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Tumour Burden (tumour + burden)
Selected AbstractsOnco-miR-155 targets SHIP1 to promote TNF,-dependent growth of B cell lymphomasEMBO MOLECULAR MEDICINE, Issue 5 2009Irene M. Pedersen Abstract Non-coding microRNAs (miRs) are a vital component of post-transcriptional modulation of protein expression and, like coding mRNAs harbour oncogenic properties. However, the mechanisms governing miR expression and the identity of the affected transcripts remain poorly understood. Here we identify the inositol phosphatase SHIP1 as a bonafide target of the oncogenic miR-155. We demonstrate that in diffuse large B cell lymphoma (DLBCL) elevated levels of miR-155, and consequent diminished SHIP1 expression are the result of autocrine stimulation by the pro-inflammatory cytokine tumour necrosis factor , (TNF,). Anti-TNF, regimen such as eternacept or infliximab were sufficient to reduce miR-155 levels and restored SHIP1 expression in DLBCL cells with an accompanying reduction in cell proliferation. Furthermore, we observed a substantial decrease in tumour burden in DLBCL xenografts in response to eternacept. These findings strongly support the concept that cytokine-regulated miRs can function as a crucial link between inflammation and cancer, and illustrate the feasibility of anti-TNF, therapy as a novel and immediately accessible (co)treatment for DLBCL. [source] Metastatic melanoma volume in sentinel nodes: objective stereology-based measurement predicts disease recurrence and survivalHISTOPATHOLOGY, Issue 7 2009Rikke Riber-Hansen Aims:, Sentinel lymph node (SLN) status is the most important prognostic factor in intermediate thickness melanoma. The amount of metastatic disease in positive SLNs varies greatly between patients, and this tumour burden appears to influence the prognosis of node-positive patients. The aim was to use objective stereological techniques to correlate accurately total SLN tumour burden with recurrence and patient survival. Methods and results:, SLNs from 327 patients were examined by complete step sectioning and immunohistochemistry. The total metastasis volume (TMV) of 156 positive SLNs from 99 patients (30.3%) was measured using stereological methods based on the 2D-nucleator and Cavalieri's principle. The maximum metastasis diameter was also measured. These two measurements were correlated with disease recurrence and patient survival. The mean TMV for SLN+ patients was 10.5 mm3 (median 0.05 mm3; range 0.0001,623.7 mm3). Median follow-up was 26.3 months. On multivariate analysis, TMV was an independent predictor of recurrence when corrected for primary tumour thickness (P = 0.001) and was a stronger prognosticator compared with the maximum metastasis diameter (P < 0.0001 versus P = 0.01). Conclusions:, Combining total step sectioning of SLNs with stereological assessment of metastases, we found metastasis volume to be a highly significant predictor of disease recurrence and survival. [source] Interaction of tumour biology and tumour burden in determining outcome after hepatic resection for colorectal metastasesHPB, Issue 2 2010Dhanny Gomez Abstract Aims:, To determine the outcome of colorectal liver metastasis (CRLM) patients based on tumour burden, represented by tumour number and size, and tumour biology as assessed by an inflammatory response to tumour (IRT) and margin positivity. Methods:, Data were collated from CRLM patients undergoing resection from January 1993 to March 2007. Patients were divided into: low (,3 metastases and/or ,3 cm); moderate (4,7 metastases and/or >3,,5 cm); and high (,8 metastases and/or >5 cm) tumour burden. Results:, Seven hundred and five patients underwent resection, of which 154 (21.8%), 262 (37.2%) and 289 (41.0%) patients were in the low, moderate and high tumour burden groups, respectively. The 5-year disease-free (P < 0.001) and overall (P < 0.001) survival were significantly different between the groups. IRT (P < 0.001), extent of resection (P < 0.001) and margin (P < 0.001) also differed between the groups. Sub-group analysis revealed that IRT was the only adverse predictor for disease-free and overall survival in the low group. In the moderate group, IRT predicted poorer disease-free survival on multi-variate analysis. In the high group, R1 resection and transfusion were predictors of poorer disease-free survival and age ,65 years, R1 resection and IRT were adverse predictors of overall survival. Conclusion:, Resection margin influenced the outcome of patients with high tumour burden, hence the importance of achieving clear margins. IRT influenced the outcome of patients with less aggressive disease. [source] The theoretical basis of cancer-stem-cell-based therapeutics of cancer: can it be put into practice?BIOESSAYS, Issue 12 2007Isidro Sánchez-García In spite of the advances in our knowledge of cancer biology, most cancers remain not curable with present therapies. Current treatments consider cancer as resulting from uncontrolled proliferation and are non-specific. Although they can reduce tumour burden, relapse occurs in most cases. This was long attributed to incomplete tumour elimination, but recent developments indicate that different types of cells contribute to the tumour structure, and that the tumour's cellular organization would be analogous to that of a normal tissue, with a main mass of differentiating cells sensitive to anti proliferative agents, together with a small percentage of quiescent, resistant stem cells responsible for replenishing the tumour: the Cancer Stem Cells (CSCs). Anti-CSCs targeted therapeutic agents would prevent tumour regeneration. New mouse models tailored to exploit this novel concept will be critical to develop CSC-based anti-cancer therapies. Here we review the biological basis and the therapeutic implications of the stem-cell model of cancer. BioEssays 29:1269,1280, 2007. © 2007 Wiley Periodicals, Inc. [source] Paclitaxel and cisplatin as intravesical agents against non-muscle-invasive bladder cancerBJU INTERNATIONAL, Issue 11 2008Boris A. Hadaschik OBJECTIVES To investigate the effects of cisplatin and paclitaxel against human bladder cancer cells in vitro, and to obtain both pharmacokinetic and pharmacodynamic data after intravesical administration in mice. MATERIALS AND METHODS Six bladder cancer cell lines (J82, KU7, RT4, SW780, T24, UMUC3) were treated with various combined doses of both drugs and cell proliferation was evaluated 3 days later. In vivo, solutions of cisplatin and micellar paclitaxel were instilled transurethrally in female mice and pharmacokinetic data were acquired using high-performance liquid chromatography-mass spectrometry and atomic absorption methods. To obtain efficacy data, mice with orthotopic KU7-luc tumours were administered cisplatin and/or micellar paclitaxel intravesically, and the tumour burden quantified using bioluminescence imaging. RESULTS In vitro, both cisplatin and paclitaxel potently decreased the proliferation of all cell lines tested, and in combination had an additive but not a synergistic effect. After intravesical instillation, mouse serum concentrations of cisplatin and paclitaxel were in the low microgram/millilitre range and bladder tissue concentrations achieved were 82 and 241 µg/g, respectively. Similar drug levels were reached using combined therapy. In vivo, all chemotherapeutic agents significantly inhibited bladder tumour growth, with the best results for combined therapy and micellar paclitaxel alone. However, there was toxicity in the combined treatment arm. CONCLUSIONS Both cisplatin and paclitaxel were absorbed at effective amounts into bladder tissues. As intravesical agents, paclitaxel had slightly stronger anticancer potency than cisplatin. Due to increased adverse events, caution should be exercised when combining both cisplatin and paclitaxel intravesically. [source] Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2010Peter Ruf WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The trifunctional antibody catumaxomab is a highly effective anti-cancer therapeutic that is administered to patients suffering from malignant ascites intraperitoneally (i.p.) in microgram (µg) doses. So far, no clinical pharmacokinetic data are available. WHAT THIS STUDY ADDS , Catumaxomab attains effective local concentrations in the ascites fluid and shows low systemic exposure with an acceptable safety profile confirming the appropriateness of the i.p. application scheme. AIMS Catumaxomab is the first EMEA approved trifunctional anti-EpCAM×anti-CD3 antibody for the treatment of cancer patients with malignant ascites. A phase II pharmacokinetic study was conducted to determine local and systemic antibody concentrations and anti-drug antibody (ADA) development. METHODS Thirteen cancer patients with symptomatic malignant ascites were treated with four ascending doses of 10, 20, 50, and 150 µg catumaxomab intraperitoneally (i.p.) infused on days 0, 3, 6 or 7 and 10. The pharmacokinetics of catumaxomab were studied by implementation of supportive data from a non clinical mouse tumour model. Additionally, ADA development was monitored. RESULTS Ten out of 13 patients were evaluable for pharmacokinetic analysis. Catumaxomab became increasingly concentrated in ascites during the course of treatment, attaining effective concentrations in the ng ml,1 range. Catumaxomab remained immunologically active even after several days in the circulation. The observed systemic catumaxomab exposure was low (<1%), with a maximal median plasma concentration (Cmax) of 403 pg ml,1. The mean elimination half-life in the plasma was 2.13 days. All patients developed ADA, but not before the last infusion. High observed inter-individual variability and low systemic exposure may be explained by the inverse correlation between tumour burden, effector cell numbers and systemic antibody bioavailability as demonstrated in a defined mouse tumour model. CONCLUSIONS Based on the high and effective local concentrations, low systemic exposure and acceptable safety profile, we confirmed that the i.p. application scheme of catumaxomab for the treatment of malignant ascites is appropriate. [source] Expression of the stem cell marker nestin in peripheral blood of patients with melanomaBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2010A. Fusi Summary Background, There is continued interest in markers indicative of circulating melanoma cells. Nestin is a neuroepithelial intermediate filament protein that was found to be expressed in melanoma and in various cancer stem cells. Objectives, We investigated expression of nestin in peripheral blood of patients with melanoma. Methods, We analysed nestin expression by flow cytometry and by quantitative reverse transcription,polymerase chain reaction both in tissues (n = 23) and in blood samples (n = 102) from patients with American Joint Committee on Cancer stage III,IV melanoma. Forty-six negative controls were also added. Results, Flow cytometry did not reveal nestin-expressing cells in peripheral blood of healthy volunteers. In patients with melanoma, however, nestin protein was expressed in a proportion of melanoma cells enriched from peripheral blood by immunomagnetic sorting. In melanoma tissue samples a significant correlation was found between mRNAs coding for nestin and tyrosinase (P = 0·001) and melan-A (P = 0·002), whereas in blood a significant correlation was observed only for tyrosinase (P = 0·015), but not for melan-A (P = 0·53). Nestin expression was higher in stage IV patients compared with stage III/IV with no evidence of disease, in patients with high tumour burden, and was positively correlated to expression of tyrosinase and melan-A. Conclusions, Nestin was found to be an additional marker of interest for circulating melanoma cells. Prospective studies should investigate its potential added informative value in comparison with markers already in use for melanoma cell detection. [source] Sentinel lymph node biopsy in melanoma: a micromorphometric study relating to prognosis and completion lymph node dissectionBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2007S. Debarbieux Summary Background, Sentinel lymph node (SLN) positivity has been found to be strongly associated with a poor prognosis in melanoma. Objectives, This large referral centre study was conducted: (i) to confirm the powerful prognostic value of SLN biopsy (SLNB); (ii) to correlate patient prognosis to the micromorphometric features of SLN metastasis in SLN-positive patients; and (iii) to correlate these micromorphometric features to the likelihood of positive completion lymph node dissection (CLND). Patients and methods, SLNB was performed in 455 cases of primary melanoma between January 1999 and December 2004; for patients with positive SLN, the following micromorphometric features were registered: size of the largest metastasis (two diameters), depth of metastasis, number of millimetric slices involved, maximum number of metastases on a single section, presence of intracapsular lymphatic invasion and extracapsular spread. Kaplan,Meier survival curves were compared with the log-rank test; multivariate analysis was performed using a Cox regression model. Dependence of CLND status on micromorphometric features of SLN was assessed by the ,2 test and predictive values of the different features were evaluated by multivariate analysis using a logistic regression model. Results, A positive SLN was identified in 98 of our 455 cases. Survival was significantly shorter in SLN-positive patients than in SLN-negative patients. Extracapsular invasion was found to be an independent prognostic factor of disease-free survival; ulceration of the primary and the maximum diameter of the largest metastasis were identified as independent predictive factors of disease-specific survival. Age and the lowest diameter of the largest metastasis were identified as independent predictive criteria of positive CLND, whereas depth of metastasis was not. Positivity of CLND was not significantly associated with a worse prognosis. Conclusions, Our study confirms the previously demonstrated strong prognostic value of SLNB. It also confirms the relationship between tumour burden in the SLN (evaluated by the maximum diameter of the largest metastasis) and clinical outcome. We point out a new micromorphometric feature of SLN, which seems to be predictive of CLND status: the lowest diameter of the largest metastasis. [source] Rare occurrence of CD30+ circulating cells in patients with cutaneous CD30+ anaplastic large cell lymphoma: a study of nine patientsBRITISH JOURNAL OF DERMATOLOGY, Issue 2 2003O. Dereure SummaryBackground The presence of a significant percentage of circulating atypical lymphocytes in peripheral blood has already been demonstrated in systemic CD30+ anaplastic large cell lymphoma (ALCL), which implies that a leukaemic component may be present in this subset of lymphomas. However, no similar data are available for the cutaneous counterpart of this particular lymphoproliferation. Objectives To assess the presence of atypical cells, CD30+ lymphocytes and of a dominant T-cell clone in peripheral blood in a series of patients with cutaneous CD30+ ALCL. Materials and methods Nine patients with either primary (four) or secondary (five) cutaneous CD4+ CD30+ ALCL were selected. The percentage of CD30+ CD4+ lymphocytes among peripheral blood mononuclear cells (PBMC) was determined by flow cytometry and the presence of a dominant circulating T-cell clone was assessed by polymerase chain reaction targeting the T-cell receptor , chain. A control group composed of apparently healthy individuals was similarly studied at the same time. Results The mean percentage of CD30+ cells in PBMC was slightly higher in patients than in controls (3·9% vs. 2·7%) but the difference was not statistically significant. Only two patients displayed more than 5% CD30+ cells, both of whom had a minor tumour burden. A dominant circulating T-cell clone was detected in only three cases, including these two latter patients. Conclusions The occurrence of a significant percentage of CD30+ CD4+ circulating cells is rare in active cutaneous CD30+ ALCL, either primary or secondary. This percentage is not related to the apparent skin tumour burden but a significant figure appeared to be correlated with the detection of a dominant T-cell clone in peripheral blood. Overall, these data show that, unlike mycosis fungoides, peripheral blood involvement seems infrequent in cutaneous CD30+ ALCL. The hypothesis that a high percentage of CD30+ circulating cells might be related to the presence of a cryptic systemic disease cannot be ruled out. [source] Pharmacokinetics and pharmacokinetic/pharmacodynamic associations of ofatumumab, a human monoclonal CD20 antibody, in patients with relapsed or refractory chronic lymphocytic leukaemia: a phase 1,2 studyBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2010Bertrand Coiffier Summary The purpose of this phase 1,2 study was to investigate the association between the pharmacokinetic properties of ofatumumab, a human monoclonal CD20 antibody, and outcomes in 33 patients with relapsed/refractory chronic lymphocytic leukaemia receiving 4 weekly infusions of ofatumumab. The ofatumumab concentration profiles were fitted well by a two-compartment model with different elimination rate constant at first infusion compared to the remaining infusions in line with the observed rapid and sustained B-cell depletion. Exposure to ofatumumab was linked to clinical outcomes: high exposure was associated with higher probability of overall clinical response and longer progression-free survival. This association still remained statistically significant even when adjusting for relevant baseline covariates including tumour burden. The trial was registered at http://www.clinicaltrials.gov (NCT00093314). [source] Inhibitor of DASH proteases affects expression of adhesion molecules in osteoclasts and reduces myeloma growth and bone diseaseBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2009Angela Pennisi Summary Dipeptidyl peptidase (DPP) IV activity and/or structure homologues (DASH) are serine proteases implicated in tumourigenesis. We previously found that a DASH protease, fibroblast activation protein (FAP), was involved in osteoclast-induced myeloma growth. Here we further demonstrated expression of various adhesion molecules in osteoclasts cultured alone or cocultured with myeloma cells, and tested the effects of DASH inhibitor, PT-100, on myeloma cell growth, bone disease, osteoclast differentiation and activity, and expression of adhesion molecules in osteoclasts. PT-100 had no direct effects on viability of myeloma cells or mature osteoclasts, but significantly reduced survival of myeloma cells cocultured with osteoclasts. Real-time PCR array for 85 adhesion molecules revealed upregulation of 17 genes in osteoclasts after coculture with myeloma cells. Treatment of myeloma/osteoclast cocultures with PT-100 significantly downregulated 18 of 85 tested genes in osteoclasts, some of which are known to play roles in tumourigenesis and osteoclastogenesis. PT-100 also inhibited osteoclast differentiation and subsequent pit formation. Resorption activity of mature osteoclasts and differentiation of osteoblasts were not affected by PT-100. In primary myelomatous severe combined immunodeficient (SCID)-hu mice PT-100 reduced osteoclast activity, bone resorption and tumour burden. These data demonstrated that DASH proteases are involved in myeloma bone disease and tumour growth. [source] Overexpressed growth hormone (GH) synergistically promotes carcinogen-initiated liver tumour growth by promoting cellular proliferation in emerging hepatocellular neoplasms in female and male GH-transgenic miceLIVER INTERNATIONAL, Issue 2 2001Kenneth J. Snibson Abstract:Background/Aims: Growth hormone (GH), when overexpressed in male and female GH-transgenic mice, is known to induce liver tumours within 1 year. This study aimed to gain a clearer understanding of the interaction between GH and tumour cells in vivo. Methods/Results: The carcinogen diethylnitrosomine (DEN) was administered to neo-natal transgenic and non-transgenic mice maintained in a "hepatocarcinogenesis resistant" genetic background (C57BL/6J). Macroscopic, microscopic and liver weight/body weight ratio analyses revealed that carcinogen-induced hepatocarcinogenesis was dramatically accelerated in young GH-transgenic mice compared to non-transgenic counterparts. Image analysis of microscopic hepatocellular neoplasms showed rapidly increasing tumour burdens, and neoplastic foci size over time in young adult GH-transgenic mice. The magnitude of enhanced tumour growth was equivalent in both male and female transgenic mice, whereas much lower and sexually dimorphic tumour growth rates (males>females) were observed in non-transgenic mice treated with DEN. BrdU labelling experiments demonstrated that rapid tumour growth in carcinogen-treated GH-transgenic mice was due to the promotion of cell proliferation in emerging lesions. Tumour cell proliferation in young GH-transgenic mice was 2.6- and 4-fold higher, respectively, than that observed in similar age male and female non-transgenic mice. Interestingly, both GH-transgenic and non-transgenic mice displayed progressively slower tumour growth rates in older animals. Conclusion: Overall, GH synergistically promotes carcinogen-induced hepatocarcinogenesis in both sexes of GH-transgenic mice by stimulating tumour cell proliferation. [source] | |||||||||||||