2012 to January 2014 for EGFR testing - including 204 LBC specimens and 158 smears. Exon 19 deletions and the L858R point mutation in exon 21, detected by fragment assay and TaqMan assay, respectively, were confirmed by direct sequencing or by high-resolution melting. RESULTS: Although the direct smears showed a higher DNA yield (60.94 vs. 23.07 ng/µl) and were more frequently cell-rich (54%) than the LBC slides (31.4%), the differences in adequacy (direct smears: 97.4%; LBCs: 94.1%) and in mutant rate (direct smears: 10.3%; LBCs: 14.0%) between the two sample types did not reach statistical significance. CONCLUSIONS: Not only direct smears but also LBC slides represent an effective preparation and storage medium for cytological material to be used for EGFR molecular testing.


Assuntos
Citodiagnóstico/métodos , Análise Mutacional de DNA/métodos , DNA de Neoplasias/genética , Receptores ErbB/genética , Hospitais Universitários , Pulmão/enzimologia , Mutação Puntual , Deleção de Sequência , Manejo de Espécimes/métodos , DNA de Neoplasias/isolamento & purificação , Éxons , Humanos , Itália , Valor Preditivo dos Testes , Encaminhamento e Consulta , Reprodutibilidade dos Testes
19.
Semin Diagn Pathol ; 30(4): 284-97, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24342285

RESUMO

In an increased number of settings, cytology represents the only source of sampling and it often substitutes histology as an independent diagnostic modality. Thus, DNA molecular targets to stratify patients for targeted therapy are often evaluated on cytology. In addition, DNA mutational tests may refine indeterminate thyroid and pancreas cytology. This review discusses the applications and limitations of DNA mutational testing on cytology. With respect to histology, most cytological samples have the advantages of a purer population of tumor cells, with low stromal component, a better preserved DNA, and assessing at the same time of sample collection cellular adequacy for DNA testing. However, since in vitro diagnostic tests are licensed only for paraffin-tissue, all mutational assays on cytology are "home brew," requiring a rigorous validation process. This should take into account not only the performance characteristics of the molecular assay but also features inherent to any given cytological samples, such as its source, preparation type, fixation and staining modalities, and the most effective tumor cell enrichment methods. This calls for a change of cytotechnologists and cytopathologists mentality to collect and process the cytological samples not only for microscopy but also to assess clinically relevant molecular markers.


Assuntos
Citodiagnóstico/métodos , Análise Mutacional de DNA/métodos , Neoplasias/genética , Oncogenes/genética , Humanos , Mutação , Manejo de Espécimes/métodos
20.
Acta Cytol ; 57(3): 309-12, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23635480

RESUMO

BACKGROUND: Warthin tumor (WT) is a common parotid lesion reliably diagnosed by fine-needle aspiration (FNA). Worrisome metaplastic changes may occur in WT. Their interpretation as mucoepidermoid carcinoma represents a diagnostic pitfall. Moreover, WT and mucoepidermoid carcinoma may coexist, making this distinction difficult. So it is worthwhile to report unusual WT features. We describe a WT with signet-ring cells (SRCs). CASE: A 61-year-old male presenting with a 3.6-cm right parotid gland mass underwent FNA with rapid on-site evaluation. DiffQuik-stained smears showed groups of oncocytic cells with abundant granular cytoplasm in a background rich with debris, foamy macrophages and lymphoid cells. SRCs were observed on Papanicolaou-stained smears prepared from a second pass. A WT with SRC features was diagnosed. Histology revealed a WT with post-FNA infarctual changes. CONCLUSION: To avoid false-positive diagnoses, the cytopathologist should be aware that SRC features may occur in WT. The concomitant presence of oncocytes and SRCs is useful to correctly diagnose this unusual WT variant.


Assuntos
Adenolinfoma/patologia , Carcinoma de Células em Anel de Sinete/patologia , Citodiagnóstico , Neoplasias Complexas Mistas/patologia , Neoplasias Parotídeas/patologia , Adenolinfoma/cirurgia , Biópsia por Agulha Fina , Carcinoma de Células em Anel de Sinete/cirurgia , Citodiagnóstico/métodos , Erros de Diagnóstico/prevenção & controle , Reações Falso-Positivas , Células Espumosas/patologia , Humanos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Complexas Mistas/cirurgia , Neoplasias Parotídeas/cirurgia , Valor Preditivo dos Testes , Coloração e Rotulagem
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