| 1. |
- Bouwhuis, Marna G, et al.
(author)
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Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon.
- 2009
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 101:12, s. 869-77
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Journal article (peer-reviewed)abstract
- BACKGROUND: Appearance of autoantibodies and clinical manifestations of autoimmunity in melanoma patients treated with adjuvant interferon (IFN)-alpha2b was reported to be associated with improved prognosis. We assessed the association of the appearance of autoantibodies after initiation of treatment with recurrence-free interval in two randomized trials that compared intermediate doses of IFN with observation for the treatment of melanoma patients. METHODS: Serum levels of anticardiolipin, antithyroglobulin, and antinuclear antibodies were determined using enzyme-linked immunosorbent assays in 187 and 356 patients in the European Organization for Research and Treatment of Cancer (EORTC) 18952 and Nordic IFN trials, respectively, immediately before and up to 3 years after random assignment. The association of the presence of at least one of the three autoantibodies with risk of recurrence was assessed by three Cox models in patients negative for all three autoantibodies at baseline (125 from the EORTC 18952 trial and 230 from the Nordic IFN trial): 1) a model that considered appearance of autoantibodies as a time-independent variable, 2) one that considered a patient autoantibody positive once a positive test for an autoantibody was obtained, and 3) a model in which the status of the patient was defined by the most recent autoantibody test. All statistical tests were two-sided. RESULTS: When treated as a time-independent variable (model 1), appearance of autoantibodies was associated with improved relapse-free interval in both trials (EORTC 18952, hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.25 to 0.68, P < .001; and Nordic IFN, HR = 0.51, 95% CI = 0.34 to 0.76, P < .001). However, on correction for guarantee-time bias, the association was weaker and not statistically significant (model 2: EORTC 18952, HR = 0.81, 95% CI = 0.46 to 1.40, P = .44; and Nordic IFN, HR = 0.85, 95% CI = 0.55 to 1.30, P = .45; model 3: EORTC 18952, HR = 1.05, 95% CI = 0.59 to 1.87, P = .88; and Nordic IFN, HR = 0.78, 95% CI = 0.49 to 1.24, P = .30). CONCLUSIONS: In two randomized trials of IFN for the treatment of melanoma patients, appearance of autoantibodies was not strongly associated with improved relapse-free interval when correction was made for guarantee-time bias.
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| 2. |
- Davies, John R, et al.
(author)
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Inherited variation in the PARP1 gene and survival from melanoma
- 2014
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 135:7, s. 1625-1633
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Journal article (peer-reviewed)abstract
- We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04-1.28, p=0.005, eleven cohorts) and MSS (HR=1.20 per allele, 95% CI 1.01-1.39, p=0.03, eight cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS. What's new? Although staging systems predict outcome fairly well for melanoma, survival still varies among individual patients. In this meta-analysis, the authors found that inheritance of a rare genetic variant of PARP1 was associated with improved survival of melanoma patients. Increased expression of PARP1 has been associated with poorer outcome, and depletion of PARP1 may reduce both melanoma growth and angiogenesis. The identification of this and other germline variants that affect survival may help to identify key biological pathways active in host/tumor interactions, which may lead to the discovery of new therapeutic targets for treating advanced melanoma. Epidemiology
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| 3. |
- Irenaeus, Sandra, 1984-
(author)
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Intratumoral CD40 stimulating therapy in patients with advanced cancer
- 2021
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Doctoral thesis (other academic/artistic)abstract
- CD40-CD40L interaction activates DCs to become highly efficient APCs and skews the adaptive immune response towards a Th I phenotype driving cytotoxic T cells, M1 macrophages and natural killer cells. Furthermore, engagement of CD40L to CD40 positive cancer cells can have direct anti-proliferative effects, induce apoptosis and increase expression of MHC and other co-stimulatory molecules, thereby enhancing cancer cell recognition. Hence, activating the CD40-CD40L pathway may lead to several potential anti-tumoral effects. In this thesis we evaluated activation of the CD40-CD40L pathway in patients with solid cancer by investigating three medicinal products administered mainly through intratumoral injection: ADC1013 - an agonistic CD40 antibody, AdCD40L - a replication deficient adenovirus carrying the gene for CD40L and LOAd703 - an oncolytic adenovirus carrying two immunostimulatory genes: TMZ-CD40L and 4-1BBL. In paper I, ADC-1013 was investigated in patients with metastatic cancer (n=23) in a phase I trial. ADC-1013 was injected intratumorally (n=18) or intravenously (n=5). AdCD40L was investigated in a phase I/II study reported in paper II and III, respectively. In one cohort (paper II), patients with metastatic malignant melanoma (n=9) were treated with four weekly intratumoral injections with AdCD40L preceded by radiotherapy (single fraction 8 Gy) of the metastasis to subsequently be injected. Concomitant low dose cyclophosphamide was administered before the first and fourth intratumoral injection. In another cohort (paper III), patients with metastatic non melanoma solid cancer (n=6) were treated with the same schedule except from radiotherapy. Paper III also reports the results of the first-ever patient treated with AdCD40L. In paper IV, the preliminary results of phase I of a phase I/II study investigating LOAd703 administered intratumorally at a two-week interval are presented. LOAd703 was given as an add-on to standard-of-care chemotherapy, or with gemcitabine conditioning in patients having received established treatments. Patients (n=9) had locally advanced or metastatic pancreatic cancer, metastatic ovarian cancer or colorectal cancer. We conclude that treatment with all three medicinal products was safe and tolerable. For ADC-1013, the therapeutic ratio seemed to be more favorable for intratumoral injections into superficial metastases compared to deep metastases. We demonstrated that AdCD40L can be combined with radiotherapy without increasing toxicity although radiotherapy did not enhance treatment efficacy. Further, LOAd703 was safe to combine with chemotherapy. Although the number of patients treated in each trial was limited, and almost all patients were considered refractory to standard treatment at inclusion, some patients seemed to benefit from treatment which is encouraging.
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| 4. |
- Nsengimana, Jérémie, et al.
(author)
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Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort.
- 2015
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:13, s. 11683-11693
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Journal article (peer-reviewed)abstract
- Development and validation of robust molecular biomarkers has so far been limited in melanoma research. In this paper we used a large population-based cohort to replicate two published gene signatures for melanoma classification. We assessed the signatures prognostic value and explored their biological significance by correlating them with factors known to be associated with survival (vitamin D) or etiological routes (nevi, sun sensitivity and telomere length). Genomewide microarray gene expressions were profiled in 300 archived tumors (224 primaries, 76 secondaries). The two gene signatures classified up to 96% of our samples and showed strong correlation with melanoma specific survival (P=3x10-4), Breslow thickness (P=5x10-10), ulceration (P=9.x10-8) and mitotic rate (P=3x10-7), adding prognostic value over AJCC stage (adjusted hazard ratio 1.79, 95%CI 1.13-2.83), as previously reported. Furthermore, molecular subtypes were associated with season-adjusted serum vitamin D at diagnosis (P=0.04) and genetically predicted telomere length (P=0.03). Specifically, molecular high-grade tumors were more frequent in patients with lower vitamin D levels whereas high immune tumors came from patients with predicted shorter telomeres. Our data confirm the utility of molecular biomarkers in melanoma prognostic estimation using tiny archived specimens and shed light on biological mechanisms likely to impact on cancer initiation and progression.
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