Outcomes after HLA-matched sibling transplantation or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research.

In children with acute lymphoblastic leukemia (ALL) with isolated central nervous system (CNS) relapse and a human leucocyte antigen (HLA)-matched sibling, the optimal treatment after attaining second remission is unknown. We compared outcomes in 149 patients enrolled on chemotherapy trials and 60 HLA-matched sibling transplants, treated in 1990-2000. All patients achieved a second complete remission. Groups were similar, except the chemotherapy recipients were younger at diagnosis, less likely to have T-cell ALL and had longer duration (> or = 18 months) first remission. To adjust for time-to-transplant bias, left-truncated Cox's regression models were constructed. Relapse rates were similar after chemotherapy and transplantation. In both treatment groups, relapse rates were higher in older children (11-17 years; RR 2.81, P=0.002) and shorter first remission (< 18 months; RR 3.89, P<0.001). Treatment-related mortality rates were higher after transplantation (RR 4.28, P=0.001). The 8-year probabilities of leukemia-free survival adjusted for age and duration of first remission were similar after chemotherapy with irradiation and transplantation (66 and 58%, respectively). In the absence of an advantage for one treatment option over another, the data support use of either intensive chemotherapy with irradiation or HLA-matched sibling transplantation with total body irradiation containing conditioning regimen for children with ALL in second remission after an isolated CNS relapse.

Combined clotting factor deficiencies: experience at a single hemophilia treatment center.

We describe a series of patients with combined factor deficiencies and von Willebrand's disease (VWD) at one haemophilia treatment centre. Although the incidence of VWD is at least 1% in the general population, combined coagulation defects have been infrequently described in the medical literature and are likely under diagnosed. This entity should be considered in patients with a known factor deficiency and either an unexpectedly severe bleeding phenotype, or bleeding that is unresponsive to factor replacement.

Improved survival of children with isolated CNS relapse of acute lymphoblastic leukemia: a pediatric oncology group study .

PURPOSE: Isolated meningeal relapse in children with acute lymphoblastic leukemia (ALL) usually has been followed by bone marrow relapse and limited survival. The purpose of this study was to prevent marrow relapse by administering intensive therapy before delayed craniospinal radiation. PATIENTS AND METHODS: Eighty-three patients with ALL in first bone marrow remission with an isolated CNS relapse were treated with systemic chemotherapy known to enter into the CSF and intrathecal chemotherapy for 6 months. Craniospinal irradiation (24 Gy cranial/15 Gy spinal) was then administered, followed by 1.5 years of maintenance chemotherapy. RESULTS: All 83 patients achieved a second remission. The 4-year event-free survival (EFS) rate was 71.1% +/- 5.3%. There was a fourfold increased risk of relapse for children whose initial remission was less than 18 months. The 4-year EFS rate for patients with a first complete remission >/= 18 months was 83.3% +/- 5.3%, and for those with a first complete remission less than 18 months, it was 46.2% +/- 10.2% (P =.0002.) There was a low incidence of neurologic toxicity and an unexpectedly high rate of allergic reactions to L-asparaginase. Five patients developed secondary malignancies: two with acute nonlymphoblastic leukemia during therapy, one with myelodysplasia after therapy, and two with brain tumors 1.5 to 2 years after cessation of therapy. CONCLUSION: For children with ALL and an isolated CNS relapse, treatment that delays definitive craniospinal irradiation by 6 months to allow for more intensive systemic and intrathecal chemotherapy results in better EFS than has been previously reported. Using this approach, the long-term prognosis for children with first complete remission >/= 18 months is comparable to that at the time of original diagnosis of ALL.

A survey of pediatric malignancy in West Virginia.

The occurrence of malignancy in the pediatric age group is an uncommon but serious event. Since little data are available on the extent, nature or referral patterns of childhood cancer in West Virginia, we conducted a survey of 782 primary care physicians and 17 regional referral centers. The results showed that 249 cases of malignancy in the pediatric age group were reported and that 68% of children with newly diagnosed childhood malignancy were referred to institutions within West Virginia. We conclude that the incidence and distribution of types of malignancy in childhood in West Virginia parallels that of the nation, although there is some regional variation within the state.

An unusual histiocytic disorder responding to cyclosporine therapy: a case report.

PURPOSE: To describe the clinical and pathologic presentation and course of a 7-week-old girl with anemia, thrombocytopenia, and organomegaly who was found to have a histiocytic disorder distinct from previously reported cases. METHODS: Bone marrow specimens were studied with conventional methods. A liver biopsy specimen was evaluated by routine and immunohistochemical methods and electron microscopy. RESULTS: The patient was found to have a unique histiocytic disorder in which lesional cells displayed an atypical phenotype. Cyclosporine therapy was associated with a prompt, complete, and apparently permanent resolution of disease. CONCLUSION: This case appears to represent an atypical histiocytic disorder with unique clinical and pathologic features. The disorder resolved after the initiation of cyclosporine therapy.

Transient-evoked otoacoustic emissions in children after cisplatin chemotherapy.

Little is known about cisplatin ototoxicity in pediatric patients. Measurement of otoacoustic emissions is a rapid, reproducible, objective method of evaluating hearing. We examined whether transient-evoked otoacoustic emissions in pediatric patients exposed to cisplatin in the past correlated with audiographic findings. Twelve patients were entered into the study (mean age at treatment 7.8 years, mean cumulative dose 442.5 mg/mm2, mean 7.1 doses). Hearing at 3000 Hz was preserved in 82.6% of patients. In the higher frequencies significant sensorineural hearing loss was noted: 43.5% at 4 kHz; 81.0% at 6 kHz; and 90.5% at 8 kHz. Transient-evoked otoacoustic emissions were measurable in 11 of 12 patients. Middle ear disease accounted for abnormal otoacoustic emission seen in three patients (1 with effusion, 2 with significant negative middle ear pressure). When the middle ear was normal, a statistically significant correlation was seen between the transient-evoked otoacoustic emissions reproducibility and pure-tone threshold (correlation coefficient = -0.69, p = 0.008). Increased hearing loss was also associated with young age at first dose of cisplatin (p = 0.044), high number of chemotherapy cycles (p = 0.042), and high cumulative dose (p = 0.042).

The use of heparinase to neutralize residual heparin in blood samples drawn through pediatric indwelling central venous catheters.

Routine-coagulation screening is unreliable if obtained through a previously heparinized central venous catheter. Screening tests were performed on 14 paired peripheral and central venous catheter samples without and with heparinase. The heparinase treated central venous catheter samples correlated well with the peripheral samples and can be used to atraumatically screen for hemostatic abnormalities.

Curing children with leukemia in West Virginia.

Leukemia is the most common cancer in childhood with acute lymphoblastic leukemia (ALL) the most common subtype. While once uniformly fatal, today leukemia is a highly curable disease. To determine the outcomes of children with acute lymphoblastic leukemia in West Virginia, we performed a retrospective analysis of the results of treatment of children and adolescents with B-lineage ALL diagnosed between 2/86 and 1/91 and treated by the pediatric oncology teams at Morgantown or Charleston. Forty-one children with B-lineage ALL were identified and treated by a uniform protocol. Twenty-nine (71%) have remained disease-free for more than two years off therapy and are considered cured. Of the 10 patients who relapsed, five have now been off rescue therapy for greater than two years and are likely to be cured. Thirty-five of the original cohort of 41 children are alive and disease-free yielding an overall survival of 85%. The results of treatment of childhood leukemia in West Virginia are comparable to national data. Children with ALL diagnosed and treated by pediatric oncology teams in West Virginia have a very good chance of being cured.

Elevated levels of tumor necrosis factor-beta, gamma-interferon, and IL-6 mRNA in Castleman's disease.

Castleman's disease (CD) is a lymphoproliferative disorder characterized by enlarged hyperplastic lymph nodes. CD may be localized or multifocal, and is often associated with signs and symptoms of generalized inflammation. The systemic manifestations of CD have been previously attributed to an overproduction of interleukin-6 (IL-6) by the tumor, although there is evidence that IL-6 is not responsible for all of the symptoms. We describe a 9-year-old boy who developed Castleman's disease with systemic findings of hypochromic microcytic anemia, growth arrest, inflammation, and hyperimmunoglobulinemia. Following surgical resection, all of the symptoms and laboratory abnormalities resolved. Using reverse transcriptase polymerase chain reaction (RT-PCR) analysis of the tumor, we found elevated levels of IL-6 mRNA as expected, but also elevated levels of tumor necrosis factor beta (TNF-beta) and gamma interferon (gamma-IFN) mRNA. Because these cytokines are mediators of immune regulation and inflammation, we propose that TNF-beta and gamma-IFN also play an important role in the pathophysiology of Castleman's disease.

Individual differences in pediatric cancer patients' reactions to invasive medical procedures: a repeated measures analysis.

Previous research on child distress in pediatric cancer has addressed the issue of habituation to invasive procedures using correlational methodology. In addition, most studies have focused on the bone marrow aspiration (BMA); few have examined children's reactions to the lumbar puncture (LP) separately. The present investigation examined 13 pediatric cancer patients over time as they experienced five BMAs or LPs. Direct observation of child behavior during procedures was employed to assess distress responses using a 12-category measure. Individual patients demonstrated a range of distress patterns. Only two children were observed to habituate to these procedures. The importance of individual patient characteristics and differences in the execution of the procedures are discussed, as is the need for greater use of treatments for child distress.

An investigation of the validity of the quality of Well-Being Scale with pediatric oncology patients.

The usefulness of the Quality of Well-Being scale (QWB) in a sample of pediatric cancer patients was investigated. The parents of 30 children who were 4 to 18 years old and who were being treated for cancer, were administered the QWB. Performance status ratings from the parents and physician, toxicity ratings, treatment information, and routine laboratory values were also collected. Correlational analyses indicated that QWB scores were significantly related to ratings of performance status and that children who had experienced more surgeries and hospitalizations were assessed as more impaired on the QWB. The child's age, toxicity of treatment experience to date, and laboratory values were not significantly related to QWB findings. The potential utility of the QWB as a component of quality-of-life assessment is discussed.

Acute myeloid leukemia (AML) in Down's syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498.

The treatment of acute myeloid leukemia (AML) in children with Down's syndrome (DS) has engendered considerable controversy. Because of the concerns for toxicity and increased rate of infections, treatment approaches varied considerably in the past with mixed results. However, experience on the recently completed Pediatric Oncology Group (POG) 8498 AML study suggests that DS children with AML constitute a distinct subgroup that responds well to therapy. Twelve of 285 children on POG 8498 (protocol for newly diagnosed AML) had DS. Children with DS and AML were predominantly male (9 of 12) and were quite younger at diagnosis (< 24 months in 10). The white blood cell count was less than 50 x 10(3)/microL in all 12 and French-American-British types M6 and M7 were frequent (5 of 12). An abnormal cytogenetic marker, in addition to constitutional trisomy 21, was present in 9 of 12 and involved chromosome 8 in 4 of 9. All cases studied (n = 5) were positive for myeloid cell surface markers (CD33, CD13, or CD11b) and, interestingly, were also positive for the CD7 antigen. Chemotherapy included daunorubicin, cytarabine (Ara-C), and 6-thioguanine for remission induction and featured high-dose Ara-C (3 g/m2 per dose) with or without L-asparaginase early in remission. Compared with children without DS, children with DS had a superior event-free survival (EFS at 4 years 100% v 28% +/- 6.2%; P = .003). The EFS remained superior even when compared with non-DS children less than 2 years of age with a white blood cell count less than 10 x 100,000/microL (100% v 48% +/- 17.3%; P = .01).

Treatment of occult or late overt testicular relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study.

PURPOSE: The Pediatric Oncology Group (POG) designed a randomized two-arm protocol (8304) to improve the survival of children with acute lymphoblastic leukemia (ALL) who experience an isolated testicular relapse and to evaluate the efficacy of teniposide (VM-26) and doxorubicin as intensification agents during second remission. The outcome and toxicity observed in 80 patients with isolated testicular leukemia treated on POG 8304 are presented. PATIENTS AND METHODS: The following are common features of POG 8304: (1) remission reinduction therapy with vincristine, prednisone, and doxorubicin; (2) bilateral testicular irradiation (2,600 cGy) during reinduction therapy; (3) CNS prophylaxis with intrathecal hydrocortisone, methotrexate (MTX), and cytarabine (Ara-C); and (4) continuation therapy (for 80 weeks) with alternating 6-week cycles of oral mercaptopurine (6-MP)/MTX and intravenous vincristine and cyclophosphamide. Treatment differences consisted of pulses (administered every 7 weeks) of either prednisone and doxorubicin (arm 1) or VM-26 and Ara-C (arm 2) during continuation therapy and a 4-week late intensification phase with either vincristine, prednisone, and doxorubicin (arm 1) or VM-26 and Ara-C (arm 2). RESULTS: Fifty-five boys with ALL had isolated microscopic testicular leukemia detected by an elective biopsy at completion of initial treatment, and 25 had a late (greater than or equal to 6 months off-therapy) isolated overt testicular relapse. All patients with overt testicular leukemia attained a second clinical remission, and no patient with microscopic testicular leukemia progressed during reinduction. Of 42 patients on arm 1, 11 have relapsed compared with 18 of 38 patients on arm 2 (log-rank analysis, P = .22), indicating no significant difference between an anthracycline and an epipodophyllotoxin-Ara-C combination in the treatment of testicular leukemia. The overall 4-year event-free survival (EFS) among boys with occult testicular relapse was 53% +/- 8%. Age greater than 10 years at initial diagnosis, a WBC count greater than 50,000/microL at diagnosis, and black race were associated with a worse outcome. The 4-year EFS for boys with a late overt testicular relapse was 84% +/- 10%, and these patients fared significantly better than patients with occult disease (P = .007). CONCLUSION: The treatment approach reported here can secure a prolonged second remission in many patients with occult or late overt testicular leukemia.

Hemophilia--an ancient disease with new problems and new solutions.

A bleeding disorder occurring in brothers was described by Talmudic rabbis in 500 A.D. Hemophilia A is now known to be due to a sex-linked deficiency of plasma factor VIII activity. The isolation of factor VIII from plasma in lyophilized concentrate has provided effective treatment and resulted in significant health and economic benefits for individuals with hemophilia. Treatment associated viral hepatitis and HIV infection have spurred the development of serologic screening of blood donors and viral inactivation techniques which have resulted in improved safety of plasma derived concentrate. Knowledge of the gene for factor VIII has led to development of recombinant factor VIII concentrate, and provides promise for gene replacement therapy in the future. The presence of the Human Immunodeficiency Virus (HIV) in plasma products exposed many individuals with hemophilia to the risk of developing the Acquired Immune Deficiency Syndrome (AIDS). Their medical care now includes testing for HIV exposure, AIDS risk reduction counseling, monitoring of immune parameters with prophylactic anti-HIV therapy for immunocompromised individuals, and treatment of opportunistic infections in those developing AIDS.

Lymphadenopathy in children: a concise review.

Lymphadenopathy is commonly found in sick children and the cause of the enlarged nodes is usually evident. However, lymphadenopathy of a prolonged duration or with larger than anticipated nodes often presents a diagnostic dilemma. Knowledge of the normal pattern of lymph node size in children and the mechanisms of lymphadenopathy are prerequisites to approaching the diagnosis. Historical and physical clues help to guide the diagnostic evaluation and may indicate the need for certain laboratory tests, a trial of antibiotics, immediate biopsy, or simply close observation. If a biopsy is performed, comprehensive evaluation of the lymph node is critical to the diagnosis and subsequent treatment. Although most children with peripheral adenopathy have reactive hyperplasia of unknown etiology, it is important to monitor children with persistent lymphadenopathy until a diagnosis is made or the adenopathy resolves.

Recruitment in the Cooperative Study of Sickle Cell Disease (CSSCD).

The Cooperative Study of Sickle Cell Disease (CSSCD) is a multiinstitutional investigation of the natural history of clinical course of sickle cell disease from birth through adulthood. The study is not a trial; rather, it involves data collection at 23 institutions in a uniform, standardized fashion on 3800 patients. Recruitment aspects that were addressed include issues related to recruitment of different age groups, ranging from newborns to pregnant women to patients over 50 years of age; the need to include mildly affected patients to ensure that the study would not reflect only a severe hospital-based population; recruitment from rural populations; and the need to screen and enter a newborn population at birth. The recruitment goal of entering 3200 patients, including 2100 patients with SS hemoglobinopathy, over a 24-month period was accomplished after 27 months.

Iron deficiency in children. Update on an old problem.

Over the past 25 years the incidence of iron deficiency anemia has decreased remarkably. This decline has resulted directly from a program of prevention that is based on a detailed understanding of iron lack in infants and children. However, iron deficiency without anemia--subtle iron deficiency--remains a problem. The negative impact of iron deficiency on brain function has recently been demonstrated in animal as well as human studies. The behavioral effects noted in infants and toddlers can be seen with subtle iron deficiency as well as with anemia. Although behavioral abnormalities in the very young appear to be correctable by iron treatment, prolonged iron deficiency may lead to irreversible effects on brain function. These recent findings should further encourage continued vigilance in preventing the old problem of iron deficiency.