Recent studies have shown that isocitrate dehydrogenase1 ⁄ 2 (IDH1 ⁄ 2) mutations occur frequently in secondary glioblastoma. This study aimed to investigate their impact on temozolomide chemosensitivity and relationship with O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation in secondary glioblastoma. Searches for IDH1 and IDH2 mutations, 1p19q codeletion, MGMT promoter methylation, and p53 expression were carried out in a series of 86 secondary glioblastomas and correlated with progression-free survival and overall survival. Response to temozolomide was evaluated by progression-free survival, as well as by tumor size on successive MRI scans, then correlated with molecular alterations. IDH (IDH1 or IDH2) mutations were found in 58 ⁄ 79 patients (73.4%). IDH mutation, MGMT promoter methylation, and 1p19q codeletion were associated with prolonged progression-free survival in univariate (P < 0.001, P < 0.001, P = 0.003, respectively) and multivariate analysis (P < 0.001, P < 0.001, P = 0.035, respectively). IDH mutation (P = 0.001) and MGMT promoter methylation (P = 0.011) were correlated with a higher rate of objective response to temozolomide. Further analysis of response to temozolomide showed that patients with both IDH mutation and MGMT promoter methylation had the best response rate to temozolomide. IDH mutation appears to be a significant marker of positive chemosensitivity in secondary glioblastoma. Use of IDH status combined with MGMT promoter status as a stratification factor seems appropriate in future clinical trials involving temozolomide for the treatment of patients with secondary glioblastoma. (Cancer Sci 2012; 103: 269-273) G lioblastomas (GBMs), the most common and malignant primary brain tumors in adults, may develop rapidly after a short history and without evidence of less malignant precursor lesions (primary GBM, pGBM), or through progression from low-grade or anaplastic gliomas (secondary GBM, sGBM).(1-3)In GBM, the clinical value of O(6)-methylguanine DNA methyltransferase (MGMT) promotor methylation status in predicting benefit from alkylating agents has been validated by several clinical trials, both in patients treated with nitrosourea and in those with temozolomide (TMZ). (4,5) In the European Organization for Research and Treatment of Cancer (EORTC) ⁄ National Cancer Institute of Canada (NCIC) 26981 ⁄ 22981 trial evaluating the effect of radiotherapy plus concomitant and adjuvant TMZ versus radiotherapy alone in GBM, methylation of MGMT promotor emerged as the strongest predictor for outcome and benefit from chemotherapy.(6,7) However, all of these studies were based on newly diagnosed GBMs, most of which were pGBMs. So far, there is no clear evidence that MGMT promotor methylation plays the same role in sGBMs, as these two subtypes constitute distinct disease entities and develop through different genetic pathways. (2,3,8) In 2008, a genome-wide sequencing study identified somatic mutations on codon 132 in a gene encoding isocitrate dehydrogenase-1 (IDH1) in 12% s...

Abstract. Mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) appear to occur frequently and selectively in gliomas. Our aim was to assess whether IDH mutations are common in Chinese glioma patients and whether the mutations predict good response to concomitant chemoradiotherapy. In this study IDH1 and IDH2 mutations were detected in a series of 203 gliomas. IDH1 mutations were present in 75 of the 203 cases (36.9%) while IDH2 mutations in 5 of the 203 cases (2.5%). No tumor was mutated in both IDH1 and IDH2. IDH1/2 mutations were associated with prolonged overall survival in the whole series of patients exclusive of pilocytic astrocytoma (P<0.001), WHO grade Ⅱ patients who received no adjuvant therapy after surgery (P= 0.014) and WHO grade Ⅲ patients who received concomitant chemoradiotherapy (standard schedule) after surgery (P=0.033). Furthermore, there was no correlation between IDH1/2 mutations and reponse to concomitant chemoradiotherapy in anaplastic gliomas. Our results suggest that IDH1 mutations also occur freuqently in Chinese glioma patients but the frequency of IDH1 mutations is below the findings reported by North American and European groups. Furthermore, we confirm the prognostic significance of IDH1/2 mutations in gliomas, but the mutations cannot predict a favorable response to concomitant chemoradiotherapy in anaplastic gliomas. IntroductionGliomas are the most frequent and lethal brain tumors and display a wide diversity with location, morphology, genetic status and response to therapy. These tumors have been classified as grade I to grade IV based on histopathological and clinical criteria established by the World Health Organization (WHO) (1). Despite intensive therapies, including surgery, radiotherapy (RT) and chemotherapy (CT), the outcome of glioma patients remain depressing (2,3). Especially, glioblastoma multiforme (GBM), the most prevalent form of brain tumors, has one of the worst prognosis among all types of gliomas with a median progression-free survival (PFS) of 6.9 months and a median overall survival (OS) of 14.6 months through surgery plus standard concomitant chemoradiotherapy (CCRT) (2,4).A combined understanding of the genetic basis and pathology of gliomas provides insight into biologically based tumor classification and identifies molecular prognostic biomarkers. In turn, this information is the route by which the most effective therapy can be focused (5). The latest breakthrough came in 2008, when the gene encoding isocitrate dehydrogenase 1 (IDH1) was initially found to be mutated in approximately 12% of GBM (6) followed by the observation that it was mutated in the majority of WHO grade II and III gliomas (7-11). IDH1 (encoded by IDH1 gene on chromosomal 2q33.3 and located in the cytoplasm and peroxisomes) or its mitochondrial counterpart IDH2, is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate thereby leading to NADPH (Nicotinamide Adenine Dinucleotide Phosphate) production (12). In the vast majority of the c...

Objective: To evaluate the factors effecting the long term survival of refractory leukemia patients who received the therapy of HLA haploidentical peripheral blood stem cells transplantation. Methods: To analysis the factors effecting long term survival of refractory leukemia patients who underwent HLA haploidentical peripheral blood stem cells transplantation. The HLA mismatched locus between the donors and patients, the disease status of patients at transplant, the grafted mononucleaer cells number, and the occurrence of GVHD, the age of patients and other factors were considered and analyzed by data reduction SSP11. From July, 1998 to May, 2004, 30 Patients with refractory leukemia patients including 13 cases of acute non-lymphocytes leukemia, 10 cases of acute lymphocytes leukemia, 6 cases chronic myeloid leukemia and 1 cases of non-Hodgkin lymphoma underwent HLA haploidentical peripheral blood stem cells transplantations. The median age was 25 years old (3– 52 years old). Twelve patients received stem cells from parents, four from daughter and son, and the other from sibling donors. Twelve patients received three HLA locus mismatched stem cells, thirteen patients received two HLA mismatched donors stem cells, and five patients received one HLA mismatched donors stem cells. The conditioning regime consisted of fludara (25mg/m2 X5d), busufan (4mg/kg X4d) and cyclophosphamide ( 60mg/kg X2d). Median dose of rabbit anti-human lymphocyte globulin (5mg/kg X5d) was added in the in some patients. A mean of 6.0 x 108 /kg (3–9 x108 /kg) mono-nucleated cells was grafted. The mean CD34+ cells number was 5.5 x106 /Kg (3–6.5 x106/kg). Results: Twenty-nine patients were successfully grafted and one failed to graft. The mean time of white cell count more than 1x109/L was 13 days (10–18 days) and 12 days (9–16) respectively. Severe acute graft versus host disease occurred in six patients, and four died. Seven patients suffered from intensive chronic graft versus host disease. Nine patients relapsed and died. The mean relapse time was 10 months (3 months to 24 months). Four patients died from intensive chronic graft versus host disease. Fourteen patients are still disease free survival with high karnofsky performs. The relapse of leukemia was the main cause of death. Five the patients less than 20 year’s old age are still disease free survival with high karnofsky performs scores. Conclusion: HLA haploidentical peripheral blood stem cells transplantation may be an effect therapy for refractory leukemia. Although graft versus leukemia effect may be strong in HLA haploidentical blood stem cells transplantation, leukemia relapse is still the main cause to death. We suggest that for these patients with leukemia who can not find full matched donor perform related HLA mismatched peripheral blood stem cells transplantation as earlier as to get the better long term outcome.