Ib Jarle Christensen

Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model

We aimed to create a prognostic model in metastatic melanoma based on independent prognostic factors in 321 patients receiving interleukin-2 (IL-2)-based immunotherapy with a median follow-up time for patients currently alive of 52 months (range 15–189 months). The patients were treated as part of several phase II protocols and the majority received treatment with intermediate dose subcutaneous IL-2 and interferon-α. Neutrophil and monocyte counts, lactate dehydrogenase (LDH), number of metastatic sites, location of metastases and performance status were all statistically significant prognostic factors in univariate analyses. Subsequently, a multivariate Coxs regression analysis identified elevated LDH (P<0.001, hazard ratio 2.8), elevated neutrophil counts (P=0.02, hazard ratio 1.4) and a performance status of 2 (P=0.008, hazard ratio 1.6) as independent prognostic factors for poor survival. An elevated monocyte count could replace an elevated neutrophil count. Patients were assigned to one of three risk groups according to the cumulative risk defined as the sum of simplified risk scores of the three independent prognostic factors. Low-, intermediate- and high-risk patients achieved a median survival of 12.6 months (95% confidence interval (CI), 11.4–13.8), 6.0 months (95% CI, 4.8–7.2) and 3.4 months (95% CI, 1.2–5.6), respectively. The low-risk group encompassed the majority of long-term survivors, whereas the patients in the high-risk group with a very poor prognosis should probably not be offered IL-2-based immunotherapy.

Intact and cleaved forms of the urokinase receptor enhance discrimination of cancer from non-malignant conditions in patients presenting with symptoms related to colorectal cancer

Background:Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality in developed countries. It is known that early detection results in improved survival, and consequently there is a need for improved diagnostic tools in CRC. The plasma level of soluble urokinase plasminogen activator receptor (suPAR) was proposed as a marker in CRC patients. This study was undertaken to evaluate the individual molecular forms of suPAR as discriminators in a group of patients undergoing endoscopical examination following symptoms related to colorectal cancer.Methods:In a case–control study comprising 308 patients undergoing endoscopical examination following CRC-related symptoms, 77 CRC patients with adenocarcinoma were age and gender matched to: 77 patients with adenomas; 77 with other non-malignant findings, and 77 with no findings. The different uPAR forms were measured in citrate plasma collected before endoscopical examination, using three different Time Resolved – Fluorescence Immuno Assays (TR-FIAs).Results:All soluble uPAR forms were found to be significantly higher in cancer patients than in patients presenting with other non-malignant findings; uPAR(I) P=0.0006, suPAR(I–III) P<0.0001 and suPAR(I–III)+(II–III) P<0.0001, whereas no significant difference was found when performing similar comparisons for patients presenting with adenomas. The odds ratio (OR) for the comparison of uPAR(I) in patients with CRC to subjects with other non-malignant findings was 3.44 (95% CI:1.86–6.37). CRC patients had a mean elevated level of 20.9% (95% CI:10.2–32.6) for suPAR(I–III) and 18.5% (95% CI:9.0–28.8) for suPAR(I–III)+(II–III) compared with subjects with non-malignant findings.Conclusions:The findings confirm reports on increased uPAR expression in cancer patients and in particular elevated levels of suPAR in blood from CRC patients and indicate that suPAR levels in blood are increasing during carcinogenesis. Although none of the measured uPAR forms were cancer specific, our findings suggest that uPAR expression could be useful in the early detection of CRC when combined with other markers and clinical variables.

Angiotensinogen and HLA class II predict bevacizumab response in recurrent glioblastoma patients

Bevacizumab combination therapy is among the most frequently used treatments in recurrent glioblastoma and patients who achieve response to bevacizumab have improved survival as well as quality of life. Accordingly, the aim of this study was to identify predictive biomarkers for bevacizumab response in recurrent glioblastoma patients.

Increased serological cancer-associated biomarker levels at large bowel endoscopy and risk of subsequent primary cancer†

Abstract Background: Frequently, subjects offered colonoscopy due to symptoms of colorectal neoplasia are diagnosed with diverticula. The symptoms may, however, also be related to extra-colonic neoplasia. The present retrospective study evaluated a possible association between increased levels of predefined biomarkers in subjects diagnosed with diverticula and risk of developing a primary malignant disease. Methods: During 2004/2005, about 4509 subjects were included in a multicenter study with collection of blood samples before bowel endoscopy. The aim was to evaluate a relation between the protein biomarkers CEA, TIMP-1, CA19-9 and YKL-40 and findings at endoscopy. Diverticula were diagnosed in 1021 subjects. By 31 December 2012, subjects who had developed primary malignancy were identified retrospectively and relation between biomarker levels at endoscopy and risk of developing primary malignancy was calculated. The relation with the four biomarkers was divided into three groups: 0u2009=u2009none increased; 1u2009=u2009one increased and 2u2009=u2009two or more increased. Results: In the observation period, 148 subjects developed a primary malignant disease. Univariable analyzes of the biomarker levels showed that CEA, TIMP-1 and CA19-9 were significantly associated with development of primary malignancy. A multivariable analysis showed that increased levels were associated with development of malignancy (pu2009<u20090.0001). The 1- and 5-year cumulative risks of being diagnosed with a primary malignancy were: group 0: 1.1%/5.5%; group 1: 4.2%/10.1% and group 2: 11.4%/18.8%, respectively. Conclusion: Increased levels of CEA, TIMP-1 and CA19-9 at endoscopy with findings of diverticula were associated with a significantly increased risk of being diagnosed with a subsequent primary malignant disease.

Blood-based Biomarkers at Large Bowel Endoscopy and Prediction of Future Malignancies

Soluble cancer-related protein biomarker levels may be increased in subjects without findings at large bowel endoscopy performed due to symptoms associated with colorectal cancer. The present study focused on a possible association between increased biomarker levels in such subjects and subsequent development of malignant diseases. In a major study of 4,990 subjects undergoing large bowel endoscopy, 691 were without pathology and comorbidity. Plasma levels of TIMP-1, CEA, CA19-9, and YKL-40 were determined in samples collected just before endoscopy and compared with subsequent development of a malignant disease within a period of 7-8 years. The upper 90% limits of the reference levels of every single protein were used to differentiate between normal and increased levels. The levels were separated into three groups: 0, none of the biomarkers increased; 1, one biomarker increased; 2, two or more biomarkers increased. A total of 43 subjects developed a primary malignant disease in the observation period. Univariatly, increase of all four biomarkers was significantly associated with subsequent development of a malignant disease. A multivariate analysis showed that increased biomarker levels were associated with subsequent development of a malignant disease (P = 0.002). The cumulative risk of developing malignant disease within the first 5 years after endoscopy was group 0, 3.3%; group 1, 5.8%; group 2, 7.8%. It is concluded that increased levels of plasma TIMP-1, CEA, CA19-9, and serum YKL-40 at large bowel endoscopy without findings may be associated with an increased risk of developing a subsequent malignant disease.

Soluble urokinase plasminogen activator receptor in blood transfusion components

Summary.u2002 Post‐transfusion infectious complications associated with allogeneic blood components may depend on storage time and may be related to extracellular accumulation of bioactive substances during storage. The glycoprotein, soluble urokinase plasminogen activator receptor (suPAR), which is located in specific granules of neutrophils, plays a role in inflammation and remodelling of the extracellular matrix. Using enzyme‐linked immunosorbent assay, suPAR was determined in serum, plasma and blood cell lysates. In addition, suPAR was measured in whole blood (WB), buffy‐coat‐depleted saline‐adenine‐glucose‐mannitol (SAGM) blood, platelet‐rich plasma (PRP) and buffy‐coat‐derived platelet (BCP) pools with and without pre‐storage leucofiltration, and in non‐filtered WB, SAGM blood and platelet concentrates prepared using apheresis (APC) at different time points during storage. Mean suPAR concentration was significantly higher in cell lysates, compared to that in a corresponding serum (Pu2003=u20030·007) and in plasma samples (Pu2003=u20030·004). Mean suPAR levels in WB, BCP and SAGM were significantly reduced using leucofiltration (WB: 3·4 versus 2·0u2003ngu2003mL−1; BCP: 1·6 versus 1·1u2003ngu2003mL−1; SAGM: 2·8 versus 0·19u2003ngu2003mL−1), whereas no difference was observed in PRP. In non‐filtered WB, SAGM and APC, extracellular suPAR accumulated significantly in a storage‐time‐dependent manner (WB: Pu2003<u20030·01; SAGM: Pu2003<u20030·001; APC: Pu2003<u20030·001). The present study demonstrates that cell lysates contain significantly more suPAR, compared to both serum and plasma. This can be explained by the release of suPAR from intracellular granules during cell lysis. The amount of suPAR is significantly increased during storage of blood transfusion components, an accumulation that is reduced using pre‐storage leucofiltration.

Soluble Interleukin-7 receptor levels and risk of acute graft-versus-disease after allogeneic haematopoietic stem cell transplantation

Interleukin-7 is a cytokine essential for T cell homeostasis. IL-7 binds to cellular IL-7 receptors in competition with a soluble form of the receptor (sIL-7Rα). We hypothesized that altered sIL-7Rα levels may cause adverse outcomes in patients undergoing HSCT. In parallel, we investigated the impact of the IL-7Rα SNP rs6897932, which has been associated with release of IL-7R. The sIL-7Rα levels decreased during HSCT (from 114ng/ml before to 48ng/ml at day +14 (P<0.0001)). This pattern was inversely mirrored by IL-7. The IL-7/sIL-7Rα ratio at day +14 was significantly higher in patients developing grades II-IV aGVHD (OR=4.3, P=0.026). Furthermore, donor carriage of the rs6897932 T allele was associated with reduced sIL-7Rα levels, increased risk of grades II-IV aGVHD (OR=2.4, P=0.055) and increased transplant-related mortality (CC=4.5%, CT=21.4% and TT=27.3%, P=0.0037). In conclusion, this study suggests an impact of sIL-7Rα levels and rs6897932 donor genotype on alloreactivity and outcome after HSCT.

Toxicity and efficacy of lomustine and bevacizumab in recurrent glioblastoma patients

The combination of lomustine and bevacizumab is a commonly used salvage treatment for recurrent glioblastoma (GBM). We investigated the toxicity and efficacy of lomustine plus bevacizumab (lom-bev) in a community-based patient cohort and made a comparison to another frequently used combination therapy consisting of irinotecan plus bevacizumab (iri-bev). Seventy patients with recurrent GBM were treated with lomustine 90xa0mg/m2 every 6 weeks and bevacizumab 10xa0mg/kg every 2 weeks. Toxicity was registered and compared to the toxicity observed in 219 recurrent GBM patients who had previously been treated with irinotecan 125xa0mg/m2 and bevacizumab 10xa0mg/kg every 2 weeks. The response rate was 37.1% for lom-bev and 30.1% for iri-bev. Median progression-free survival (PFS) was 23 weeks for lom-bev and 21 weeks for iri-bev (pu2009=u20090.9). Overall survival (OS) was 37 weeks for lom-bev and 32 weeks for iri-bev (pu2009=u20090.5). Lom-bev caused a significantly higher frequency of thrombocytopenia (11.4% grade 3–4) compared to iri-bev (3.5% grade 3–4). Iri-bev patients had more gastrointestinal toxicity with regard to nausea, vomiting, diarrhea, constipation and stomatitis. Within the limitations of the study lom-bev is a well-tolerated treatment for recurrent GBM, although hematological toxicity may be a dose limiting factor. No significant differences between lom-bev and iri-bev were observed with regard to PFS or OS. The differences in toxicity profiles between lom-bev and iri-bev could guide treatment decision in recurrent GBM therapy as efficacy is equal and no predictive factors for efficacy exist.

Biomarkers in Recurrent Grade III Glioma Patients Treated with Bevacizumab and Irinotecan

ABSTRACT Predictive biomarkers and prognostic models are required to identify recurrent grade III glioma patients who benefit from existing treatment. In this study of 62 recurrent grade III glioma patients, a range of clinical and paraclinical factors are tested for association with progression-free survival, overall survival, and response to bevacizumab and irinotecan therapy. Significant factors from univariate screening are included in multivariate analysis. Biomarkers previously advanced as predictive or prognostic in the first-line setting did not affect outcome in this patient cohort. Based on the optimized model for overall survival, comprising performance status and p53 expression, a prognostic index is established.

Serological biomarkers in triage of FIT-positive subjects?

Abstract FIT-based colorectal cancer screening has been implemented in many countries including Denmark, where 916 colorectal cancer and 4468 high- or medium-risk adenoma patients were identified within April–December 2014, among 16,806 subjects with a positive FIT test. Screening increases the overall requirements for colonoscopy, which may challenge the current capacity. Some countries have increased their initial FIT cut-off level in order to comply with lack of colonoscopy capacity. Many patients with neoplasia will not be detected, however, by using increased FIT cut-off levels. The number of patients with neoplastic lesions missed by increased cut-off levels appears to be much higher than expected. Therefore, tests that identify those patients missed by increased FIT cut-off levels must be developed. Preliminary results of determination of one of several biomarker entities currently under investigation show that nucleosome blood tests may be one option for identifying some of these patients. Implementation of a triage test consisting of FIT, blood-based biomarkers and plus/minus colonoscopy is suggested to identify subjects with FIT levels between the initial and the increased cut-off level that must be offered colonoscopy. In addition, triage may reduce the frequency of unnecessary colonoscopies by 25%.