Aims: The aim of this study was to compare the outcomes of radiofrequency thermal ablation (RFTA), percutaneous ethanol injection (PEI), and percutaneous acetic acid injection (PAI) in the treatment of hepatocellular carcinoma (HCC). Patients and methods: A total of 187 patients with HCCs of 3 cm or less were randomly assigned to RFTA (n = 62), PEI (n = 62), or PAI (n = 63). Tumour recurrence and survival rates were assessed. Results: One, two, and three year local recurrence rates were 10%, 14%, and 14% in the RFTA group, 16%, 34%, and 34% in the PEI group, and 14%, 31%, and 31% in the PAI group (RFTA v PEI, p = 0.012; RFTA v PAI, p = 0.017). One, two, and three year survival rates were 93%, 81%, and 74% in the RFTA group, 88%, 66%, and 51% in the PEI group, and 90%, 67%, and 53% in the PAI group (RFTA v PEI, p = 0.031; RFTA v PAI, p = 0.038). One, two, and three year cancer free survival rates were 74%, 60%, and 43% in the RFTA group, 70%, 41%, and 21% in the PEI group, and 71%, 43%, and 23% in the PAI group (RFTA v PEI, p = 0.038; RFTA v PAI, p = 0.041). Tumour size, tumour differentiation, and treatment methods (RFTA v PEI and PAI) were significant factors for local recurrence, overall survival, and cancer free survival. Major complications occurred in 4.8% of patients (two with haemothorax, one gastric perforation) in the RFTA group and in none in two other groups (RFTA v PEI and PAI, p = 0.035). Conclusions: RFTA was superior to PEI and PAI with respect to local recurrence, overall survival, and cancer free survival rates, but RFTA also caused more major complications.

Although the clinical features of the Isocitrate dehydrogenase 2 (IDH2) mutation in acute myeloid leukemia (AML) have been characterized, its prognostic significance remains controversial and its stability has not been investigated. We analyzed 446 adults with primary non-M3 AML and found IDH2 R172, R140 and IDH1 R132 mutations occurred at a frequency of 2.9, 9.2 and 6.1%, respectively. Compared with wild-type IDH2, mutation of IDH2 was associated with higher platelet counts, intermediate-risk or normal karyotype and isolated þ 8, but was inversely correlated with expression of HLA-DR, CD34, CD15, CD7 and CD56, and was mutually exclusive with WT1 mutation and chromosomal translocations involving core-binding factors. All these correlations became stronger when IDH1 and IDH2 mutations were considered together. Multivariate analysis revealed IDH2 mutation as an independent favorable prognostic factor. IDH2 À /FLT3-ITD þ genotype conferred especially negative impact on survival. Compared with IDH2 R140 mutation, IDH2 R172 mutation was associated with younger age, lower white blood cell count and lactate dehydrogenase level, and was mutually exclusive with NPM1 mutation. Serial analyses of IDH2 mutations at both diagnosis and relapse in 121 patients confirmed high stability of IDH2 mutations. In conclusion, IDH2 mutation is a stable marker during disease evolution and confers favorable prognosis.

The TP53 mutation is frequently detected in acute myeloid leukemia (AML) patients with complex karyotype (CK), but the stability of this mutation during the clinical course remains unclear. In this study, TP53 mutations were identified in 7% of 500 patients with de novo AML and 58.8% of patients with CK. TP53 mutations were closely associated with older age, lower white blood cell (WBC) and platelet counts, FAB M6 subtype, unfavorable-risk cytogenetics and CK, but negatively associated with NPM1 mutation, FLT3/ITD and DNMT3A mutation. Multivariate analysis demonstrated that TP53 mutation was an independent poor prognostic factor for overall survival and disease-free survival among the total cohort and the subgroup of patients with CK. A scoring system incorporating TP53 mutation and nine other prognostic factors, including age, WBC counts, cytogenetics and gene mutations, into survival analysis proved to be very useful to stratify AML patients. Sequential study of 420 samples showed that TP53 mutations were stable during AML evolution, whereas the mutation was acquired only in 1 of the 126 TP53 wild-type patients when therapy-related AML originated from different clone emerged. In conclusion, TP53 mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression.

Conventionally, acute myeloid leukemia (AML) patients are categorized into good-, intermediate- and poor-risk groups according to cytogenetic changes. However, patients with intermediate-risk cytogenetics represent a largely heterogeneous population regarding treatment response and clinical outcome. In this study, we integrated cytogenetics and molecular mutations in the analysis of 318 patients with de novo non-M3 AML who received standard chemotherapy. According to the mutation status of eight genes, including NPM1, CEBPA, IDH2, RUNX1, WT1, ASXL1, DNMT3A and FLT3, that had prognostic significance, 229 patients with intermediate-risk cytogenetics could be refinedly stratified into three groups with distinct prognosis (P<0.001); patients with good-risk genotypes had a favorable outcome (overall survival, OS, not reached) similar to those with good-risk cytogenetics, whereas those with poor-risk genotypes had an unfavorable prognosis (OS, 10 months) similar to those with poor-risk cytogenetics (OS, 13.5 months), and the remaining patients with other genotypes had an intermediate outcome (OS, 25 months). Integration of cytogenetic and molecular profiling could thus reduce the number of intermediate-risk AML patients from around three-fourth to one-fourth. In conclusion, integration of cytogenetic and molecular changes improves the prognostic stratification of AML patients, especially those with intermediate-risk cytogenetics, and may lead to better decision on therapeutic strategy.

Arsenic trioxide (As 2 O 3 ) is a novel anticancer agent, which has been found to induce remission in acute promyelocytic leukaemic patients following daily intravenous administration. The therapeutic value of As 2 O 3 in other cancers is still largely unknown. Cytotoxic tests in a panel of cancer cell lines showed that bladder cancer, acute promyelocytic leukaemic and gastrointestinal cancer cells were the most sensitive to As 2 O 3 among 17 cell lines tested. Cellular glutathione (GSH) system plays an important role in arsenic detoxification in mammalian cells. Cancer cells that were intrinsically sensitive to As 2 O 3 contained lower levels of GSH, whereas resistant cancer cells contained higher levels of GSH. On the other hand, there was no association of glutathione-S-transferase-π or multidrug resistance-associated protein 1 levels with arsenic sensitivity in these cancer cells. Multidrug-resistant cancer cells that were cross-resistant to arsenic contained higher levels of GSH or multidrug-resistance-associated protein 1 than their drug-sensitive parental cells. Cancer cells become more sensitive to arsenic after depletion of cellular GSH with L -buthionine sulphoximine. We concluded that cellular GSH level is the most important determinant of arsenic sensitivity in cancer cells. Cellular GSH level and its modulation by buthionine sulphoximine should be considered in designing clinical trials using arsenic in solid tumours. © 1999 Cancer Research Campaign

Acute myeloid leukemia bearing t(7;11)(p15;p15) is a distinct cytogenetic entity with poor outcome and a distinct mutation profile: comparative analysis of 493 adult patients Acute myeloid leukemia (AML) with t(7;11)(p15;p15), which results in a NUP98-HOXA9 fusion, is a distinct entity, but this subtype has not been characterized in detail. In a comprehensive study comparing 11 such patients with another 482 adult patients, we found that those with t(7;11) were younger (P ¼ 0.0076) and female (P ¼ 0.0111), with almost all having the M2-subtype of AML (Po0.0001). Even when those with low-risk karyotypes were excluded, patients with t(7;11) had poorer overall survival than the other AML group (median 13.5 and 20 months, respectively, P ¼ 0.045) and poorer relapse-free survival (median 6 and 12 months, respectively, P ¼ 0.003). The NUP98-HOXA9 fusion was strongly associated with KRAS and WT1 mutations (P ¼ 0.015 and P ¼ 0.0018, respectively). We characterized four varieties of this fusion, among which NUP98 exon 12/HOXA9 exon 1b was present in all 11 patients. We developed a highly sensitive and specific assay to quantify the abundance of leukemic cells, and found that the fusion remained detectable in morphological complete remission, even after allogeneic stem cell transplantation, suggesting that this disease was highly refractory to very intensive treatment. AML with NUP98-HOXA9 fusion therefore appears to have a distinct clinical and biological profile, and should be regarded as a poor prognostic group.

Recently, mutations of the additional sex comb-like 1 (ASXL1) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1, EZH2, IDH, NRAS, JAK2, SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1-mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1-mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1, NRAS, KRAS, SF3B1, SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1-wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression.

No abstract