Childhood Hematological Malignancies Research Articles

Haploidentical Hematopoietic Stem Cell Transplantation without In Vitro T Cell Depletion for Treatment of Hematological Malignancies in Children.

Objective: To evaluate the efficacy and safety of haploidentical hematopoietic stem cell transplantation (HCT) for children with donors from family members.Patients and methods: Forty-two children under fourteen years old with hematologic malignancies underwent haploidentical HCT. The outcome was analyzed.Results: Four (9.5%) of the forty-two patients/donor pairs mismatched in one HLA locus, fifteen (35.7%) pairs in two loci and twenty three (54.8%) in three loci. They were followed up for a median of 612 (40–1779) days. All patients achieved stable engraftment. The cumulative incidence of acute graft-versus-host disease (GVHD) grade 2–4 was 57.2%, and that of grade 3–4 was 13.8%. The cumulative incidence of total and extensive chronic GVHD was 56.7% and 29.5%, respectively. The probability of leukemia-free survival was 65.1% in standard-risk group and 49.6% in high-risk group. Fourteen patients died, four from infection, six from relapse of leukemia, two from heart failure, one from severe acute GVHD, and one from lymphoproliferative disorders. The probability of relapse was 13.8% at 1 year and 27.9% at 2 year after transplantation.Conclusion: The results in this study encourage extending the haploidentical HCT without T-cell depletion to children with an indication for transplantation.

Obesity in Survivors of Childhood Acute Lymphoblastic Leukemia and Lymphoma

We evaluated the long-term effects of treatment on the body mass index (BMI) of children with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma who received one of three CNS-directed therapies: intrathecal methotrexate with intravenous high-dose methotrexate (1 g/m2), intrathecal methotrexate with 18 Gy cranial radiation, or intrathecal methotrexate with 24 Gy cranial radiation. Between 1979 and 1984, 456 children with newly diagnosed ALL and lymphoma were enrolled onto a single protocol at St Jude Children's Research Hospital (Memphis, TN). The heights and weights of 422 of the children were measured at diagnosis, during treatment, at the end of therapy, and approximately every 6 to 12 months thereafter. Patients who had attained their adult height at the time of analysis (n = 248) were placed in weight categories based on their BMI, BMI percentile, or weight-for-length percentile depending on age. The overall percentage of survivors who were overweight or obese approximated rates prevalent in the general population of the United States. Young age (< 6 years) and overweight/obesity at diagnosis were the best predictors of obesity at adult height. The rate of BMI increase did not differ significantly between children who received radiation and those who did not, nor between patients who received 18 or 24 Gy of cranial radiation. BMI weight category at diagnosis, rather than type of CNS treatment received, predicted adult weight in long-term survivors of childhood hematologic malignancies.

Survival following relapse in childhood haematological malignancies diagnosed in 1974-2003 in Yorkshire, UK.

We examined population-based information on relapsed childhood haematological cancers, investigating factors that might influence both overall survival and survival following relapse among the 1177 children (0–14 years) diagnosed with a haematological malignancy in Yorkshire from 1974 to 2003, of whom 342 (29%) relapsed at least once. Leukaemia patients from more deprived areas were significantly less likely to relapse (odds ratio=0.54, 95% confidence interval 0.32–0.93 for most deprived quintile vs least deprived quintile; Ptrend=0.06), especially those with acute myeloid leukaemia (P=0.04). Neither ethnic group nor distance to the main treatment centre was associated with risk of relapse. Overall, patients who relapsed at least once had 5-year survival rates of 46% (41–51%) compared with 79% (76–81%) of those who did not. Five-year survival rates from the time of first relapse increased from 20% in 1974–1983 to 45% in 1984–2003. Length of first remission was a strong predictor of survival for leukaemia with a 46% reduced risk of death for every additional year of event-free survival. Of children who experienced a relapse, 46% survived at least 5 years, whereas just under half of patients survived 5 years beyond disease recurrence. This provides a baseline for future comparisons and demonstrates that relapsed childhood cancer need not imply a poor outcome.

Methods of minimal residual disease (MRD) detection in childhood haematological malignancies

The appropriate management of haematological disorders must rely on a precise and long-term monitoring of the patient's response to chemotherapy and radiotherapy. Clinical data are not sufficient and that is why in the last decade it became the most important to improve the knowledge of haematological diseases on the basis of molecular techniques and molecular markers. The presence of residual malignant cells among normal cells is termed minimal residual disease (MRD). Nowadays a great progress has been made in the treatment of malignant diseases and in the development of reliable molecular techniques, which are characterised by high sensitivity (10-3- 10-6) and ability to distinguish between normal and malignant cells at diagnosis and during follow-up. Especially, MRD data based on quantitative analysis (RQ-PCR, RT-RQ-PCR) appear to be crucial for appropriate evaluation of treatment response in many haematological malignancies. Implementation of standardized approaches for MRD assessment into routine molecular diagnostics available in all oncohaematological centres should be regarded nowadays a crucial point in further MRD study development.

Prevalence of Norwegian patients diagnosed with childhood cancer, their working ability and need of health insurance benefits

The object of this study was in a population-based material to investigate the prevalence of patients diagnosed with childhood cancer, and compared to the general population to assess working ability, yearly income and need for health insurance benefits in patients surviving at least five years after treatment for childhood CNS tumours or hematological malignancies. During the period January 1, 1970 to December 31, 2002 the prevalence in the Norwegian population of patients diagnosed with any childhood cancer increased from 12.2 (473/3 888 305) to 65.1 (2944/4 524 066) per 100 000 population. The proportion of survivors in need of any health insurance benefit was for CNS tumours 47.1% and for hematological malignancies 21.0%. The proportion in the age group 16–67 receiving disability pension for CNS tumours was 94/454 (20.7%) compared to 21/575 (3.7%) for patients treated for hematological malignancies (p <0.001). Of patients given radiotherapy 25/70 (35.7%) received disability pension, compared to 90/959 (9.4%) in unirradiated patients, p <0.001. Yearly income and working ability was particularly low for CNS tumour survivors.This study illustrates loss of working capability associated with pediatric cancer and treatment and long-term requirement of health insurance benefits.

Interferon therapy for giant cell tumor of bone

Purpose of reviewInhibition of key regulators of angiogenesis has gained momentum as a promising approach for the treatment of vascular tumors. Antitumor activity of interferons has been observed in childhood hemangiomas, hematologic malignancies and giant cell lesions of the mandible. The response

Facial Paralysis as a Presenting Symptom of Leukemia

Facial paralysis may occur as a complication of central nervous system leukemias in children, but it is rarely a presenting symptom. This report describes an 8-month-old child who presented with peripheral facial palsy, failure to thrive, anemia, and otitis media. Antibiotic and steroid treatment led to an improvement in the clinical condition, but not the paralysis. At readmission 3 weeks later, physical examination revealed bluish, firm, palpable masses on the scalp and facial areas, and laboratory and imaging studies confirmed the diagnosis of acute myeloid leukemia. This case should alert physicians to consider hematologic malignancies in children with facial paralysis.

Late Effects and Quality of Life of Survivors of Childhood Hematologic Malignancies Treated Mainly during 80's in Japanese Group Study.

Persons who were treated mainly in 80's were reviewed and assessed for the present status including late effects, school, social life, marital state.Questionaire was sent to individual institutions and answers were returned from physicians or survivors themselves.From 1881 to 1994, there were five clinical protocols in ALL, four in AML, and three in NHL. Registered and surviving numbers were 1,023 and 642 in ALL, 309 and 164 in AML, 200 and 166 in NHL. Of surviving numbers, responded number was 521 in ALL, 142 in AML, 103 in NHL. Of these 1,262 survivors, 128 persons have proven to have some kinds of late effects. Mean age of survivors was 6.7 at the onset of disease and 18.6 at the time of this survey. Questionair was as followings; diagnosis, gender, age, presence or absence of late effects, detail of late effects, and present status. As a result, 128 survivors (male/female; 78/50, ALL; 75, AML; 30, NHL; 23) have 169 items of late effects. The overall incidence of late effects was 13% in ALL and 20% in AML and NHL. There was no difference of incidence between each treatment protocols in ALL.Additionally, 10 persons died with late effects. Of those, the cause of death was as followings; leukoencephalopathy; 3, cardiac toxicity 3, of them, one boy was in remission after completion of chemotherapy and died during running, relapse of primary disease; 1, secondary cancer; 1, measles; one who was in remission at the time of infection, ARDS; one who received stem cell transplantation. The late effects were classified as following categories (sALL/hALL/AML/NHL); hepatic 30(14/7/6/3), cardiac 7 (3/2/0/2), central nervous system 33 (13/6/6/8), short stature 29 (14/6/5/4), gonad 16 (3/4/9/0), thyroid 4 (1/1/2/0), renal 8 (3/1/2/2), pulmonary 6 (1/2/2/1), cGVHD 4 (1/2/1/0), secondary cancer 6 (4/0/0/2), others 26 (5/3/11/7).The number of each category of late effects was so small, that decreasing tendency was not apparent with time course of this studying period except hepatic disorder, which is related to post-transfusion hepatitis C. CNS disorders include leukoencephalopathy, mental retardation, epilepsy, and visual disturbances. More than one half of short stature was found in the standard risk ALL. Most of gonad dysfunction, persistent alopecia, pulmonary and renal disorders were related to stem cell transplantation. Psychological or mental disturbance, which are related school troubles, was also observed. Second cancer found in six persons. Primary diagnosis of secondary cancer was ALL in 4 and NHL in 2.For these persons who have late effects, present state of individual life was evaluated and classified into four categories; (1) usual life without handicapped and medical service, (2) no handicapped, but necessary medical service, (3) handicapped, but unnecessary medical service, (4) handicapped, and necessary medical service. Each category was found in any primary disease or type of treatment.Discussion: The several major late effects of survivors will not decrease in near future, considering the number of survivors is increasing for these decades. Novel system for survivors should be build up as to make their lives healthier.

Phenotype associated with recessively inherited mutations in DNA mismatch repair (MMR) genes

The MMR (DNA mismatch repair) system helps to maintain the integrity of the genome. This involves eliminating base-base mismatches and insertion/deletion loops, which can lead to microsatellite instability, as seen in tumour cells. Hereditary non-polyposis colon cancer is the result of dominant mutations in MMR genes, such as MLH1, MSH2 and MSH6. More recently there have been case reports of biallelic mutations in the MMR genes MLH1, MSH2 and PMS2. These result in a distinct autosomal recessive cancer predisposition syndrome. The syndrome is characterized by childhood haematological malignancies, brain tumours and the presence of café au lait patches. Second primaries occur frequently in this condition, and survival into adulthood is rare.

Appendicitis in childhood hematologic malignancies: analysis and comparison with typhilitis

Background/Purpose Recognition of appendicitis in the child with hematologic malignancy may be difficult particularly in the setting of neutropenia and multiple medications causing an altered inflammatory response. Typhilitis may produce a similar constellation of clinical findings causing further diagnostic confusion. This review compares the relative frequency of these two conditions in children with hematologic malignancy with a focus on the clinical presentation, distinguishing features, surgical management, and outcome for patients with appendicitis. Methods This institutional review board–approved retrospective study evaluated 464 pediatric patients treated for hematologic malignancy at our institution from 1997 to 2003. From this cohort, we identified all children with a diagnosis of appendicitis or typhilitis. Data include demographics, clinical presentation, laboratory studies, and computed tomography (CT) scan findings. Groups were compared using the Fisher exact test. Significance was defined as P < .05. Results Eight (1.7%) of 464 children were diagnosed with typhilitis and 7 (1.5%) with appendicitis. There were no demographic differences between patients with appendicitis and typhilitis. Distinguishing clinical features in children with typhilitis included presence of fever and diarrhea. Clinical presentation in children with appendicitis was atypical in 5 of 7 cases yielding an incorrect preoperative diagnosis in all 5. Radiographic evaluation by CT scan accurately defined typhilitis, but not appendicitis. An operation was performed on all 7 children with appendicitis with no operative morbidity or mortality. Conclusions Appendicitis and typhilitis occur with similar frequency in children with leukemia and lymphoma. Typhilitis is accurately diagnosed with clinical findings of fever, diarrhea, abdominal pain, and typical CT scan findings. Appendicitis tends to present with atypical findings, but can be successfully managed with standard surgical care.

Dental abnormalities of a long-term survivor of a childhood hematological malignancy

The treatment of haematological malignancy is multimodal and involves chemotherapy, radiotherapy and/or bone marrow transplants. With the advancement in cancer therapy, there is an increase in the survival of many children with childhood haematological malignancy. In addition, the late effect of the oncology treatment to the orofacial and dental development becomes significant in terms of the potential clinical impact that may affect the quality of life of the survivor. The severity of the long-term effects is dependent on the age of the child at initiation of treatment and whether chemotherapy is combined with radiation or not. The dental treatment may become more complex if the patient requires advanced restorative dental care and the roots malformation may complicate orthodontic treatment. Therefore these patients may require a scheduled careful preventive programme, long-term follow up, with prophylactic treatment and intervention at appropriate time to minimize the consequences of the disease and the given therapy.

Mutations of the PTPN11 Gene in Childhood Hematological Malignancies.

The PTPN11 gene encodes SHP2, which is a protein tyrosine phosphatase functioning as signal transducer downstream to growth factors and cytokine receptors and its function is mediated, at least in part, through the Ras/Raf/ERK cascade in hematopoietic and non-hematopoietic cells. Recently, it has been reported that germline mutations in PTPN11 cause Noonan syndrome and a gain-of-function somatic mutations in PTPN11 has also been reported in juvenile myelomonocytic leukemia (JMML). To investigate the prevalence of mutations in PTPN11 in childhood acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), we screened the hot spot of PTPN11, exon 3, in 80 cell lines, including 14 AML, 5 chronic myeloid leukemia, 14 T-cell ALL and 47 B-precursor ALL cell lines, and 207 fresh samples, including 20 myelodysplastic syndrome (MDS), 3 JMML, 85 AML, 57 B-precursor ALL patients as well as 42 infant leukemia patients (6 AMLs, 35 ALLs, 1 mixed lineage leukemia), using polymerase chain reaction-single strand conformation polymorphism and direct sequencing analyses. In exon 3, mutations were observed in 2 of 14 (14.3%) AML cell lines (Asp61Val and Glu76Gly). A missense mutation (Ala72Val) was detected in 1 of 85 (1.2%) AML patients (a 9-year-old girl with FAB-M0). In 20 MDSs, a missense mutation (Asp61Val) (5%) was identified in a RAEB-T patient. In 3 JMMLs, 2 missense mutations (66.7%) were detected; one was Gly60Ala, and the other was Glu76Val. In 42 infant leukemia patients, we detected only one missense mutation (Ala72Asp) (2.4%) in an AML-M5b patient. However, we did not detect any mutations of exon 3 in 61 ALL cell lines and 92 ALL patients including 35 infant ALL patients. The screening for other coding regions is still undergoing although more than 90% of the reported mutations were clustered in exon 3. In conclusion, our data suggest that the PTPN11 mutations are involved in myeloid hematological malignancies rather than ALL.

Residential proximity to high-voltage power lines and risk of childhood hematological malignancies.

BACKGROUND: Epidemiologic studies of electromagnetic fields and childhood cancers have focused on home exposure. The authors investigated whether residence in districts near high-voltage power lines is associated with childhood hematological malignancies, using small area analysis.METHODS: Among 50,000 children in a city in Japan, 14 cases aged younger than 15 years were diagnosed with these malignancies in the period from 1992 through 2001. A total of 294 districts constituting this city were classified according to their proximity to high-voltage power lines (either 66 kV or 220 kV). Mantel-Haenszel rate ratio is used to calculate incidence rate ratio and its 95% confidence interval (CI).RESULTS: Compared to districts of which no area fell within 300 m of high-voltage power lines, districts in which at least 50% of the area fell within 300 m of high-voltage power lines demonstrated an increased risk (incidence rate ratio: 2.2; 95% CI: 0.5-9.0). The association was strengthened for homes in which patients had resided for the longest interval of their lives (incidence rate ratio: 3.4; 95% CI: 0.9-13.2). Point-in-time measurements showed no increase in magnetic field levels for patient homes in districts near the lines.CONCLUSION: An increased, albeit nonsignificant, risk of childhood hematological malignancies associated with residential proximity to high-voltage power lines warrants further investigations.

Papel de la genética molecular en el cáncer infantil

In the last few years molecular genetic studies of childhood cancer have acquired great importance. Advances in these techniques have increased knowledge of the various genes involved in tumoral development. Genetic alterations can occur in three large groups of genes: oncogenes, tumor suppressor genes, and DNA repair genes. Cytogenetic analyses (karyotyping) are complemented by various molecular techniques, such as fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR) and spectral karyotyping (SKY). These are the most reliable techniques and improve the sensitivity of karyotyping. The present article reviews the most representative and best characterized genes involved in the molecular etiology of childhood cancer, both hematologic malignancies (leukemia and lymphoma) and solid tumors (brain tumors, neuroblastoma, Wilms' tumor, hepatoblastoma, rhabdomyosarcoma, Ewing's sarcoma and retinoblastoma). Molecular techniques have enabled more precise diagnosis as well as identification of new prognostic factors and the development of more effective treatments. These techniques can also be useful in identifying minimal residual disease during and after treatment for leukemias, neuroblastomas and sarcomas, with the aim of predicting recurrence.

Interventional radiology techniques for the diagnosis of lymphoma or leukemia.

Fluid aspiration, percutaneous biopsy, and catheter drainage are standard minimally invasive methods of diagnosing lymphoma or leukemia in adults. To determine the effectiveness of interventional radiologic techniques in diagnosing specific hematologic malignancies in children. During a 4-year period, 22 patients (16 male, 6 female; median age, 13 years) underwent 25 percutaneous biopsies, 6 fluid aspirations, 3 catheter drainages, and 1 needle localization for diagnosing suspected hematologic malignancy. For Hodgkin's disease, the procedures yielded 6 true-positive (TP) results, 2 true-negative (TN) results, and 2 false-negative (FN) results; for non-Hodgkin lymphoma (NHL), 14 TP results, 1 TN result, and 3 FN results; and for leukemia, 4 TP results and 3 FN results. Percutaneous biopsies yielded 16 TP results, 3 TN results, and 6 FN results. Aspirations and drainages yielded 8 TP results and 1 FN result. The one needle localization yielded a FN result. Overall sensitivity was 75%+/-7.3%; specificity, 100%; and accuracy, 77%+/-7.1%. Percutaneous biopsy of lymphoma is usually diagnostic. Drainage or aspiration of a fluid collection associated with NHL or leukemia is often diagnostic and is less invasive than biopsy. These procedures are minimally invasive and effective for diagnosing pediatric hematologic malignancies.

Nursing interventions in the management of chemotherapy side effects in childhood hematological malignancies

Nursing interventions in the management of chemotherapy side effects in childhood hematological malignancies

Pegaspargase-induced pancreatitis.

The purpose of this study is to report the incidence of pancreatitis in patients treated with pegaspargase in our hospital during a 2-year period. We identified episodes of pancreatitis related to the intramuscular administration of pegaspargase 2,500 IU/m(2) for the treatment of childhood hematological malignancies during a 2-year period (May 1996-April 1998). Patients were evaluated clinically and by sequential serum amylase and lipase determinations and radiographic examinations. For comparison, episodes of pancreatitis in patients who only received native Escherichia coli L-asparaginase were examined during the same time period. Nine children with acute lymphoblastic leukemia (ALL) of 50 (18%) patients who received pegaspargase were diagnosed to have pancreatitis. All had prior therapy with native L-asparaginase. These children developed symptoms consisting of abdominal pain, nausea, vomiting, and decreased appetite within a median of 15 days from the onset of pegaspargase administration. Six patients became symptomatic after their initial dose. Seven patients developed severe or unacceptable toxicity (grades 3 and 4), measured by increased amylase (>2 times normal) and lipase levels or radiographic evidence of pancreatic inflammation or pseudocyst. One patient also developed hyperammonemia and encephalopathy. In contrast, only one out of 52 (1.9%) ALL patients who received native E. coli L-asparaginase during the same time period developed pancreatitis (P= 0.007). Clinicians should be aware of a possible higher incidence of pancreatitis associated with pegaspargase.

Pegaspargase-induced pancreatitis

Background The purpose of this study is to report the incidence of pancreatitis in patients treated with pegaspargase in our hospital during a 2-year period. Procedure We identified episodes of pancreatitis related to the intramuscular administration of pegaspargase 2,500 IU/m2 for the treatment of childhood hematological malignancies during a 2-year period (May 1996–April 1998). Patients were evaluated clinically and by sequential serum amylase and lipase determinations and radiographic examinations. For comparison, episodes of pancreatitis in patients who only received native Escherichia coli L-asparaginase were examined during the same time period. Results Nine children with acute lymphoblastic leukemia (ALL) of 50 (18%) patients who received pegaspargase were diagnosed to have pancreatitis. All had prior therapy with native L-asparaginase. These children developed symptoms consisting of abdominal pain, nausea, vomiting, and decreased appetite within a median of 15 days from the onset of pegaspargase administration. Six patients became symptomatic after their initial dose. Seven patients developed severe or unacceptable toxicity (grades 3 and 4), measured by increased amylase (>2 times normal) and lipase levels or radiographic evidence of pancreatic inflammation or pseudocyst. One patient also developed hyperammonemia and encephalopathy. In contrast, only one out of 52 (1.9%) ALL patients who received native E. coli L-asparaginase during the same time period developed pancreatitis (P= 0.007). Conclusion Clinicians should be aware of a possible higher incidence of pancreatitis associated with pegaspargase. Med Pediatr Oncol 34:200–205, 2000. © 2000 Wiley-Liss, Inc.

Total body irradiation: techniques, dosimetry, and complications

Total-body irradiation (TBI) has an established role in many preparative regimens used before bone marrow transplantation (BMT) in the treatment of hematological malignancies in children and adults. Better choice in TBI techniques and dosimetry have permitted better homogeneity of dose, and therefore a significant sparing of critical tissues. Advances in treatments over the past 20 years have greatly improved survival; therefore, the evaluation of early and late complications, with a sufficient follow-up, according to different conditioning regimens is important. In this article, we review and compare different TBI techniques and dosimetry, and their influence on the distribution and homogeneity of dose, and the possible relationship to the risk of complications. We also describe the acute and late effects of TBI in children and adults appearing in the first month post-BMT as veno-occlusive disease, interstitial pneumonitis, or after 3 months, i.e., endocrinal late effects and growth in children, cataracts, neurological and bone or other complications, secondary tumors and alteration in the quality of life. The responsibility of TBI in the increased rate of certain complications is difficult to assess from chemotherapy or allograft side effects (chronic graft vs. host disease) or from other associated medical treatments, such as long term steroid therapy.

Therapy-Related Myelodysplastic Syndrome in Adults with Neurofibromatosis

Although an increased risk of hematologic malignancies in children with Neurofibromatosis-1 (NF-1) is well established, whether adults with NF-1 have an increased risk of such malignancies is unclear. We currently describe two adult patients with NF-1 who rapidly developed secondary myelodysplastic syndromes with abnormalities of chromosome 7 following chemotherapy for AML. We propose that adults with NF-1 also have abnormalities of hematologic progenitor cells.