The Effects of O6-methyl Guanine DNA-methyl Transferase Promotor Methylation and CpG1, CpG2, CpG3 and CpG4 Methylation on Treatment Response and their Prognostic Significance in Patients with Glioblastoma.

This retrospective study examined the prognostic significance and treatment effect of promoter methylation of O6- methyl guanine methyl transferase (MGMT) and meth-ylation of CpG 1, CpG2, CpG3 and CpG4 in glioblastoma (GB) patients received postoperative radiotherapy (PORT), with or without adjuvant temozolomide (TMZ). One hundred patients with GB who received PORT with concomitant TMZ plus adjuvant TMZ or PORT alone, were included. The MGMT promoter methylation of CpG1, CpG2, CpG3 and CpG4 islands were examined. Overall, MGMT-methylation emerged as a significant prognostic factor for better overall survival (OS) and progression-free survival (PFS) [odds ratio (OR): 0.609, 95% confidence interval (95% CI): 0.395-0.939, p = 0.02; OR: 0.662,95% CI: 0.430-1019, p = 0.5, respectively]. The methylation of each CpG1, CpG2, CpG3 and CpG4 islands was found to have no significant effects on OS and the methylation of each CpGl, CpG2 and CpG4 islands had no significant effect on PFS (p <0.05 for all). On the other hand, the methylation of CpG3 had a positive prognostic effect on PFS (OR: 2.1, 95% CI: 0.99-4.67, p = 0.04). In the group that only received radiotherapy (RT), CpG1 and CpC3 methylations were found to have a positive prognostic significance in terms of PFS (OR: 266, 95% CI: 1.05-6.75, p -0.03 for CpG1; OR: 2.4, 95% CI: 1.01-5.92, p = 0.04 for CpG3). The MGMT promoter methylation represents an important biomarker for predicting response to therapy. Individual islands, particularly CpG3, deserves further investigation as a prognostic marker. Further studies need to be done with larger sample sizes to clarify the results.

Urinary Type III Procollagen Is Associated With Chronic Allograft Dysfunction and Predicts Graft Survival.

BACKGROUND: Chronic allograft dysfunction (CAD) is the most important clinical problem in solid organ transplantation. Interstitial fibrosis and tubular atrophy contribute to long-term renal allograft failure. Urinary type III procollagen N-terminal propeptide (PIIINP), has been shown to associate fibrotic processes. METHODS: One hundred sixty patients with CAD who underwent allograft biopsies were evaluated, and 52 patients with chronic or sclerosing allograft nephropathy were enrolled in the study. The subjects were divided into 2 groups according to the level of urinary PIIINP to creatinine (u-PIIINP-to-Cr): high procollagen group and low procollagen group. The association between u-PIIINP-to-Cr level at the time of biopsy and renal endpoints during 36 months of follow-up was assessed by multivariate Cox analysis. RESULTS: Interstitial fibrosis and proteinuria were higher in the high procollagen group compared with the low urinary procollagen group. Correlation analysis showed that levels of u-PIIINP-to-Cr were positively associated with fibrosis scores. During the follow-up, glomerular filtration rate (GFR) decreased in both study groups; however, GFR declined more in the high procollagen group than in low procollagen group. Cox regression model showed that the u-PIIINP-to-Cr levels, GFR, and proteinuria were independent risk factors associated with graft survival. CONCLUSION: u-PIIINP-to-Cr level is a potentially useful noninvasive marker for graft survival in patients with CAD.

Urologic Disorders in Living Renal Donors and Outcomes of Their Recipients.

BACKGROUND: There is an expanding gap between the number of patients listed for kidney transplantation and the number of kidney transplantations performed annually. The use of sensitive imaging methods results in increased discovery of many urologic asymptomatic problems, such as urolithiases, renal cysts, and solid renal masses. This result has brought the question of whether all donors with these urologic disorders should be rejected for donation. METHODS: We retrospectively analyzed donor and recipient records of all living kidney transplantations performed from 2004 to 2014. RESULTS: Among 251 living-related donor kidney transplantations, 51 donors (20.3%) had urologic disorders. Mean donor age was significantly higher in donors with urologic disorders than in the standard donor group (50 y vs 41 y). The identified disorders were 32 renal cysts, 8 urolithiases, 3 renal tumors, 6 adrenal adenomas, and 2 microscopic hematurias. After nephrectomy, the graft kidneys with cysts were inspected carefully and all of the cortical-peripheral cysts were decorticated. Renal tumors were excised in 3 renal units. Transplantations had proceeded after the confirmation of low malignancy potentials of the lesions with safe surgical margins. Two out of 8 patients had undergone stone removal with ex vivo ureteroscopy and 1 by means of pyelotomy incision because of calix neck stenosis. None of those donors and recipients developed clinically significant renal stone disease with a mean follow-up of 28 months. Neither donors nor recipients of asymptomatic microscopic hematuria patients developed any problem with a mean 28 months' follow-up period. CONCLUSIONS: Asymptomatic urologic problems are very common. The significance of these asymptomatic pathologies is unclear. Our results suggest that in a selected group, at least some of these candidates can be accepted for donation.

Spinal intradural abscess caused by hematogenous spread of Prevotella oralis in a 3-year-old child with an asymptomatic congenital spinal abnormality.

STUDY DESIGN: Case Report. OBJECTIVES: To report a case of spinal intradural abscess caused by hematogenous spread of Prevotella oralis and discuss the treatment. SETTING: Department of Neurosurgery, Ankara Education and Research Hospital, Ankara, Turkey. METHOD: We report a 3-year-old child with progressive paraparesis who was diagnosed with an intradural spinal abscess, epidermoid cyst and dermal sinus. The patient was treated surgically followed by antimicrobial treatment. RESULT: Intraoperative abscess culture was positive for Prevotella oralis, which has not been reported before as a single isolate in literature. The patient's neurologic status was significantly improved after surgical treatment. CONCLUSION: Prophylactic antimicrobial therapies should cover the anaerobic bacteria in spinal intradural abscess. Surgical decompression with laminectomy and duraplasty may be warranted to achieve immediate neurologic improvement in such cases.

Utility of the Doppler ultrasound parameter, resistive index, in renal transplant histopathology.

BACKGROUND: Doppler ultrasonography is routinely used by many clinicians during long-term follow-up to identify high-risk patients without diagnosing the exact cause of graft dysfunction. Despite a number of studies showing a correlation between intrarenal resistive index (RI) and renal function in patients with kidney diseases, correlations between RI and renal histopathologic characteristics have not been sufficiently evaluated in renal transplant recipients. The aim of this study was to examine this relationship in grafted kidneys. PATIENTS AND METHODS: The intrarenal RI was retrospectively compared with biopsy findings in 28 kidney recipients. All renal biopsy specimens were reviewed by light microscopy and immunofluorescence staining. For glomerulosclerosis, we considered the percentage of glomeruli showing this change; for interstitial fibrosis/tubular atrophy and interstitial infiltration, we graded abnormalities according to the methods of Kliem et al (Kidney Int 49:666, 1996). RESULTS: The percentage of globally sclerosed glomeruli was significantly greater among patients with RI values higher than 0.75 than below this level (23% vs 47%; P = .022). Patients with grade 1 interstitial fibrosis and tubular atrophy (n = 14) showed lower RI values (0.68 +/- 0.03 vs 0.74 +/- 0.06; P = .047) than those with grade 3 fibrosis (n = 12). Similarly, lower RI values (0.66 +/- 0.02 vs 0.73 +/- 0.05; P = .014) were observed among patients with grade 1 (n = 13) compared with grade 3 interstitial infiltration (n = 13). CONCLUSION: RI seemed to provide a prognostic marker for the graft rather than yielding an exact diagnosis of renal graft dysfunction.

The role of proinflammatory cytokine gene polymorphisms for development of insulin resistance after renal transplantation.

BACKGROUND: Insulin resistance, a frequent prediabetic metabolic complication after renal transplantation, is generally linked to immunosuppressive drugs including corticosteroids, cyclosporine (CsA) or tacrolimus, as well as to age, cadaveric donors and ethnic factors. Cytokines are known to be inflammation modulatory substances that contribute to metabolic derangements after transplantation. The present study investigated the effects of cytokine gene polymorphisms on insulin resistance in renal transplant recipients. PATIENTS AND METHODS: Sixty-one renal transplant recipients (37 men, 24 women; mean age: 39.3 +/- 10.8 years) who attended regular clinical visits without a known history of diabetes were enrolled in the study. All patients were on a regimen of steroid, CsA, and mycophenolate mofetil. Venous blood samples were collected for biochemical analyses after an overnight fast at 08:00 pm. CsA trough levels, C-reactive protein, and fibrinogen were also estimated. Additional 10 mL of blood was withdrawn into an ethylenediamine tetraacetic acid-containing tube to determine cytokine genotypes (tumor necrosis factor-alpha [TNF-alpha] -238 G/A, transforming growth factor-beta [TGF-beta] codon 10 -869 T/C). Insulin resistance was calculated by the homeostasis model assessment (HOMA) method using the values of fasting blood glucose (FBG) and insulin levels. Anthropometric indices as well as body height, weight, waist and hip circumferences were measured simultaneously to calculate body mass index (kg/m2) and waist-to-hip ratio. Impaired fasting glucose (IFG) was described as an FBG > or = 110 but < 126 mg/dL. RESULTS: IFG was detected in 27.9% of this study group. The HOMA index was significantly higher among patients with IFG compared with normal FBG (NoGT) (6.3 +/- 4.5 vs 3.7 +/- 1.5; P = .01). Neither FBG and insulin nor HOMA values correlated with antrophometric, metabolic, or inflammatory parameters. Cytokine genotype allele frequencies, age, sex, immunosuppressive and antihypertensive drug type and doses, CsA trough levels, and donor source (cadaveric/living) were similar for patients with IFG and NoGT. Mutant allele carrier genotypes (AA + GA) for TNF-alpha -238 G/A showed higher fasting insulin (14.0 +/- 7.9 vs 34.1 +/- 17.7 microIU/mL; P = .04) and HOMA (4.01 +/- 2.01 vs 7.95 +/- 5.44; P = .002) levels than GG homozygote subjects. FBG, HOMA, and other metabolic and anthropometric indices were similar between TGF-beta codon 10 -869 T/C genotypes. The daily dose of steroid (mg/d) and A allele frequency for TNF-alpha -238 G/A genotype were significant predictors of HOMA index in linear regression analysis. CONCLUSION: The present study revealed that beside the daily dose of steroids, TNF-alpha -238 G/A genotype may contribute to insulin resistance in renal transplant recipients. Further investigations may highlight the effects of cytokine gene heterogenity on insulin resistance in those patients.

Pure red cell aplasia preceding malignant lymphoma in a renal transplant patient.

Malignant disorders are one of the major causes of morbidity and mortality in transplant patients. We present herein a renal transplant recipient with malignant lymphoma which preceded by pure red cell aplasia (PRCA). Acquired PRCA is a rare hematologic disorder in renal transplant recipients. It has been associated with a variety of disorders of immunologic dysfunction and neoplasms, exposure to drugs and toxins, infectious diseases, pregnancy and severe nutritional deficiency. This is the first case with PRCA preceding the malign lymphoma in a renal transplant patient. Treatment of lymphoma and lymphoma-related humoral and cellular changes or other undefined effects that may be related to therapy may be responsible of the resolving of PRCA in this patient. In this regard, renal transplant patients with acquired PRCA, must be closely followed for an underlying neoplastic disorder.

Bone mineral density in haemodialysis patients: A comparative study of dual-energy X-ray absorptiometry and quantitative ultrasound.

BACKGROUND: Quantitative ultrasound (QUS) of bone is a relatively new technique that appears to assess 'bone quality' in addition to bone mineral density. The purpose of this study was to evaluate the diagnostic potential of QUS of calcaneum and to correlate it with dual energy X-ray absorptiometry (DEXA) in chronic haemodialysis patients. METHODS: Broad-band ultrasound attenuation (BUA; dB/MHz) and speed of sound (SOS; m/s) of calcaneum and DEXA (g/cm(2)) measurements of the lumbar spine and hip were made in 39 patients. The indices obtained by either method were compared with age-and sex-matched controls. Calcaneal measurements were correlated to DEXA and relevant clinical and biochemical data of patients. RESULTS: BUA and SOS values were markedly reduced in dialysis patients compared to controls (59.1+/-13.8 vs 73.0+/-16.2 dB/MHz, P:<0.001 and 1533+/-28 vs 1560+/-29 m/s, P:=0.014 respectively). There was a moderate, but significant association between calcaneal parameters and DEXA (r=0.32-0.53, P:<0.05). Both BUA and SOS scores were inversely correlated with age (r=-0.69, P:<0.001) and duration of menopause (r=-0.74, P:<0.01). Additionally, BUA values showed a moderate negative association with serum intact parathyroid values (r=-0.38, P:=0.018). CONCLUSION: Chronic haemodialysis patients have reduced calcaneal BUA and SOS scores. QUS of the calcaneum is an easy-to-apply and radiation-free technique. It could be a useful substitute for assessment of bone density in such patients. However, further studies in large patient groups and comparisons with plasma markers of bone turnover and bone biopsy findings are needed to assess its potential place in the management of renal osteodystrophy.

Serum thrombopoietin levels in haemodialysis patients: involvement of arteriovenous fistula.

BACKGROUND: Thrombopoietin (Tpo) is a recently cloned growth factor which plays a critical role in the regulation of thrombopoiesis. Tpo has also been shown to stimulate in vitro and in vivo erythroid cell growth. Although Tpo transcripts were detected in hepatocytes, proximal tubules and endothelium, mechanisms regulating the level of circulating Tpo have not been fully delineated. Changes in the vessel wall and blood flow in arteriovenous fistula (AVF) might alter Tpo activity. METHODS: Serum thrombopoietin levels and serum erythropoietin levels in samples concurrently obtained from venous returns of AVF and contralateral peripheral veins in 31 haemodialysis patients were determined and compared with 12 healthy controls. Levels were also compared between 14 haemodialysis patients (group I) treated with recombinant human erythropoietin (rHu-Epo) and 17 haemodialysis patients (group II) not requiring rHu-Epo. RESULTS: Serum Tpo levels (44.8 +/- 23.9 pg/ml, vs 129.9 +/- 113.6 pg/ml, P<0.05) and platelet counts (194 +/- 55, 10(6)/ml vs 273 +/- 94. 10(6)/ml, P<0.05) of haemodialysis patients were lower than healthy controls. Serum Tpo levels were inversely correlated with platelet counts in the control group (R=-0.61, P<0.05), but not in haemodialysis patients. Tpo concentrations of AVF samples were lower than peripheral venous samples (31.6 +/- 17.7 pg/ml vs 44.8 +/- 23.9 pg/ml, P=0.001). No significant difference was present between the serum Tpo concentrations of haemodialysis patients in group I and group II. Serum Tpo levels were not correlated with haemoglobin levels or serum erythropoietin levels in haemodialysis patients. CONCLUSION: Decreased serum Tpo levels despite low platelet counts in haemodialysis patients suggest that the proposed feedback mechanism of platelet uptake of Tpo is not fully operative in these patients. Moreover, AVF might affect the local production and/or catabolism of this growth factor.

Thrombopoietin and thrombospondin in renal allograft recipients.

Recipients of renal transplants appear to be at increased risk of thromboembolic events. Despite accumulating evidence for the hyperreactivity of platelets, the primary regulator of thrombopoiesis, thrombopoietin (TPO), has not yet been studied in renal transplant recipients. Thus, the aim of the present study was to quantify the levels of TPO and to assess its contribution to increased platelet reactivity in recipients of renal allografts. Serum concentrations of thrombospondin (TSP) were also determined in patients undergoing renal transplants in order to evaluate the role of this multifunctional protein in platelet hyperaggregability. Serum levels of TPO were significantly lower in renal transplant recipients (n = 27) than in healthy controls (30.8+/-20.6 pg/ml versus 129.9+/-113.6 pg/ml, P = 0.001). Serum concentrations of TPO were correlated neither with serum levels of creatinine nor duration of transplantation. However, levels of TPO were negatively correlated with platelet counts (r = -0.50, P = 0.007) in recipients of renal transplants. Plasma levels of TSP were higher in renal transplant patients than in the control group (104.5+/-54.7 ng/ml versus 63.4+/-41.5 ng/ml, P = 0.003). No significant correlation was found between levels of TPO and TSP. We conclude that, rather than the allograft function, the platelet mass determines the levels of TPO in recipients of renal transplants. Despite the low serum levels of TPO, and increased concentrations of TSP, TPO might still play a role in the hyperaggregability of platelets in patients undergoing renal transplants.

Environmentally-induced malignant pleural mesothelioma and HLA distribution in Turkey.

SETTING: A large university hospital in Ankara, Turkey. OBJECTIVE: To investigate the potential links, if any, between the occurrence of malignant pleural mesothelioma (MPM) and the presence and distribution of human leukocyte antigens (HLA) in patients environmentally exposed to asbestos and erionite in rural Anatolia, Turkey. DESIGN: A case-control study design was used to compare the relative frequency and distribution of HLA among 31 MPM patients originating from the fibrous zeolite (erionite) and asbestos villages in central Anatolia, and two sets of controls. The cases represented all of the MPM cases diagnosed between 1995 and 1997 in our clinic at the Hacettepe University Hospital. One control group of 119 healthy individuals was drawn from Tuzköy, which has the largest population of three erionite villages, a very high prevalence of mesothelioma due to environmental exposure to erionite, and accounted for 16 of the MPM cases in the study. A second control group composed of 118 renal transplant donors was formed for external comparison. RESULTS: A significant relation was found with the HLA-B41 antigen in 19.4% of the patients compared to 0.8% of the Tuzköy inhabitants (odds ratio [OR] 28.3; 95% confidence interval [CI] 3.1-652.5) and 1.7% of the referent renal donor population (OR 13.9; 95% CI 2.3-106.7). The frequency of the HLA-B58 and -DR16 antigens was also observed to be significantly higher in patients with MPM compared to the two control groups. The odds ratios of MPM in those with HLA-B58 were 8.6 (95% CI 1.2-72.4) and 8.5 (95% CI 1.2-71.8), respectively, compared to those of the Tuzköy inhabitants and renal donors. CONCLUSION: The predictive role of the HLA antigens -B41, -B58 and -DR16 for MPM needs to be further investigated. This will help in screening the population at risk, and facilitate preventive measures such as family counselling and gene therapy.