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1.
Nature ; 587(7834): 377-386, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32894860

RESUMO

Here we describe the LifeTime Initiative, which aims to track, understand and target human cells during the onset and progression of complex diseases, and to analyse their response to therapy at single-cell resolution. This mission will be implemented through the development, integration and application of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during the progression from health to disease. The analysis of large molecular and clinical datasets will identify molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. The timely detection and interception of disease embedded in an ethical and patient-centred vision will be achieved through interactions across academia, hospitals, patient associations, health data management systems and industry. The application of this strategy to key medical challenges in cancer, neurological and neuropsychiatric disorders, and infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Atenção à Saúde/métodos , Atenção à Saúde/tendências , Medicina/métodos , Medicina/tendências , Patologia , Análise de Célula Única , Inteligência Artificial , Atenção à Saúde/ética , Atenção à Saúde/normas , Diagnóstico Precoce , Educação Médica , Europa (Continente) , Feminino , Saúde , Humanos , Legislação Médica , Masculino , Medicina/normas
2.
Br J Cancer ; 129(5): 772-781, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37443346

RESUMO

BACKGROUND: The immune landscape of uveal melanoma liver metastases (UMLM) has not been sufficiently studied. METHODS: Immune cell infiltrates (ICIs), PD-1 and PD-L1 were characterised in 62 UMLM and 28 primary uveal melanomas (PUM). ICI, PD-1 and PD-L1 were scored as: (1) % tumoral area occupied by tumour-infiltrating lymphocytes or macrophages (TILs, TIMs) and (2) % perTumoral (perT) area. ICIs and other variables including histopathologic growth patterns (HGPs), replacement and desmoplastic, of UMLM were analysed for their prognostic value. RESULTS: ICIs recognised by haematoxylin-eosin-saffron (HES) and IHC (e.g., T cells (CD3), B cells (CD20). Macrophages (CD68), (CD163), were primarily localised to the perT region in PUM and UMLM and were more conspicuous in UMLM. HES, CD3, CD4, FoxP3, CD8, CD20, PD-1 TILs were scant (<5%). TIMs were more frequent, particularly in UMLM than in PUM. Both CD68+ TIMs and HGPs remained significant on multivariate analysis, influencing overall (OS) and metastasis-specific overall survival (MSOS). CD68 + , CD163+ and CD20+ perT infiltrates in UMLM predicted increased OS and MSOS on univariate analysis. CONCLUSIONS: TILs and PD-L1 have no predictive value in PUM or UMLM. CD68+ and CD163+TIMs, CD20+ perT lymphocytes, and HGPs are important prognostic factors in UMLMs.


Assuntos
Neoplasias Hepáticas , Melanoma , Humanos , Antígeno B7-H1 , Receptor de Morte Celular Programada 1 , Melanoma/patologia , Neoplasias Hepáticas/patologia , Linfócitos do Interstício Tumoral , Prognóstico , Biomarcadores Tumorais/análise
3.
Ann Surg ; 278(4): e827-e834, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36847256

RESUMO

OBJECTIVE: We report here the results of a prospective study of circulating tumor DNA (ctDNA) detection in patients undergoing uveal melanoma (UM) liver metastases resection (NCT02849145). BACKGROUND: In UM patients, the liver is the most common and often only site of metastases. Local treatments of liver metastases, such as surgical resection, have a likely benefit in selected patients. METHODS: Upon enrollment, metastatic UM patients eligible for curative liver surgery had plasma samples collected before and after surgery. GNAQ / GNA11 mutations were identified in archived tumor tissue and used to quantify ctDNA by droplet digital polymerase chain reaction which was then associated with the patient's surgical outcomes. RESULTS: Forty-seven patients were included. Liver surgery was associated with a major increase of cell-free circulating DNA levels, with a peak 2 days after surgery (∼20-fold). Among 40 evaluable patients, 14 (35%) had detectable ctDNA before surgery, with a median allelic frequency of 1.1%. These patients experienced statistically shorter relapse-free survival (RFS) versus patients with no detectable ctDNA before surgery (median RFS: 5.5 vs 12.2 months; hazard ratio=2.23, 95% CI: 1.06-4.69, P =0.04), and had a numerically shorter overall survival (OS) (median OS: 27.0 vs 42.3 months). ctDNA positivity at postsurgery time points was also associated with RFS and OS. CONCLUSIONS: This study is the first to report ctDNA detection rate and prognostic impact in UM patients eligible for surgical resection of their liver metastases. If confirmed by further studies in this setting, this noninvasive biomarker could inform treatment decisions in UM patients with liver metastases.


Assuntos
DNA Tumoral Circulante , Neoplasias Hepáticas , Humanos , DNA Tumoral Circulante/genética , Prognóstico , Estudos Prospectivos , Recidiva Local de Neoplasia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Biomarcadores Tumorais/genética , Mutação
4.
J Low Genit Tract Dis ; 27(1): 56-67, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36282979

RESUMO

OBJECTIVES: Small cell carcinoma of the vagina (SmCCV) is an extremely rare disease. Evidence-based data and specific guidelines are lacking. We conducted the first systematic review of case reports to provide the most overall picture of SmCCV. MATERIALS AND METHODS: Literature search in PubMed and Scopus was performed using the terms "small cell carcinoma" and "vagina." English-language case reports of primary SmCCV up to January 2022 were included. RESULTS: Twenty-nine articles describing 44 cases met our inclusion criteria. We report a new case of our hospital. The global median overall survival (mOS) was 12.00 months (95% CI = 9.31-14.69). The mOS was not reached for stage I, and it was 12.00, 12.00, 9.00, and 8.00 months for stages II, III, IVA, and IVB, respectively (statistically significant differences between stage I and stages II, III, or IVA [log rank p = .003-.017]). Thirty-five cases received local treatments (77.8%). The mOS of patients treated with surgery ± complementary chemotherapy, radiotherapy ± complementary chemotherapy, chemoradiation ± complementary chemotherapy, and surgery + radiotherapy ± complementary chemotherapy were 11.00, 12.00, 17.00, and 29.00 months, respectively. The use of adjuvant or neoadjuvant chemotherapy (64.5%, mostly platinum + etoposide) showed longer mOS (77.00 vs 15.00 months). Four of 5 tested cases presented human papillomavirus infection, 3 of them presenting type 18. CONCLUSIONS: Small cell carcinoma of the vagina shows dismal prognosis. Multimodal local management plus complementary chemotherapy seems to achieve better outcomes. Human papillomavirus could be related to the development of SmCCV. A diagnostic-therapeutic algorithm is proposed.


Assuntos
Carcinoma , Terapia Neoadjuvante , Feminino , Humanos , Algoritmos , Estadiamento de Neoplasias , Prognóstico , Vagina
5.
Int J Mol Sci ; 24(14)2023 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-37511180

RESUMO

Despite a multimodal radical treatment, mortality of advanced epithelial ovarian cancer (AEOC) remains high. Host-related factors, such as systemic inflammatory response and its interplay with the immune system, remain underexplored. We hypothesized that the prognostic impact of this response could vary between patients undergoing primary debulking surgery (PDS) and those undergoing interval debulking surgery (IDS). Therefore, we evaluated the outcomes of two surgical groups of newly diagnosed AEOC patients according to the neutrophil, monocyte and platelet to lymphocyte ratios (NLR, MLR, PLR), taking median ratio values as cutoffs. In the PDS group (n = 61), low NLR and PLR subgroups showed significantly better overall survival (not reached (NR) vs. 72.7 months, 95% confidence interval [CI]: 40.9-95.2, p = 0.019; and NR vs. 56.1 months, 95% CI: 40.9-95.2, p = 0.004, respectively) than those with high values. Similar results were observed in progression free survival. NLR and PLR-high values resulted in negative prognostic factors, adjusting for residual disease, BRCA1/2 status and stage (HR 2.48, 95% CI: 1.03-5.99, p = 0.043, and HR 2.91, 95% CI: 1.11-7.64, p = 0.03, respectively). In the IDS group (n = 85), ratios were not significant prognostic factors. We conclude that NLR and PLR may have prognostic value in the PDS setting, but none in IDS, suggesting that time of surgery can modulate the prognostic impact of baseline complete blood count (CBC).


Assuntos
Neutrófilos , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário , Monócitos , Proteína BRCA1 , Prognóstico , Procedimentos Cirúrgicos de Citorredução , Estudos Retrospectivos , Proteína BRCA2 , Linfócitos , Neoplasias Ovarianas/diagnóstico
6.
Lab Invest ; 102(11): 1214-1224, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35672380

RESUMO

The replacement histopathologic growth pattern (rHGP) in melanoma liver metastases connotes an aggressive phenotype (vascular co-option; angiotropic extravascular migratory spread) and adverse prognosis. Herein, replacement and desmoplastic HGP (dHGP) were studied in uveal melanoma liver metastases (MUM). In particular, L1CAM and a "laminin vascular network" were detected at the advancing front of 14/20 cases (p = 0.014) and 16/20 cases (p = 6.4e-05) rHGPs, respectively, but both were absent in the dHGP (8/8 cases) (p = 0.014, and p = 6.3e-05, respectively). L1CAM highlighted progressive extension of angiotropic melanoma cells along sinusoidal vessels in a pericytic location (pericytic mimicry) into the hepatic parenchyma. An inverse relationship between L1CAM expression and melanin index (p = 0.012) suggested differentiation toward an amelanotic embryonic migratory phenotype in rHGP. Laminin labeled the basement membrane zone interposed between sinusoidal vascular channels and angiotropic melanoma cells at the advancing front. Other new findings: any percentage of rHGP and pure rHGP had a significant adverse effect on metastasis-specific overall survival (p = 0.038; p = 0.0064), as well as predominant rHGP (p = 0.0058). Pure rHGP also was associated with diminished metastasis-free survival relative to dHGP (p = 0.040), possibly having important implications for mechanisms of tumor spread. In conclusion, we report for the first time that L1CAM and a laminin vascular network are directly involved in this high-risk replacement phenotype. Further, this study provides more detailed information about the adverse prognostic effect of the rHGP in MUM.


Assuntos
Neoplasias Hepáticas , Melanoma , Molécula L1 de Adesão de Célula Nervosa , Neoplasias Uveais , Humanos , Laminina , Melaninas , Melanoma/metabolismo
8.
Int J Food Sci Nutr ; 73(5): 610-629, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35184668

RESUMO

The change in consumers' lifestyle promoted "snackification" favouring the commercialisation of on-the-go products such as cereal bars (CBs). Manufacturers are encountering challenges to develop healthy, natural, tasty, and affordable CBs. This article focuses on production methods, the current and emerging market trends, and practical implications for developing new CBs. The future of the CBs industry is associated with finding the right balance between nutritional value, sensory attributes, naturalness, and sustainability. Manufactures have a toolbox with a large portfolio of ingredients and processing techniques to develop CBs that can be a meal substitute, a supplement, or a snack.


Assuntos
Grão Comestível , Lanches , Comércio , Valor Nutritivo , Paladar
9.
Int J Cancer ; 145(7): 1852-1859, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30714617

RESUMO

Anal squamous cell carcinoma (ASCC) is a rare tumour, but its incidence is increasing. Standard chemoradiotherapy fails to cure 20% of patients and no targeted therapy is currently approved for recurrent ASCC. The PI3K/Akt/mTOR pathway is frequently altered in this poorly characterised carcinoma. IGF2 was identified here as a key factor in ASCC oncogenesis, as IGF2 was shown to play a crucial role in the PI3K pathway with frequent (~60%) and mutually exclusive genomic alterations in IGF2, IGF1R, PTEN and PIK3CA genes. We also demonstrated that IGF2 expression is mainly due to cancer-associated fibroblasts and that IGF2 secreted by cancer-associated fibroblasts from ASCC samples promotes proliferation of a human ASCC cell line via IGF2 paracrine signalling. Altogether, these results highlight the key role of the IGF2/PI3K axis, and the major role of cancer-associated fibroblasts in tumour growth via IGF2 secretion, suggesting a major role of IGF2/IGF1R inhibitors in ASCC therapies.


Assuntos
Neoplasias do Ânus/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Carcinoma de Células Escamosas/metabolismo , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Animais , Neoplasias do Ânus/genética , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Mutação , Transplante de Neoplasias , Comunicação Parácrina , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais
10.
Int J Mol Sci ; 19(10)2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30347758

RESUMO

Homologous recombination (HR) is a DNA repair pathway that is deficient in 50% of high-grade serous ovarian carcinomas (HGSOC). Deficient HR (DHR) constitutes a therapeutic opportunity for these patients, thanks to poly (ADP-ribose) polymerases (PARP) inhibitors (PARPi; olaparib, niraparib, and rucaparib are already commercialized). Although initially, PARPi were developed for patients with BRCA1/2 mutations, robust clinical data have shown their benefit in a broader population without DHR. This breakthrough in daily practice has raised several questions that necessitate further research: How can populations that will most benefit from PARPi be selected? At which stage of ovarian cancer should PARPi be used? Which strategies are reasonable to overcome PARPi resistance? In this paper, we present a summary of the literature and discuss the present clinical research involving PARPi (after reviewing ClinicalTrials.gov) from a translational perspective. Research into the functional biomarkers of DHR and clinical trials testing PARPi benefits as first-line setting or rechallenge are currently ongoing. Additionally, in the clinical setting, only secondary restoring mutations of BRCA1/2 have been identified as events inducing resistance to PARPi. The clinical frequency of this and other mechanisms that have been described in preclinics is unknown. It is of great importance to study mechanisms of resistance to PARPi to guide the clinical development of drug combinations.


Assuntos
Recombinação Homóloga , Neoplasias Ovarianas/genética , Pesquisa Translacional Biomédica , Animais , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
11.
Lab Invest ; 97(6): 746-759, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28240745

RESUMO

Angiotropism is a marker of extravascular migration of melanoma cells along vascular and other structures and a prognostic factor in cutaneous melanoma. Because of this biological and prognostic importance in cutaneous melanoma, angiotropism was studied in uveal melanoma (UM). This retrospective study performed at a single ocular oncology referral center included 89 patients from the study period 2006-2008. All patients were diagnosed with UM from the choroid and/or ciliary body. All patients underwent enucleation for prognostic purposes and definitive therapy. Clinical, histopathological, and molecular variables included patient age, gender, extraocular extension, tumor location (ciliary body or not), optic nerve invasion, angiotropism, neurotropism, melanoma cell type, BAP1 mutation, and monosomy 3. Angiotropism was defined as melanoma cells arrayed along the abluminal vascular surfaces without intravasation in the sclera and/or episcleral tissue. The study included 51 women (57.3%) and 38 men with mean and median age: 63 years (range: 25-92). Mean follow-up was 4.4 years (range: 0.2 to 11). Fifty-three (59.6%) patients developed metastases and 48 (53.9%) were dead from metastases at last follow-up. Other principal variables recorded were angiotropism in 43.8%, extraocular extension in 7.9%, epithelioid/mixed cell type in 73.1%, BAP1 mutation in 41.3%, and monosomy 3 in 53.6% of cases. On multivariate analysis, extraocular extension, angiotropism, and monosomy 3 were predictive of metastasis, whereas tumor diameter, epithelioid cell type, angiotropism, and monosomy 3 were predictive of death. Chi-square test confirmed an association between angiotropism and metastasis and death but none with BAP1 mutation and monosomy 3. In conclusion, angiotropism and monosomy 3 were independent prognostic factors for both metastases and death in UM. However, irrespective of any prognostic value, the true importance of angiotropism is its biological significance as a marker of an alternative metastatic pathway.Laboratory Investigation advance online publication, 27 February 2017; doi:10.1038/labinvest.2017.16.

12.
Br J Cancer ; 114(12): 1387-94, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-27219019

RESUMO

BACKGROUND: A better understanding of the molecular profile of anal squamous cell carcinomas (ASCCs) is necessary to consider new therapeutic approaches, and the identification of prognostic and predictive factors for response to treatment. METHODS: We retrospectively analysed tumours from ASCC patients for mutational analysis of KRAS, NRAS, HRAS, BRAF, PIK3CA, MET, TP53 and FBXW7 genes by HRM and Sanger sequencing analysis. RESULTS: Specimens from 148 patients were analysed: 96 treatment-naive tumours and 52 recurrences after initial radiotherapy (RT) or chemoradiotherapy (CRT). Mutations of KRAS, PIK3CA, FBXW7 and TP53 genes were present in 3 (2.0%), 30 (20.3%), 9 (6.1%) and 7 tumours (4.7%), respectively. The distribution of the mutations was similar between treatment-naive tumours and recurrences, except for TP53 mutations being more frequent in recurrences (P=0.0005). In patients treated with abdominoperineal resection (APR) after relapse (n=38, median follow-up of 18.2 years), overall survival (OS) was significantly correlated with HPV16 status (P=0.048), gender (P=0.045) and PIK3CA mutation (P=0.037). The PIK3CA status retained its prognostic significance in Cox multivariate regression analysis (P=0.025). CONCLUSIONS: Our study identified PIK3CA mutation as an independent prognostic factor in patients who underwent APR for ASCC recurrence, suggesting a potential benefit from adjuvant treatment and the evaluation of targeted therapies with PI3K/Akt/mTor inhibitors in PIK3CA-mutated patients.


Assuntos
Neoplasias do Ânus/genética , Neoplasias do Ânus/cirurgia , Mutação , Fosfatidilinositol 3-Quinases/genética , Terapia de Salvação/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ânus/metabolismo , Neoplasias do Ânus/patologia , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Fosfatidilinositol 3-Quinases/metabolismo , Estudos Retrospectivos
13.
Br J Cancer ; 114(2): 177-87, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26695443

RESUMO

BACKGROUND: Oestrogen receptor-negative (ER-) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer. METHODS: Gene and protein expression profiles were analysed in a panel of ER- breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively. RESULTS: The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN-inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN-inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN-related genes was associated with human IFN-γ secretion by tumour cells. CONCLUSIONS: Treatment-induced activation of the IFN/STAT1 pathway in tumour cells is associated with chemotherapy response in ER- breast cancer. Further validations in prospective clinical trials will aim to evaluate the usefulness of this signature to assist therapeutic strategies in the clinical setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Interferon gama/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Fator de Transcrição STAT1/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal , Animais , Antígenos/efeitos dos fármacos , Antígenos/genética , Antígenos/metabolismo , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Capecitabina/farmacologia , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Caspase 3/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/efeitos dos fármacos , Caspase 7/genética , Caspase 7/metabolismo , Cisplatino/farmacologia , Citocinas/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Proteínas do Citoesqueleto/efeitos dos fármacos , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização In Situ , Interferon beta/efeitos dos fármacos , Interferon beta/genética , Interferon beta/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Proteínas Mitocondriais/efeitos dos fármacos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteínas de Resistência a Myxovirus/efeitos dos fármacos , Proteínas de Resistência a Myxovirus/genética , Proteínas de Resistência a Myxovirus/metabolismo , Transplante de Neoplasias
14.
J Theor Biol ; 407: 1-17, 2016 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-27449789

RESUMO

In experimental studies on tumor growth, whenever the time evolution of the relative volume of a tumor in an untreated (control) group can be fitted by a Gompertz diffusion process there is a possibility that an antiproliferative therapy, which modifies the growth rate of the process that fits the treated group, may also affect its variability. The present paper proposes several procedures for the estimation of the time function included in the infinitesimal variance of the new process, as well as the time function affecting the growth rate (which is included in the infinitesimal mean). Also, a hypothesis testing is designed to confirm or refute the need for including such a time-dependent function in the infinitesimal variance. In order to validate and compare the proposed procedures a simulation study has been carried out. In addition, a proposal is made for a strategy aimed at finding the optimal combination of procedures for each case. A real data application concerning the effects of cisplatin on a patient-derived xenograft (PDX) tumor model showcases the advantages of this model over others that have been used in the past.


Assuntos
Modelos Biológicos , Neoplasias/patologia , Neoplasias/terapia , Animais , Proliferação de Células , Simulação por Computador , Difusão , Humanos , Camundongos
15.
Int J Gynecol Cancer ; 26(6): 1105-10, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27177278

RESUMO

OBJECTIVE: The prognosis of endometrial cancer depends on the correct surgical staging. In early stages, 18% to 30% rate of positive lymph nodes is reported with a myometrial invasion of 50% or more. According to this, patients with International Federation of Gynecology and Obstetrics stage Ib would benefit from staging lymphadenectomy. Therefore, it is important to classify these patients preoperatively to plan the surgery. In the recent years, 3-dimensional (3D) ultrasound and diffusion-weighted magnetic resonance imaging (DW-MRI) have been incorporated in the preoperative management of these patients. The aim of this study was to assess the usefulness of 3D ultrasound and DW-MRI as predictor of myometrial invasion in endometrial cancer. MATERIAL AND METHODS: We retrospectively compared the assessment of myometrial invasion by 3D ultrasound and DW-MRI with final pathologic evaluation on hysterectomy specimens, in 98 patients diagnosed of early-stage endometrial cancer, who underwent surgery at the Hospital Clinic of Barcelona between 2012 and 2015. RESULTS: Evaluation of the depth of myometrial invasion with 3D ultrasound had a sensitivity, specificity, and accuracy of 77%, 83% and 81%, respectively. Evaluation of the depth of myometrial invasion with DW-MRI had a sensitivity, specificity, and accuracy of 69%, 86%, and 81%, respectively. Association of both techniques improved all the values, showing a sensitivity, specificity, and accuracy of 87%, 93%, and 91%, respectively. In both 3D ultrasound and DW-MRI, the presence of leiomyomas was the first detectable cause of false negative (3% and 4%, respectively) and false-positive (3% and 1%, respectively). CONCLUSIONS: We conclude that the implementation of the 2 studies in early-stage endometrial cancer provides low false-negatives and false-positives rates. In cases of patients with leiomyomas, adenomiosis, or intrauterine fluid collection, definitive evaluation of myometrial invasion could be better deferred to intraoperative biopsy in an attempt to reduce false-negatives and false-positives rates.


Assuntos
Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/patologia , Miométrio/diagnóstico por imagem , Miométrio/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Imageamento Tridimensional/métodos , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Cuidados Pré-Operatórios , Reprodutibilidade dos Testes , Estudos Retrospectivos , Ultrassonografia/métodos
16.
Int J Cancer ; 137(8): 1890-900, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25892415

RESUMO

The treatment of epithelial ovarian cancer (EOC) is narrowly focused despite the heterogeneity of this disease in which outcomes remain poor. To stratify EOC patients for targeted therapy, we developed an approach integrating expression and genomic analyses including the BRCAness status. Gene expression and genomic profiling were used to identify genes recurrently (>5%) amplified and overexpressed in 105 EOC. The LST (Large-scale State Transition) genomic signature of BRCAness was applied to define molecular subgroups of EOC. Amplified/overexpressed genes clustered mainly in 3q, 8q, 19p and 19q. These changes were generally found mutually exclusive. In the 85 patients for which the genomic signature could be determined, genomic BRCAness was found in 52 cases (61.1%) and non-BRCAness in 33 (38.8%). A striking mutual exclusivity was observed between BRCAness and amplification/overexpression data. Whereas 3q and 8q alterations were preferentially observed in BRCAness EOC, most alterations on chromosome 19 were in non-BRCAness cases. CCNE1 (19q12) and BRD4 (19p13.1) amplification/overexpression was found in 19/33 (57.5%) of non-BRCAness cases. Such disequilibrium was also found in the TCGA EOC data set used for validation. Potential target genes are frequently amplified/overexpressed in non-BRCAness EOC. We report that BRD4, already identified as a target in several tumor models, is a new potential target in high grade non-BRCAness ovarian carcinoma.


Assuntos
Cromossomos Humanos Par 19/genética , Ciclina E/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fatores de Transcrição/genética , Carcinoma Epitelial do Ovário , Proteínas de Ciclo Celular , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 8/genética , Feminino , Amplificação de Genes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade
17.
Br J Cancer ; 113(9): 1249-53, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26505679

RESUMO

The past few years have witnessed major advances in the understanding of the molecular landscape of uveal melanoma (UM). The discovery of a mutational background that is completely different from the one of skin melanoma has granted to UM a stand-alone status. The absence of effective therapy for metastatic disease offers now a chessboard for targeted therapy but at the same time urges preclinical science to develop accordingly, to guide the use of economical resources to the best profit of patients. This review describes the current knowledge on the biology of this disease and discusses the challenges that must be undertaken to translate this knowledge into real benefit for patients.


Assuntos
Melanoma/genética , Neoplasias Uveais/genética , Animais , Humanos , Mutação/genética , Neoplasias Cutâneas , Melanoma Maligno Cutâneo
18.
J Theor Biol ; 364: 206-19, 2015 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-25242298

RESUMO

A modified Gompertz diffusion process is considered to model tumor dynamics. The infinitesimal mean of this process includes non-homogeneous terms describing the effect of therapy treatments able to modify the natural growth rate of the process. Specifically, therapies with an effect on cell growth and/or cell death are assumed to modify the birth and death parameters of the process. This paper proposes a methodology to estimate the time-dependent functions representing the effect of a therapy when one of the functions is known or can be previously estimated. This is the case of therapies that are jointly applied, when experimental data are available from either an untreated control group or from groups treated with single and combined therapies. Moreover, this procedure allows us to establish the nature (or, at least, the prevalent effect) of a single therapy in vivo. To accomplish this, we suggest a criterion based on the Kullback-Leibler divergence (or relative entropy). Some simulation studies are performed and an application to real data is presented.


Assuntos
Melanoma/patologia , Neoplasias/patologia , Neoplasias Uveais/patologia , Algoritmos , Animais , Antineoplásicos/química , Apoptose , Morte Celular , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Humanos , Melanoma/terapia , Camundongos , Modelos Biológicos , Transplante de Neoplasias , Reprodutibilidade dos Testes , Neoplasias Uveais/terapia
19.
Int J Gynecol Cancer ; 25(1): 12-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25365589

RESUMO

OBJECTIVE: Current evidence suggests that the presence of tumor-initiating cells (TICs) in epithelial ovarian cancer (EOC) has a role in chemoresistance and relapse. Surface markers such as CD44(+)/CD24(-), CD117(+), and CD133(+) expression have been reported as potential markers for TICs related to ovarian cancer and tumorigenic cell lines. In this study, we have investigated if spheroid forms are TIC specific or whether they can also be produced by somatic stem cells from healthy tissue in vitro. In addition, we also investigated the specificity of surface markers to identify TICs from papillary serous EOC patients. METHODS: Cells were obtained from fresh tumors from 10 chemotherapy-naive patients with EOC, and cells from ovarian and tubal epithelium were obtained from 5 healthy menopausal women undergoing surgery for benign pathology and cultured in standard and in selective medium. Cells forming nonadherent spheroids were considered TICs, and the adherent cells were considered as non-TIC-like. Percentages of CD24(+), CD44(+), CD117(+), CD133(+), and vascular endothelial growth factor receptor (VEGF-R)(+) cell surface markers were analyzed by flow cytometry. RESULTS: Four of 10 EOC cell tissues were excluded from the study. Tumor cells cultured in selective medium developed spheroid forms after 1 to 7 weeks in 5 of 6 EOC patients. No spheroid forms were observed in cultures of cells from healthy women. Unlike previously published data, low levels of CD24(+), CD44(+), CD117(+), and VEGF-R(+) expression were observed in spheroid cells, whereas expression of CD133(+) was moderate but higher in adherent cells from papillary serous EOC cells in comparison with adherent cells from controls. CONCLUSIONS: Papillary serous EOC contains TICs that form spheroids with low expression of CD44(+), CD24(+), CD117(+) and VEGF-R(+). Further research is required to find specific surface markers to identify papillary serous TICs.


Assuntos
Cistadenocarcinoma Seroso/patologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/patologia , Ovário/patologia , Esferoides Celulares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Cistadenocarcinoma Seroso/metabolismo , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Ovário/metabolismo , Projetos Piloto , Prognóstico , Esferoides Celulares/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Acta Obstet Gynecol Scand ; 94(9): 954-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26084939

RESUMO

INTRODUCTION: Our objective was to compare the feasibility and safety of surgical procedures to treat gynecological pathologies with intestinal involvement performed by skilled gynecological surgeons and by a multidisciplinary team of gynecologists plus colorectal surgeons. MATERIAL AND METHODS: We performed a comparative, observational, prospective study at a tertiary referral center. The population included all women undergoing bowel surgery for gynecological pathologies over a 3-year period. Cases were analyzed by the specialty of the main surgeon performing the intestinal procedure. The main outcome measures were surgical procedure characteristics and postoperative outcomes and complications. RESULTS: A total of 65 women were included. Surgery was exclusively performed by a subspecialized gynecologist in 30.8% of the women, and undertaken by a multidisciplinary team (colorectal surgeons and gynecologists) in 69.2%. The main demographic and clinical characteristics were comparable in both groups. Main indications for bowel resection in gynecological surgery were advanced ovarian cancer and deep infiltrating endometriosis. In addition to the standard gynecological surgical procedures, a total of 135 intestinal segments were resected, with sigmoid colon the most frequent intestinal segment resected in both groups (53% in the gynecologist group and in 60% in the multidisciplinary group). No significant differences were observed between the two groups in the distribution and frequency of surgical techniques used, rate of complications, mean hospitalization time or frequency of re-intervention. CONCLUSION: Skilled gynecological surgeons appear to be equally good at handling common intestinal problems as a team of gynecologist and colorectal surgeons.


Assuntos
Colectomia , Cirurgia Colorretal , Endometriose/cirurgia , Ginecologia , Neoplasias Ovarianas/cirurgia , Equipe de Assistência ao Paciente , Adulto , Idoso , Estudos de Coortes , Endometriose/patologia , Estudos de Viabilidade , Feminino , Gastrectomia , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Adulto Jovem
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