Leylagul Kaynar

Role of Grape Seed Extract on Methotrexate Induced Oxidative Stress in Rat Liver

UNLABELLED The efficacy of methotrexate (MTX), a widely used cytotoxic chemotherapeutic agent, is often limited by its severe hepatotoxicity. Regarding the mechanisms of these adverse effects, several hypotheses have been put forward, among which oxidative stress is noticeable. The present study was undertaken to determine whether grape seed extract (GSE), a new natural free radical scavenger, could ameliorate the MTX-induced oxidative injury in the rat liver. The animals were divided into 3 groups. Each group consisted of 12 animals. MTX-GSE group: rats were given GSE (100mg/kg body weight) orally for 15 days, and a single dose of MTX (20 mg/kg, intraperitoneally) was added on the 10th day. MTX group: these received placebo distilled water (orally) instead of GSE for 15 days and the same MTX protocol applied to this group on the 10th day. CONTROL GROUP rats were given distilled water (orally) through 15 days and physiological saline (intraperitoneally) instead of MTX was administered on the 10th day in a similar manner. On the 16th day, liver tissue samples were obtained under deep anaesthesia. The level of malondialdehyde (MDA), an end product of lipid peroxidation, and the activities of süperoxide dismutase (SOD) and catalase (CAT), two important endogenous antioxidants, were evaluated in the tissue homogenates. MTX administration increased the MDA level and decreased the SOD and CAT activities in the liver homogenates (p < 0.001), while these alterations were significantly reversed by GSE treatment (p < 0.001). MTX led to significantly reduced whole blood count parameters (p < 0.05). When GSE was supplemented, no significant changes in blood count parameters were noted. It appears that GSE protects the rat liver and inhibits methotrexate-induced oxidative stress. These data indicate that GSE may be of therapeutic benefit when used with MTX.

Therapeutic plasma exchange in patients with neurologic diseases: Retrospective multicenter study

Therapeutic plasma exchange (TPE) is commonly used in many neurological disorders where an immune etiology was known or suspected. We report our experience with TPE performed for neuroimmunologic disorders at four university hospitals. The study was a retrospective review of the medical records of neurological patients (n=57) consecutively treated with TPE between April 2006 and May 2007. TPE indications in neurological diseases included Guillain-Barrè Syndrome (GBS) (n=41), myasthenia gravis (MG) (n=11), acute disseminated encephalomyelitis (ADEM) (n=3), chronic inflammatory demyelinating polyneuropathy (CIDP) (n=1) and multiple sclerosis (MS) (n=1). Patient median age was 49; there was a predominance of males. Twenty-two patients had a history of other therapy including intravenous immunoglobulin (IVIG), steroid, azothioprin, and pridostigmine prior to TPE. Another 35 patients had not received any treatment prior to TPE. All patients were classified according to the Hughes functional grading scores pre- and first day post-TPE for early clinical evaluation of patients. The TPE was carried out 1-1.5 times at the predicted plasma volume every other day. Two hundred and ninety-four procedures were performed on 57 patients. The median number of TPE sessions per patient was five, and the median processed plasma volume was 3075mL for each cycle. Although the pre-TPE median Hughes score of all patients was 4, it had decreased to grade 1 after TPE. While the pre-TPE median Hughes score for GBS and MG patients was 4, post-TPE scores were decreased to grade 1. Additionally, there was a statistically significant difference between post-TPE Hughes score for GBS patients with TPE as front line therapy and patients receiving IVIG as front line therapy (1 vs. 3.5; p=0.034). Although there was no post-TPE improvement in Hughes scores in patients with ADEM and CIDP, patients with MS had an improved Hughes score from 4 to 1. Mild and manageable complications such as hypotension and hypocalcemia were also observed. TPE may be preferable for controlling symptoms of neuroimmunological disorders in early stage of the disease, especially with GBS.

Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: risk factors and response to treatment

High fevers and/or rashes prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (⩾12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (⩾13.2 Gy)-based myeloablative conditioning. Tacrolimus (n=35) or CYA (n=22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (⩾38.5 °C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% confidence interval) of PES was 77% (66–88%). The incidence of PES was significantly higher in patients who received CYA as a GVHD prophylaxis than those who received tacrolimus (P<0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact OS or tumor relapse, although it may have increased non-relapse mortality (P=0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of CYA for GVHD prophylaxis increases the risk of PES following dual UCB transplantation.

Factors influencing the early mortality in haematological malignancy patients with nosocomial Gram negative bacilli bacteraemia: a retrospective analysis of 154 cases

BACKGROUND The aim of this study is to assess the factors influencing the early mortality (7-day after index blood culture) in haematological malignancy patients with Gram negative bacilli (GNB) bacteraemia. METHODS Infection control committee records were reviewed to identify the cases between March 2006 and June 2011. Only one bacteraemic episode per patient was included in the study. RESULTS A total of 154 patients with GNB bacteraemia were identified. The early mortality rate was 19.5% (30 out of 154). Blood cultures revealed Enterobacteriacea in 120 patients (Escherichia coli; 86, Klebsiella spp.; 28, Enterobacter cloacea; 6) and glucose non-fermenting GNB in 34 patients (Pseudomonas aeruginosa; 15, Acinetobacter baumannii; 11, Stenotrophomonas maltophilia; 7, Burkholderia cepacia; 1). Forty (33.3%) out of 120 Enterobacteriaceae were extended spectrum beta-lactamase (ESBL) producers and 18 (52.9%) out of 34 glucose non-fermenting GNB were multidrug resistant. Carbapenems were administered as first line therapy in 139 out of 154 patients. In univariate analysis Pitts bacteraemia score, presence of aplastic anaemia, bacteraemia caused by glucose non-fermentating GNB, inappropriate empirical antibacterial treatment, presence of severe sepsis or septic shock, unable to achieve microbiological cure, and intensive care unit (ICU) acquired bacteraemia were associated with mortality. Multivariate analysis showed ICU acquired bacteraemia (OR, 12.55; 95% CI, 2.34-67.38, p=0.003) as an independent factor associated with early mortality. CONCLUSION Haematological malignancy patients who require ICU care are at high risk for early mortality related to GNB bacteraemia. Based on the local findings pointing out high rate of multidrug resistance, carbapenems combined with colistin seems to be a reasonable approach as empirical treatment of these patients. However, increasing carbapenem resistance rate is of concern.

What should be the optimal cut-off of serum 1,3-β-d-glucan for the detection of invasive pulmonary aspergillosis in patients with haematological malignancies?

Abstract Background: The detection of 1,3-β-d-glucan (BDG), a cell wall component of several medically important fungi, is a promising tool for the diagnosis of invasive pulmonary aspergillosis. The aim of this study was to evaluate the diagnostic accuracy of the BDG test in invasive pulmonary aspergillosis (IPA) by focusing on the optimal cut-off value. Methods: The records of the Infection Control Committee were reviewed to identify patients with haematological malignancies and stem cell transplantation who had at least 1 BDG (Fungitell kit) measurement during the period January 2008 through April 2011. The European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) criteria (independent of BDG results) were used to categorize the patients with IPA. Patients with possible IPA were not included in the study. Results: A total of 128 patients (50 with proven or probable IPA) were included in the study. At the manufacturers recommended cut-off value of 80 pg/ml, the sensitivity of BDG was 66% (95% CI 51.2–78.7), specificity 75.6% (95% CI 64.6–84.5), positive predictive value (PPV) 63.4%, and negative predictive value (NPV) 77.6%. A receiver operating characteristic (ROC) curve was constructed to define the optimum serum BDG cut-off for the diagnosis of IPA. At a cut-off value of 181 pg/ml, the sensitivity was 52% (95% CI 37.4–66.3), specificity 94.8% (95% CI 87.4–98.6), PPV 86.7%, and NPV 75.5%. Conclusions: Although higher cut-off levels increased the specificity of the BDG test, sensitivity decreased to an unacceptable level; the commercially recommended cut-off value appears to be appropriate for screening purposes.

Can bacteraemia lead to false positive results in 1,3-beta-D-glucan test? Analysis of 83 bacteraemia episodes in high-risk patients for invasive fungal infections.

BACKGROUND Although bacteraemia has been reported to be related to false positive results in the 1,3-beta-D-glucan (BDG) test, the evidence for this interaction is limited. AIMS To investigate the association between bacteraemia and the BDG test. METHODS Records of the Infection Control Committee were reviewed to identify bacteraemia in patients who were hospitalized in the haematology ward and stem cell transplantation unit. Patients who had undergone the BDG test at least once within 5 days of a positive blood culture were included in the study. BDG levels in the sera were assayed using the Fungitell kit (Associates of Cape Cod, East Falmouth, MA) according to the manufacturers specifications. The cutoff for BDG positivity was 80 pg/mL. RESULTS Eighty-three bacteraemic episodes were identified in 71 patients. BDG positivity was detected in 14 patients with bacteraemia, and only 1 patient with Escherichia coli bacteraemia had high BDG levels (over 80 pg/mL) despite having no evidence of invasive fungal infection (IFI). CONCLUSIONS Our study suggests that the cross-reactivity of the BDG test with a concomitant or recent bacteraemia is a very rare condition. Patients with risk factors for IFI should be evaluated cautiously when a positive BDG test is reported.

Comparison of total body irradiation plus cyclophosphamide with busulfan plus cyclophosphamide as conditioning regimens in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplant

Abstract Conditioning regimens used during stem cell transplant provide prolonged control or cure of the disease in patients with acute lymphoblastic leukemia (ALL). In this study, we present a comparison of treatment results for 95 patients with ALL who underwent allogeneic hematopoietic stem cell transplant (AHSCT) with total body irradiation plus cyclophosphamide (TBI + Cy) or busulfan plus cyclophosphamide (Bu + Cy) as conditioning regimen. Median age was 25 (range: 9–54) years. Median follow-up was 24 (range: 3–107) months. Median overall survival (OS) was found to be 29 months. Median event-free survival (EFS) was 9 months. Median OS was 37 months in the TBI + Cy arm, while it was 12 months in the Bu + Cy arm, suggesting a significant advantage favoring the TBI + Cy arm (p = 0.003). Median EFS was 13 months in the TBI + Cy arm, while it was 4 months in the Bu + Cy arm, indicating a significant difference (p = 0.006). In univariate and multivariate analysis, it was found that high OS and EFS were significantly correlated with TBI + Cy conditioning regimen and lack of transplant-related mortality (p < 0.05). The TBI + Cy conditioning regimen was found to be superior to the Bu + Cy regimen in patients with ALL undergoing AHSCT regarding both OS and EFS.

TcRαβ-depleted haploidentical transplantation results in adult acute leukemia patients

ABSTRACT Introduction: The use of αβ+ T-cell-depleted grafts is a novel approach to prevent graft failure, graft-versus-host disease (GVHD), and non-relapse mortality (NRM) in patients undergoing haploidentical hematopoietic stem cell transplantation. Patient and method: Thirty-four patients with acute leukemia and lacking a match donor were treated with αβ T-cell-depleted allografts from haploidentical family donors. A total of 24 patients had acute myeloid leukemia (AML) and 10 had acute lymphoblastic leukemia. 84.4% of patients were in the high-risk group, and 55.9% were not in remission. The preparative regimen included thiotepa, melphalan, fludarabine, and anti-thymocyte globulin-Fresenius. Grafts were peripheral blood stem cells engineered by TcR-alpha/beta depletion. Results: Neutrophil and platelet engraftment was achieved on days +12 (range, 10.5–15) and +11 (range, 10–12). All but three patients were engrafted with full donor chimerism. Grade III-IV acute GVHD occurred in two (5.9%) patients and chronic GVHD in two (6.1%). Disease-free survival and overall survival were 42 and 54% at 1 year, respectively. AML as disease type (HR: 4.87, 95% CI: 1.50–15.87) and mother as donor (HR: 1.05, 95% CI: 1.00–1.11) were found to be independent risk factors on patient survival. Mortality and NRM in the first 100 days were 5 of 34 (14.7%) and 4 of 34 (11.7%). Relapse was the main cause of death (56.3%). T-cell reconstitution appears to be faster than that reported in published data with CD3/CD19-depleted grafts. Conclusion: αβ T-cell-depleted haploidentical transplantation may be a good alternative for high-risk patients if there are no human leukocyte antigen matched donors.

Effects of Imatinib Mesylate on Renin-Angiotensin System (RAS) Activity During the Clinical Course of Chronic Myeloid Leukaemia

The renin–angiotensin system (RAS) is involved in cell growth, proliferation and differentiation in bone marrow in an autocrine–paracrine manner, and it modulates normal and neoplastic haematopoietic cell proliferation. This study aimed to assess expressions of the RAS components, renin, angiotensinogen and angiotensin-converting enzyme (ACE), during imatinib mesylate treatment of patients with chronic myeloid leukaemia (CML). Expressions of RAS components were studied in patients with CML at the time of diagnosis (n = 83) and at 3, 6 and 12 months after diagnosis (n = 35) by quantitative real-time polymerase chain reaction. De novo CML patients had increased ACE, angiotensinogen and renin mRNA levels and these expression levels decreased following administration of imatinib. The RAS activities were significantly different among Sokal risk groups of CML, highlighting the altered biological activity of RAS in neoplastic disorders. The results of this study confirm that haematopoietic RAS affects neoplastic cell production, which may be altered via administration of tyrosine kinase inhibitors such as imatinib mesylate.

Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience

Background Reed-Sternberg cells of classical Hodgkins lymphoma (cHL) are characterized by genetic alterations at the 9p24.1 locus, leading to over-expression of programmed death-ligand 1 and 2. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed or refractory cHL, with an acceptable safety profile. Patients and methods We present a retrospective analysis of 82 patients (median age: 30 years; range: 18-75) with relapsed/refractory HL treated with nivolumab in a named patient program from 24 centers throughout Turkey. The median follow-up was 7 months, and the patients had a median of 5 (2-11) previous lines of therapy. Fifty-seven (70%) and 63 (77%) had been treated by stem-cell transplantation and brentuximab vedotin, respectively. Results Among 75 patients evaluated after 12 weeks of nivolumab treatment, the objective response rate was 64%, with 16 complete responses (CR; 22%); after 16 weeks, it was 60%, with 16 (26%) patients achieving CR. Twenty patients underwent subsequent transplantation. Among 11 patients receiving allogeneic stem-cell transplantation, 5 had CR at the time of transplantation and are currently alive with ongoing response. At the time of analysis, 41 patients remained on nivolumab treatment. Among the patients who discontinued nivolumab, the main reason was disease progression (n = 19). The safety profile was acceptable, with only four patients requiring cessation of nivolumab due to serious adverse events (autoimmune encephalitis, pulmonary adverse event, and two cases of graft-versus-host disease aggravation). The 6-month overall and progression-free survival rates were 91.2% (95% confidence interval: 0.83-0.96) and 77.3% (0.66-0.85), respectively. Ten patients died during the follow-up; one of these was judged to be treatment-related. Conclusions Nivolumab represents a novel option for patients with cHL refractory to brentuximab vedotin, and may serve as a bridge to transplantation; however, it may be associated with increased toxicity.