Imatinib mesylate for children with dermatofibrosarcoma protuberans (DFSP)

Dermatofibrosarcoma protuberans (DFSP) is a rare malignant soft tissue tumor in children. DFSP is characterized by a specific fusion of the platelet‐derived growth factor β (PDGFβ) with the collagen type 1α1 (COL1α1) gene which renders these tumors responsive to targeted therapy with tyrosine kinase inhibitors, such as imatinib mesylate, as is reported in adults. In the current report, we describe the first small pediatric DFSP series, in which response to imatinib mesylate contributed to successful treatment outcome. Pediatr Blood Cancer. 2010;55:369–373. © 2010 Wiley–Liss, Inc.     

Mobilization of Ph chromosome-negative peripheral blood stem cells in a child with chronic myeloid leukemia after imatinib-induced complete molecular remission

Chronic myelogenous leukemia (CML) is rare in the pediatric population. Allogeneic stem cell transplant remains the only curative therapy; however, identifying a fully matched donor is not always possible. Imatinib mesylate has been shown to induce hematologic and cytogenetic response in adults and children with CML. We describe a child who achieved molecular remission with imatinib mesylate. BCR-ABL negative peripheral blood stem cells (PBSC) were successfully collected after mobilization with filgrastim.     

Initial testing of JNJ-26854165 (Serdemetan) by the pediatric preclinical testing program

JNJ-26854165 was originally developed as an activator of p53 capable of inducing apoptosis in cancer cell lines. In vitro, JNJ-26854165 demonstrated cytotoxic activity. The ALL cell line panel had a significantly lower median IC(50) (0.85 μM) than the remaining cell lines. In vivo JNJ-26854165 induced significant differences in EFS distribution compared to control in 18 of 37 solid tumors and in 5 of 7 of the evaluable ALL xenografts. Objective responses were observed in 4 of 37 solid tumor xenografts, and 2 of 7 ALL xenografts achieved PR or CR. Responses were noted in xenografts with both mutant and wild-type p53.     

紫铆因抗急性淋巴细胞白血病细胞的体外作用及机制研究

目的探讨紫铆因对急性淋巴细胞白血病(ALL)细胞增殖及细胞凋亡的体外作用及其机制。方法采用Ficoll-Paque分离液分离4例初发ALL患儿骨髓原代细胞及4例正常儿童骨髓单个核细胞并购买HK-2、Nalm-6、Jurkat、sup-B15及MOLT-3 ALL细胞株;用MTS技术检测紫铆因对细胞增殖的影响;采用流式细胞技术检测紫铆因对细胞凋亡的影响,并用蛋白印迹技术(Western Blot)检测cleaved caspase-3、Bim、Puma及cleaved PARP的表达。结果紫铆因对正常单个核细胞无明显抑制增殖作用,对人ALL原代细胞及ALL细胞株均具有明显的抑制增殖作用,并呈现出剂量效应和时间效应关系;紫铆因能逆转氟美松耐药细胞株对氟美松的敏感性;紫铆因能明显促进人ALL细胞株的细胞凋亡,并且随着紫铆因剂量的增加,细胞凋亡越明显;随着紫铆因浓度的增加,凋亡相关蛋白cleaved caspase-3、Bim、Puma及cleaved PARP表达量也逐渐增多。结论紫铆因对ALL细胞包括氟美松耐药细胞株具有抑制细胞增殖和促进细胞凋亡的作用。     

In vitro sensitivity to dasatinib in lymphoblasts from a patient with t(17;19)(q22;p13) gene rearrangement pre-B acute lymphoblastic leukemia

Patients with t(17;19) acute lymphoblastic leukemia (ALL) have a dismal prognosis even with the most intensive current therapies that include stem cell transplant. We present the case of a patient with t(17;19)(q22;p13) gene rearranged B-cell precursor ALL whose lymphoblasts were found to have significant in vitro sensitivity to dasatinib. The patient tolerated the addition of dasatinib with combination therapy and remained in remission for over nine months until his recurrence. Therefore, future studies will be needed to interrogate whether dasatinib has any therapeutic benefit in children with t(17;19) B-cell precursor ALL.     

The treatment of children suffering from chronic myelogenous leukemia: A comparison of the result of treatment with imatinib mesylate and allogeneic hematopoietic stem cell transplantation

HSCT is the only proven treatment option for CML, a rare disease in children. Recently, there are promising reports on the advantageous effect of imatinib mesylate for pediatric patients with CML. We conducted a retrospective study on 33 pediatric patients suffering from CML. Fourteen underwent HSCT and the rest were treated with imatinib. With a median follow‐up of 24 months, the two‐yr OS in the HSCT group and the imatinib group was 84% and 87%, respectively (p = 0.714). The probabilities of two‐yr DFS were 59% in the HSCT group and 82% in the imatinib group, either (p = 0.880). Relapse occurred in 5 (35.7%) patients of the HSCT group, and 8 (42.1%) patients showed relapse in the imatinib group. Among nine patients who died, five were in the HSCT group and the rest were in the imatinib group. The probability of relapse in the patients of the imatinib group followed up for several consecutive years may be higher than observed in the HSCT group, so we cannot easily conclude which way is more reliable.     

Marked regression of metastatic pilocytic astrocytoma during treatment with imatinib mesylate (STI-571, Gleevec): a case report and laboratory investigation

Pilocytic astrocytomas are the most common childhood glioma. Most children with pilocytic astrocytomas survive many years with their tumor, but alternative treatment approaches are needed for those with refractory or metastatic disease. Signaling by the platelet-derived growth factor tyrosine kinase receptor pathways have been postulated to contribute to the development of gliomas. The authors treated a single patient with refractory, metastatic pilocytic astrocytoma with the tyrosine kinase inhibitor imatinib mesylate and observed marked, transient regression of tumor during treatment. Immunohistochemistry was used to assess expression of reported target genes of imatinib mesylate in this patient's tumor tissue and of the PDGFR in pilocytic astrocytomas from 19 other patients. Immunohistochemistry showed that the patient's tumor cells did not express any of the reported target molecules inhibited by imatinib mesylate. PDGFR expression was detected in tumor vasculative in the panel of 20 tumors, and not in the tumor cells. The authors suggest that the PDGFR-signaling pathway postulated to contribute to the development of gliomas in adults might not contribute to pilocytic astrocytomas in children, and that treatment with imatinib mesylate should be considered in patients with refractory pilocytic astrocytoma.     

Treatment of CML in pediatric patients: Should imatinib mesylate (STI‐571, Gleevec) or allogeneic hematopoietic cell transplant be front‐line therapy?

BACKGROUND: Long-term survival of pediatric patients with chronic myelogenous leukemia (CML) receiving myeloablative hematopoietic stem cell transplantation from fully-matched related and unrelated donors has been reported between 60 and 75%, but is associated with significant morbidity. Imatinib mesylate (STI-571, Gleevec) and reduced intensity conditioning stem cell transplantation (RIC) are two promising new tools that offer potential for decreasing therapy associated morbidity for patients with CML. RESULTS: Large trials have shown significant responses in chronic phase patients treated with imatinib and reasonable but short-lived responses in advanced phase CML. Data from adult studies is beginning to define populations likely to progress or have prolonged responses to imatinib, and some adult treatment paradigms are moving toward reserving transplantation until patients are at risk of failure with imatinib. Early trials of RIC transplantation in CML show decreased transplant related morbidity with efficacy similar to conventional transplantation, but the approach has yet to be verified in phase III studies. Data in pediatric patients with imatinib and RIC transplantation is limited. CONCLUSIONS: Studies with imatinib are underway in pediatrics, but whether pediatric dosing schemes will lead to outcomes similar to adults is unknown. Because HLA-matched myeloablative transplantation offers a high rate of cure in the pediatric population, clinical studies assessing the role of imatinib mesylate and RIC transplantation should be planned carefully in order to avoid sub-optimal outcomes.     

Lack of response of a metastatic renal perivascular epithelial cell tumor (PEComa) to successive courses of DTIC based-therapy and imatinib mesylate

An 11 year-old girl presented with two large abdominal masses in the left flank and epigastrium and left supraclavicular lymphadenopathy. Subsequent investigations led to the diagnosis of metastatic perivascular epithelioid cell tumor (PEComa) arising from the left kidney. Effective treatment for this rare tumor is not yet known. The tumor did not respond to an initial treatment of two cycles of a dacarbazine (DTIC) based regimen. She was placed on a trial of imatinib mesylate based on tumor expression of c-KIT, a tyrosine kinase targeted by this drug. This report highlights the first documented case of the use of imatinib for PEComa. Lack of response and adverse effects of the drug required discontinuation of therapy.     

Treatment and biology of pediatric acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. In the past ALL was intractable but now the survival probability is as high as 80–90%. Improved supportive care, treatment stratification based on relapse risk, biological features of leukemic cells, and optimization of treatment regimens by nationwide and international collaboration have contributed to this dramatic improvement. While including traditional risk factors (e.g. age and leukocyte count at diagnosis), the treatment has been modified based on biological characteristics (aneuploidy and translocation) and treatment response (assessed by minimal residual disease). Treatment for pediatric ALL typically consists of induction therapy with steroids, vincristine, and asparaginase with or without anthracycline, followed by multi‐agent consolidation including high‐dose methotrexate and re‐induction therapy. After consolidation, less intensive maintenance therapy is required for 1–2 years to maintain event‐free survival. Recently, using advanced genomic analysis technology, novel sentinel genomic alterations that may provide more precise stratification or therapeutic targets, were identified. Moreover, in the last decade germline variations have been recognized as similarly important contributors to understanding the etiology and sensitivity of ALL to treatment. A more individualized approach based on genomic features (somatic and germline) and treatment response, the introduction of newly developed agents such as molecular targeted drugs or immunotherapy, and social support including long‐term follow up are required for further improvement.     

Detection of orphan receptor tyrosine kinase (ROR-1) expression in Egyptian pediatric acute lymphoblastic leukemia

Receptor tyrosine kinases, a group of tumor-associated antigens, were introduced as targets for cancer intervention strategies. The human orphan receptor tyrosine kinase-1 (ROR-1) is a member of this family. Overexpression of ROR1 has been reported in B-cell chronic lymphocytic leukemia. The aim of this study was to detect the expression profile of ROR1 in 54 pediatric acute lymphoblastic leukemia (ALL) patients. ROR1 was overexpressed in ALL as the ROR1/ β-actin ratio was higher in ALL children than in control group (P = 0.024). ROR1 is a potential tool for targeted immunotherapy in pediatric ALL patients.     

BIM基因与儿童急性淋巴细胞白血病对糖皮质激素耐药的相关性

急性淋巴细胞白血病(ALL)是儿童时期最常见的恶性血液系统疾病。糖皮质激素作为ALL化疗方案中的主要用药,可通过多种途径诱导白血病细胞的凋亡,但仍有约10%的儿童ALL对糖皮质激素不敏感。研究发现糖皮质激素通过上调BIM基因表达介导ALL细胞的凋亡,BIM基因与儿童ALL对糖皮质激素耐药有关。本综述概括了近年关于儿童急性淋巴细胞白血病对糖皮质激素耐药相关研究,主要包括BIM基因及其表达产物在该过程中的作用。     

The geldanamycin derivative 17-AAG decreases VEGF secretion and leukemia growth support by trisomy 8 myelodysplastic syndrome bone marrow stromal cells

Stromal cells from a child with constitutional trisomy 8 who developed myelodysplastic syndrome (MDS) were found to produce abnormal levels of various cytokines, including VEGF, and supported the growth of leukemic cells in co-culture assays. This study shows that the geldanamycin derivative 17-AAG effectively reduces the VEGF expression by MDS stromal cells. In co-culture experiments this agent also blocks the ability of the MDS stromal cells to stimulate the growth of leukemic cells. These data provide important initial evidence for the effect of 17-AAG on the marrow microenvironment and its potential use in the treatment of MDS and leukemia.     

In vitro drug sensitivity and apoptosis induction in newly diagnosed pediatric acute lymphoblastic leukemia: correlation with overall survival

The present study looked for any associations between in vitro drug sensitivity and clinical outcome in pediatric acute lymphoblastic leukemia (ALL) with the standard drugs used for leukemia therapy. A total of 72 samples were analyzed. In vitro sensitivity to drugs was tested by a methylthiazol-tetrazolium assay in 6 serial fold dilutions. Apoptosis was determined by TUNEL assay and apoptotic index was calculated for each sample. Patients sensitive to prednisone, asparginase, vincristine, and 6-mercapto purine had higher overall survival compared to patients whose tumor cells were resistant to these drugs (p < .01). For the other drugs tested, overall survival did not vary from that of the resistant patients. For doxorubicin, asparginase, vincristine, prednisone combination sensitivity, there was a significant worsening of prognosis from the extremely sensitive patients through an intermediate sensitive group to a most resistant group. The present study thus shows that in vitro drug-sensitivity testing provides significant prognostic information in childhood ALL.     

Imatinib mesylate: an attractive alternative in young children with large, surgically challenging dermatofibrosarcoma protuberans

To document the clinical activity of imatinib mesyalte in a child with a dermatofibrosarcoma protuberans (DFSP). An 18-month-old girl presented with a large extremity DFSP. As surgical resection would have caused unacceptable functional defects, imatinib mesylate was administered to induce tumor reduction and or stabilization. After 23 weeks of therapy, magnetic resonance imaging (MRI) of the tumor showed a reduction in the subcutaneous thickness in the transverse plane. The drug was tolerated well without any adverse reactions. Imatinib mesylate offers a non-surgical alternative for the treatment of large DFSP in children.     

雷帕霉素逆转急性淋巴细胞白血病CEM-C1细胞对糖皮质激素耐药的研究

目的探讨雷帕霉素是否可以逆转地塞米松(DEX)耐药的急性T淋巴细胞白血病(T-ALL)细胞株CEM-C1细胞的GC耐药性。方法以儿童T-ALL GC耐药株CEM-C1和GC敏感株CEM-C7为研究对象,MTT法检测不同浓度(1 000 ng/ml、100 ng/ml、10 ng/ml、1 ng/ml和0.1 ng/ml)雷帕霉素及其联合1μmol/L地塞米松(DEX)作用后对细胞增殖的影响;细胞离心甩片瑞氏染色法观察细胞形态学变化;Annexin V/PI染色法检测对细胞凋亡的影响;PI染色法检测细胞周期改变。结果①不同浓度雷帕霉素作用于CEM-C1和CEM-C7细胞,对细胞生长的抑制作用均呈时间和浓度依赖性,联合应用1μmol/L DEX后,这一生长抑制作用显著增强,24 h IC50约为100 ng/ml。②以终浓度100 ng/ml雷帕霉素作用于CEM-C1和CEM-C7细胞18、24及48 h,细胞形态学与对照相比均无明显变化;Annexin V-PI双染流式细胞术检测均未见明显凋亡;细胞周期测定发现两种细胞均阻滞于G1期,S期细胞比例均明显降低。③以终浓度100 ng/ml雷帕霉素联合1μmol/L DEX作用于CEM-C1细胞后,瑞氏染色发现CEM-C1细胞于24 h出现细胞核改变,48 h出现明显凋亡;Annexin V/PI双染细胞凋亡检测显示细胞凋亡率较单用雷帕霉素及DEX时显著增加,18 h时早期凋亡细胞开始增多,24 h时最为明显;细胞周期测定显示S期细胞比率较单用雷帕霉素时显著降低,而G1期细胞显著增多。结论雷帕霉素能够逆转CEM-C1细胞对GC的耐药性,其机制有待进一步深入研究。     

IN VITRO DRUG SENSITIVITY AND APOPTOSIS INDUCTION IN NEWLY DIAGNOSED PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA: Correlation with Overall Survival

The present study looked for any associations between in vitro drug sensitivity and clinical outcome in pediatric acute lymphoblastic leukemia (ALL) with the standard drugs used for leukemia therapy. A total of 72 samples were analyzed. In vitro sensitivity to drugs was tested by a methyl-thiazol-tetrazolium assay in 6 serial fold dilutions. Apoptosis was determined by TUNEL assay and apoptotic index was calculated for each sample. Patients sensitive to prednisone, asparginase, vincristine, and 6-mercapto purine had higher overall survival compared to patients whose tumor cells were resistant to these drugs (p <. 01). For the other drugs tested, overall survival did not vary from that of the resistant patients. For doxorubicin, asparginase, vincristine, prednisone combination sensitivity, there was a significant worsening of prognosis from the extremely sensitive patients through an intermediate sensitive group to a most resistant group. The present study thus shows that in vitro drug-sensitivity testing provides significant prognostic information in childhood ALL.     

In Vitro Induction of Lymphokine-Activated Killer (Lak) Activity in Patients with Neuroblastoma

Therapy of disseminated neuroblastoma remains an unsolved problem in pediatric oncology. Therefore, new therapeutic approaches have to be developed for this malignancy. In this paper, we investigated the possibility of the in vitro generation and expansion of lymphokine-activated killer (LAK) cells in patients with disseminated neuroblastoma. Although the patients had very low Natural Killer (NK) activity, it was possible to induce LAK activity in peripheral mononuclear lymphocytes (PMNC) by incubation with Interleukin-2 (IL-2). Moreover, the PMNCs could be expanded up to 50-fold in the presence of Interleukin-2 while maintaining or even increasing their LAK activity. The target cells were neuroblastoma cell lines and, in one case, autologous neuroblastoma cells. Additionally, it was possible to induce LAK cell activity against autologous neuroblastoma cells in bone marrow-derived mononuclear cells.     

Differential mRNA expression of glucocorticoid receptor alpha and beta is associated with glucocorticoid sensitivity of acute lymphoblastic leukemia in children

BACKGROUND: Sensitivity of leukemic blasts to glucocorticoid is one of the important prognostic factors for pediatric acute lymphoblastic leukemia (ALL). Alternative splicing of the glucocorticoid receptor (GR) gene results in several isoforms. We examined an association of the expression pattern of GR isoforms in leukemic blasts with their sensitivity to glucocorticoid in childhood ALL. PROCEDURES: The relative mRNA expression of GRalpha, GRbeta, GRgamma, and GR-P was determined in leukemic blasts of 23 childhood ALL at initial presentation and of 14 ALL cell lines by quantitative RT-PCR. Glucocorticoid-sensitivity of leukemic blasts was determined by counting apoptotic cells with flow cytometry after 6-hr incubation with prednisolone (PSL). RESULTS: The relative expression of GRalpha mRNA was significantly higher in blasts of B-precursor ALL than those of others (13.6 vs. 2.24, P = 0.015), while those of GRalpha, GRbeta, and GRgamma showed no difference. GRbeta/GRalpha ratios were significantly lower in B-precursor ALL than others (0.80 vs. 4.64, P = 0.035). The proportions of apoptotic cells after PSL exposure were inversely correlated with the GRbeta/GRalpha ratios in ALL cell lines (r = -0.612, P = 0.020). PSL administration induced apoptosis efficiently in leukemic blasts with low GRbeta/GRalpha ratios compared with those of high ratios (cell lines: 4.93% vs. 1.90%, P = 0.013, primary leukemia: 11.7% vs. 3.6%, P = 0.037). CONCLUSIONS: The amounts of GR isoform mRNA in leukemic blasts were closely correlated with sensitivity to glucocorticoid exposure. The mRNA expression pattern of GR isoforms at initial presentation may provide valuable information for prognosis in children with newly diagnosed ALL.     

Fine Needle Aspiration Cytology (FNAC) of the Testes in Childhood Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma: Preliminary Report

Eighteen patients with childhood acute lymphoblastic (ALL) or non-Hodgkin's lymphoma (NHL) in remission and 2 patients with ALL in suspected testicular relapses were studied by testicular fine needle aspiration cytology (FNAC). Well-preserved testicular cells, both singly and in small clusters, were considered indicative of an adequate aspiration. Of 18 patients in remission, 17 had at least one adequate sample from each testis and one showed evidence of leukemic infiltrate. None of these patients experienced a relapse during a median follow up of 4 years. In 2 other patients with clinically suspected testicular relapses, the smears from fine needle aspirates contained numerous malignant lymphoid cells that could be readily distinguished from seminiferous tubular cells. The observations indicate that FNAC is a promising new approach to study testicular conditions in childhood ALL and NHL. A larger prospective study and accumulation of additional follow-up data is required before a definitive evaluation of the technique can be made.