| 1. |
- Farnebäck, Malin, et al.
(author)
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Expression of tumor associated transcripts in malignant melanoma metastases : with methodological aspects
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Other publication (other academic/artistic)abstract
- Several antigens expressed in malignant melanoma are involved in the immunological surveillance of the tumor. The mRNAs of these antigens, especially tyrosinase, have also been used in the detection of minimal residual disease in the blood of melanoma patients. We have therefore analyzed the expression of tyrosinase, TRP-1, TRP-2, MART-1/Melan-A, MAGE-A3, MAGE-A12, S-100 and GD2 synthase by real-time PCR in snap frozen sections from 28 regional and systemic metastases. Treatment with cisplatinum, dacarbazine and interferon-α2b was given to 15 patients before surgery. The transcript concentrations varied widely between individual metastases. However, in general the pigment-related transcripts and that of S-100 were found at higher levels than those of MAGE-A3, MAGE-A12 and GD2 synthase. Significant correlations (p<0.001) were found between tyrosinase and MART-1/Melan-A and between MAGE-A3 and MAGE-A12. TRP-2 and GD2 synthase were both influenced by the treatment, TRP-2 expression was increased in the metastases from treated patients, whereas GD2 synthase expression was decreased. Furthermore, a decrease in tyrosinase expression was found in metastases without tumor-infiltrating lymphocytes. ln this work normalization by the section area contra normalization by housekeeping genes was also evaluated and similar results were obtained with both methods.
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| 2. |
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| 3. |
- Andersson, Pia, et al.
(author)
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Marine Acidification : On effects and monitoring of marine acidification in the seas surrounding Sweden
- 2008. - 2008:92
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Reports (other academic/artistic)abstract
- Surface waters in the world oceans have already experienced a pH reduction of about 0.1 units (OSPAR, 2006.) The trend indicates further decrease of pH and is most probably due to increased uptake of atmospheric CO2 and less buffering capacity of ocean waters. The trend is similar in the waters surrounding Sweden. RESEARCH NEEDS Since there is an alarming absence of information regarding the effects of near-future levels of ocean acidification on Swedish marine taxa, there is a clear research need on: • investigations of the effects of ocean acidification on the early life-history stages of key ecosystem-structuring species, and commercially important species of fish and shellfish • ecosystem-level mesocosm studies of the impacts of ocean acidification on Swedish marine systems • improved regional-scale modelling of acidification mechanisms in Swedish coastal waters • testable ecosystem-scale food-web models to articulate with regional acidification models • improved definition of chemical equilibrium constants between pH, AT and CO2 in low saline waters. ACTIONS TO IMPROVE MONITORING At present, pH and AT are monitored monthly at standard depths at 7 stations in Skagerrak, Kattegat and Baltic Proper within the national monitoring programme. Of these are 2 located in coastal waters (Halland and Småland; Type 5 and 9). We recommend that Sweden work to improve the status of pH and AT to be Core variables instead of Main variables in HELCOM COMBINE “High frequency Sampling” program taking into account the last 15 years negative trends in pH in waters surrounding Sweden as well as in the global oceans. We recommend that besides the standard para-meters monitored in the national monitoring program, pH, AT and DIC should be monitored. For completeness, primary production should also be monitored. Below are three monitoring recommendations, where the first is divided into a lowest level and a recommended level. 1. Lowest level: Within the national monitoring program, at least one station per open sea area and all costal stations measure acidification parameters on a monthly basis in the entire water column at standardized depths. The national and regional monitoring programmes should be upgraded in the Gulf of Bothnia so that pH and AT is monitored at standard depths at least monthly at one station each in the Bothnian Bay and Bothnian Sea. Also 2 coastal stations in the Gulf of Bothnia should be established. In addition, one coastal station should be established within Type 14 in the Baltic Proper. 1. Recommended level: the national monitoring program should have at least one station per open sea area and if the area is characterized by strong gradients or other features, there should be more than one station. Some of the stations in the regional monitoring programmes should be upgraded with acidification parameters, for a better geographical coverage. The acidification parameters should be measured on a monthly basis in the entire water column at standardized depths. 2. We recommend that an investigative monitoring is established by extending the parameters that are needed to firmly improve the chemical stability constants between pH, AT, DIC and pCO2 in low saline waters. This can be done by just extending the sampling program at selected monitoring stations. Sampling should cover a period of 2 to 3 years. 3. We recommend that direct water measurement of pCO2 for monitoring purposes should be assessed after the recommendation above is evaluated and that ongoing research projects on pCO2 measurements using ferryboxes are finalised. RECOGNISED PROBLEM AREAS • There are only few long time series of acidification parameters. The time period of measurements is rather short. • The geographical coverage of measurements is rather limited in the waters surrounding Sweden. • The chemical stability constants between pH, AT, DIC and pCO2 are not optimized in low saline waters. • pH budgets are difficult to calculate. • Models need to be improved in order to display present and future small and large scale scenarios. • Little is known of the biological, ecological and economical effects of the current and near future marine acidification. Further research is required.
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| 4. |
- Bernsen, MR, et al.
(author)
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On the biological relevance of MHC class II and B7 expression by tumour cells in melanoma metastases
- 2003
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 88:3, s. 424-431
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Journal article (peer-reviewed)abstract
- A large number of studies have indicated that specific immune reactivity plays a crucial role in the control of malignant melanoma. In this context, expression of MHC I, MHC II and B7 molecules by melanoma cells is seen as relevant for the immune response against the tumour. For a better understanding of the biological relevance of MHC II and B7 expression by tumour cells in metastatic melanoma, we studied the expression of these molecules in melanoma metastases in relation to the inflammatory response, regression of the tumour and survival from 27 patients treated with biochemotherapy (30 mg m-2 Cisplatin and 250 mg m-2 decarbazine (dimethyl-triazene-imidazole-carboxamide, DTIC) on days 1-3 i.v., and 107 IU IFN-a2b 3 days a week s.c., q. 28d). In 19 out of 27 lesions studied, we found expression of MHC II by the tumour cells, while only in one out of II tumour biopsies obtained from untreated metastatic melanoma patients, MHC II expression was detected. Expression of B7.1 and B7.2 by tumour cells was found in nine out of 24 and 19 out of 24 lesions, respectively. In all cases where B7.1 expression was found, expression of B7.2 by the tumour cells was also seen. In general, no or only few inflammatory cells positive for B7 were found. Expression of MHC II by tumour cells was positively correlated with the presence of tumour-infiltrating lymphocytes, regression of the lesion, and with time to progression (TTP) and overall survival (OS) of the patient. However, no significant correlation between B7.1 or B7.2 expression and regression of the tumour, TTP or OS was found. In light of other recent findings, these data altogether do support a role as biomarker for MHC II expression by tumour cells, however, its exact immunological pathomechanism(s) remain to be established. ⌐ 2003 Cancer Research UK.
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| 5. |
- Bernsen, Monique R, et al.
(author)
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Heparan sulphate epitope-expression is associated with the inflammatory response in metastatic malignant melanoma
- 2003
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In: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 52:12, s. 780-783
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Journal article (peer-reviewed)abstract
- Heparan sulphate (HS) represents a heterogeneous class of molecules on cell membranes and extracellular matrices. These molecules are involved in a variety of biological processes, including immune responses, through their binding and functional modulation of proteins. Recently a panel of HS-epitope-specific, human single chain antibodies have been generated by phage display, facilitating analysis of the structural heterogeneity of HS in relation to pathological conditions. In a pilot study a heterogeneous staining pattern in melanoma metastases was observed with one of the clones (EW4G1). Using a double-staining technique, the expression of this epitope was studied in 12 metastatic melanoma lesions in relation to the presence of a CD3 + cell infiltrate. Different staining patterns with EW4G1 were observed in the different lesions. The different staining patterns were associated with the presence and pattern of inflammation with CD3+ cells. A pronounced staining pattern of blood vessels with EW4G1 was associated with a more or less brisk presence of CD3+ cells, while a pronounced staining of tumour cells or tumour cell matrix or absence of staining with EW4G1 was associated with absence of CD3+ cells. These results suggest a dualistic role for HS in the recruitment and intratumoural migration of CD3+ cells, depending on the location of expression of its epitope recognized by EW4G1. Further characterization of the structural diversity of HS and its function in T-cell recruitment and migration is therefore warranted, since detailed understanding of this relation may provide new targets for therapeutic intervention, such that better homing and migration of T cells (in)to tumours might be achieved in immunologically based treatment strategies.
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| 6. |
- Clinchy, Birgitta, 1957-, et al.
(author)
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Preoperative interleukin-6 production by mononuclear blood cells predicts survival after radical surgery for colorectal carcinoma
- 2007
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In: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 109:9, s. 1742-1749
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Journal article (peer-reviewed)abstract
- BACKGROUND. Colorectal cancer is one of the most common forms of cancer in the Western world. Staging based on histopathology is currently the most accurate predictor of outcome after surgery. Colorectal cancer is curable if treated at an early stage (stage I-III). However, for tumors in stages II and III there is a great need for tests giving more accurate prognostic information defining the patient population in need of closer follow-up and/or adjuvant therapy. Furthermore, tests that provide prognostic information preoperatively could provide a guide both for preoperative oncologic treatment and the surgical procedure. METHODS. Peripheral blood mononuclear cells (PBMCs) were isolated preoperatively, within a week before primary surgery, from 39 patients undergoing surgery for colorectal cancer. The PBMCs were cultured in vitro for 24 hours in the presence of autologous serum and lipopolysaccharide (LPS). Interleukin-6 (IL-6) production was measured with enzyme-linked immunosorbent assay (ELISA). Staging based on histopathology was performed in all patients. Patients were followed for at least 54 months. RESULTS. A production of >5000 pg/mL of IL-6 identified colorectal cancer patients with a poor prognosis. Eight out of 13 patients with >5000 pg/mL IL-6 died from cancer within the follow-up period, whereas no cancer-related deaths were recorded among 21 patients with 5000 pg/mL IL-6 or less. A multivariate Cox regression analysis, stratified for T- and N-stage, identified IL-6 production as an independent prognostic factor. CONCLUSIONS. IL-6 production in vitro by PBMC can predict survival after radical surgery for colorectal cancer. © 2007 American Cancer Society.
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| 7. |
- Håkansson, Annika, 1962-, et al.
(author)
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Bcl-2 expression in metastatic malignant melanoma. Importance for the therapeutic efficacy of biochemotherapy
- 2003
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In: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 52:4, s. 249-254
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Journal article (peer-reviewed)abstract
- For the majority of patients with metastatic malignant melanoma the prognosis is poor. Immunotherapy and biochemotherapy have shown promise with a subset of durable responses, but there is still a great need for a better understanding of the mechanisms of action during treatment to optimize future treatment schedules. In the present study Bcl-2 expression was studied in biopsies from ten patients with metastatic malignant melanoma (five with regional disease and five with systemic disease) treated with biochemotherapy, (cisplatinum 30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 i.v. and Interferon-a2b 10 MIU s.c. 3 days a week, on a 28-day cycle). The expression of Bcl-2 by the tumour cells was separately recorded in areas of histopathological regressive changes and in areas of unaffected tumour growth. Comparisons were made with biopsies from 14 untreated patients. In 10 of 10 treated patients a high expression of Bcl-2 by the tumour cells was found in areas of unaffected tumour growth. In contrast, only in 5 of 13 untreated patients was a high expression of Bcl-2 by the tumour cells found in these areas (P = 0.008). A significant difference was also found in the expression of Bcl-2 by the tumour cells between areas of unaffected tumour growth and areas of histopathological regressive changes (P=0.03). The significantly higher expression of Bcl-2 by the tumour cells in areas of unaffected tumour growth in treated patients compared to untreated patients indicates that clones with a high expression of Bcl-2 may be present after therapy, preventing apoptosis and eventually in many patients resulting in progressive disease. Supporting this concept, a difference was also found between the expression of Bcl-2 in areas of unaffected tumour growth, i.e. in areas of treatment failure, and the expression in areas of histopathological regressive changes. Thus immunohistochemical analysis of tumour biopsies shortly after therapy seems to be a good surrogate endpoint that allows a detailed analysis of Bcl-2 expression. The high expression of Bcl-2 shown in unaffected tumour areas after therapy suggests the need for additional treatment, e.g. Bcl-2 antisense therapy.
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| 8. |
- Håkansson, Annika, 1962-, et al.
(author)
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Biochemotherapy of metastatic malignant melanoma. On down-regulation of CD28
- 2002
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In: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 51:9, s. 499-504
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Journal article (peer-reviewed)abstract
- Immunotherapy and combination treatments such as biochemotherapy have shown promise, with higher response rates and a subset of durable responses, however, as the majority of responses are still of short duration, they do not provide any survival benefit. There is therefore a great need to better understand the mechanisms whereby tumours escape immune surveillance. The present study examines the expression of CD28 in patients with untreated and treated melanoma metastases. Twenty-eight patients with metastatic malignant melanoma were treated by biochemotherapy (cisplatinum 30 mg/m2 days 1-3, DTIC 250 mg/m2 days1-3 i.v., and IFN-a2b 10 million IU s.c. three days a week for 28 days treatment cycle). Tumours were resected post-biochemotherapy and analysed for the expression of CD28 in CD4+ and CD8+ lymphocytes in areas where histopathological regressive changes had occurred, and close to tumour cells in areas of unaffected tumour growth using a double-staining technique. A high percentage of the lymphocytes in areas with regressive changes were found to be CD4+ CD28-. In contrast, the vast majority of CD4+ lymphocytes migrating close to the tumour cells were found to be CD28+ (P<0.001). A similar difference in the expression of CD28 was also found for the CD8+ subset (P=0.004). A difference in down-regulation of the expression of CD28 was found between CD4+ and CD8+ lymphocytes both in the areas of regressive changes and in the unaffected tumour areas. The present study demonstrates that extensive down-regulation of the co-stimulatory factor CD28 is found in metastases following biochemotherapy. These results indicate that parameters of importance for the immune function have already undergone modification after one or two treatment cycles and that this down-regulation occurs in particular in areas with regressive tumour changes.
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| 9. |
- Håkansson, Annika, 1962-, et al.
(author)
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Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes
- 2001
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 85:12, s. 1871-1877
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Journal article (peer-reviewed)abstract
- The therapeutic efficacy of biochemotherapy in metastatic malignant melanoma still carries a low remission rate, but with some durable responses. It would therefore be of considerable importance if patients with a high probability of responding could be identified using predictive tests. The response to interferon-alpha (IFN-a) correlates with the occurrence of CD4+ lymphocytes identified by fine-needle aspirates from melanoma metastases (Hσkansson et al, 1996). The present investigation studies a possible correlation between tumour-infiltrating CD4+ lymphocytes in malignant melanoma metastases and the therapeutic effect of biochemotherapy. A total of 25 patients with systemic and 16 with regional metastatic melanoma were analysed before initiation of biochemotherapy (cis-platinum 30 mg/m2 d.1-3, DTIC 250 mg/m2 d.1-3 i.v. and IFN-a2b 10 million IU s.c. 3 days a week, q. 28d.). A monoclonal antibody, anti-CD4, was used to identify tumour-infiltrating lymphocytes in fine-needle aspirates before start of treatment. The presence of these lymphocytes was correlated to response, time to progression and overall survival. A statistically significant correlation (P = 0.01) was found between the occurrence of CD4+ lymphocytes and tumour regression during biochemotherapy in patients with systemic disease. Out of 14 patients with moderate to high numbers of infiltrating CD4+ lymphocytes, 12 achieved tumour regression. In contrast, among patients with low numbers of these cells in metastatic lesions, 8 out of 11 had progressive disease. We also found a significantly longer time to progression (P < 0.003) and overall survival (P < 0.01) among patients with moderate to high numbers of these cells compared to patients with low numbers of these cells before initiation of biochemotherapy. Furthermore, in patients with regional disease, we found a significantly longer time to progression (P = 0.01) and a trend toward a longer overall survival time (P = 0.09). Based on these results and as previously shown with IFN-a therapy alone, there seems to be a need for CD4+ lymphocytes infiltrating the tumours before the start of biochemotherapy to make the treatment successful. Determination of these cells in fine-needle aspirates seems to be a method to predict responders to biochemotherapy, thus increasing the cost-benefit of this treatment strategy considerably, both in terms of patient adverse reactions and health care costs. ⌐ 2001 Cancer Research Campaign.
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