High Frequency of Acute Promyelocytic Leukemia in Northwest Iran

Acute promyelocytic leukemia (APL) or M3 is a subtype of acute myeloid leukemia, according to the French- ‍American-British group classification. High frequencies of APL have been reported previously by many investigators. ‍We here studied AML patients to determine the frequency of APL in Tabriz in northwest Iran. We reviewed 483 ‍AML patients from 1996-2003. M2 and M3 cases accounted for 43.4% and 19.4% of the total, respectively. Our ‍study thus provides further evidence of high frequencies of APL associated with geographical areas. Further studies ‍should now be performed to evaluate genetic and environmental predisposing factors in Iran.     

Clinical Relevance of all-trans Retinoic Acid Pharmacokinetics and Its Modulation in Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is uniquely sensitive to treatment with all-trans retinoic acid (ATRA) which exerts its action via a well-documented cytodifferentiating mechanism. The combination of this retinoid with anthracyclines gives high percentages of complete remission and is now considered the optimal induction treatment for APL patients. Continuous treatment with ATRA, however, induces accelerated drug catabolism, with progressive decline in plasma drug concentrations potentially to below the levels required to maintain differentiation of leukemic cells. This process, which occurs rapidly and consistently has led to the hypothesis that the development of acquired clinical resistance to ATRA in APL has a pharmacologic basis. The rapid autoinduction of the hypercatabolic state precludes maintenance with continuous ATRA oral dosing, and is a limitation of better use of the drug both in APL and in other disorders in which it could be beneficial. Here we briefly review the pharmacologic alterations of ATRA metabolism induced by continuous oral administration, the clinical implications of this phenomenon, and the strategies currently under investigation to prevent or overcome the induced catabolism of this retinoid.     

Prognostic Factors in Acute Promyelocytic Leukemia: A Retrospective Study of 67 Cases

In a cohort of 67 adult patients with newly diagnosed untreated acute promyelocytic leukemia (APL), the initial clinical and biological parameters were submitted to multivariate analysis for potential prognostic significance. Median age of the patients was 40 years and the hematologic characteristics of the patients were those regularly seen. Complete remission (CR) was achieved in 43 cases (64%). Fourteen patients died within 4 weeks of diagnosis, due to severe hemorrhage. Factors predictive of hemorrhagic death in the multivariate analysis were hyperuricemia (p = 0.001), splenomegaly (p = 0.009), anemia (p = 0.02), high serum levels of LDH (p = 0.02), increased prothrombin time (p = 0.04), and hypercreatininemia (p = 0.05). Pretreatment patient characteristics for poor prognosis and achieving CR were hyperuricemia (p = 0.0002), splenomegaly (p = 0.01), anemia (p = 0.02), and lymphadenopathy (p = 0.04). The median disease-free survival (DFS) was 15.6 months. Poor prognostic factors for DFS were hyperuricemia (p = 0.007), and splenomegaly (p = 0.03). Maintenance chemotherapy had no statistically significant impact on CR duration. Median survival duration was 10 months. Poor prognostic factors for survival were hyperuricemia (p = 0.0005), and elevated serum LDH levels (p = 0.01).     

乳腺增生病p53基因第8外显子突变及p53蛋白表达

目的：探讨p53基因在乳腺癌发生早期的作用。方法：用免疫组化检测36例乳腺单纯增生，31例不典型增生，30例乳腺癌组织中p53蛋白表达，用PCR－RFLP检测p53基因第8外显子第278密码子突变。结果：乳腺单纯性增生，不典型增生和乳腺癌中p53蛋白表达率分别为0，22．6％，46．7％。p53基因第8外显子的突变率分别为0，3．2％，10．0％，均为杂合子突变。结论：乳腺癌不典型增生中存在p53蛋白表达和该基因第8外显子突变，该突变可能在乳腺增生病向乳腺癌进展过程中起一定作用。     

急性早幼粒细胞白血病诱导分化治疗中的组织浸润——附2例报告

 2例急性早幼粒细胞白血病(APL)患者经全反式维甲酸(ATRA)诱导缓解治疗中出现血管穿刺部位浸润块伴有面部、肢体肿胀, 和外周血白细胞计数增高过程一致, 随病情缓解消退, 对其发生机制和治疗进行了探讨。     

p53 Mutations are present in colorectal cancer with cytoplasmic p53 accumulation

Previous studies have shown that nuclear p53 over-expression is an indicator of p53 mutations whereas cytoplasmic p53 accumulation is related to wild-type p53 in several kinds of tumors. Cytoplasmic p53 accumulation has been demonstrated to be an independent prognostic factor in colorectal adenocarcinomas. The purpose was to examine whether mutations occur in cases with p53 accumulated in the cytoplasm and whether there are any differences in the frequency and characteristics of p53 mutations in different staining patterns. In the present study, we identified p53 mutations using PCR single-strand conformation polymorphism (SSCP) and DNA sequencing in 75 primary colorectal adenocarcinomas with different staining patterns (negative, nucleus, cytoplasm, nucleus and cytoplasm). The results show that the frequency and nature of mutations in tumors with cytoplasmic p53 accumulation were similar to those with nuclear p53 expression. However, the tumors with accumulation in both the nucleus and cytoplasm demonstrated a higher mutation rate. We suppose that the role of cytoplasmic p53 accumulation in predicting prognosis in patients with colorectal cancer may be dependent on both mutational and non-mutational mechanisms.     

Expression of the Annexin VIII Gene Acute Promyelocytic Leukemia

Annexin VIII is preferentially expressed in APL, but its level of expression in other subtypes of AML is much lower. Annexin VIII was originally found to be a vascular anticoagulant, but evidence obtained from our recent studies suggests that it does not play a role in hemorrhage diathesis in APL. The specific expression of annexin VIII in APL may relate to its possible role in hematopoietic cell differentiation. The expression of annexin VIII is developmentally regulated in APL-derived NB4 cells. It can be downregulated as a response to induction by ATRA, an agent which is also capable of inducing maturation of NB₄ cells. Our current understanding is that annexin VIII is most likely involved in signal transduction and may have a role as a modulator of PKC. A change in cellular PKC activity is expected to have a significant impact on cell differentiation and proliferation. The biological function of annexin VIII is currently unknown, but its expression in APL and its possible role in differentiation and proliferation of the leukemia cells would provide an excellent model system to study and elucidate this intriguing question.     

Absence of ras Mutations and Low Incidence of p53 Mutations in Renal Cell Carcinomas Induced by Ferric Nitrilotriacetate

Renal cell carcinomas induced in male Wistar rats by iron chelate of nitrilotriacetate (Fe-NTA) were examined for mutations in ras oncogenes and p53 tumor suppressor gene. Fourteen primary tumors and two metastatic tumors from 11 animals were evaluated. Exons 1 and 2 of the H-, K-, and N- ras genes were amplified by polymerase chain reaction (PCR), and the presence of mutations was examined by direct sequencing. Exon 5 through exon 7 of p53 gene, including the 3'half of the conserved region II and the entire conserved region III through V, were surveyed for point mutations by PCR-single stranded conformation polymorphism (SSCP) analysis. Direct sequencing of the ras genes showed no mutations in codon 12, 13, or 61 among the tumors evaluated. SSCP analysis of p53 gene exon 6 indicated conformational changes in two primary tumors. One tumor had a CCG-to-CTG transition at codon 199, and the other had an ATC-to-ATT transition at codon 229 and two nonsense C-to-T transitions. These results suggest that neither ras genes nor p53 gene play a major role in the development of renal cell carcinomas induced by Fe-NTA.     

Mutations in the p53 tumor suppressor gene in human cutaneous squamous cell carcinomas.

In this study, we analyzed 10 human squamous cell carcinomas (SCCs) for alterations in the p53 tumor suppressor gene in exons 4 through 9 by single-strand conformation polymorphism (SSCP) analysis. We found that 2 of 10 SCCs displayed unusual SSCP alleles at exon 7 of the p53 gene. Subsequent cloning and sequencing of PCR-amplified exon 7 DNA from these two tumors revealed that one had a G----A transition at the first position of codon 244, predicting a glycine-to-serine amino acid change, while the other tumor exhibited a G----T base change at the second nucleotide of codon 248, predicting an arginine-to-leucine substitution. Because the mutations in the p53 tumor suppressor gene in both tumors were located opposite potential pyrimidine dimer sites (C-C), it is consistent with these mutations having been induced by the ultraviolet radiation present in sunlight. These studies demonstrate that inactivation of the p53 tumor suppressor gene, as well as activation of ras oncogenes, may be involved in the pathogenesis of some human skin cancers.     

白血病细胞p53基因蛋白表达的研究

为研究Ｐ５３基因突变与人类白血病的关系，应用免疫组化方法对４５例不同类型的白血病标本进行了Ｐ５３蛋白的检测。结果发现Ｐ５３蛋白表达阳性率为２４．４％，其中在急生髓系白血病为１８．２％，而在急性淋系白血病中为２７．３％，急性髓，淋两系白现间Ｐ５３蛋白的表达差异无显著性，Ｐ５３蛋白的表达量与病人年龄，外周血血红蛋白水平，白细胞计数，血小板计数间也无显著性相关。     

全反式维甲酸对急性早幼粒细胞白血病的疗效

我们用国产全反式维甲酸治疗急性早幼粒细胞白血病34例,完全缓解率97％。在治疗中,所有病人都先有白细胞数增高现象,但未发生弥散性血管内凝血。主要副作用有皮肤及口唇干燥、头痛等,我们认为维甲酸是当前诱导分化治疗急性早幼粒细胞白血病的一个理想药物。     

Mutations of the p53 Gene in B-cell Lymphoma

Mutations of p53 gene have been recognized to be the most common genetic changes in human cancers. Recently, p53 gene mutations have been found in some patients with common subtypes of B-cell lymphoma (9/48:18.8%), Burkitt lymphoma (9/27:33.3%) and chronic lymphocytic leukemia (6/40:15%). Evidences to suggest that p53 gene mutations are associated with the disease progression in B-cell lymphoma have emerged. Functions of wild-type p53 and its mutant's probable role in B-cell lymphomagenesis are described in this review     

Outcome of Adolescents and Young Adults Compared With Pediatric Patients With Acute Myeloid and Promyelocytic Leukemia

BackgroundStudies on the outcome of adolescents and young adults (AYAs) with acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) are limited.MethodsWe compared the outcome of AYA (19-30 years) patients with AML and PML and pediatric (0-18 years) patients with AML (pAMLs) and APL (pAPLs) utilizing the Surveillance Epidemiology and End Results-18 registry. Early mortality rate (EMR), defined as mortality within 1 month of diagnosis, was used as a surrogate for treatment-related mortality. Survival statistics were computed using the Kaplan-Meier method. Multivariate analysis was done using logistic regression and the Cox proportional hazard regression model.ResultsA total of 6343 patients with AML were identified; 44.7% were AYAs. pAMLs had lower EMR (6.2% vs. 9.2%; P < .01) and higher overall survival (OS) (1-year, 70.3% vs. 62.1%; 5-year, 48.2% vs. 36.4%; P < .01). Nine hundred twenty patients with APL were also identified; 59.5% were AYAs. No statistically significant difference was found between AYAs with APL and pAPLs in EMR (11.4% vs. 14.1%; P = .23) and OS (1-year, 83.8% vs. 81.2%; P = .31 and 5-year, 68.2% vs. 73.1%; P = .11]. Comparing all patients with AML and APL, AYAs with APL and pAPLs had higher EMR (11.4% and 14.1% vs. 6.2% and 9.2%; P ≤ .01) but better OS than AYAs with AML and pAMLs (5-year OS, 68.2% and 73.1% vs. 48.2% and 36.4%; P ≤ .01).ConclusionOur analysis shows AYAs with AML have worse EMR and OS compared with pAMLs. AYAs with APL and pAPLs have similar outcomes. To our knowledge, this is the first study reporting outcomes of AYAs with APL and pAPLs using a large population-based registry and their comparison with same age patients with AML.     

Molecular Heterogeneity of the PML Gene Rearrangement in Acute Promyelocytic Leukemia: Prevalence and Clinical Significance

We determined the breakpoints of the RAR -α and PML genes in acute promyelocytic leukemia (APL) cells from 40 patients using Southern blot analysis. We also analyzed the relationship between the location of breakpoints, the clinical features of APL and the response to all-trans retinoic acid (ATRA). While the breakpoints of the RAR -α gene were consistently within intron 2, we found two major clusters in the breakpoints of the PML gene. The two breakpoint clusters in the PML gene were separated by 10 kb; 5'breakpoints were in intron 3, and 3'breakpoints were around introns 5 and 6. Twenty percent of the patients had 5'breakpoints in the PML gene and 70% had 3'breakpoints. No rearrangement was observed in the remaining 10% of patients in spite of the presence of t(15;17) translocation. There was no relationship between the location of the PML breakpoints, the clinical features at diagnosis and the response to ATRA.     

脑胶质瘤p53基因突变与临床病理的关系

[目的]探讨p53突变在脑胶质瘤发生发展中的作用及其与临床病理特征的关系.[方法]利用聚合酶链反应-单链构象多态性分析(PCR-SSCP)及LSAB免疫组化法对已确诊的48例脑胶质瘤进行p53基因突变以及蛋白表达的检测.[结果]48例胶质瘤中p53蛋白阳性表达率41.7%(20/48).在高级别(Ⅲ、Ⅳ级)中p53表达率明显高于低级别(Ⅱ级)的肿瘤,分别是63.2%、27.6%(P＜0.05).PCR-SSCP检测发现17例(35.4%)呈现p53基因突变,均位于5～8外显子,突变例数依次为7(41.2%)、1(5.9%)、4(23.5%)、5(29.4%).两种方法检测的符合率为89.6%(43/48).p53基因的突变与患者性别、年龄、肿瘤部位及大小无关.[结论]胶质瘤中p53突变多在第5～8外显子,p53基因突变在胶质瘤的发生进展中起重要作用.     

NK/T细胞淋巴瘤p53和β-catenin基因突变的探讨

目的:探讨p53和β-catenin基因在鼻型NK/T细胞淋巴瘤的突变情况.方法:用PCR-SSCP和基因测序的方法检测20例鼻型NK/T细胞淋巴瘤p53基因外显子4～8,β-catenin外显子3的突变情况.结果:8例p53基因发生突变,突变方式主要为错义突变,G:C→A:T转换多见;6例β-catenin基因发生突变,均为错义突变.结论:p53基因突变可能是鼻型NK/T细胞淋巴瘤发生的生物学机制之一,但突变位点并不集中,无明显的突变热点;错义突变是鼻型NK/T细胞淋巴瘤p53和β-catenin基因突变的主要方式.     

Proliferative Effect of Human Granulocyte Colony-stimulating Factor on Blast Cells of Acute Promyelocytic Leukemia

The effect of human granulocyte colony-stimulating factor (G-CSF) on leukemic cells of acute promyelocytic leukemia (APL) was examined. Mononuclear cells obtained from bone marrow cells containing more than 90% blasts from seven APL patients were incubated in the presence of G-CSF using semisolid and liquid culture systems. On day 7, the cells from all the patients produced many clusters consisting of 8–40 cells. These cells appeared to be promyelocyte-like blast cells in four patients and had differentiated to more mature neutrophils in three patients. On day 14, the number of clusters decreased except for two patiens. Blast cells from the two patients showing the increase of blast clusters could proliferate in a liquid culture containing G-CSF. Blast cells cultured for 14 days formed many secondary cultures after replating on a methylcellulose medium. Moreover, chromosomal analyses of blasts cultivated in the presence of G-CSF for 7 days showed t(15;17) in all metaphases in one patient. It appears that the leukemic cells from APL patients could proliferate in the presence of G-CSF.     

Clinical Significance of Serum p53 and Epidermal Growth Factor Receptor in Patients with Acute Leukemia

Background: Pretreatment serum p53 and epidermal growth factor receptor (EGFR) were assessedusing enzyme-linked immunosorbent assay (ELISA) in patients with acute leukemia to analysis their roles incharacterization of different subtypes of the disease. Materials and Methods: Serum samples from thirty twopatients with acute myeloid leukemia (AML) and fourteen patients with acute lymphoid leukemia (ALL) wereanalysed, along with 24 from healthy individuals used as a control group. Results: The results demonstrateda significant increase of serum p53 and EGFR in patients with AML (p<0.0001) compared to the controlgroup. Also, the results showed a significant increase of both markers in patients with ALL (p<0.05, p<0.0001respectively). Sensitivities and specificities for these variables were 52% and 100% for p53, and 73.9%, 95.8%for EGFR. Serum p53 and EGFR could successfully differentiate between M4 and other AML subtypes, whilethese variables failed to discriminate among ALL subtypes. A positive significant correlation was noted betweenp53 and EGFR. Negative significant correlations were observed between these variables and both of hemoglobin(Hg) content and RBC count. Conclusions: Mutant p53 and EGFR are helpful serological markers for diagnosisof patients with AML or ALL and can aid in characterization of disease. Moreover, these markers may reflectcarcinogenesis mechanisms.