Oguz Kara

Serum RANTES, MIP-1α, and MCP-1 levels in Behçet’s disease

Behçet’s disease (BD) is a multisystemic vasculitis of unknown etiology characterized by oral and genital ulceration and eye, skin, joint, gastrointestinal, and neurological manifestations. Besides elevated levels of tumor necrosis factor alpha (TNF-a) in sera of patients with BD [1], increased TNF-a and interleukin (IL)-1 production has been shown in lipopolysaccharide-stimulated peripheral blood monocytes [2]. Additionally, TNF-a and IL-1b mRNA have been shown to be increased in attack-free periods in patients with familial Mediterranean fever (FMF) [3]. It is generally accepted that certain chemokines such as regulated-on-expression, normal-T-cell-expressedand-secreted (RANTES), macrophage inflammatory protein (MIP)-1, and monocyte chemotactic protein (MCP)-1 are stimulated in response to more proximal mediators such as TNF-a and IL-1 [4]. Elevated plasma and whole blood MCP-1 levels have been reported in patients with BD, regardless of activity [5]. To gain information about the role of chemokines in the inflammation of patients with BD and their relation to disease activity, serum levels of the CC chemokines RANTES, MIP-1a, and MCP-1 were measured. Patients with familial Mediterranean fever (FMF) and healthy study participants were taken as controls. Serum samples from 21 patients with BD (mean age 38.95±1.6 years, ten females and 11 males, 11 active and ten inactive) meeting the criteria of the International Study Group for BD were taken. Except for two patients from the active and inactive disease groups, all BD patients were on colchicine (0.5–1.5 mg daily). Those having new onset or exacerbation of at least one of the clinical manifestations including genital ulcer, uveitis, arthritis, erythema nodosum, thrombophlebitis, and central nervous system or gastrointestinal disease were considered as active. Patients using corticosteroids or immunosuppressives were excluded. Twenty-seven patients with FMF meeting Tel Hashomer criteria for the disease (mean age 34.3± 10.2 years, 14 females and 13 males, 13 during attack and 14 in attack-free periods) and 27 healthy participants (mean age 37±6.6 years, 13 females and 14 males) were taken as the control groups. The study was conducted at the rheumatology outpatient clinic of Cukurova University Hospital in Adana, Turkey. Written informed consent was taken from all patients, and the study was approved by the institutional review board. It was performed in compliance with the Helsinki Declaration. RANTES, MIP-1a, and MCP-1 levels were measured from the serum samples by enzyme-linked immunosorbent assay (ELISA) at one occasion by the same person. Commercial human ELISA kits (Endogen, USA) were used for each chemokine measurement. Assay ranges were 51.2–2000 pg/ml, 0–1000 pg/ml, and 51–2000 pg/ ml for RANTES, MIP-1a, and MCP-1, respectively. Four exon-10 mutations of the MEFV gene (M694V, M680I, V726A, and M694I) were sought by amplification refractory mutation [6]. Kruskal-Wallis analysis of variance (ANOVA) was used for comparison among three groups, and the Mann-Whitney-U test was used for comparing two groups. Correlation analyses were done by nonparametric Spearman’s correlation test. Mean serum MIP-1a levels were found to differ among the groups (P=0.012, ANOVA). The level in BD (mean±SEM 126.80±36.10 pg/ml) was significantly higher (P=0.005) than in the controls (80.93±43.38 pg/ ml) but not significantly different from that of the FMF patients (78.94±29.24 pg/ml). Mean MIP-1a levels of H. T. E. Ozer (&) Æ E. Erken Æ R. Gunesacar Rheumatology-Immunology Division, Cukurova University Faculty of Medicine, Adana, 01330 Turkey E-mail: teozer@cu.edu.tr Tel.: +90-533-7178442 Fax: +90-322-3386721

Evaluation of PTEN, PI3K, MTOR, and KRAS expression and their clinical and prognostic relevance to differentiated thyroid carcinoma

Aim of the study Important signalling pathways play fundamental roles in the pathogenesis of thyroid carcinoma (TC). PTEN, mTOR, PI3K-p85 and K-Ras are the principal factors involved in these signalling pathways. To immunohistochemically examine the expressions of PI3K, mTOR and PTEN in patients suffering from follicular TC, papillary TC or variants thereof, as well as to investigate KRAS mutations via PCR to determine their clinical and prognostic relevance to differentiated thyroid cancer. Material and methods The expression of PTEN, PI3K-p85 and mTOR was immunohistochemically examined, and the mutation of K-Ras was examined via PCR. The results obtained were compared to the clinico-pathologic characteristics of the patients. Results A significant correlation was found between p85 expression and lymphovascular invasions and between PTEN expression and multifocality (p = 0.048 and p = 0.04, respectively), and a correlation between p85 and capsular invasion was found, with a borderline statistical significance (p = 0.056). No expression of PTEN, p85 or Mtor was detected in normal tissue. K-Ras mutation was examined in 66 of the 101 patients (57.4%), and the percentage of patients exhibiting a K-Ras mutation was 17.4%. All of the patients exhibiting a K-Ras mutation were women (p = 0.047). The disease-free survival was 44.6 months (95% CI: 37.9–51.3) and was statistically significantly higher in the group that displayed level 1 or lower expression of p85 (p = 0.043). Conclusions The expression levels of the aforementioned markers were significantly higher in TC cells than in normal tissue. A significant correlation was detected between K-Ras mutation and gender. This study demonstrates that p85 and PTEN are markers that should be evaluated in further studies of TC.

Tc-99m MIBI uptake in traumatic vertebral fractures and metastatic vertebral lesions: Comparison with Tc-99m MDP

This study compared technetium-99m-hexakis-2-methoxyisobutyl-isonitrile (Tc-99m MIBI) with technetium-99m methylene diphosphonate (Tc-99m MDP) to determine whether Tc-99m MIBI could distinguish vertebral metastases from traumatic vertebral fractures. Twenty patients with traumatic vertebral fracture (and no malignant disease) and 14 patients with metastatic vertebral lesions were evaluated. Three to 4 hours after intravenous injection of Tc-99m MDP, images of the vertebrae in all patients were obtained. Corresponding Tc-99m MIBI images were acquired within 4 days after the Tc-99m MDP bone images were obtained. Computed tomography and magnetic resonance imaging demonstrated 24 vertebral traumatic fractures and 44 vertebral metastases. On conventional bone scans, Tc-99m MDP activity was increased in 92% of vertebral fractures and in 100% of vertebral metastases. However, on MIBI scans, no abnormal findings were observed in the vertebrae with fracture, although increased activity was seen in 73% of vertebral metastases. In this study, traumatic vertebral fractures tended to display no pathologic increases in Tc-99m MIBI uptake, whereas bone metastases usually appeared with high uptake. In light of the excellent specificity of Tc-99m MIBI scans compared with Tc-99m MDP bone scans, imaging studies that use Tc-99m MIBI scans may play an important complementary role in differentiating vertebral metastases from traumatic vertebral fractures.

Biosimilar filgrastim vs filgrastim: a multicenter nationwide observational bioequivalence study in patients with chemotherapy-induced neutropenia

Background We studied the comparative effectiveness of biosimilar filgrastim vs original filgrastim in patients with chemotherapy-induced neutropenia. Patients and methods This multicenter, observational study was conducted at 14 centers. The study included 337 patients experiencing neutropenia under chemotherapy. Patients were given either filgrastim 30 MIU or 48 MIU (Neupogen®) or biosimilar filgrastim 30 MIU (Leucostim®). Data regarding age, chemotherapeutic agents used, number of chemotherapy courses, previous diagnosis of neutropenia, neutrophil count of patients after treatment, medications used for the treatment of neutropenia, and duration of neutropenia were collected. Time to absolute neutrophil count (ANC) recovery was the primary efficacy measure. Results Ambulatory and hospitalized patients comprised 11.3% and 45.1% of the enrolled patients, respectively, and a previous diagnosis of neutropenia was reported in 49.3% of the patients, as well. Neutropenia occurred in 13.7% (n=41), 45.5% (n=136), 27.4% (n=82), 11.4% (n=34), and 2.0% (n=6) of the patients during the first, second, third, fourth, and fifth cycles of chemotherapy, respectively. While the mean neutrophil count was 0.53±0.48 before treatment, a significant increase to 2.44±0.66 was observed after treatment (p=0.0001). While 90.3% of patients had a neutrophil count <1.49 before treatment, all patients had a neutrophil count ≥1.50 after treatment. Neutropenia resolved within ≤4 days of filgrastim therapy in 60.1%, 56.7%, and 52.6% of the patients receiving biosimilar filgrastim 30 MIU, original filgrastim 30 MIU, and original filgrastim 48 MIU, respectively. However, there was no significant difference between the three arms (p=0.468). Similarly, time to ANC recovery was comparable between the treatment arms (p=0.332). Conclusion The results indicate that original filgrastim and biosimilar filgrastim have comparable efficacy in treating neutropenia. Biosimilar filgrastim provides a valuable alternative; however, there is need for further studies comparing the two products in different patient subpopulations.