RESUMO
INTRODUCTION: The endothelium and angiogenesis are therapeutic targets in cancer. Response to treatment may be assessed by laboratory plasma markers such as circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), von Willebrand factor (vWf), soluble E selectin, vascular endothelial growth factor (VEGF) and angiogenin. We hypothesised that these markers, obtained before surgery, would predict 2-year outcome after surgery with or without anti-angiogenic therapy for colorectal cancer (CRC). METHODS: We recruited 154 patients with CRC, of whom 51 were treated with surgery alone, 74 were treated with standard chemotherapy (5-fluorouracil) and 29 were treated with standard chemotherapy plus anti-VEGF therapy (Avastin). Peripheral blood was taken before surgery. CD34(+)/CD45(-)/CD146(+) CECs and CD34(+)/CD45(-)/CD309 [KDR](+) EPCs were measured by flow cytometry and plasma markers by ELISA. RESULTS: After a mean of 2.1 years follow-up (range 1.9-2.3 years), 52 of the patients (33.7 %) experienced a poor outcome (radiological and/or histological evidence of tumour spread or recurrence, or death [n = 26]). In univariate analysis, poor outcome was linked to Dukes' stage (p < 0.001), American Joint Committee on Cancer (AJCC) stage (p < 0.001), type of treatment (surgery alone, standard chemotherapy with or without anti-antigenic therapy) (p = 0.047), CECs (p < 0.02) and EPCs (p < 0.01). In subsequent binary logistic regression analysis, only Dukes' stage (hazard ratio 2.3, 95 % confidence interval 1.0-5.3, p = 0.047) and modified AJCC stage (4.62, 1.88-11.33, p < 0.001) predicted a poor outcome. CONCLUSION: Endothelial cell markers (CECs, EPCs, vWf, soluble E selectin) and growth factors (VEGF and angiogenin), measured before surgery, have nothing extra to offer in predicting 2-year outcome in colorectal cancer when compared to Dukes' or AJCC stage.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Células Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Idoso , Idoso de 80 Anos ou mais , Contagem de Células , Colo/irrigação sanguínea , Colo/patologia , Neoplasias Colorretais/sangue , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neovascularização Patológica , Período Pré-Operatório , Reto/irrigação sanguínea , Reto/patologia , Resultado do TratamentoRESUMO
INTRODUCTION: The importance of the endothelium in angiogenesis and cancer is undisputed, and its integrity may be assessed by laboratory markers such as circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), plasma von Willebrand factor (vWf), soluble E selectin, vascular endothelial growth factor (VEGF) and angiogenin. Antiantigenic therapy may be added to standard cytotoxic chemotherapy as a new treatment modality. We hypothesised that additional antiangiogenic therapy acts in a contrasting manner to that of standard chemotherapy on the laboratory markers. METHODS: We recruited 68 patients with CRC, of whom 16 were treated with surgery alone, 32 were treated with surgery followed by standard chemotherapy (5-flurouracil), and 20 were treated with surgery followed by standard chemotherapy plus anti-VEGF therapy (Avastin). Peripheral blood was taken before surgery, and again 3 months and 6 months later. CD34(+)/CD45(-)/CD146(+) CECs and CD34(+)/CD45(-)/CD309[KDR](+) EPCs were measured by flow cytometry, plasma markers by ELISA. RESULTS: In each of the three groups, CECs and EPCs fell at 3 months but were back at pre-surgery levels at 6 months (P<0.05). VEGF was lower in both 3-and 6-month samples in the surgery-only and surgery plus standard chemotherapy groups (P<0.05), but in those on surgery followed by standard chemotherapy plus anti-VEGF therapy, low levels at 3 months (P<0.01) increased to pre-surgery levels at 6 months. In those having surgery and standard chemotherapy, soluble E selectin was lower, whereas angiogenin was higher at 6 months than at baseline (both P<0.05). CONCLUSIONS: We found disturbances in endotheliod cells regardless of treatment, whereas VEGF returned to levels before surgery in those on antiangiogenic therapy. These observations may have clinical and pathophysiological implications.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores/análise , Neoplasias Colorretais/metabolismo , Células Endoteliais/metabolismo , Neovascularização Patológica/diagnóstico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Leucovorina/administração & dosagem , Masculino , Estadiamento de Neoplasias , Neovascularização Patológica/sangue , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Prognóstico , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Angiogenesis is a key process in cancer biology, and justifies focus on the endothelium. Separate studies have looked at different aspects of angiogenesis and vascular biology, primarily focusing on certain laboratory and imaging techniques that generally reflect one particular aspect of the assessment of the endothelium. These techniques include the secretion/release of molecules (such as growth factors) into the plasma, by the presence of mature and progenitor endothelial cells themselves in the circulation, but also by examination of peripheral blood flow and the local circulation of the tumour, and cells of the tumour itself. However, a limitation of this approach is that these methods, although themselves being useful, have often been viewed in isolation and thus can provide only a part of the vascular picture. The authors submit that this approach is weak, and introduce 'the angiome' as a term which fuses several different aspects of endothelial and tumour biology into a single concept. The authors suggest that the adoption of the concept of the angiome will bring improved insights into angiogenesis and thus cancer cell biology. In justifying this concept, the authors review the current understanding of endothelial biology and the methods of its assessment, and hypothesise that a more multifactorial approach to the angiome will be a crucial determinant of outcomes of and treatment strategies for diseases, in particular antiangiogenics for cancer therapy.
Assuntos
Endotélio Vascular/fisiopatologia , Neoplasias/irrigação sanguínea , Neovascularização Patológica , Neovascularização Fisiológica , Animais , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Neoplasias/patologiaRESUMO
BACKGROUND: Selecting patients for sentinel node biopsy, based on grade and size of the primary tumour, often results in the need for a second operation of axillary clearance since intra-operative pathological assessment of sentinel node is in its evolution at present. It may be possible to refine the clinical criteria to select patients for the type of axillary surgery. AIM: By using a score based on clinicopathological predictors of axillary lymph node involvement, we hypothesise that it may be possible to identify patients at high or low risk of nodal involvement. This information can be used to assist patients to make informed decision regarding risks and benefits of sentinel node biopsy or axillary clearance. PATIENTS AND METHODS: A score was devised based on the clinicopathological variables of 113 patients to assess the likelihood of lymph node positivity. This score was validated on an independent data set of 89 patients who underwent sentinel node biopsy and axillary surgery. Based on the score, patients were divided into two groups, high score and low score groups. For the low score group, lymph node positivity was 18% for the original score and 24% for the validation score. Lymph node positivity rate was 67% for the high score group for the original series and 65% for the validation series of patients. CONCLUSION: A clinicopathological scoring system can assist in selecting patients with breast cancer for sentinel node biopsy.
Assuntos
Neoplasias da Mama/patologia , Biópsia de Linfonodo Sentinela , Adulto , Idoso , Axila , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Pessoa de Meia-Idade , Seleção de Pacientes , Curva ROC , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
Cancer, a proliferative disease hallmarked by abnormal cell growth and spread, is largely dependent on tumor neoangiogenesis, with evidence of vascular endothelial dysfunction. Novel ways to assess vascular function in cancer include measuring levels of circulating endothelial cells (CEC). Rare in healthy individuals, increased CEC in peripheral blood reflects significant vascular damage and dysfunction. They have been documented in many human diseases, including different types of cancers. An additional circulating cell population are endothelial progenitor cells (EPC), which have the ability to form endothelial colonies in vitro and may contribute toward vasculogenesis. At present, there is great interest in evaluating the role of EPC as novel markers for tumor angiogenesis and drug therapy monitoring. Recently, exocytic procoagulant endothelial microparticles (EMP) have also been identified. CEC, EPC, and EMP research works may have important clinical implications but are often impeded by methodological issues and a lack of consensus on phenotypic identification of these cells and particles. This review aims to collate existing literature and provide an overview on the current position of CEC, EPC, and EMP in cell biology terms and to identify their significance to clinical medicine, with particular emphasis on relationship with cancer.
Assuntos
Células Endoteliais/fisiologia , Endotélio Vascular/fisiopatologia , Neoplasias/patologia , Células-Tronco/fisiologia , Apoptose , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Medula Óssea/patologia , Células Endoteliais/patologia , Endotélio Vascular/patologia , Humanos , Necrose , Células-Tronco/patologiaAssuntos
Fenômenos Eletromagnéticos/instrumentação , Corpos Estranhos/terapia , Reto , Adulto , Humanos , Masculino , MetaisRESUMO
As circulating levels of vascular endothelial growth factor (VEGF-A) are raised in malignancy, the aim of this study was to investigate whether similar changes occur in two related factors, VEGF-D and the soluble VEGF-A receptor FIt-1 (sFIt-1). Circulating levels of VEGF-A, VEGF-D and sFIt-1 were determined by ELISA in 51 patients with primary breast cancer and matched healthy controls. Results were correlated with clinicopathological data. Whilst there was a difference in VEGF-A levels between patient and control groups (p = 0.03), no such difference was observed for sFIt-1 or VEGF-D levels and there was no association between individual factors and the clinicopathological variables examined. However, there was a positive correlation between VEGF-A and sFIt-1 levels in both patient and control groups (p < 0.0001). In addition, the ratio of sFIt-1 to VEGF-A was significantly different between patients and controls (p < 0.0001) and was also associated with tumour size (p = 0.01) within the patient group. During tumour progression there is a change in the relative amounts of sFIt-1 and VEGF-A in the circulation. Measuring the sFIt-1:VEGF-A ratio may have more significance than VEGF-A alone and further studies are needed to determine whether the ratio is of use as a prognostic marker or as a means of monitoring response to anti-angiogenic therapy in cancer.
Assuntos
Neoplasias da Mama/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Fator D de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Biomarcadores Tumorais/sangue , Neoplasias da Mama/patologia , Humanos , Pessoa de Meia-Idade , Solubilidade , Fator A de Crescimento do Endotélio Vascular/químicaRESUMO
BACKGROUND: Angiogenesis is essential for tumour growth and metastasis, and is coordinated by several classes of growth factors mediating their effect through receptors linked, in turn, to tyrosine kinase. These growth factors include angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF), which act through receptors Flt-1 and Tie-2. MATERIALS AND METHODS: In order to further determine abnormalities in levels of Ang-1, Ang-2, Tie-2, sFlt-1 and VEGF in human cancer (and their interrelationships), these molecules were measured in plasma from 30 patients with breast cancer, 30 patients with prostate cancer and 12 healthy controls per cancer group. RESULTS: In breast cancer, levels of Ang-1 (P=0.0005), Ang-2 (P=0.0173), Tie-2 (P=0.0001), and VEGF (P=0.0001) were all significantly raised, and plasma levels of sFlt-1 (P=0.045) were significantly reduced compared with controls. However, in prostate cancer, only levels of VEGF and Tie-2 were significantly higher (both P=0.001). There were no significant differences between levels of any molecule between the two groups of cancer. The only difference between the healthy control groups was lower Ang-1 in the women compared with men. Significant correlations were found between levels of Ang-1 and Tie-2 both in breast (r=0.498, P=0.005) and prostate cancer (r=0.643, P=<0.001). Angiopoietin-1 was also positively correlated with Ang-2 in both breast (r=0.422, P=0.02) and prostate cancer (r=0.543, P=0.002). CONCLUSIONS: Abnormal levels of Ang-1, Ang-2 and their receptor, Tie-2, are present in breast and prostate cancer, and their interrelationships may be important in the pathophysiology of these conditions.
Assuntos
Angiopoietina-1/sangue , Angiopoietina-2/sangue , Neoplasias da Mama/sangue , Proteínas de Neoplasias/sangue , Neoplasias da Próstata/sangue , Adulto , Idoso , Estudos Transversais , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor TIE-2/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangueRESUMO
A 76 year old woman presented acutely with non-traumatic splenic rupture, which was successfully treated by emergency splenectomy. Histological examination of the spleen revealed the coexistence of metastatic adenocarcinoma cells, together with low grade B cell non-Hodgkin lymphoma. Splenic rupture as a consequence of malignant disease is discussed, together with a brief review of the literature.
Assuntos
Neoplasias da Mama/complicações , Carcinoma Lobular/complicações , Linfoma de Células B/complicações , Neoplasias Primárias Múltiplas/complicações , Neoplasias Esplênicas/complicações , Ruptura Esplênica/etiologia , Idoso , Neoplasias da Mama/patologia , Neoplasias da Mama/secundário , Carcinoma Lobular/patologia , Carcinoma Lobular/secundário , Antagonistas de Estrogênios/uso terapêutico , Feminino , Humanos , Linfoma de Células B/patologia , Linfoma de Células B/cirurgia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia , Ruptura Espontânea , Esplenectomia , Neoplasias Esplênicas/patologia , Neoplasias Esplênicas/cirurgia , Ruptura Esplênica/patologia , Tamoxifeno/uso terapêuticoRESUMO
AIMS: Limitations of sentinel lymph node biopsy (SLNB) include the occurrence of false negative (FN) results and the need to further treat SLNB positive axillae. The aims of this study were to: (1) compare the accuracy of SLNB alone to a combined SLNB and axillary sampling procedure (SLNB+AS). (2) evaluate if the additional AS could identify those SLNB positive cases with no further disease in the axilla. METHODS: Sixty-seven combined SLNB+AS procedures were performed prospectively in 66 patients, followed by Level II axillary dissection. Additionally sampled nodes were recorded if they were clinically suspicious or not at intra-operative palpation. RESULTS: The FN rate for SLNB alone was 14.3%, whilst that for SLNB+AS was reduced to 3.6%. However, the benefit of additional sampling was only seen in those cases with tumours >/=3 cm and clinically suspicious nodes (n=12). Of 12 cases with a positive SLN but negative AS, 4 (30%) were found to have disease elsewhere in the axilla. CONCLUSION: SLNB is inaccurate in the presence of suspicious nodes found at operation and careful palpation and sampling of these nodes is recommended, especially with larger tumours. In SLNB positive patients, AS is unreliable in predicting those patients with no further disease in the axilla.
Assuntos
Neoplasias da Mama/cirurgia , Excisão de Linfonodo , Linfonodos/patologia , Biópsia de Linfonodo Sentinela , Adulto , Idoso , Idoso de 80 Anos ou mais , Axila , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos ProspectivosRESUMO
Vascular endothelial growth factor C (VEGF-C) has angiogenic and lymphangiogenic properties and is associated with the development of lymphatic metastases in a number of epithelial malignancies. The aim of this study was to determine VEGF-C protein expression in a series of breast carcinomas and correlate this with axillary lymph node (LN) metastases, the presence of lympho-vascular invasion (LVI), bone marrow micro-metastases (BMM) and other clinico-pathological data including oestrogen receptor (ER) and c-erbB2 status. VEGF-C expression was determined by immunohistochemistry (IHC) in 51 tumours. ER and c-erbB2 were also assessed by IHC. Bone marrow analysis was performed using a combination of immunomagnetic separation and immunocytochemistry. Overall, 30/51 (59%) of the tumours were positive for VEGF-C. There was no significant correlation between VEGF-C expression and LN status, LVI, BMM, tumour size, grade or ER status. However, there was an association between c-erbB2 and VEGF-C expression (P=0.013). The correlation between VEGF-C and c-erbB2 suggests a functional relationship and may, in part, explain the aggressive phenotype associated with c-erbB2-positive tumours.
Assuntos
Neoplasias da Medula Óssea/secundário , Neoplasias da Mama/metabolismo , Fatores de Crescimento Endotelial/metabolismo , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Medula Óssea/metabolismo , Feminino , Humanos , Imuno-Histoquímica/métodos , Metástase Linfática , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Fator C de Crescimento do Endotélio VascularRESUMO
The relative importance of different proteinases, and their inhibition, in the breakdown of human endothelial basement membrane (BM) by MDA-MB-231 and MCF7ADR human breast cancer cell lines has been studied using 35S-labelled BM-coated 96-well culture plates. Basement membrane degradation (BMD) was independent of cell proliferation above the seeding density. Inhibitors of aspartic (pepstatin and PD 134678-0073) and cysteine proteinases (E64) had little effect on BMD under normal culture conditions, suggesting that cathepsins D, B and L have only a minor role. In contrast, inhibitors of urokinase-type plasminogen activator (uPA) and/or plasminogen activation to plasmin (aprotinin, amiloride, EACA, tranexamic acid, anti-uPA antibody) all reduced BMD by MDA-MB-231 cells by approximately 30-40%, but only in the presence of serum or plasminogen. BB94, an inhibitor of matrix metalloproteinases (MMPs), also reduced BMD by about 30% under these conditions but was similarly effective in serum-free medium. Combinations of BB94 with any of the uPA/plasminogen activation inhibitors in serum-containing medium had additive effects, while BB94 with pepstatin and E64 under serum-free conditions reduced BMD to 16% of control. Serum-containing conditioned medium exhibited appreciable BMD, largely due to aprotinin-inhibitable activity. Although small reductions in cell proliferation were seen with some inhibitors, the combination of BB94 with E64 or E64d reduced the cell population by about 60% under serum-containing conditions. These in vitro observations suggest that combinations of proteinase inhibitors, particularly of uPA/plasminogen activation and MMPs, may merit clinical evaluation as potential antimetastatic therapy for breast cancer.
Assuntos
Membrana Basal/metabolismo , Neoplasias da Mama/patologia , Inibidores de Proteases/farmacologia , Divisão Celular/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Humanos , Metaloendopeptidases/fisiologia , Invasividade Neoplásica , Células Tumorais Cultivadas , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidoresRESUMO
Specimen scrape cytology (SSC) and tumour bed biopsy (TBB) were used to assess adequacy of wide local excision of breast cancer. Thirty-nine (49%) of 80 cases were SSC positive and 18 (23%) TBB positive. When the main specimen contained ductal carcinoma in situ (DCIS) 21 (66%) of 32 cases were SSC positive compared to 18 (38%) of 48 when DCIS was absent (chi 2 = 9.17, P < 0.01). TBB results were not affected by the presence of DCIS. These findings may reflect the multifocal nature of breast cancer and especially DCIS. It is postulated that positive specimen cytology could be a better indicator of inadequate local surgical treatment than involved tumour bed biopsies or positive margins judged by conventional histology.
Assuntos
Biópsia , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Mastectomia Segmentar , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma in Situ/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Four oestrogen-regulated proteins of reported prognostic value, oestrogen receptor (ER), progesterone receptor (PR), pS2 and cathepsin D (Cat D), have been quantified by immunoassays, and the latter studied by immunohistochemistry (IHC) in primary tumours from clinically node-negative early breast cancer patients, entered into a trial of breast conservation therapy in which all the patients received adjuvant tamoxifen. ER, PR and pS2 significantly co-correlated but none correlated with Cat D. ER, PR and pS2, but not Cat D, were significantly associated with tumour size and grade, although Cat D tended to show an inverse relationship with the latter. Cat D (radioimmunoassay) in pmol/mg significantly correlated with the IHC score for Cat D in carcinoma cells as well as the number of Cat D-expressing macrophages. At a median follow-up of only 16 months, recurrence was significantly more common in patients with tumours having negative status for ER, PR and pS2 but was not associated with Cat D status.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Catepsina D/análise , Proteínas de Neoplasias/análise , Proteínas , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Prognóstico , Radioimunoensaio , Tamoxifeno/uso terapêutico , Fator Trefoil-1 , Proteínas Supressoras de TumorAssuntos
Neoplasias da Mama/química , Receptores de Esteroides/análise , Feminino , Humanos , PrognósticoRESUMO
The vertebra prominens is found most frequently at C7 in both sexes (78.7% of 47 females, 58.8% of 17 males). It is frequently at T1 in females (3 of 47: 6.4%) though not uncommonly so in males (6 of 17: 35%). The first spinous process felt at the lower end of the nuchal furrow is an unreliable guide to the vertebra prominens in the female (being at C6 in 59.6% of female subjects and coinciding with the vertebra prominens in only 46.8%). The sacral dimples have a wide distribution in vertebral level and are unreliable as surface vertebral landmarks. The generally accepted vertebral level of sacral dimples being at S2 is disputed, being present at this level in only 5 of 68 subjects (7.4%). There is a significant sex difference in the location of sacral dimples, being higher relative to vertebrae in females than in males, P less than 0.05. This finding is related particularly to the greater pelvic height of adolescent girls compared with boys.