T. Korse

CSF protein profiling using Multiplex Immuno-assay : A potential new diagnostic tool for leptomeningeal metastases.

ObjectiveThe diagnosis of leptomeningeal metastases (LM) is based on clinical symptoms, magnetic resonance imaging (MRI) of brain and spine and cytological analysis of cerebrospinal fluid (CSF). The clinical picture of LM is highly variable and both cytological CSF analysis and contrast-enhanced MRI are limited in sensitivity. More sensitive tools are needed to diagnose LM. We measured a profile of proteins involved in adhesion and inflammation in the CSF of LM and control patients and determined their potential diagnostic value for LM.Patients and methodsUsing Multiplex Immuno-Assay (MIA), the CSF concentrations of nine soluble adhesion molecules, cyto- and chemokines were measured in patients with cytologically proven LM (n=57) and control patients with a systemic malignancy (n=20), aseptic/viral meningitis (n=11) or other (non-)neurological diseases (n=19).ResultsWe found high CSF levels of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), soluble Intercellular Adhesion Molecule-1 (sICAM-1), Interleukin-8 (IL-8), Pulmonary and Activation Regulated Chemokine (PARC), Interleukin-18 (IL-18) and Interferon-γ inducible protein (IP-10) in patients with LM. The CSF protein profile in LM patients differed significantly from the profile found in control patients. Multivariate logistic regression and ROC analysis showed that the MIA-measured CSF protein profile has an additive discriminating value for LM above standard CSF parameters. A combination of total protein, glucose, IL-8, PARC and IP-10 CSF levels proved to be most discriminative between LM and non-LM patients.ConclusionOur results warrant a prospective study to determine whether a CSF protein profile, including IL-8, PARC and IP-10 has diagnostic value compared with CSF cytology, the golden standard for LM.

Hot flashes are not predictive for serum concentrations of tamoxifen and its metabolites

BackgroundTamoxifen has dramatically reduced the recurrence and mortality rate of estrogen receptor positive breast cancer. However, the efficacy of tamoxifen varies between individuals and 40% of patients will have a recurrence despite adjuvant tamoxifen treatment. Factors that predict tamoxifen efficacy would be helpful for optimizing treatment. Serum concentrations of the active metabolite, endoxifen, may be positively related to treatment outcome. In addition, hot flashes are suggested to be positively associated with tamoxifen treatment outcome.MethodsWe investigated in a series of 109 patients whether the frequency and severity of hot flashes were related to concentrations of tamoxifen and its metabolites. A serum sample of all patients was analyzed for the concentration of tamoxifen, N-desmethyltamoxifen, endoxifen and 4-hydroxytamoxifen, as well as for estradiol concentrations and several single nucleotide polymorphisms in CYP2D6. Additionally, these patients completed a questionnaire concerning biometric data and treatment side effects.ResultsWe found no evidence supporting an association between concentrations of tamoxifen or metabolites and either the frequency or severity of hot flashes in the covariate unadjusted analyses. However, including interactions with menopausal status and pre-treatment hot flash (PTHF) history indicated that post-menopausal women with PTHF experienced an increasing frequency of hot flashes with increasing serum concentrations of tamoxifen and its metabolites. This finding was not altered when adjusting for potential confounding factors (duration of tamoxifen treatment, CYP2D6 phenotype, estradiol serum concentration, age and body mass index). In addition we observed a positive association between body mass index and both hot flash frequency (p = 0.04) and severity (p < 0.0001). We also observed that patients with lower estradiol levels reported more severe hot flashes (p = 0.02).ConclusionsNo univariate associations were observed between concentrations of active tamoxifen metabolites and either the frequency or severity of hot flashes during treatment. However, the frequency of hot flashes may be exacerbated by higher serum concentrations of tamoxifen and its metabolites in post-menopausal women with a history of hot flashes prior to tamoxifen treatment.

Interleukin-8 CSF levels predict survival in patients with leptomeningeal metastases

Median survival of patients with leptomeningeal metastases (LM) is 4 to 6 months, with a few long-term survivors. Current prognostic factors for survival have limited value. The authors measured the CSF levels of nine inflammatory proteins in 57 patients with LM and determined their prognostic value. High interleukin (IL)-8 CSF levels predicted short-term survival independently. The data indicate that IL-8 CSF levels may serve as a prognosticator in patients with LM, but prospective validation is needed.

157P: Serum tumor markers and the response to immunotherapy in advanced non-small cell lung carcinoma.

correlation of its baseline values to the efficacy of pemetrexed and performed a dynamic monitoring study in NSCLC patients who underwent first-line platinum-based chemotherapy. Methods: This study enrolled 70 NSCLC patients who received first-line platinum-based chemotherapy. The CTCs were quantified by negative enrichment using immunomagnetic beads in combination with folate receptor-directed PCR that allows secondary amplification of tiny amounts of CTCs in peripheral blood. In this study, the CTC levels were examined by collecting 3mL of anti-EDTA whole blood samples before the treatment and after every chemotherapy, and followed up until progressive disease (PD) or completion of first-line chemotherapy. Results: Of twenty-two patients who received pemetrexed disodium/platinum combined therapy (AP/AC), the patients harboring high levels of folate receptor showed greater efficacy than those with low expression levels (8.7 < CTC level < 16, n = 7; PFS: 448 vs.94 days, P = 0.0199; ORR: 75% vs.11%). In the dynamic monitoring study, the CTC level (AUC=0.8026, P = 0.0033), the CTC ratio (AUC=0.8422, P = 0.0003), the rate of CTC changes (OR=102.005, P = 0.0012) after the second chemotherapy and the CTC level (AUC=0.9487, P < 0.0001), the CTC ratio (AUC=0.8889, P < 0.0001), the changing rate of CTCs (OR=51.662, P = 0.0031) after the fourth chemotherapy positively correlated to the disease progression. Conclusions: The patients with high expression of folate receptor-positive CTCs appear to have superior response to pemetrexed than those with low expression. Additionally, the changes of CTC count can be used as a dynamic monitoring indicator in the treatment process to evaluate tumor burden and therapeutic outcomes. Legal entity responsible for the study: Shanghai Pulmonary Hospital, Tongji University of Medicine Funding: Genosaber Biotech Co.Ltd Disclosure: All authors have declared no conflicts of interest.

A proteomics-based approach identifies secreted protein acidic and rich in cysteine as a prognostic biomarker in malignant pleural mesothelioma.

Background:We aimed to identify prognostic blood biomarkers using proteomics-based approaches in malignant pleural mesothelioma (MPM).Methods:Plasma samples from 12 MPM patients were used for exploratory mass spectrometry and ELISA analyses. The significance of secreted protein acidic and rich in cysteine (SPARC) was examined in sera from a Dutch series (n=97). To determine the source of the circulating SPARC, we investigated SPARC expression in MPM tumours and healthy controls, as well as the expression and secretion from cell lines and xenografts.Results:Secreted protein acidic and rich in cysteine was identified as a putative prognostic marker in plasma. Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P=0.01). In multivariate analyses, serum SPARC remained as an independent predictor (HR 1.55; P=0.05). In MPM tumour samples, SPARC was present in the tumour cells and stromal fibroblasts. Cellular SPARC expression was higher in 5 out of 7 cell lines compared with two immortalized mesothelial lines. Neither cell lines nor xenograft tumours secreted detectable SPARC.Conclusions:Low circulating SPARC was associated with favourable prognosis. Secreted protein acidic and rich in cysteine was present in both tumour cells and stromal fibroblasts; and our in vitro and in vivo experiments suggest that stromal fibroblasts are a potential source of circulating SPARC.