Reproductive history, infertility treatment, and the risk of acute leukemia in children with down syndrome: a report from the Children's Oncology Group

BACKGROUND: Children with Down syndrome (DS) have from 10 to 20 times the risk of developing acute leukemia than the general pediatric population. There is mixed evidence for associations between reproductive history or infertility and acute leukemia among children without DS. METHODS: The authors conducted a case-control study of acute leukemia among children with DS to investigate possible risk factors in this population. From 1997 to 2002, 158 children aged <20 years with DS who had a diagnosis of acute leukemia (97 children with acute lymphoblastic leukemia [ALL] and 61 children with acute myeloid leukemia [AML]) were enrolled at Children's Oncology Group (COG) institutions. Controls with DS (n = 173) were selected from the cases' primary care clinic and frequency matched to cases on age. Telephone interviews were conducted with mothers of cases and controls assessing reproductive history, infertility, and infertility treatment. RESULTS: Null results were observed overall and by subtype for reproductive factors, including previous pregnancy outcomes and contraceptive use, and for most infertility outcomes. There was an increased risk of AML among children with DS whose parents had ever tried for >/=1 year to become pregnant (odds ratio [OR], 2.22; 95% confidence interval [95% CI], 1.14-4.33). A 1-year increase in maternal age also was associated with AML (OR, 1.06; 95% CI, 1.01-1.12). CONCLUSIONS: Although the questionnaire was limited in this area, the results suggested that the risk for AML may be raised in children with DS because of infertility. In that the risk of infertility, along with having a child with DS, increase with age, these results warrant more research.     

Comparative genomic hybridization and BUB1B mutation analyses in childhood cancers associated with mosaic variegated aneuploidy syndrome

We previously demonstrated that constitutional BUB1B mutations cause mosaic variegated aneuploidy, a condition characterized by constitutional aneuploidies and childhood cancer predisposition. To further investigate the role of BUB1B in cancer predisposition we performed comparative genomic hybridization analysis in an embryonal rhabdomyosarcoma from an MVA case with biallelic BUB1B mutations, revealing aneuploidies typical of sporadic E-RMS, with gain of chromosomes 3, 8, 13 and loss of chromosomes 9, 14, X. To investigate whether somatic BUB1B mutations occur in sporadic childhood cancers we screened 30 Wilms tumours, 10 acute lymphoblastic leukemias, nine rhabdomyosarcomas and 11 rhabdomyosarcoma cell lines for BUB1B mutations. We identified seven exonic and six intronic variants. Six of the exonic variants were synonymous and one resulted in a non-synonymous conservative missense alteration that was also present in a control. These data suggest that the genetic progression in rhabdomyosarcoma from MVA and non-MVA cases may be similar, but that somatic BUB1B mutations are unlikely to be common in sporadic childhood cancers known to be associated with MVA.     

Centrosome amplification induced by hydroxyurea leads to aneuploidy in pRB deficient human and mouse fibroblasts

Alterations in the number and/or morphology of centrosomes are frequently observed in human tumours. However, it is still debated if a direct link between supernumerary centrosomes and tumorigenesis exists and if centrosome amplification could directly cause aneuploidy. Here, we report that hydroxyurea treatment induced centrosome amplification in both human fibroblasts expressing the HPV16 -E6-E7 oncoproteins, which act principally by targeting p53 and pRB, respectively, and in conditional pRB deficient mouse fibroblasts. Following hydroxyurea removal both normal and p53 deficient human fibroblasts arrested. On the contrary pRB deficient fibroblasts entered the cell cycle generating aneuploid cells. Also the majority of conditional Rb deficient MEFs showed supernumerary centrosomes and aneuploid cells which increased over time. Finally, our results suggest that pRB dysfunction both in human and murine fibroblasts transiently arrested in G1/S by hydroxyurea allows centrosomes amplification, in the absence of DNA synthesis, that in turn could drive aneuploidy.     

Cancer incidence of persons with Down syndrome in Finland: a population-based study

Individuals with Down syndrome (DS) have a predisposition to leukaemia and testicular cancer, but data on the incidence of cancers are yet sparse. A cohort of 3,581 persons with DS was identified from a National Registry of Finnish persons with intellectual disability collected between 1978 and 1986 and followed-up for cancer incidence until 2002. Standardised incidence ratios (SIRs) were defined as ratios of observed number of cancer cases to those expected from the national cancer incidence rates, by age and sex. The overall cancer risk was equal to that of the general population, but a significantly high risk of leukaemia (SIR 10.5, CI 95% 6.6-15.8) and testicular cancer (SIR4.8, CI 95% 1.8-10.4) was found.     

Antigenic and chromosomal changes in thymus and spleen of Balb/Mo mice during leukemogenesis

The Balb/Mo mouse strain carries a single copy of the germ line integrated Moloney leukemia virus (M-MuLV) and shows a high leukemia frequency. According to the clinical manifestations lymphomas can be divided into two major categories. In one type the thymus appears to be the primary site for lymphoma development. The second type is dominated by the generalized enlargement of spleen and lymph nodes. Individual lymphomas differ in the cell surface expression of Thy 1.2 MCSA (designated operationally as the M-MuLV-determined cell surface antigen) and viral p30 antigens. In addition, spleen and thymus of the same leukemic animal often differ antigenically. The karyotype of cells from enlarged organs in diploid or shows trisomy of chromosomes 15. Lymphomas developing in Balb/Mo mice are thus heterogeneous with regard to clinical manifestations, cell surface antigens and karyotype and, in this respect, do not differ from lymphomas arising after the inoculation of exogenous M-MuLV. Amplification of the M-MuLV genome in young Balb/Mo mice is not accompanied by the appearance of MCSA on thymus cells. Still, 32% of lymphomas are MCSA positive. The results suggest that MCSA is related to a virus activated in a minority of Balb/Mo mice during the late phase of leukemogenesis.     

Low-dose cytarabine: chromosomal findings suggesting its cytostatic as well as differentiating effect

Chromosome analysis of bone marrow cells of two leukemic patients treated with low-dose cytarabine were performed before initiation of therapy and after a complete remission had been achieved. Results suggest that low-dose cytarabine had a mainly cytostatic effect in one patient and a more differentiating effect in the other.     

Multiplex ligation-dependent probe amplification for detection of chromosomal abnormalities in myelodysplastic syndrome and acute myeloid leukemia

Current strategies for detecting chromosome abnormalities in MDS/AML include FISH or traditional cytogenetics. MLPA detects abnormalities in multiple loci simultaneously, with higher resolution and throughput. Peripheral blood from 50 healthy subjects was used to establish probe-specific reference ranges, increasing MLPA sensitivity and specificity. MLPA was then performed on 110 FISH-tested blood or bone marrow samples from suspected leukemia patients. Our novel MLPA analysis system combined maximum stringency with sensitive detection of low-frequency abnormalities. Accuracy/specificity of MLPA were excellent compared to FISH. Our MLPA analysis/interpretation method provides a clinically robust, high-throughput, high-resolution option for detection of abnormalities associated with MDS/AML.     

The somnolence syndrome in leukemic children following reduced daily dose fractions of cranial radiation

A group of children with acute lymphocytic leukemia was studied to investigate if a reduction in daily dose fraction of cranial radiation would reduce the incidence of somnolence syndrome. Thirty-one evaluable patients received 100 rad X 18 cranial radiation therapy. Sixty-six similar evaluable patients were given 180 rad X 10. Both groups received the same chemotherapy including intrathecal methotrexate. Clinically detectable somnolence appeared in 58% of ech group without significant differences in the overall frequency or severity of somnolence (p greater than 0.5). This study failed to substantiate a radiation dose fraction size dependence for somnolence syndrome in children with acute lymphocytic leukemia.     

Specific chromosomal changes in patients with acute nonlymphocytic leukemia from India

We analysed forty consecutive patients with acute nonlymphocytic leukemia (ANLL) using methotrexate cell synchronization and 24 h-unstimulated cultures of bone marrow cells to determine the incidence of chromosomal aberrations and the association of specific anomalies with FAB morphological subtypes, in an Indian population. All patients demonstrated an abnormal karyotypic pattern. The specific chromosomal changes viz., t(9;22), t(8;21), t(15;17), t/del(11q), 12p- were found in M 1(3/5), M2(8/15), M3(8/8), M4(1/1) M5(2/4) and M2Ba(1/1) (M2 with Basophilia) patients. Abnormalities of 11q were also noted in two M2 patients showing monocytic involvement. A translocation involving chromosomes 6 and 9 was seen in one patient with M1 and two patients with M2. An inv(16) was observed in M1 (one case), M2 (two cases) and M6 (one case). A del(16) was noted in an M4 case. Although t(9;22) is frequently associated with M1 patients, it was also detected in M2 (two patients) and M4 (one patient). Among all the FAB specific anomalies described above, t(8;21) and t(15;17) were observed only in M2 and M3 patients, respectively. Interestingly, one M2 patient had two independent clones, one with t(8;21) and t(9;11). Deletion or translocation involving 11q was found in a Ph positive M4 patient. New structural rearrangements such as t(1;7) (q32;q36) in association with t(8;21), and t(14;22) (q32;q11) in association with del(11)(q23) were detected in a M2 and a M5 patient, respectively. In conclusion, our studies have revealed that the incidence of FAB specific abnormalities viz., t(8;21); t(15;17), t(9;22), t/del(11q) and also other recurrent anomalies viz., -7/7q-, +8 is much higher in our patients, as compared with other countries. This difference may be attributed to the influence of differential environmental exposure to unknown carcinogenic agents.     

Evolution of multiple cytogenetic clones and leukemic transformation in a case of myelodysplastic syndrome

The cytogenetic follow-up of a case of refractory anemia with excess of blasts (RAEB) that rapidly evolved to acute myeloblastic leukemia (Ml-FAB type) is described. Bone marrow analysis at presentation revealed two chromosomally abnormal clones that shared an interstitial deletion of the long arm of chromosome 5 (5q−) and a terminal deletion of the short arm of chromosome 12 (12p-), but that differed from one another in the localization of a very similar segment of chromosome 17 (i.e. 17q11−12qter) on two clearly distinct karyotypic sites: 2q37 and 17q25. Fourteen percent of the metaphases examined bore the 2q+ marker and 38% the 17q+ marker; the remaining cells had a normal karyotype. A second study carried out 4 months later, at onset of the acute phase, revealed that the clone with normal karyotype had almost completely disappeared and that there had been an inversion in the ratio of the two abnormal cell populations. In the final study, made 1 month before death, the cells with t(2;17) had totally effaced the other clone. These findings seem to indicate that, among the karyotypic changes that occurred in an original clone with 5q− and 12p−, only the t(2;17) could have played a crucial role in the final leukemic transformation.     

骨髓增生异常综合征原癌基因Bmi-1表达的检测

目的：检测原癌基因Bmil在骨髓增生异常综合征（myelodysplastic syndrome,MDS）患者中的表达,探讨其在MDS中的临床意义。方法：选择201009—04—2013—01-10在泰山医学院附属医院就诊的69例MDS患者及30例非恶性血液病患者骨髓标本,应用SYBRGreen相对定量RT—PCR方法,进行Bmi-1基因的检测。结果：Bmi—1基因在非恶性血液病患者中无表达。在69倒MDS患者中均有表达（2．28±0．84）,且表达水平明显高于非恶性血液病患者组,t=14．787,P〈0．001。其中,RA组明显高于对照组（P〈0．001）,RAEB组明显高于RA组,P=0．001。Bmil基因高表达组CD34＋CD38-CD123＋／CD34＋为（10．77±5．51）％,低表达组为（4．65±3．36）％,差异有统计学意义,t=5．741,P=0．037。Bmi-1基因高表达组,骨髓原始细胞≥5％的病例数（17例）高于低表达组（14例）,χ2=7．057,P=0．012;Bmi1基因高表达组具有预后不良染色体核型的有6例,Bmi-1低表达组仅有3例,但两组间差异无统计学意义,χ2=2．794,P=0．144。结论：MDS患者的骨髓单个核细胞中均存在Bmi-1基因不同程度的表达升高,为MDS的诊断及预后的评价提供了新的方向。     

Richter syndrome: pathogenesis and management

Richter syndrome (RS) is the development of an aggressive lymphoma in patients with a previous or concomitant diagnosis of chronic lymphocytic leukemia (CLL). The incidence rate RS is ~0.5% per year of observation. Two biomarkers (NOTCH1 mutations and subset 8 configuration of the B-cell receptor) may help identifying CLL patients at risk of RS to be considered for close monitoring and a careful biopsy policy. In the presence of clinical features suspicious of RS, diagnosis of transformation and choice of the site of biopsy may take advantage of fluorine 18 fluorodeoxyglucose (¹⁸FDG) positron emission tomography (PET)/computed tomography (CT). Molecular lesions of regulators of tumor suppression (TP53), cell cycle (CDKN2A), and cell proliferation (NOTCH1, MYC) overall account for ~90% of RS and may be responsible for the aggressive clinical phenotype observed in this disease because of the combined effect of chemoresistance and rapid disease kinetics. The prognosis of RS is generally highly unfavorable. However, the pattern of survival is not homogeneous and the most important prognostic factor is the clonal relationship between the CLL and the aggressive lymphoma clones. Rituximab-containing polychemotherapy represents the backbone for induction treatment in RS. Younger patients who respond to induction therapy should be offered stem cell transplant (SCT) to prolong survival.     

Severe toxicity following induction chemotherapy for acute myelogenous leukemia in a patient with Werner's syndrome

Werner's syndrome is an autosomal recessive disorder resulting in premature aging. Most patients die in their fifth decade from malignancies or heart disease. The gene for Werner's syndrome (WRN) encodes a recQ helicase. Cells from patients with Werner's syndrome have increased sensitivity to DNA-damaging drugs in vitro. Here we present a patient with Werner's syndrome who developed severe chemotherapy-induced toxicity during treatment for acute myelogenous leukemia. We propose that lack of WRN resulted in increased sensitivity of the patient's cells to the toxicity of chemotherapy.     

Spontaneous abnormalities in normal fibroblasts from patients with Li-Fraumeni cancer syndrome: aneuploidy and immortalization

Families of patients with the Li-Fraumeni cancer syndrome have an inherited pattern of sarcomas and various other types of cancers that follow a dominant mode of transmission, an early age of onset, and exhibit multiple primary tumors. As soft tissue sarcomas (including fibrosarcomas) are frequently observed with this syndrome, the in vitro growth characteristics of fibroblasts derived from skin biopsies of Li-Fraumeni syndrome patients were studied. Control fibroblasts maintained a normal morphology and eventually senesced in culture. Fibroblasts from seven of eight affected individuals developed changes in morphology, anchorage-independent growth, and chromosomal abnormalities. In a fashion similar to that of fibroblasts from normal donors they underwent a growth crisis during which their growth was slow, but they continued to grow past the point at which control samples had stopped dividing (35 population doublings). Fibroblasts from Li-Fraumeni cancer patients escape senescence, growing well beyond 35 population doublings with growth rates similar to early-passage cells. Patient fibroblasts maintain the morphology of a transformed cell but remain nontumorigenic in nude mice. These observations of the behavior of fibroblasts from patients with the Li-Fraumeni syndrome may have predictive value for the determination of gene carriers within these families who are at high risk of cancer.     

Intensive chemotherapy for acute non-lymphoblastic leukemia after primary myelodysplastic syndrome

Twenty-five patients with a primary myelodysplastic syndrome (MDS) transformed into acute non-lymphoblastic leukaemia (ANL) were treated with intensive chemotherapy. A complete remission (CR) was obtained in six patients (24 per cent). In five of these six patients two courses of chemotherapy were needed to achieve CR. In eight patients chemotherapy cleared the bone marrow of blasts, but the aplasia was fatal. A partial effect on bone marrow blasts was seen in four patients and no effect in another six. Eleven patients (44 per cent) died from the consequences of chemotherapy-induced cytopenia. A short interval between MDS and transformation into ANL was associated with a better chance of achieving complete remission. Age, karyotype, type of MDS, peripheral blood or bone marrow findings had no influence on the result of chemotherapy. The median survival from start of treatment was 5 months (range 0.5-24 months). In the patients who achieved a CR, the median duration of the remission was 7 months (range 3-12 months). The poor response rate, the short duration of the remissions and the high treatment-related mortality suggest that current intensive anti-leukemic chemotherapy in ANL after primary MDS is of limited benefit.     

Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis

Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia to aggressive lymphoma. We explored intraclonal diversification (ID) of immunoglobulin genes in order to (i) follow the evolutionary history of the RS clone (ii) compare the role of ID in clonally related RS vs. clonally unrelated cases. Most (10/11, 90.9%) clonally related RS stem from the predominant clone observed at CLL diagnosis. One single RS had a transformation pattern compatible with sequential evolution from a secondary CLL subclone. Once RS transformation had occurred, all secondary CLL subclones disappeared and were substituted by the dominant RS clone with its own descendants. These observations suggest that genetic lesions associated with RS transformation are acquired by a cell belonging to the original CLL clone, rather than being progressively accumulated by later CLL subclones. Accordingly, most (9/11, 81.1%) clonally related RS harbored a genetic lesion disrupting TP53 that was already present, though at subclonal levels, in 5/11 (45.5%) samples of the paired CLL phase. A fraction of clonally related RS switched off ID (4/11, 36.4%) or reduced the levels of ID (5/11, 45.4%) at transformation. Conversely, all clonally unrelated RS harbored ID and were characterized by a significantly higher mutation frequency compared to clonally related RS (median: 1.18 × 10(-3) vs. 0.13 × 10(-3); p =0.002). These data indicate that (i) clonally related RS stems from a cell that is already present within the initial CLL clone and (ii) clonally unrelated and clonally related RS are biologically distinct disorders also in terms of antigen affinity maturation.     

急性淋巴细胞白血病化疗后可逆性后部白质脑病综合征一例并文献复习

目的 探讨急性淋巴细胞白血病巩固化疗后可逆性后部白质脑病综合征(RPLS)的临床表现、诊治及其预后情况.方法 回顾分析1例急性淋巴细胞白血病患者的临床及影像学资料并结合文献进行复习.结果 该患者主要临床表现为腹胀、反复发热,伴乏力症状,经血常规及骨髓相关检查,诊断为早前B细胞性高危组急性淋巴细胞白血病,经诱导缓解化疗及巩固化疗后患者出现血压增高及神经系统症状,结合影像学检查诊断为RPLS,经积极治疗后完全恢复,影像学表现迅速改善.结论 RPLS可由多种病因产生,临床表现及影像学检查缺乏特异性,一般预后较好,早期作出正确诊治是关键.     

Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on Children's Oncology Group trial A2971: A report from the Children's Oncology Group

BACKGROUND:

Children who are treated for myeloid leukemia associated with Down syndrome (DS) experience superior survival compared with children who have myeloid leukemia without DS. To maintain excellent outcomes while avoiding toxicity, the Children's Oncology Group (COG) conducted the phase 3 trial COG A2971, the first trial solely designed to provide uniform treatment of myeloid leukemia in North American children with DS. A2971 eliminated 2 induction drugs and 3 months of maintenance therapy from the standard‐timing regimen of dexamethasone, cytarabine, 6‐thioguanine, etoposide, and rubidomycin/daunomycin (DCTER) used in the previous study (Children's Cancer Group [CCG] 2891).

METHODS:

COG A2971 was a multi‐institutional, nonrandomized, clinical trial that enrolled 132 patients who had DS with either acute myeloid leukemia (n = 91) or myelodysplastic syndrome (n = 41).

RESULTS:

The median follow‐up was 4.8 years (range, 0.8‐8.6 years), the median age at diagnosis was 1.7 years (range, 0.3‐13.6 years), and the median white blood cell count was 6200/μL (range, 900‐164,900/μL). The remission rate (92.7% ± 6%) was similar to that reported in the CCG 2891 study (91.3% ± 5%; P = .679). The 5‐year event free survival (EFS) rate was 79% ± 7% (vs 77% ± 7% in CCG 2891; P = .589), the disease‐free survival (DFS) rate was 89% ± 6% (vs 85% ± 6% in CCG 2891; P = .337), and the overall survival rate was 84% ± 6% (vs 79% ± 7% in CCG 2891; P = .302). Induction day‐14 bone marrow response trended toward a more favorable outcome (EFS: P = .12). Age >4 years was an adverse risk factor (5‐year EFS rate: 33% ± 38% for children aged >4 years [median, 8.5 years; n = 6] vs 81% ± 7% for children ages 0‐4 years [median, 1.7 years; n = 126]; P = .001).

CONCLUSIONS:

The COG A2971 trial reduced the chemotherapy dose and maintained survival to that achieved by the CCG 2891 trial in children who had myeloid leukemia associated with DS. Cancer 2012. © 2012 American Cancer Society.