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ABSTRACT: PURPOSE: To investigate the efficacy and safety of zoledronic acid (ZA) combined with targeted therapy (TT). MATERIALS AND METHODS: A retrospective study was performed in patients with metastatic renal cell carcinoma treated with ZA and TT. RESULTS: Twenty-one patients received ZA and TT to prevent skeletal-related events and no pretherapy oral and maxillofacial (OM) examination (cohort A). Six patients (29%) developed osteonecrosis of the jaw (ONJ), which was observed only in patients receiving sunitinib and ZA. Sixteen patients received TT and ZA for hypercalcemia and no pretherapy OM examination (cohort B). In these patients, no ONJ was observed. Nine patients received ZA and TT and pretherapy OM examination (cohort C). One patient (11%) developed ONJ during sunitinib and ZA treatment. Mean skeletal morbidity rates were 0.8 for cohort A and 1.2 for cohort C. In the combined cohort (A plus C; n = 30), 47% developed skeletal-related events, 7% pathologic fracture, 7% medullary compression, and 37% progression of bone metastases. Patients who developed ONJ had a significantly improved median survival of 31.6 months compared with 14.5 months in patients without ONJ (P = .039). CONCLUSION: The combination of ZA and TT resulted in high, clinically meaningful activity. ONJ may be exacerbated by concomitant ZA and sunitinib. Regular OM examinations before and during treatment are recommended.
Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons 05/2013; · 1.58 Impact Factor
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ABSTRACT: Tumor cell and host immune cell interaction plays a key role in carcinogenesis. Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in cancer and believed to be an important mediator of tumor-induced immunosuppression. This paper aims to describe the prognostic impact of neutrophil and dendritic cell infiltration in primary melanoma and the association of this infiltration with activated STAT3 (pSTAT3) in primary melanoma cells.
Formalin-fixed, paraffin-embedded primary melanomas from 186 stage-I/II melanoma patients surgically resected from 1997 to 2000. Infiltrating neutrophils (CD66b), dendritic cells (CD123+ and DC-LAMP+), T-lymphocytes (CD8) and pSTAT3 melanoma cell expression were studied by immunohistochemistry and evaluated as present or absent. DC-LAMP+ cell infiltration was evaluated as absent/few versus dense. Study endpoints: relapse-free survival, melanoma-specific, and overall survival.
The median observation time was 12.2 years (range, 10.4-14.2 years). Fifty-one deaths were observed of which 38 (20%) were melanoma-specific. In a multivariate Cox proportional hazards model including ulceration and melanoma thickness, neutrophil and CD123+ dendritic cell infiltration were independently associated with poor prognosis (CD66b: hazard ratio [HR] = 3.13; 95% confidence interval [CI], 1.43-6.83; P = .004; CD123: HR = 2.45; 95% CI, 1.22-4.92; P = .012). The association between melanoma cell pSTAT3 expression and immune infiltration (neutrophils and CD123+ cells) was strong. pSTAT3 expression, CD8 and DC-LAMP infiltration were not independently associated with poor prognosis.
Neutrophil infiltration and CD123+ dendritic cell infiltration in primary melanoma are independently associated with poor prognosis. Melanoma cell expression of pSTAT3 is strongly associated with the surrounding immune infiltrate.
Cancer 09/2011; 118(9):2476-85. · 4.77 Impact Factor
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Anders Elm Pedersen,
Anette Stryhn,
Sune Justesen,
Mikkel Harndahl,
Susanne Rasmussen, Frede Donskov,
Mogens H Claesson,
Johannes W Pedersen,
Hans H Wandall,
Inge Marie Svane,
Søren Buus
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ABSTRACT: Mutation in the p53 gene based on single amino acid substitutions is a frequent event in human cancer. Accumulated mutant p53 protein is released to antigen presenting cells of the immune system and anti-p53 immune responses even against wt p53 is induced and observed in a number of human cancer patients. Detection of antibodies against wt p53 protein has been used as a diagnostic and prognostic marker and discovery of new T-cell epitopes has enabled design of cancer vaccination protocols with promising results. Here, we identified wt p53-specific antibodies in various cancer patients and identified a broad range of responses against wt p53 protein and 15-mer peptides using a novel print array technology. Likewise, using bioinformatic tools in silico, we identified CD8 T-cell specificity or reactivity against HLA-A*02:01 binding peptides wt p53(65-73), wt p53(187-197), and wt p53(264-272) in breast cancer patients and against HLA-A*01:01 binding peptide wt p53(226-234) and HLA-B*07:02 binding peptide wt p53(74-82) in renal cell cancer and breast cancer patients, respectively. Finally, we analyzed antibody and T-cell responses against wt p53 15-mer peptides in patients with metastatic renal cell carcinoma who were alive with no evidence of disease after a follow-up period of minimum 5 years after treatment with IL-2 ± IFN-α ± histamine containing immunotherapy to identify novel epitopes for use in immunotherapy and for potential response biomarkers. However, none of the wt p53 reactivity observed justified use of 15-mer or was related to survival in this rare patient population.
Journal of immunotherapy (Hagerstown, Md.: 1997) 12/2010; 34(9):629-40. · 3.20 Impact Factor
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ABSTRACT: We have previously demonstrated a significant negative impact of intratumoral neutrophils in metastatic renal cell carcinoma. This study assessed intratumoral neutrophils in localized clear cell renal cell carcinoma (RCC).
The study comprised 121 consecutive patients who had a nephrectomy for localized RCC. Biomarkers (intratumoral CD8+, CD57+ immune cells, CD66b+ neutrophils, and carbonic anhydrase IX [CA IX]) were assessed by immunohistochemistry, and the relationship with clinical and histopathologic features and patient outcome was evaluated.
The intratumoral neutrophils ranged from zero to 289 cells/mm(2) tumor tissue. The presence of intratumoral neutrophils was statistically significantly associated with increasing tumor size, low hemoglobin, high creatinine, and CA IX < or = 85%. In multivariate analysis, the presence of intratumoral neutrophils (hazard ratio [HR], 3.0; 95% CI, 1.7 to 5.4; P < .0001), pT stage T3b/T4 (HR, 2.1; 95% CI, 1.2 to 3.6; P = .007), and low hemoglobin (HR, 1.8; 95% CI, 1.0 to 3.1; P = .03) were independent prognostic factors significantly associated with short recurrence-free survival. The presence of intratumoral neutrophils was also an independent prognostic factor for cancer-specific survival (HR, 3.5; 95% CI, 1.9 to 6.4; P < .0001) and overall survival (HR, 3.1; 95% CI, 1.9 to 5.0; P < .0001). Applying the prognostic value of intratumoral neutrophils to the Leibovich low-/intermediate-risk group (n = 78) showed a 5-year recurrence-free survival of 53% (95% CI, 34.6% to 71.8%; presence of intratumoral neutrophils) versus 87% (95% CI, 77.8% to 96.8%; absence of intratumoral neutrophils). The estimated concordance index was 0.74 using the Leibovich risk score and 0.80 when intratumoral neutrophils were added.
The presence of intratumoral neutrophils is a new, strong, independent prognostic factor for short recurrence-free, cancer-specific, and overall survival in localized clear cell RCC.
Journal of Clinical Oncology 08/2009; 27(28):4709-17. · 18.37 Impact Factor
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ABSTRACT: The administration of interleukin-2 (IL-2) may increase the frequency of peripherally circulating FOXP3-positive regulatory immune cells, thus potentially compromising this treatment option for patients with metastatic renal cell carcinoma. The impact of IL-2-based therapy on the accumulation of FOXP3-positive immune cells in the tumor microenvironment in metastatic renal cell carcinoma is unknown.
Baseline (n = 58) and on-treatment (n = 42) tumor core biopsies were prospectively obtained from patients with clear cell metastatic renal cell carcinoma before and during IL-2-based immunotherapy. Immunohistochemical expression of FOXP3 was estimated by stereological counting technique and correlated with other immune cell subsets and overall survival.
A significant increase in absolute intratumoral FOXP3-positive immune cells was observed comparing baseline (median 23 cells/mm2; range, 0-183) and on-treatment biopsies (median, 89 cells/mm2; range, 11-388; P < 0.001). The relative increase in individual patients was median 4.7-fold, range 0.3 to 230. FOXP3-positive cells were positively correlated with CD3-positive, CD4-positive, and CD8-positive tumor-infiltrating immune cells at baseline and during treatment (P < 0.05 in all comparisons). All patients achieving high numbers (>180 cells/mm2) of on-treatment FOXP3-positive intratumoral immune cells were dead within 22 months (n = 11), whereas patients with low numbers (<180 cells/mm2) of on-treatment FOXP3-positive cells (n = 31) had a 5-year survival rate of 19% (hazard ratio, 2.2; confidence interval, 1.03-4.5; P = 0.043). All long-term survivors were characterized by low-baseline FOXP3-positive cells and a modest absolute rise in FOXP3-positive cells.
Intratumoral FOXP3-positive regulatory immune cells significantly increased during IL-2-based immunotherapy, and high numbers of on-treatment FOXP3-positive cells were correlated with poor prognosis in patients with metastatic renal cell carcinoma.
Clinical Cancer Research 02/2009; 15(3):1052-8. · 7.74 Impact Factor
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BJU International 07/2008; 101 Suppl 4:41-4. · 2.84 Impact Factor
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Frede Donskov
Ugeskrift for laeger 01/2008; 169(51):4463-5.
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Frede Donskov
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ABSTRACT: The present thesis consists of 8 published articles focusing on interleukin-2 based immunotherapy in metastatic renal cell carcinoma (mRCC). This disease represents a significant challenge, as the tumor is resistant to current chemotherapy, hormonal therapy and radiation therapy. However, IL-2 based immunotherapy may induce dramatic durable tumor regression by manipulating the immune system, however, only in a minority of patients. Two critical questions have driven the present thesis. First, which properties of the immune system are responsible for the dramatic tumor regression seen in some patients with mRCC following IL-2 administration? And second, can histamine increase the efficacy of IL-2 based immunotherapy by ending the immune suppression induced by phagocyte-generation of reactive oxygen species? 120 Danish patients, 41 UK patients and 20 Swedish patients were treated with low- or intermediate dose IL-2 based immunotherapy in an outpatient setting. As monitoring of the Danish patients, 443 serial blood samples and 225 serial tumor core biopsies were obtained. The regimen of outpatient low-dose subcutaneous IL-2 and IFN-alpha in mRCC is safe and active. In the Danish patients, an estimated 5-year survival rate of 16% was observed. From the blood and tumor analysis, an understanding emerged that IL-2 based immunotherapy is a "targeted therapy" requiring intratumoral immune cells (CD4+, CD8+, CD56+, CD57+ T- and NK cells) for treatment effect. In contrast, monocytes and neutrophils were harmful for the outcome of IL-2 based immunotherapy. In progressing patients, the leukocyte subsets in blood and tumor tissue remained unaffected by cytokine therapy. The fate of a patient with mRCC prior to IL-2 and IFN-alpha based immunotherapy cannot be determined by measuring baseline tumor features of FasL expression or Ki-67 (MIB-1) proliferation marker. We established a biological rationale for the potential use of histamine in conjunction with IL-2 in mRCC. A large confirmatory randomised phase III trial of IL-2 with and without histamine in mRCC appropriately stratified for monocytes and neutrophils in blood and tumor tissue is warranted. In a multivariate analysis, 5 clinical features (PS, bone metastases, lymph node metastases, low hemoglobin and high LDH) plus 3 supplemental immunological factors (intratumoral CD57+ NK cells <50 cells/mm(2), intratumoral neutrophils >0 and blood neutrophils >6.0) were independent prognostic factors of short survival in patients with mRCC receiving IL-2, identifying subgroups with estimated 5-year survival rates of 60%, 25% and 0%, respectively. These features may help to select patients more likely to benefit from IL-2 based immunotherapy.
Danish medical bulletin 12/2007; 54(4):249-65. · 0.75 Impact Factor
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ABSTRACT: The purpose of this study was to evaluate the impact of immunologic prognostic factors in combination with established clinical prognostic factors in patients with metastatic renal cell carcinoma (mRCC).
A total of 120 consecutive patients with mRCC received interleukin-2 (IL-2) -based immunotherapy. Baseline tumor biopsies were available from 85 of these patients. Potential prognostic factors were analyzed by univariate and multivariate analyses.
Multivariate analysis (N = 120) identified high lactate dehydrogenase, lymph node metastases, low hemoglobin, low Karnofsky performance status, and bone metastases as independent poor prognostic clinical factors. The impact of these clinical factors has been demonstrated by others. Multivariate analysis (n = 85) also identified a high blood neutrophil count (> 6.0 x 10(9)/L; hazard ratio, 2.0; P = .015), the presence of intratumoral neutrophils (> 0 cells/mm2 tumor tissue; hazard ratio, 2.3; P = .001), and low intratumoral CD57+ natural killer cell count (< 50 cells/mm2 tumor tissue; hazard ratio, 2.1; P = .01) as independent poor prognostic immunologic factors. These three independent immunologic parameters had significant discriminatory power as supplemental risk factors in prognostic models based on the clinical risk factors, identifying subgroups within the favorable clinical group with estimated 5-year survival rates of 60%, 25%, and 0%, respectively. These findings were apparent in both our own prognostic model and in an extended Memorial Sloan-Kettering Cancer Center (New York, NY) prognostic model.
This study points on five clinical and three supplemental immunologic independent prognostic factors of survival in patients with mRCC receiving IL-2.
Journal of Clinical Oncology 06/2006; 24(13):1997-2005. · 18.37 Impact Factor
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ABSTRACT: It has been hypothesized that tumor cells expressing Fas ligand (FasL) might be able to counterattack and neutralize tumor-infiltrating lymphocytes. We assessed the effect of FasL tumor counterattack on the clinical outcome of interleukin-2 (IL-2)-based immunotherapy in metastatic renal cell carcinoma.
Tumor core needle biopsies were obtained before IL-2-based immunotherapy in 86 patients and repeated within the first cycle in 57 patients. Tumor cells expressing FasL and intratumoral lymphocyte subsets expressing CD4, CD8, CD56, and CD57 were analyzed by immunohistochemistry.
At baseline, negative FasL staining in tumor cells was seen in 10 of 86 (12%) biopsies, whereas intense FasL staining was seen (a) in fewer than 10% of tumor cells in 26 (30%) biopsies; (b) in 11 to 50% of tumor cells in 25 (29%) biopsies; (c) in 51 to 90% of tumor cells in 18 (21%) biopsies; and (d) in >90% of tumor cells in 7 (8%) biopsies. On treatment, tumor FasL expression did not change from baseline levels. Moreover, tumor FasL expression was not correlated with objective response or survival whereas the absolute number of CD4(+), CD8(+), CD56(+), and CD57(+) cells per mm(2) tumor tissue at baseline was significantly higher in responding patients compared with nonresponding patients (P = 0.01, P = 0.008, P = 0.015, and P < 0.001, respectively). During the first course of immunotherapy, the absolute number of CD4(+), CD8(+), and CD57(+) cells per mm(2) tumor tissue was significantly higher in responding patients compared with nonresponding patients (P = 0.034, P < 0.001, and P < 0.001, respectively). However, no correlation was observed between the number of intratumoral lymphocytes and tumor FasL expression level.
These observations do not support the hypothesis that FasL tumor "counterattack" has an effect on the clinical outcome in metastatic renal cell carcinoma during IL-2-based immunotherapy.
Clinical Cancer Research 01/2005; 10(23):7911-6. · 7.74 Impact Factor
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ABSTRACT: With the objective of evaluating leukocyte orchestration in situ, serial blood samples and tumour tissue core needle biopsies were obtained at baseline and repeated after 1 month of therapy, among 49 consecutive single-institution patients with metastatic renal cell carcinoma (mRCC). Patients were treated with outpatient low-dose subcutaneous interleukin 2 (IL-2) and interferon alpha (IFN-alpha) alone (n = 23) or in combination with histamine dihydrochloride (n = 26). Objective responses were achieved in ten of 49 patients (20%) with an overall median survival of 14 months and an estimated 1- to 4-year survival rate of 57, 35, 24 and 22%, respectively. Toxicity was mild to moderate with no treatment-related deaths. High numbers of blood monocytes and neutrophils were significantly correlated to short survival. By contrast, high numbers of intratumoural CD3+, CD4+, CD8+ and CD57+ lymphocytes were positively correlated to objective response and/or long-term survival. Intratumoural lymphocytes showed low zeta expression, whereas blood lymphocytes showed almost normal levels of zeta expression. Neutrophils, the most frequent peripheral blood leukocyte subset, were scarce within the tumour tissue. Intratumoural eosinophils were not observed. In progressing patients, both the absolute number and the relative composition of leukocyte subsets in blood and tumour tissue remained unaffected by cytokine therapy. However, in responding patients, cytokine therapy was followed by an absolute and relative increase in T cells in blood as well as tumour tissue, an absolute and relative reduction in neutrophils in peripheral blood and a relative reduction of intratumoural macrophages. Histamine did not influence levels of intratumoural or blood leukocyte numbers, zeta-chain expression or cytotoxicity. In conclusion, the present regimen of outpatient low-dose subcutaneous IL-2 and IFN-alpha in mRCC should attract interest based on response, survival and toxicity. In responding patients, cytokine therapy was followed by substantial changes in the blood and tumour tissue leukocyte composition, correlated to response and survival. No discernable differences in immunologic parameters studied could be detected between histamine- and nonhistamine-treated patients.
Cancer Immunology and Immunotherapy 09/2004; 53(8):729-39. · 3.70 Impact Factor
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Ugeskrift for laeger 03/2003; 165(8):809-10.
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ABSTRACT: Interleukin-2 and interferon-alpha are pleiotropic immuno-activating cytokines with clinical efficacy in malignant melanoma. The anti-melanoma activity of these cytokines is believed to result from the triggering of lymphocyte-mediated killing of tumour cells. In ongoing clinical trials, histamine dihydrochloride is used as an adjuvant to IL-2 and IFN-alpha with a view to protecting lymphocytes from oxidative inhibition induced by tumour-infiltrating monocyte/macrophages. In this study, we have serially monitored mononuclear cells in peripheral blood and tumour biopsies from 13 patients with metastatic malignant melanoma treated under a protocol comprising histamine, IFN-alpha and low-dose IL-2. One complete and 3 partial responses were observed, while 3 patients had stable disease and 6 progressed. A trend towards a gradual increase in the absolute number of circulating CD56+/CD3- NK cells in patients maintaining stable disease during therapy was noted. In tumour tissues, the extent of leukocyte infiltration prior to treatment correlated with tumour response. Additional infiltration by NK cells (CD56+) and monocytes during treatment was seen only in responding patients. Patients with progressive disease exhibited a low density of leukocytes infiltrating tumour tissues at the onset of treatment as compared to the surrounding tissues. Our data indicate that the degree and localization of mononuclear infiltration before and during immunotherapy under this protocol may determine therapeutic anti-tumour responses.
Anticancer research 23(1B):537-42. · 1.73 Impact Factor
