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1.
Tumori ; 110(1): 49-59, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37574933

RESUMO

INTRODUCTION: The synthesis of the periprosthetic capsule during implant-based breast reconstruction is the result of a coordinate cascade of inflammatory events ending in a fibrous tissue deposition around the expander or implant. Although the development of small volumes of fluid is one of the complications of prosthetic-based breast reconstruction, the characterization of the periprosthetic effusions coupled with the micro-textured devices, that have been recently introduced after the recall of macro-textured ones, is still lacking. The investigation of these periprosthetic effusions and paired capsules in terms of immunological content were the primary and secondary aims of the present study, respectively. METHODS: For this, 68 women, 41 of whom had periprosthetic effusions at the time of expander replacement with implant, were recruited. For each case, capsule and healthy dermal tissues were taken and for women with periprosthetic effusion, peripheral blood was also collected. Periprosthetic effusions and peripheral blood were characterized by cytometry while capsules and dermal tissues by immunohistochemistry and Nanostring analysis. RESULTS: The results showed an increase of Th1, Th2 lymphocytes and a HLA-DR+bright CD16+ cells (likely representing monocytes-derived macrophages) in periprosthetic effusions in respect to peripheral blood. These pro-inflammatory cells were counterbalanced by the gain of suppressive CD4 Treg cells. In the corresponding capsules, immunohistochemistry revealed the absence of Th1 cells and the presence of tissutal FOXP3 Treg. No significant difference in expression of inflammatory-related genes between capsules and dermal tissues was present. CONCLUSIONS: These results suggest the presence of a Treg-controlled inflammation in both periprosthetic effusions and capsules.


Assuntos
Implantes de Mama , Neoplasias da Mama , Mamoplastia , Feminino , Humanos , Mamoplastia/métodos , Inflamação
2.
Cancer Biomark ; 38(3): 301-309, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37545217

RESUMO

BACKGROUND: Pan-TRK inhibitors Entrectinib and Larotrectinib have been recently approved as tumor-agnostic therapies in NTRK1-2-3 rearranged patients and there is therefore an urgent need to identify reliable and accessible biomarkers for capturing NTRK fusions in the real-world practice. OBJECTIVE: We aim to assess the analytical validity of the recently released pan-TRK assay (Ventana), running a head-to-head comparison between immunohistochemistry and Archer FusionPlex Lung Panel (ArcherDX) that is designed to detect key fusions in 13 genes, also including NTRK1-3. METHODS: Pan-TRK IHC and NGS analysis were conducted on a retrospective/prospective cohort of 124 cancer patients (carcinomas, 93 cases; soft tissue sarcomas, 19; primary central nervous system tumours, 10; and neuroblastomas, 2). FISH data were available in most of the IHC/NGS discordant cases. RESULTS: A comparison between IHC and NGS results was carried out in 117 cases: among 30 pan-TRK positive cases, NTRK rearrangement by NGS was found in 11 (37%), while one of the 87 (1.1%) pan-TRK negative cases (a case of NSCLC) showed a TPM3-NRTK1 rearrangement by NGS. Accordingly, sensitivity and specificity of IHC in predicting NTRK status were 91.7% and 81.9%, respectively, while negative (NPV) and positive predictive value (PPV) were 98.8% and 36.7%, respectively. CONCLUSIONS: These data lead to suggest that IHC with VENTANA pan-TRK antibody can be a reliable screening tool for the identification of patients potentially bearing NTRK rearranged tumours.


Assuntos
Neoplasias Pulmonares , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Estudos Prospectivos , Estudos Retrospectivos , Fluxo de Trabalho
3.
Biomedicines ; 11(7)2023 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-37509688

RESUMO

In pseudomyxoma peritonei (PMP), KRAS and GNAS mutations are frequent. We hypothesized that these mutations may contribute to the suppression of antitumor immunity: KRAS may induce GMCSF expression, while GNAS may enhance the expression of cyclic adenosine monophosphate and A2AR signaling. This study aimed to explore possible mechanisms facilitated by KRAS and GNAS mutations for escaping immune surveillance. Additionally, we looked for new potential therapeutic and prognostic targets in this rare disease which is poorly characterized at the molecular level. GM-CSF, A2AR, CD73, CD39, and PD-L1 expression was investigated by immunohistochemistry in 40 PMPs characterized for GNAS and KRAS mutational status. Immune cell populations were studied by immunohistochemistry and nanostring nCounter®. Following the criteria of a prognostic nomogram reported for PMP, we stratified the patients into two different risk groups, with 28 "low-risk" and 12 "high-risk" patients. We observed the expression of GM-CSF (74%); CD39 (37%); CD73 (53%); A2AR (74%); and PD-L1 (16%) which was unrelated to GNAS or KRAS status. The tumor microenvironment showed the presence of CD4+ T cells (86%); CD8+ T cells (27%); CD20+ B (67%); CD15+ cells (86%); and CD163+ M2 macrophages (67%), while CD56+ NK cells were absent. CD163 expression (27%) in PMP tumor cells was associated with poor prognosis. GNAS mutation and A2AR expression were not associated with a specific immune transcriptional signature. However, the expression assay revealed 21 genes associated with prognosis. The "high-risk" patients exhibited worse progression-free survival (HR = 2.3, CI 95%: 1.1-5.1, p = 0.034) and significant downregulation of MET, IL8, PPARG, DTX4, HMGA1, ZIC2, WNT5B, and CCRL2. In conclusion, we documented the presence of immunosuppressive factors such as GM-CSF, A2AR, and PD-L1 in PMP. These factors were not associated with GNAS and KRAS status and could be explored as therapeutic molecular targets. Additionally, a set of potential prognostic biomarkers, including CD163 expression in tumor cells, deserve further investigation.

4.
Int J Mol Sci ; 24(4)2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36834892

RESUMO

Most oropharyngeal squamous cell carcinomas (OPSCCs) are human papillomavirus (HPV)-associated, high-risk (HR) cancers that show a better response to chemoradiotherapy and are associated with improved survival. Nucleophosmin (NPM, also called NPM1/B23) is a nucleolar phosphoprotein that plays different roles within the cell, such as ribosomal synthesis, cell cycle regulation, DNA damage repair and centrosome duplication. NPM is also known as an activator of inflammatory pathways. An increase in NPM expression has been observed in vitro in E6/E7 overexpressing cells and is involved in HPV assembly. In this retrospective study, we investigated the relationship between the immunohistochemical (IHC) expression of NPM and HR-HPV viral load, assayed by RNAScope in situ hybridization (ISH), in ten patients with histologically confirmed p16-positive OPSCC. Our findings show that there is a positive correlation between NPM expression and HR-HPV mRNA (Rs = 0.70, p = 0.03), and a linear regression (r2 = 0.55; p = 0.01). These data support the hypothesis that NPM IHC, together with HPV RNAScope, could be used as a predictor of transcriptionally active HPV presence and tumor progression, which is useful for therapy decisions. This study includes a small cohort of patients and, cannot report conclusive findings. Further studies with large series of patients are needed to support our hypothesis.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Proteínas Oncogênicas Virais , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Carcinoma de Células Escamosas/patologia , Inibidor p16 de Quinase Dependente de Ciclina , DNA Viral/genética , Papillomavirus Humano , Nucleofosmina , Proteínas Oncogênicas Virais/genética , Neoplasias Orofaríngeas/patologia , Papillomaviridae/genética , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carga Viral
6.
Front Mol Biosci ; 9: 996434, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36225259

RESUMO

Background: Previous data, mostly from clinical trials, reported that HER2-low status is associated with low pathological complete response (pCR), and favourable prognosis. Since these findings suggest the existence of an additional breast cancer subtype, we questioned if the predictive/prognostic value of HER2-low was also relevant in the real world. Methods: Data from non-metastatic breast cancer patients treated with neoadjuvant chemotherapy and surgery (2009-2020) were retrieved from our institutional prospectively-maintained registry. Univariable and multivariable logistic models were implemented to study the association between pCR and baseline HER2 status. Univariable analysis of disease-free survival (DFS) was performed through Kaplan-Meier survival curves and log-rank tests. Results: Starting from a total of 790 consecutive cases, we identified 444 newly-diagnosed breast cancer patients featuring HER2 immunohistochemistry (IHC) 0 (HER2-0, n = 109), and 1 + or IHC 2+/in situ hybridization negative (HER2-low, n = 335) receiving anthracycline and taxane-based regimens in 88.9% of cases. Most of the patients were diagnosed with stage II (67.3%) and there was no difference of disease presentation according to HER2-status. pCR was attained by 71 (16.0%) patients and was significantly associated with increased DFS (p = 0.031). Compared to HER2-0, HER2-low cases were more likely hormone receptor-positive (81.2% vs. 43.1%, p < 0.001), well-differentiated (47.5% vs. 26.6%, p = 0.001), less proliferative (21.5% vs. 8.3%, p = 0.001) and less responsive to treatment (pCR 11.6% vs. 29.4%, p < 0.0001). There was no difference in DFS according to HER2 status, though hormone-receptor (HR) negative/HER2-low cases tended to have a worse prognosis compared to HR-negative/HER2-0. By pCR achievement, 3-years DFS was 87.5.% (75.1-100%) vs. 71.6% (65.9-77.8%) (p = 0.161) in HER2-low and 89.1% (75.8-100%) vs. 72.1% (59.7-87.0%) (p = 0.092) in HER2-0. Conclusion: Our real-world data show that HER2-low breast cancer patients represent roughly a half of the cases treated with neoadjuvant therapy, and have poor treatment response. In absence of pCR, HER2-low breast cancer patients have a dismal prognosis, especially when primary tumor hormone receptor status is negative. Studies are therefore needed to define the biology of these tumors for new therapeutic targets and to incorporate HER2-targeting agents in early-stage treatment.

7.
Oncologist ; 25(9): 780-786, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32272500

RESUMO

BACKGROUND: Epstein-Barr virus (EBV)-positive gastric cancers (GCs) have been recently identified as a molecular subgroup showing excellent outcomes after surgery for early-stage disease and responsiveness to immune checkpoint inhibitors (ICIs) for metastatic stage. No data are available on the prevalence, clinical characteristics, and prognosis of this subgroup of GCs in the metastatic setting. MATERIALS AND METHODS: In this cohort study, we assessed the impact of EBV status in patients with metastatic GC treated with chemotherapy at two Italian institutions. RESULTS: Among the 175 cases analyzed, only 7 (4%) were EBV positive and all showed long-lasting and even complete responses to first-line chemotherapy with fluorouracil and platinum and a significantly better survival compared with EBV-negative patients (3-year overall survival: 80% vs. 20.1%; hazard ratio: 0.12). CONCLUSION: If confirmed in larger data sets, our results may give a strong rationale for investigating the addition of ICIs to chemotherapy, in order to maximize the chance of achieving durable and complete responses in this uncommon subtype of GC. IMPLICATIONS FOR PRACTICE: To date, no data are available on the prevalence and clinical characteristics of patients with Epstein-Barr virus (EBV)-positive metastatic gastric cancer (GC), a specific subtype of GC showing excellent outcomes after radical surgery in early-stage disease and responsiveness to immune checkpoint inhibitors (ICIs). This cohort study showed that patients with EBV-positive GC who did not receive ICIs had exceptional, long-lasting, and even complete responses to first-line chemotherapy with fluorouracil and platinum and a significantly better survival compared with EBV-negative patients. If confirmed in larger series, these results may give a strong rationale for investigating the combination of chemotherapy and ICIs to achieve durable and potentially complete response in this uncommon subtype of GC.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Estudos de Coortes , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Humanos , Prognóstico , Neoplasias Gástricas/tratamento farmacológico
9.
Int J Mol Sci ; 20(22)2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752449

RESUMO

Background-There are currently no effective therapies for diffuse malignant peritoneal mesothelioma (DMPM) patients with disease recurrence. In this study, we investigated the biology of DMPM by analyzing the EGFR family, Axl, and MET, in order to assess the presence of cross-talk between these receptors, suggesting the effectiveness of combined targeted treatments in DMPM. Method-We analyzed a series of 22 naïve epithelioid DMPM samples from a single institute, two of which showed higher-grade malignancy ("progressed"). EGFR, HER2, HER3, Axl, and MET activation and expression were investigated by biochemical analysis, real-time PCR immunofluorescence, immunohistochemistry, next-generation sequencing, miRNA, and mRNA in situ hybridization. Results-In most DMPMs, a strong EGFR activation was associated with HER2, HER3, Axl, and MET co-activation, mediated mainly by receptor heterodimerization and autocrine-paracrine loops induced by the expression of their cognate ligands. Axl expression was downregulated by miRNA34a. Mutations in MET Sema domain were exclusively found in two "progressed" DMPMs, and the combined Axl and MET inhibition reduced cellular motility in a DMPM cell line obtained from a "progressed" DMPM. Conclusion-The results indicate that the coordinated activity of multiple cross-talks between RTKs is directly involved in the biology of DMPM, suggesting the combined inhibition of PIK3 and mTOR as an effective strategy that may be easily implemented in clinical practice, and indicating that the combined inhibition of EGFR/HER2 and HER3 and of Axl and MET deserves further investigation.


Assuntos
Neoplasias Pulmonares/genética , Mesotelioma/genética , Neoplasias Peritoneais/genética , Adulto , Idoso , Linhagem Celular Tumoral , Terapia Combinada/métodos , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Mesotelioma/tratamento farmacológico , Mesotelioma Maligno , MicroRNAs/genética , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Neoplasias Peritoneais/tratamento farmacológico , Peritônio/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , RNA Mensageiro/genética
10.
Otolaryngol Head Neck Surg ; 161(4): 635-642, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31286827

RESUMO

OBJECTIVE: There is no consensus on the follow-up modalities in patients with head and neck cancer. This study aims to describe the pattern and survival outcomes of recurrences/second primary cancers in patients undergoing an intensive radiologic and clinical follow-up. STUDY DESIGN: Retrospective analysis. SETTING: Single academic tertiary care center. SUBJECTS AND METHODS: All patients with stage III-IV head and neck cancer treated with chemoradiotherapy at our institution between 1998 and 2010 were retrospectively reviewed. Persistent/recurrent disease within 6 months since the curative treatment and second primary cancers outside the upper aerodigestive tract were excluded. Data were analyzed by descriptive statistics. Surveillance was planned every 3 months in the first year, then with increasing intervals till the fifth year. RESULTS: A total of 326 patients were included. Out of all detected cancer recurrences (n = 106, 32%), 38 (36%) were locoregional, 44 (41%) were distant, and 24 (23%) were second primary cancers. Approximately 70% of recurrences were clinically and/or radiologically discovered, while 30% were diagnosed due to the patients' symptoms. Of all clinically and/or radiologically discovered recurrences/second primary cancers (n = 74), 26 (35%) were curatively treated, with respect to 9 of the 32 (28%) diagnosed by symptoms. Median overall survival of recurrent curable cases did not significantly differ according to the detection modality (89 months by clinical/radiologic examination vs 85 by symptoms). CONCLUSIONS: Clinical and radiologic follow-up identified more recurrences/second primary cancers than the symptom-driven monitoring, but the curability of cancer recurrence was similar regardless of detection modality. Prospective trials are needed to define the most effective follow-up strategy in head and neck cancer.


Assuntos
Assistência ao Convalescente , Neoplasias de Cabeça e Pescoço/terapia , Recidiva Local de Neoplasia/diagnóstico por imagem , Centros Médicos Acadêmicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/terapia , Segunda Neoplasia Primária/terapia , Vigilância da População , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Terapia de Salvação , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Adulto Jovem
11.
Sci Rep ; 9(1): 3545, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837627

RESUMO

The HER2 splice variant characterized by the deletion of exon 16 and denominated as d16HER2, is associated with HER2-positive breast cancer (BC) aggressiveness, stemness, and trastuzumab susceptibility and is considered to be a "flag" of HER2 dependence. However, with the exception of quantitative real-time PCR analysis, easily reproducible assays are still lacking to clinically detect and quantify the d16HER2 expression. Further, no data on d16HER2 expression and its potential role are available in HER2-positive gastrointestinal malignancies. Here, we used a novel RNA in situ hybridization technique (BaseScope) to discriminate d16HER2 variant expression from the wild type isoform (WTHER2) and to assess their levels across different HER2-positive histological samples. Our results demonstrate the existence of outliers, with d16HER2 mRNA high scores restricted to HER2-positive gastric cancer (GC) and colorectal cancer (CRC) coupled with increased d16HER2 expression compared with BC. Consistent with previously reported data on BC, experiments performed in HER2-positive GC patient-derived xenografts suggest that increased d16HER2 expression is associated with a clinical benefit/response to single-agent trastuzumab. Therefore, d16HER2 may be considered as a "flag" of HER2 dependence in GC and can be clinically investigated as a marker of trastuzumab susceptibility in several other HER2-driven cancers, including CRC. As a clinical proof-of-concept, we indicate that high d16HER2 mRNA scores are exclusively found in patients with a long-term benefit from trastuzumab exceeding 12 months (clinical "outliers"), and that d16HER2 expression is also increased in circulating tumor-released exosomes obtained from baseline plasma samples of long-term responders.


Assuntos
Neoplasias da Mama/patologia , Éxons/genética , Regulação Neoplásica da Expressão Gênica , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Transformação Celular Neoplásica , Humanos , Células MCF-7 , Camundongos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
12.
Eur Urol Focus ; 5(4): 689-692, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28855072

RESUMO

Pan-fibroblast growth-factor receptor (FGFR) inhibitors hold promise in FGFR-altered patients, but such alterations are rare in advanced urothelial carcinoma. In order to assess whether we may increase the number of eligible patients by using different molecular techniques for detecting alterations, we pooled the results of the centralised FGFR mutation/translocation assays that were performed in Clinical Laboratory Improvement Amendments-certified laboratories within multiple phase 2 trials. At our centre, the same tissue blocks were used to analyse FGFR1-3 messenger RNA expression through messenger RNA in situ hybridisation (ISH; RNAscope 2.5 assay). From October 2016 to March 2017, 52 cases were analysed. Seventeen patients (32.7%) had an upper tract primary tumour. Ten patients (19.2%) had FGFR DNA alterations. Twenty-nine (55.8%) had positive ISH analysis: N=17 score 3, N=12 score 4. Of note, concordance between the two tests was obtained in seven out of 10 patients. Sixty percent of mutated patients had an upper tract primary tumour versus 31% of ISH-positive patients. PATIENT SUMMARY: We found three-fold higher frequency of fibroblast growth-factor receptor alterations at the RNA versus DNA level in advanced urothelial carcinoma, with a different distribution according to the method used and the site of the primary tumour. The evaluation of the therapeutic response to pan-fibroblast growth-factor receptor inhibitors according to the method of assessment is warranted.


Assuntos
Carcinoma de Células de Transição/genética , DNA de Neoplasias/genética , RNA Mensageiro/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Neoplasias Urológicas/genética , Idoso , Carcinoma de Células de Transição/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Urológicas/patologia
13.
Expert Rev Mol Diagn ; 18(3): 259-277, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29431533

RESUMO

INTRODUCTION: Bright-field in situ hybridization (ISH) methods detect gene alterations that may improve diagnostic precision and personalized management of cancer patients. Areas covered: This review focuses on some bright-field ISH techniques for detection of gene amplification or viral infection that have already been introduced in tumor pathology, research and diagnostic practice. Other emerging ISH methods, for the detection of translocation, mRNA and microRNA have recently been developed and need both an optimization and analytical validation. The review also deals with their clinical applications and implications on the management of cancer patients. Expert commentary: The technology of bright-field ISH applications has advanced significantly in the last decade. For example, an automated dual-color assay was developed as a clinical test for selecting cancer patients that are candidates for personalized therapy. Recently an emerging bright-field gene-protein assay has been developed. This method simultaneously detects the protein, gene and centromeric targets in the context of tissue morphology, and might be useful in assessing the HER2 status particularly in equivocal cases or samples with heterogeneous tumors. The application of bright-field ISH methods has become the gold standard for the detection of tumor-associated viral infection as diagnostic or prognostic factors.


Assuntos
Biomarcadores Tumorais/genética , Hibridização In Situ/métodos , Técnicas de Diagnóstico Molecular/métodos , Neoplasias/genética , Medicina de Precisão/métodos , Biomarcadores Tumorais/metabolismo , DNA Viral/genética , Rearranjo Gênico , Humanos , Neoplasias/patologia , Neoplasias/virologia
14.
Clin Cancer Res ; 24(5): 1082-1089, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29208673

RESUMO

Purpose: Refining the selection of HER2-positive metastatic gastric cancer patient candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways.Experimental Design: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications. Hypothesizing a prevalence of candidate alterations of 30% and 0% in resistant and sensitive HER2-positive patients, respectively, 20 patients per group were needed.Results: AMNESIA panel alterations were significantly more frequent in resistant (11 of 20, 55%) as compared with sensitive (0% of 17) patients (P < 0.001), and in HER2 IHC 2+ (7 of 13, 53.8%) than 3+ (4 of 24, 16.7%) tumors (P = 0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free [5.2 vs. 2.6 months; HR, 0.34; 95% confidence interval (CI), 0.07-0.48; P = 0.001] and overall survival (16.1 vs. 7.6 months; HR, 0.38; 95% CI, 0.09-0.75; P = 0.015). The predictive accuracy of the AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of the AMNESIA panel and HER2 IHC was 84%.Conclusions: Our panel of candidate genomic alterations may be clinically useful to predict primary resistance to trastuzumab in patients with HER2-positive metastatic gastric cancer and should be further validated with the aim of molecularly stratifying HER2-addicted cancers for the development of novel treatment strategies. Clin Cancer Res; 24(5); 1082-9. ©2017 AACR.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Medicina de Precisão/métodos , Intervalo Livre de Progressão , Estudos Prospectivos , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Análise de Sobrevida , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico
15.
Hum Pathol ; 74: 32-42, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28993274

RESUMO

The aim of this study is to compare 2 in situ hybridization (ISH) detection methods for human papilloma virus (HPV) 16 E6/E7 mRNA, that is, the RNAscope 2.0 High Definition (HD) and the upgraded RNAscope 2.5 HD version. The RNAscope 2.5 HD has recently replaced the RNAscope 2.0 HD detection kit. Therefore, this investigation starts from the need to analytically validate the new mRNA ISH assay and, possibly, to refine the current algorithm for HPV detection in oropharyngeal squamous cell carcinoma with the final goal of applying it to daily laboratory practice. The study was based on HPV status and on generated data, interpreted by a scoring algorithm. The results highlighted that the compared RNAscope HPV tests had a good level of interchangeability and enabled to identify oropharyngeal squamous cell carcinoma that are truly driven by high-risk HPV infection. This was also supported by the comparison of the RNAscope HPV test with HPV E6/E7 mRNA real-time reverse-transcription polymerase chain reaction in a fraction of cases where material for HPV E6/E7 mRNA real-time reverse-transcription polymerase chain reaction was available. Furthermore, the algorithm that associates p16 immunohistochemistry with the identification of HPV mRNA by RNAscope was more effective than the one that associated p16 immunohistochemistry with the identification of HPV DNA by ISH.


Assuntos
Carcinoma de Células Escamosas/virologia , Papillomavirus Humano 16/isolamento & purificação , Proteínas Oncogênicas Virais/metabolismo , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/diagnóstico , Proteínas Repressoras/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/patologia , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , RNA Viral
16.
Sci Rep ; 7(1): 15992, 2017 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-29167573

RESUMO

Metformin is a widely used and well-tolerated anti-diabetic drug that can reduce cancer risk and improve the prognosis of certain malignancies. However, the mechanism underlying its anti-cancer effect is still unclear. We studied the anti-cancer activity of metformin on colorectal cancer (CRC) by using the drug to treat HT29, HCT116 and HCT116 p53-/- CRC cells. Metformin reduced cell proliferation and migration by inducing cell cycle arrest in the G0/G1 phase. This was accompanied by a sharp decrease in the expression of c-Myc and down-regulation of IGF1R. The anti-proliferative action of metformin was mediated by two different mechanisms: AMPK activation and increase in the production of reactive oxygen species, which suppressed the mTOR pathway and its downstream targets S6 and 4EBP1. A reduction in CD44 and LGR5 expression suggested that the drug had an effect on tumour cells with stem characteristics. However, a colony formation assay showed that metformin slowed the cells' ability to form colonies without arresting cell growth, as confirmed by absence of apoptosis, autophagy or senescence. Our finding that metformin only transiently arrests CRC cell growth suggests that efforts should be made to identify compounds that combined with the biguanide can act synergistically to induce cell death.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias Colorretais/metabolismo , Metformina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Células HCT116 , Humanos , Hibridização In Situ , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
17.
Oncotarget ; 8(29): 47780-47789, 2017 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-28562354

RESUMO

The prognostic value of pre-treatment Epstein-Barr Virus (EBV) DNA viral load for non-endemic, locally-advanced, EBV-related nasopharyngeal cancer (NPC) patients is yet to be defined. All patients with EBV encoded RNA (EBER)-positive NPC treated at our Institution from 2005 to 2014 with chemotherapy (CT) concurrent with radiation (RT) +/- induction chemotherapy (ICT) were retrospectively reviewed. Pre-treatment baseline plasma EBV DNA (b-EBV DNA) viral load was detected and quantified by PCR. Median b-EBV DNA value was correlated to potential influencing factors by univariate analysis. Significant variables were then extrapolated and included in a multivariate linear regression model. The same variables, including b-EBV DNA, were correlated with Disease Free Survival (DFS) and Overall Survival (OS) by univariate and multivariate analysis.A total of 130 locally-advanced EBER positive NPC patients were evaluated. Overall, b-EBV DNA was detected in 103 patients (79.2%). Median viral load was 554 copies/mL (range 50-151075), and was positively correlated with T stage (p=0.002), N3a-b vs N0-1-2 stage (p=0.048), type of treatment (ICT followed by CTRT, p=0.006) and locoregional and/or distant disease recurrence (p=0.034). In the overall population, DFS and OS were significantly longer in patients with pre-treatment negative EBV DNA than in positive subjects at the multivariate analysis.Negative b-EBV DNA can be considered as prognostic biomarker of longer DFS and OS in NPC in non-endemic areas. This finding needs confirmation in larger prospective series, with standardized and inter-laboratory harmonized method of plasma EBV DNA quantification.


Assuntos
DNA Viral , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/genética , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/etiologia , Carga Viral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/terapia , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Adulto Jovem
18.
Br J Cancer ; 117(3): 347-352, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28654634

RESUMO

BACKGROUND: Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAFV600E and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown. METHODS: We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data. RESULTS: We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition. CONCLUSIONS: We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , DNA de Neoplasias/sangue , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Proto-Oncogênicas c-met/genética , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/genética , Linhagem Celular , Crizotinibe , Progressão da Doença , Evolução Fatal , Amplificação de Genes , Humanos , Indóis/administração & dosagem , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Neoplasias Retais/patologia , Sulfonamidas/administração & dosagem , Vemurafenib
19.
Expert Rev Hematol ; 10(6): 505-514, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28468596

RESUMO

INTRODUCTION: Primary effusion lymphoma (PEL) is a rare B-cell lymphoid neoplasm mainly associated with HIV infection, presenting as pleural, peritoneal, and pericardial effusions. A defining property of PEL is its consistent association with Kaposi sarcoma associated herpesvirus (KSHV) infection, and, in most cases, Epstein Barr virus (EBV) co-infection. On these grounds, a review of the literature related to viral cooperation and lymphomagenesis can help to understand the complex interplay between KSHV and EBV in PEL pathogenesis. Areas covered: In this review, the authors highlight clinical, pathologic, genetic and proteomic features of PEL, in the context of viral cooperation in PEL lymphomagenesis. Expert commentary: Tumour cells are characterized by the overexpression of genes that are involved in inflammation and invasion. Coherently, PEL secretomes are enriched in proteins probably responsible for the particular tropism (cell adhesion and migration) of PEL cells. The development of PEL in HIV+ patients is multifactorial and involves a complex interplay among co-infection with oncogenic viruses (EBV and KSHV), inflammatory factors, and environmental conditions.


Assuntos
Transformação Celular Viral , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Herpesvirus Humano 8 , Linfoma de Efusão Primária , Sarcoma de Kaposi , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/metabolismo , Humanos , Linfoma de Efusão Primária/metabolismo , Linfoma de Efusão Primária/patologia , Linfoma de Efusão Primária/virologia , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/metabolismo , Sarcoma de Kaposi/patologia
20.
Oncotarget ; 8(20): 32492-32504, 2017 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-28415643

RESUMO

To gain new insights into desmoplastic small round cell tumors (DSRCTs) by means of gene expression profiling (GEP). Formalin-fixed, paraffin-embedded surgical specimens obtained from seven pretreated DSRCT patients were interrogated using GEP complemented by immunohistochemistry, a cancer stem cell array, and miRNA in situ hybridisation, including the combined chimera modules miRNA-200/ZEB1 and miRNA-34/SLUG. The chimera modules divided the cases into three classes that respectively recapitulated the traits of mesenchymal epithelial reverse transition (MErT), epithelial mesenchymal transition (EMT), and hybrid/partial EMT. This indicates a close correlation between the reprogramming governed by EMT regulators and DSRCT biology, which was further confirmed by miRNA-21 and is consistent with the broad morphological spectrum of DSRCTs. Starting from the miRNA-200/ZEB1 axis, we also found that DSRCTs carry a signature of immunological ignorance that is not responsive to PD--L1 blockade. Evidence that the up-regulation of miRNA-200 and E-cadherin, and quite a high level of miRNA-21 expression segregate with the MErT supports the idea that, in addition to the hybrid/partial state, MErT is also enriched in stemness: the androgen-positive cases, whose stemness traits were confirmed by stem cell arrays, all fell into these two classes. Our findings also confirmed that tumoral cell PDGFRA expression correlates with desmoplasia, and demonstrated the co-expression of PDGFRA and ISLR/Meflin, another marker of pluripotency. Despite the limited number of cases, these findings provide unexpectedly relevant information concerning the pathogenesis of DSRCTs, and prove the validity of miRNA-based chimera circuit modelling in the clinico-pathological setting.


Assuntos
Tumor Desmoplásico de Pequenas Células Redondas/genética , Tumor Desmoplásico de Pequenas Células Redondas/patologia , Perfilação da Expressão Gênica/métodos , Feminino , Humanos , Imuno-Histoquímica
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