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Krysander, Lennart
Publications (10 of 10) Show all publications
Håkansson, A., Gustafsson, B., Abdiu, A., Krysander, L. & Håkansson, L. (2003). Bcl-2 expression in metastatic malignant melanoma. Importance for the therapeutic efficacy of biochemotherapy. Cancer Immunology and Immunotherapy, 52(4), 249-254
Open this publication in new window or tab >>Bcl-2 expression in metastatic malignant melanoma. Importance for the therapeutic efficacy of biochemotherapy
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2003 (English)In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 52, no 4, p. 249-254Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24822 (URN)10.1007/s00262-003-0373-z (DOI)9219 (Local ID)9219 (Archive number)9219 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
Bernsen, M. R., Smetsers, T., van der Westerlo, E., Ruiter, D., Håkansson, L., Gustafsson, B., . . . Håkansson, A. (2003). Heparan sulphate epitope-expression is associated with the inflammatory response in metastatic malignant melanoma. Cancer Immunology and Immunotherapy, 52(12), 780-783
Open this publication in new window or tab >>Heparan sulphate epitope-expression is associated with the inflammatory response in metastatic malignant melanoma
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2003 (English)In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 52, no 12, p. 780-783Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25094 (URN)10.1007/s00262-003-0421-8 (DOI)9526 (Local ID)9526 (Archive number)9526 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
Bernsen, M., Håkansson, L., Gustafsson, B., Krysander, L., Rettrup, B., Ruiter, D. & Håkansson, A. (2003). On the biological relevance of MHC class II and B7 expression by tumour cells in melanoma metastases. British Journal of Cancer, 88(3), 424-431
Open this publication in new window or tab >>On the biological relevance of MHC class II and B7 expression by tumour cells in melanoma metastases
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2003 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 88, no 3, p. 424-431Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25093 (URN)10.1038/sj.bjc.6600703 (DOI)9525 (Local ID)9525 (Archive number)9525 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
Håkansson, A., Håkansson, L., Gustafsson, B., Krysander, L., Rettrup, B., Ruiter, D. & Bernsen, M. R. (2003). On the effect of biochemotherapy in metastatic malignant melanoma: An immunopathological evaluation. Melanoma research, 13(4), 401-407
Open this publication in new window or tab >>On the effect of biochemotherapy in metastatic malignant melanoma: An immunopathological evaluation
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2003 (English)In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 13, no 4, p. 401-407Article in journal (Refereed) Published
Abstract [en]

Although immunotherapy and biochemotherapy have shown promise, producing a subset of durable responses, for the majority of patients with metastatic melanoma the prognosis is still poor. Therefore there is a great need for predictive tests to identify patients with a high probability of responding. Furthermore, there is also a need for a better understanding of the mechanisms of action during treatment in order to be able to monitor the relevant antitumour reactivity during treatment and to optimize the efficacy of future immunotherapy and biochemotherapy. In the present study histopathological regression criteria were used to study the efficacy of biochemotherapy. Thirty-two patients with metastatic malignant melanoma (18 with regional disease and 14 with systemic disease) were treated with biochemotherapy (cisplatin 30 mg/m2 intravenously on days 1-3, dacarbazine 250 mg/m2 intravenously on days 1-3 and interferon-a2b 10 million IU subcutaneously 3 days a week, every 28 days). Pre-treatment fine needle aspirates were obtained from metastases to analyse the number of tumour-infiltrating CD4+ lymphocytes. Therapeutic efficacy was evaluated in metastases resected after treatment using histopathological criteria of tumour regression. Comparisons were also made with metastases from 17 untreated patients, all with regional disease. Regressive changes of 25% or more (of the section area) were found in two of the 17 untreated patients with regional disease compared with 13 of the 18 patients with regional disease and 10 of the 14 patients with systemic disease after biochemotherapy. Fifty per cent of the patients with regional disease showed a high degree of regressive changes (75-100% of the section area) after biochemotherapy. These results demonstrate the occurrence of an antitumour reactivity in the majority of patients. Patients with extensive regressive changes in 75-100% of the analysed biopsies were also found to have a longer overall survival (P = 0.019). In patients with regional disease there was a close correlation between a larger number of CD4+ lymphocytes pre-treatment and a higher degree of regressive changes post-treatment (P < 0.05). Thus, immunohistochemical analysis of tumour biopsies shortly after treatment seems to be a good surrogate endpoint This technique also allows detailed analysis of antitumour reactivity and escape mechanisms. ⌐ 2003 Lippincott Williams & Wilkins.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25095 (URN)10.1097/00008390-200308000-00010 (DOI)9527 (Local ID)9527 (Archive number)9527 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
Håkansson, A., Håkansson, L., Gustafsson, B., Krysander, L., Rettrup, B., Ruiter, D. & Bernsen, M. (2002). Biochemotherapy of metastatic malignant melanoma. On down-regulation of CD28. Cancer Immunology and Immunotherapy, 51(9), 499-504
Open this publication in new window or tab >>Biochemotherapy of metastatic malignant melanoma. On down-regulation of CD28
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2002 (English)In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 51, no 9, p. 499-504Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25090 (URN)10.1007/s00262-002-0304-4 (DOI)9522 (Local ID)9522 (Archive number)9522 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
Håkansson, A., Gustafsson, B., Krysander, L., Hjelmqvist, B., Rettrup, B. & Håkansson, L. (2001). Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes. British Journal of Cancer, 85(12), 1871-1877
Open this publication in new window or tab >>Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes
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2001 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 85, no 12, p. 1871-1877Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25087 (URN)10.1054/bjoc.2001.2169 (DOI)9518 (Local ID)9518 (Archive number)9518 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
Cohn-Cedermark, G., Rutqvist, L., Andersson, R., Breivald, M., Ingvar, C., Johansson, H., . . . Ringborg, U. (2000). Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer, 89(7), 1495-1501
Open this publication in new window or tab >>Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm
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2000 (English)In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 89, no 7, p. 1495-1501Article in journal (Refereed) Published
Abstract [en]

BACKGROUND. Large, prospective, randomized trials with long term follow-up are required to obtain an unbiased evaluation of the significance of resection margins in patients with cutaneous melanoma. METHODS, The Swedish Melanoma Study Group performed a prospective, randomized, multicenter study of patients with primary melanoma located on trunk or extremities and with a tumor thickness > 0.8 mm and less than or equal to 2 mm. Patients were allocated randomly to a 2-cm excision margin or a 5-cm excision margin. In total, 989 patients were recruited during the period 1982-1991. The median follow-up, was 11 years (range, 7-17 years) for estimation of survival and 8 years (range, 0-17 years) for evaluation of recurrent disease. RESULTS. The crude rate of local recurrence, defined as a recurrence in the scar or transplant, was < 1% (8 of 989 patients). Twenty percent of the patients (194 of 989 patients) experienced any disease recurrence, and 15% (146 of 989 patients) died of melanoma. There were no statistically significant differences between the two treatment arms. In a multivariate Cox analysis with patients allocated to wide excision as the reference group, the estimated relative hazards for overall survival and recurrence free survival among those allocated to a 2-cm resection margin were 0.96 (95% confidence interval, 0.75-1.24), and 1.02 (95% confidence interval, 0.80-1.30), respectively. CONCLUSIONS. In this long term follow-up study, local recurrences were found to be rare among patients with tumors > 0.8 mm thick and less than or equal to 2.0 mm thick. Mo difference in recurrence rate or survival between the two treatment groups was found. Patients in this category can be treated with a resection margin of 2 cm as safely as with a resection margin of 5 cm. Cancer 2000,89:1495-501. (C) 2000 American Cancer Society.

Keywords
primary melanoma, resection margins, tumor thickness 0.8-2 mm, randomized study, long term follow-up, locoregional recurrence, survival
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-49592 (URN)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12
Håkansson, A., Gustafsson, B., Krysander, L., Hjelmqvist, B., Rettrup, B. & Håkansson, L. (1999). Expression of ICAM-1 during IFN-alpha-based treatment of metastatic malignant melanoma: relation to tumour infiltrating mononuclear cells and regressive tumour changes.. Journal of Interferon and Cytokine Research, 19, 171-177
Open this publication in new window or tab >>Expression of ICAM-1 during IFN-alpha-based treatment of metastatic malignant melanoma: relation to tumour infiltrating mononuclear cells and regressive tumour changes.
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1999 (English)In: Journal of Interferon and Cytokine Research, ISSN 1079-9907, E-ISSN 1557-7465, Vol. 19, p. 171-177Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25088 (URN)9519 (Local ID)9519 (Archive number)9519 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
Håkansson, A., Gustafsson, B., Krysander, L., Hjelmqvist, B., Rettrup, B. & Håkansson, L. (1999). On down-regulation of the immune response to metastatic malignant melanoma.. Cancer Immunology and Immunotherapy, 48, 253-262
Open this publication in new window or tab >>On down-regulation of the immune response to metastatic malignant melanoma.
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1999 (English)In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 48, p. 253-262Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25092 (URN)9524 (Local ID)9524 (Archive number)9524 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
Jergovic, D., Krysander, L. & Lidman, D.Microsurgical treatment of facial palsy: 10 years of clinical experience.
Open this publication in new window or tab >>Microsurgical treatment of facial palsy: 10 years of clinical experience
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The aim of this study is to analyse retrospectively the outcome of microsurgical treatment of patients with facial palsy at the University Hospital of Linköping during the period 1990-2000. Ten patients with facial palsy during 1 year or more completed the evaluation.

Patients subjected to cross facial nerve grafting (CFNG) only included 3 females. The CFNGs appeared to be fimctional in all patients. The measurements revealed good symmetry of the eye rim at rest and at eye closure. All three patients had an asymmetric angle of the mouth with a mean dropping of 2.3 mm at rest and 5.5 mm when smiling. The House-Brackmann grade was 4-5. The average Facial Grading System score was 33. The mean decrease in quality of life was 34%. The mean improvement after treatment was 48%. The degree of post-lesional impairment and the degree of postoperative satisfaction were inversely related. All patients were aware of their disability but they had not completely accepted the current facial status.

The group of patients with CFNG and a free muscle flap transfer included six females and one male. The transferred muscle flaps were activated by the CFNGs. Symmetry of the eye rims at rest was observed in 4 cases and with closure in 3 cases. In asymmetric cases, the mean difference was 1. 8 mm at rest. With eyes closed the mean difference was 4.4 mm. The angle of the mouth was asymmetric in all patients, the mean lowering being 3 mm at rest and 7.5 mm at smile. The House Brackmann grade was 4-5 and the average Facial Grading System score was 31. Four patients with early or congenital facial palsy could not provide data on impairment of quality of life. In the others, the post-lesional impairment was 63%. For all patients in this group the average postoperative improvement was 76%. The patients expressed a rather good acceptance of the achieved status after reconstruction.

Surgical methods to correct facial paresis should be directed towards achieving a symmetric resting tone on the injured side as well as symmetric movements. At present, our methods, when utilised on proper indications and with a precise timing, can give the patient a reasonably good but not perfect result. Further refinements of the technique are needed and should be sought through experimental studies.

Keywords
facial palsy, clinical study, cross facial nerve graft, free microneurvascular muscle flap
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81517 (URN)
Available from: 2012-09-18 Created: 2012-09-18 Last updated: 2012-09-18Bibliographically approved
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