RESUMEN
In osteosarcoma, a primary mesenchymal bone cancer occurring predominantly in younger patients, invasive tumour growth leads to extensive bone destruction. This process is insufficiently understood, cannot be efficiently counteracted and calls for novel means of treatment. The endocytic collagen receptor, uPARAP/Endo180, is expressed on various mesenchymal cell types and is involved in bone matrix turnover during normal bone growth. Human osteosarcoma specimens showed strong expression of this receptor on tumour cells, along with the collagenolytic metalloprotease, MT1-MMP. In advanced tumours with ongoing bone degeneration, sarcoma cells positive for these proteins formed a contiguous layer aligned with the degradation zones. Remarkably, osteoclasts were scarce or absent from these regions and quantitative analysis revealed that this scarcity marked a strong contrast between osteosarcoma and bone metastases of carcinoma origin. This opened the possibility that sarcoma cells might directly mediate bone degeneration. To examine this question, we utilized a syngeneic, osteolytic bone tumour model with transplanted NCTC-2472 sarcoma cells in mice. When analysed in vitro, these cells were capable of degrading the protein component of surface-labelled bone slices in a process dependent on MMP activity and uPARAP/Endo180. Systemic treatment of the sarcoma-inoculated mice with a mouse monoclonal antibody that blocks murine uPARAP/Endo180 led to a strong reduction of bone destruction. Our findings identify sarcoma cell-resident uPARAP/Endo180 as a central player in the bone degeneration of advanced tumours, possibly following an osteoclast-mediated attack on bone in the early tumour stage. This points to uPARAP/Endo180 as a promising therapeutic target in osteosarcoma, with particular prospects for improved neoadjuvant therapy.
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Neoplasias Óseas/patología , Osteólisis/metabolismo , Osteosarcoma/patología , Receptores Mitogénicos/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Invasividad Neoplásica , Osteoclastos/patología , Osteólisis/etiología , Osteólisis/patologíaRESUMEN
BACKGROUND: Currently there is no consensus on the use of adjuvant radiotherapy (RT) in retroperitoneal sarcoma (RPS). We have analysed clinical outcomes in patients with localised RPS treated at two Scandinavian Sarcoma Group (SSG) centres: Haukeland University Hospital (HUH), Bergen, Norway and Skåne University Hospital (SUH), Lund, Sweden to clarify the effects of adjuvant RT on local control and overall survival (OS). MATERIAL AND METHODS: Local databases and registers at HUH and SUH as well as the SSG central register were used to identify RPS patients. Patients with localised RPS who underwent surgery in Bergen between 1988 and 2009 and in Lund from 1998 to 2009 were included. Medical records were examined for clinical data, tumour characteristics, treatment factors and follow-up status. Archived tumour sections and tumour tissue were reviewed, and when necessary, restained and reclassified. Cox regression was used to analyse the association of potential prognostic factors with local recurrence-free survival (LRFS), metastasis-free survival (MFS) and OS. RESULTS: The study included 97 patients: 52 from Norway and 45 from Sweden. The proportion of high-grade tumours was 73%. The five-year LRFS, MFS and OS were 55%, 59% and 60%, respectively. RT was significantly associated with improved local control resulting in a five-year LRFS of 77% compared with 39% without (p < 0.001). Furthermore, five-year OS was 71% in the RT group in contrast to 52% with surgery alone (p = 0.019). In the adjusted analysis RT proved to be a significant factor also for MFS (HR = 0.42, 95% CI 0.20-0.88, p = 0.021). In addition, high-grade malignancy, large tumour and positive surgical margin were risk factors for local recurrence. High malignancy grade was the only significant adverse prognostic factor for metastasis. High age and high-grade malignancy were negative prognostic factors for OS. CONCLUSION: Adjuvant RT was significantly associated with an improved five-year LRFS and OS.
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Neoplasias Retroperitoneales/radioterapia , Sarcoma/radioterapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Supervivencia sin Enfermedad , Femenino , Humanos , Leiomiosarcoma/mortalidad , Leiomiosarcoma/patología , Leiomiosarcoma/radioterapia , Leiomiosarcoma/cirugía , Liposarcoma/mortalidad , Liposarcoma/patología , Liposarcoma/radioterapia , Liposarcoma/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Noruega , Pronóstico , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante , Sistema de Registros , Neoplasias Retroperitoneales/mortalidad , Neoplasias Retroperitoneales/patología , Neoplasias Retroperitoneales/cirugía , Sarcoma/mortalidad , Sarcoma/patología , Sarcoma/cirugía , Suecia , Adulto JovenRESUMEN
The polycomb group protein enhancer of zeste homologue 2 (EZH2) has been linked to invasive properties of aggressive breast cancer. In this report, tissue microarray analysis of 190 breast carcinomas from a nested case-control study shows that EZH2 is significantly associated with interval breast cancers. Further, a strong relationship was found with tumor cell proliferation (by Ki-67 expression), locally advanced disease, metastasis at presentation, markers of the basal epithelial phenotype (positivity for cytokeratin 5/6 or P-cadherin), and p53 status. EZH2 expression was also significantly associated with glomeruloid microvascular proliferation, an aggressive angiogenic phenotype. For prediction of aggressive disease (any event of locally advanced disease, lymph node spread, or distant spread), EZH2 was the only variable of significance in multivariate analysis, whereas no additional information was given by Ki-67. Although EZH2 expression was significant in univariate survival analysis, only tumor cell proliferation and lymph node status were significant in the final multivariate model. In conclusion, our findings indicate an important relationship not only between EZH2 and markers of tumor cell proliferation but also with aggressive disease. These findings might be practically important and relevant because the polycomb group proteins have recently been suggested as candidates for targeted therapy.
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Neoplasias de la Mama/patología , Proliferación Celular , Proteínas de Unión al ADN/biosíntesis , Factores de Transcripción/biosíntesis , Análisis de Varianza , Biomarcadores de Tumor/biosíntesis , Neoplasias de la Mama/metabolismo , Proteína Potenciadora del Homólogo Zeste 2 , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Complejo Represivo Polycomb 2 , Receptores de Estrógenos/análisis , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/análisisRESUMEN
Insulinomas are uncommon tumors, and in patients with diabetes mellitus they are extremely rare. We describe a patient with type 1 diabetes who developed malignant insulinoma. When hypoglycemic episodes persist in a patient with diabetes and treatment-induced and other causes of hypoglycemia have been ruled out, an insulin-producing tumor should be considered.
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Interval breast cancer reduce the effectiveness of mammography screening programs. We studied 95 interval cancers, diagnosed during 1996 to 2001 as part of the population-based Norwegian Breast Cancer Screening Program. These cases were matched on size (+/-2.0 mm) to 95 screen-detected breast cancers, and the tumors were compared by immunohistochemical methods using tissue microarrays. Patients with interval cancers were more likely to be younger [odds ratio (OR), 4.7; P = 0.0001], to have dense breasts (OR, 3.4; P = 0.004), and to have estrogen receptor-negative tumors (OR, 2.6, P = 0.01), and p53 expression was more frequent (OR, 4.0; P = 0.001). Notably, interval cancers were more likely to have a basal epithelial phenotype, in that expression of cytokeratin 5/6 (OR, 2.3; P = 0.04) and P-cadherin (OR, 2.5; P = 0.04) was more frequent in interval cases than in size-matched, screen-detected tumors. In a logistic regression model, p53 expression, age, and breast density were independent predictors of interval cancers. Our data suggest that breast cancers with a basal epithelial phenotype are more likely than nonbasal breast cancers to present between regular mammograms.
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Biomarcadores de Tumor/análisis , Neoplasias de la Mama/diagnóstico por imagen , Carcinoma Basocelular/diagnóstico por imagen , Mamografía , Tamizaje Masivo/métodos , Adulto , Factores de Edad , Anciano , Biomarcadores de Tumor/inmunología , Mama/fisiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Cadherinas , Carcinoma Basocelular/genética , Carcinoma Basocelular/inmunología , Estudios de Casos y Controles , Colorantes , Femenino , Genes p53 , Humanos , Inmunohistoquímica , Queratinas , Modelos Logísticos , Persona de Mediana Edad , Noruega , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Receptores de Estrógenos , Factores de RiesgoRESUMEN
BACKGROUND: Gastrointestinal stromal tumour (GIST) is the most frequent mesenchymal tumour type of the digestive tract. Between 30 and 40% of patients have high-risk, malignant GIST with poor prognosis after surgery. Imatinib mesylate is a recently introduced KIT tyrosine kinase inhibitor with effect on metastatic GIST. We report our experience with imatinib mesylate in the treatment of GIST. MATERIAL AND METHODS: Nine patients diagnosed with GIST have received imatinib mesylate since August 2001. Eight patients had metastatic disease, one patient received adjuvant treatment. The patients were evaluated according to standard protocols for clinical performance, effect of treatment, and adverse effects. Tumour tissue was analysed for mutational status in KIT and PDGFRA. RESULTS: All patients with metastatic disease had palliative benefit; three had partial response and the remaining stable disease. The single patient receiving adjuvant treatment had no sign of recurrence. Side effects were mainly mild diarrhoea, nausea and vomiting. Seven patients had mutations in KIT exon 11, one in KIT exon 9, and one in PDGFRA exon 12. INTERPRETATION: The results demonstrate that imatinib mesylate is an effective drug that can stabilise and reduce disease in patients with advanced GIST.
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Antineoplásicos/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Neoplasias Intestinales/tratamiento farmacológico , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Benzamidas , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/secundario , Femenino , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/secundario , Humanos , Mesilato de Imatinib , Neoplasias Intestinales/patología , Neoplasias Intestinales/secundario , Masculino , Persona de Mediana Edad , Piperazinas/efectos adversos , Pronóstico , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Neoplasias Gástricas/patología , Neoplasias Gástricas/secundario , Resultado del TratamientoRESUMEN
INTRODUCTION: Tumor cell proliferation in breast cancer is strongly prognostic and may also predict response to chemotherapy. However, there is no consensus on counting areas or cut-off values for patient stratification. Our aim was to assess the matched level of proliferation by Ki67 when using different tissue categories (whole sections, WS; core needle biopsies, CNB; tissue microarrays, TMA), and the corresponding prognostic value. METHODS: We examined a retrospective, population-based series of breast cancer (n = 534) from the Norwegian Breast Cancer Screening Program. The percentage of Ki67 positive nuclei was evaluated by visual counting on WS (n = 534), CNB (n = 154) and TMA (n = 459). RESULTS: The median percentage of Ki67 expression was 18% on WS (hot-spot areas), 13% on CNB, and 7% on TMA, and this difference was statistically significant in paired cases. Increased Ki67 expression by all evaluation methods was associated with aggressive tumor features (large tumor diameter, high histologic grade, ER negativity) and reduced patient survival. CONCLUSION: There is a significant difference in tumor cell proliferation by Ki67 across different sample categories. Ki67 is prognostic over a wide range of cut-off points and for different sample types, although Ki67 results derived from TMA sections are lower compared with those obtained using specimens from a clinical setting. Our findings indicate that specimen specific cut-off values should be applied for practical use.
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Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Antígeno Ki-67/metabolismo , Anciano , Biopsia con Aguja Gruesa , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/cirugía , Estudios de Casos y Controles , Proliferación Celular , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Análisis de Matrices TisularesRESUMEN
PURPOSE: To our knowledge we introduce the ROC partial area under the curve (AUC) index as a method of evaluating the discriminative power of different prostate cancer predictors. Peripheral zone volume and peripheral zone prostate specific antigen (PSA) density are introduced as potential predictors and compared with other known predictors of prostate cancer. MATERIALS AND METHODS: During 1999, 220 consecutive patients with suspected early prostate cancer were examined using total PSA, free PSA, total prostate volume, transition zone volume and transrectal ultrasonography guided sextant biopsy of the prostate. The free-to-total PSA ratio, PSA density, transition zone PSA density, peripheral zone volume and peripheral zone PSA density were calculated. Usually total AUC is used to evaluate the discriminative power of different parameters. In this study parameters were evaluated by the ROC partial area index, which includes only the AUC in highly sensitivity parts of the ROC curve. Explorative analysis using logistic regression analysis was performed to investigate the ability of combinations of parameters to predict cancer. RESULTS: Of the 220 patients 75 were diagnosed with cancer. In the subgroup of 160 patients with PSA less than 10 microg/l 44 had cancer. Transition zone PSA density and PSA density had significant discriminative power in the total group, while none of the parameters were discriminative in the subgroup of patients. CONCLUSIONS: When high sensitivity is demanded, the ROC partial area index seems to be meaningful for evaluating the discriminative power of potential predictors. In our study none of the evaluated parameters had discriminative power in patients with PSA less than 10 microg/l, while transition zone PSA density and PSA density showed discriminative power in the total group of patients.
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Neoplasias de la Próstata/diagnóstico , Curva ROC , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: Potentially curable prostate cancer is a diagnostic challenge for the general practitioner (GP). In a defined catchment area we wanted to discover why patients consulted their GPs and the reasons for their referral to the urologist. MATERIAL AND METHODS: Patients remitted to our "early prostate cancer clinic" with suspected potentially curable prostate cancer between January 1997 and December 2000 were included in the study. Patient information was registered according to a prospectively designed protocol. RESULTS: Of the 872 patients examined, prostate cancer was diagnosed in 41.3% (360/872). Median age was 63.1 years and median total prostate-specific antigen (PSA) level was 8.6 microg/l. The main reason for referral to a urologist was elevated PSA alone. However, the majority of the patients had no urological symptoms when they consulted their GP. As no local or national screening recommendations existed, we believe that opportunistic PSA screening has been common. CONCLUSIONS: The most important reason for referring patients to our specialist clinic was elevated PSA, often detected by means of opportunistic PSA screening. This study shows the effect of PSA testing in real-life practice.