Methylenetetrahydrofolate reductase C677T polymorphism in adult patients with lymphoproliferative disorders and its effect on chemotherapy.

Methylenetetrahydrofolate reductase (MTHFR) is one of the most critical enzyme in folic acid metabolism, and it converts 5,10-MTHF to 5-MTHF. 5,10-MTHF is required for conversion of uridilate to thymidylate. On the other side, MTHFR enzyme causes methylation of homocysteine into methionine, leading to methylation of DNA. Chemotherapeutic agents have different effects, but DNA is the target for most of them. Because folate is the cornerstone in DNA synthesis, we analysed herein if the polymorphisms in MTHFR gene can alter the susceptibility of lymphoproliferative disease risk and if it has an effect on chemotherapy response. One hundred fifty-six patients with lymphoid malignancies and 82 healthy controls were included into the study. Neither gene frequencies nor allel frequencies were found to increase lymphoproliferative disease risk significantly in both overall group and subgroups. Although it was not statistically significant, we found a 2.7-fold increased risk in acute lymphocytic leukaemia (ALL)/Burkitt lymphoma patients with TT genotype [odds ratio (OR), 2.7; 95% confidence interval (CI), 0.88-8.2] than CC genotype but a 1.7-fold decreased risk with TT genotype in diffuse large B-cell lymphoma (DLBCL; OR, 0.58; 95% CI, 0.17-1.88) and a 1.8-fold decreased risk in Hodgkin's lymphoma with TT genotype (OR, 0.55; 95% CI, 0.10-2.87) than CC genotype. The chemotherapy response was analysed in DLBCL, Hodgkin's lymphoma and ALL/Burkitt's lymphoma because these patients received standard chemotherapy protocols. No significant difference was detected between responder and non-responders according to MTHFR T677C polymorphism, but the patients who had TT genotype respond 1.75-fold worse than CC (OR, 0.57; 95% CI, 0.07-4.64) in ALL patients (p=0.59), and in DLBCL, CT genotype revealed a 1.8-fold worse response than CC genotype (OR, 0.54; 95% CI, 0.17-1.7), but TT genotype revealed 2.6-fold better response rates than patients with CC genotype (OR, 2.6; 95% CI, 0.26-26.8). As a conclusion, MTHFR C677T polymorphism does not increase the risk of lymphoproliferative disease, and it does not have an effect on chemotherapy response significantly; however, the patients with TT genotype have a slightly increased risk for ALL, and they also respond worse than CC genotype. TT genotype slightly decreases the risk of DLBCL, and the patients have much favorable response rates.

Posttransplant lymphoproliferative disorders in transplant recipients.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation, with a reported incidence between 0.8% and 32%. The incidence of PTLD mainly depends on the transplanted organ, the immunosuppressive drugs, the viral serology, and the age of the recipient. The aim of our study was to analyze our patients diagnosed with PTLD. Among 1040 transplantations, including 931 renal, 14 heart, 55 liver and 40 allogeneic peripheral blood stem cell (PBSC), 8 patients (7 male, 1 female) were diagnosed with PTLD. Five patients had undergone renal, one cardiac, one liver, and one PBSC transplantations. Four patients were diagnosed within the first year of transplantation. Six patients presented with abdominal disease, one with convulsions, and one with peripheral lymph node involvement. According to the World Health Organization classification system, six patients were diagnosed as diffuse large B-cell lymphoma, one patient Burkitt's lymphoma, and one polymorphic PTLD. At the time of diagnosis, 7 patients showed positive Epstein-Barr virus (EBV) and cytomegalovirus (CMV) Ig G and negative Ig M; one patient, positive EBV Ig M and negative CMV Ig G and M. EBV viral load was extremely high in the plasma of two patients by polymerase chain reaction. One of these patient's pathologic tissue revealed positive EBV DNA, which was not detected in six of the other eight patients. This patient was an 8-year-old boy diagnosed with Burkitt's lymphoma at 31 months after liver transplantation. Seven patients died of disease or complications of chemotherapy. Only one patient survived after the diagnosis of PTLD. In conclusion, even with treatment the mortality rate was high among our patients with PTLD. To decrease the incidence of PTLD and related mortality, risk factors must be evaluated in multicenter studies.

The significance of autoantibodies in non-Hodgkin's lymphoma.

Lymphoproliferative diseases are the most common disorders associated with autoimmune disturbances. We determined the autoimmune phenotype of 64 non Hodgkin's lymphoma patients' and compared their clinicopathologic properties. Serum direct antiglobulin test [(DAT) n=64], indirect antiglobulin test [(IAT) n=61], platelet autoantibodies [(PAA) n=51], anti nuclear antibodies [n=33], anti-native DNA [n=29], anti phospholipid antibodies [n=40] and, lupus anticoagulant [n=33] were used as autoimmune markers. Twenty five patients (39%) displayed one or more autoimmune marker positivity (+). Three patients with (+) DAT and IAT had autoimmune hemolytic anemia and two patients with PAA had autoimmune thrombocytopenia. Male patients were more susceptible to autoimmunity in low grade lymphomas and the statistical difference was significant (p=0.035). Most of the autoimmune markers (+) patients had low grade and disseminated disease but this was not significant. Remission rates were not found to be different between autoimmune marker (+) and (-) patients. Although statistically not significant. median survival was longer in autoimmune marker (-) patients than in the others (50 versus 39 months). The significance of autoimmunity in NHL in a larger series of patients should be investigated in future studies.

Increased Serum Soluble CD23 and Soluble IL-2R Levels in Haematologic Malignancies.

Serum soluble CD23 (sCD23) and soluble IL-2 receptor (sIL-2R) levels increase not only in disorders with immune system activation, but also in hematological malignancies. They have been used as markers of disease progression and/or the response to therapy in lymphoproliferative disorders (LPD). In this study, we investigated the serum sCD23 and sIL-2R levels of 21 patients with different hematological malignancies [10 LPD, 6 multiple myeloma (MM), and 5 myelodysplastic syndrome (MDS)] before treatment, and compared them with 19 age- and sex- matched healthy subjects. Median sIL-2R levels were found to be significantly elevated in both the overall patient group and each of the subgroups. Median sCD23 levels were significantly higher in the overall patient group and in patients with LPD and MM. A positive correlation was found between sIL-2R and sCD23 levels in LPD. Our preliminary findings suggest that elevated serum levels of these soluble factors are not only markers of LPD but might be also used for other hematologic malignancies, except for MDS. Further studies should be designed to find out if it might be the result of an overactive immune system or not.

Anemia and thrombocytopenia due to parvovirus B-19 infection in a pregnant woman.

Anemia and thrombocytopenia in a patient with parvovirus B-19 and hepatitis C infection is reported. A seven month-pregnant 20 year-old patient had been first found to be anemic and thrombocytopenic 40 days before admission to our hospital and she had been given methylprednisolone and red cell transfusions. She gave birth to a healthy baby after only eight months of pregnancy. Ten days after delivery she was admitted to our hospital because of anemia and thrombocytopenia which did not respond to treatment. On admission, the blood count showed hemoglobin 8.1 g/dL, hematocrit 23.7%, white blood cells 11,200/microL, platelets 1000/microL, and reticulocytes 0.6%. Bone marrow smear and biopsy revealed erythroblastopenia and the absence of megakaryocytes. Liver enzymes were also high (alanine aminotransferase 1469 Units/L and aspartate aminotransferase 981 Units/L). In serologic studies PVB-19 IgM was found to be positive and hepatitis C virus RNA was detected. Red cell and platelet values returned to normal levels after cessation of methylprednisolone and concomitantly PVB-19 IgG was found positive in association with IgM in repeated determinations. PVB-19 was thought to be responsible for both anemia and thrombocytopenia.