Terminal care of the child with cancer at home.

One hundred paediatric patients with either leukaemia (36%), solid tumours (34%) or brain tumours (30%), treated at the Children's Hospital, University of Helsinki, Finland, died during 1987-92; 70 of them died while in organized terminal care. They were treated at home (60%), in hospital (29%), and partly at both (11%). One or both parents stayed at home to take care of their child. Personnel of the oncologic ward coordinated home care. The purpose of this study was to evaluate the advantages and disadvantages of a terminal care program, with special reference to terminal care at home. Evaluation included retrospective analysis of patients' records, as well as a structured interview with the two parents separately. The quality of life of the children during the terminal period was greatly influenced by their happiness at being at home. Relief of symptoms, particularly pain, was in most instances adequate. Most parents had no complaints to make afterwards. Only some of them complained of having received too little information, too little supervision and support, and insufficient preparation for the death of the child. Thus, the system of terminal care at home proved satisfactory for the child and the whole family in many different respects. For successful home care, the parents need continuous supervision, help and support by well-trained personnel.

Growth impairment and growth hormone therapy in children treated for malignant brain tumours.

UNLABELLED: Eighty-two children with malignant brain tumours were treated according to the "8 in 1" chemotherapy protocol in Finland during 1986 to 1993. Thirty-seven with brain tumours not involving the hypothalamic-pituitary region are still alive and tumour-free. The growth and response to growth hormone (GH) therapy in these children was analysed. Children who received craniospinal irradiation had the most severe loss of height SDS, being -1.07 within 3 years of the diagnosis. Even children with no irradiation to the hypothalamic-pituitary axis had a mean change in height SDS of -0.5 after 3 years. Fifteen of 23 children who received craniospinal irradiation and two out of eight children who received cranial irradiation have received GH therapy. A catch-up growth response to the daily GH therapy with the mean dose of 0.7 IU/kg per week was complete in 3 years (+1.87 SDS), irrespective of craniospinal irradiation, in children who were treated at prepubertal age but was seen in none of the children who had reached pubertal age. CONCLUSION: Growth impairment and GH deficiency are common in children treated for malignant brain tumours. The response to GH therapy is good in prepubertal children in terms of increased growth velocity, although the final height is not yet known.

Improving outcome of malignant brain tumours in very young children: a population-based study in Finland during 1975-93.

Sixty-four children with malignant brain tumours diagnosed at less than 3 years of age were reported to the Finnish Cancer Registry from 1975 to 1993. The survival rate has improved significantly: the 5-year survival rate was 26% for all children, 13% for children diagnosed during 1975-85 (n = 30) and 40% for those diagnosed during 1986-93 (n = 34). Of the surviving children in 1986-93, 43% were categorized in Bloom's group I or II and could lead active lives without major disabilities. The remaining children had severe neurologic late complications, such as hemiplegia, intractable seizures, and mental retardation.

Follow-up of residual disease using metaphase-FISH in patients with acute lymphoblastic leukemia in remission.

Metaphase-FISH (fluorescence in situ hybridization) was used to detect cells with a chromosomal trisomy and/or translocation in 25 patients with acute lymphoblastic leukemia (ALL) in remission. Twelve patients were treated with chemotherapy alone and 13 patients received bone marrow transplantation after initial chemotherapy. Patients were followed up for 8-56 months (median 18 months). In this study, a total of 82 bone marrow samples were analyzed. Metaphase-FISH identified chromosome morphology, even banding, in cells from which FISH signals were studied. Thus, it is as reliable as standard karyotype analysis and does not cause false positive results. Furthermore, more than 1000 cells can be analyzed in 3-6 h which equals the time it takes to analyze 20 metaphases by standard karyotype. The time span before the first positive sample seems to be insignificant with regard to the outcome of relapse. All six patients, who had more than 1% of abnormal cells detected at any sampling or whose consecutive follow-up samples showed an increasing frequency (up to 1%) of abnormal cells, relapsed. Absence or occurrence of low numbers of abnormal cells at a frequency of 0.05-0.8% followed by their disappearance was in agreement with continuing complete clinical and hematologic remission (CR) in 16 (84%) of 19 patients. Our results indicate that metaphase-FISH is a reliable technique for quantifying residual leukemic cells. The technique is available in standard cytogenetic laboratories and can be applied to routine follow-up of ALL patients who have a suitable chromosomal aberration.

Cord blood stem cell transplantation for Diamond-Blackfan anemia.

Bone marrow transplantation has been successfully employed in the treatment of Diamond-Blackfan anemia (DBA). Transplantation with bone marrow stem cells involves, however, considerable treatment-related toxicity, partially in the form of GVHD. Through the use of cord blood stem cells it may be possible to reduce the risk for both acute and chronic GVHD, although possibly in the face of an increased risk for non-engraftment. We report the successful treatment of a boy with DBA by cord blood stem transplantation from an HLA-identical sibling.

Skeletal muscle protein reserve after bone marrow transplantation in children.

To evaluate the long-term profile of nutritional status in children undergoing BMT, we carried out a 1-year follow-up of 42 consecutive patients. The skeletal muscle protein reserve was assessed by ultrasonography, and by calculating the mid-arm muscle area from skinfold and arm circumference measurements. Ultrasonography proved to be superior to anthropometry. During the first month after BMT, the skeletal muscle protein reserve decreased by 11% (95% CI -20 to -4%), and only began to recover gradually several months after BMT. The serum transferrin concentration decreased significantly during the first post-transplant month, then slowly returned to normal by the end of the first post-transplant year. The 23 patients with allogeneic transplants and 19 with autologous transplants were fully comparable in nutritional respects. Despite total parenteral nutrition the total energy intake did not reach the weight-based target level. The patients in whom pretransplant protein energy reserves were severely reduced, were at increased risk of dying of relapse. We conclude that ultrasonography is a valuable method for assessing protein energy reserves in BMT patients. Pretransplant nutritional status has a considerable impact on post-transplant survival. We emphasize the importance of both pre- and post-transplant nutritional support.

In vivo purging of bone marrow in children with poor-risk neuroblastoma for marrow collection and autologous bone marrow transplantation.

PURPOSE: To evaluate the following prospectively in poor-risk neuroblastoma (NBL) patients: (1) the feasibility and efficacy of in vivo purging of bone marrow; and (2) the outcome after autologous bone marrow transplantation (ABMT) when immunologically tumor-free, unpurged autografts were used. PATIENTS AND METHODS: Twenty-three children with poor-risk NBL were evaluated during induction chemotherapy by repeat bone marrow examinations, including aspirate, biopsy, and an immunofluorescence method using the anti-GD2 monoclonal antibody 3A7. Nineteen patients completed the program with surgery with or without local irradiation followed by ABMT. RESULTS: Autologous bone marrow grafts, both immunologically and cytologically clean, were obtained and used in 19 of 23 children. The overall 4-year disease-free survival of the 19 grafted children was 53%, with a toxic death rate of 16% and a posttransplant relapse rate of 37%. According to the in vivo purging efficacy of the 18 children with initial marrow disease, the following three groups were formed: patients with (1) perfect in vivo purging (n = 5); (2) eventually successful in vivo purging (n = 8); and (3) unsuccesful in vivo purging (n = 5). The 4-year DFS was 100%, 67%, and 0%, respectively (P < 0.001). The five patients with unsuccessful in vivo purging failed because of resistant/progressive bulky disease. CONCLUSION: In patients with poor-risk NBL, in vivo purging of bone marrow by conventional chemotherapy is feasible, can be monitored, and the purging efficacy during the first 3 months after diagnosis is a strong prognostic factor reflecting tumor responsiveness to therapy. Autografting with immunologically clean, unpurged marrows gives a DFS well comparable to previous studies using ex vivo purging.

Ototoxicity in children with malignant brain tumors treated with the "8 in 1" chemotherapy protocol.

BACKGROUND: Adjuvant chemotherapy has improved the outcome of childhood malignant brain tumors in large randomized trials. With increasing survival rates, treatment toxicity has become a matter of concern. Radiation therapy and cisplatinum are known to be ototoxic. METHODS: We evaluated the incidence and factors predisposing to ototoxicity in children treated with the "8 in 1" chemotherapy protocol in Finland during 1986--1993. Thirty-five of the 82 children survived for at least 1 year after diagnosis. Thirty of these children were old enough to have an audiogram. RESULTS: Seventeen of the 30 children had normal hearing, seven had hearing loss at high frequencies, and six (20%) had severe hearing loss in the speech range. The risk factors for severe hearing loss were young age, a high cumulative dose of cisplatinum, and deteriorating renal function. In the presence of these factors, the risk of severe hearing loss was over 50%. Hearing loss at high frequencies could occur after low cumulative doses of cisplatinum, but severe hearing loss correlated with high cumulative doses. CONCLUSIONS: Cisplatinum-induced hearing loss at high frequencies is common, but hearing loss in the speech range also occurs, particularly in children with predisposing factors, and may progress insidiously and rapidly. Therefore a hearing test before each "8 in 1" course is important.

Neuropsychologic late effects in children with malignant brain tumors treated with surgery, radiotherapy and "8 in 1" chemotherapy.

Sixty-eight children with malignant brain tumors were treated with the "8 in 1" chemotherapy protocol from 1986 to 1993 in Finland. The overall 5-year survival rate was 43%. Thirty-one children are still alive and tumor-free, and have been evaluated in the present study. Of these 31 children, 26% had hemi- or tetraplegia, 13% intractable seizures, and 30% attend special schools. The mean full scale (FS) IQ was 85 (range 45-138), 24% had an FSIQ value less than 70, and 36% more than 90. One-half of the survivors were placed in Bloom's group I or II, are able to lead an active life, and have only mild neurologic disabilities. In the other, neurologic late complications accumulated and these children were relegated to Bloom's group III or IV, with major disabilities such as hemiplegia, intractable epilepsy, or mental retardation. The most important prognostic factors were severe perioperative complications, young age at diagnosis, and cranial irradiation.

Granulocyte-colony-stimulating factor after allogeneic and autologous bone marrow transplantation in children.

We evaluated the use of granulocyte CSF (G-CSF) after both allogeneic BMT (allo-BMT) and autologous BMT (ABMT) in children. After allo-BMT, G-CSF was used in 15 children who were compared with 20 historical controls. The ABMT patients were two sequential groups: the G-CSF group of 13 children and 11 historical controls. The patients were conditioned with different high-dose chemotherapy regimens with or without total body irradiation. G-CSF was administered at 5 micrograms/kg/day s.c. and was continued until an absolute neutrophil count (ANC) of 1,000 x 10(6)/l was reached. Following allo-BMT, G-CSF accelerated myeloid engraftment with a difference of 5 days at the ANC level of 500 x 10(6)/l (P<0.02) and 9 days at 1,000 x 10(6)/l (P<0.001). In the ABMT patients, G-CSF also accelerated myeloid engraftment. The difference between the G-CSF group and the control group was 6 days at ANC 200 (P<0.05), 11 days at ANC 500 (P<0.02) and 17 days at ANC 1,000 (P<0.005). In the ABMT patients, benefit by G-CSF was also observed in a smaller number of days with fever and days on antibiotics. We conclude that G-CSG significantly accelerated myeloid engraftment, after both allogeneic and autologous BMT in children, and also decreased the duration of febrile illness in the ABMT patients.

RSV infection complicating the therapy of pediatric malignancies: report of six cases.

We describe a series of six patients with symptomatic respiratory syncytial virus (RSV) infections while receiving anticancer chemotherapy. Particularly during epidemics in the general population, RSV remains a potential cause for morbidity and even mortality among children immunocompromised through the administration of anticancer chemotherapy and especially those being transplanted. We emphasize the importance of rapid diagnostics as well as prevention of the spread of the virus in a pediatric hematology/oncology unit.

Allogeneic bone marrow transplantation in first remission for children with very high-risk acute lymphoblastic leukemia: a retrospective case-control study in the Nordic countries. Nordic Society for Pediatric Hematology and Oncology (NOPHO).

Among children with high-risk (HR) ALL there are subgroups with very-high-risk (VHR) features and poor prognosis despite developments in conventional chemotherapy for childhood ALL. We evaluated the outcome of VHR-ALL in children receiving allogeneic BMT (allo-BMT) in first remission (1CR) in a retrospective case-control study. In the population-based ALL material of the five Nordic countries, 22 children with VHR-ALL have undergone allo-BMT in 1CR between 1981-1991. We compared the outcome in these 22 children with 44 closely matched control patients who received conventional chemotherapy on HR-ALL protocols, as well as with a group of 405 children representing the remaining HR-ALL patients in the Nordic ALL database. The disease-free survival at 10 years was 73% in children receiving allo-BMT in 1CR, 50% in the matched controls (P = 0.02), and 59% in the remaining HR-ALL patients. The good prognosis of the allo-BMT group was due to a low relapse rate of 9%, as opposed to 41% in the group of matched controls. The superiority of allo-BMT as therapy in 1CR was mainly apparent in those with a very high WBC of > or = 100 x 10(9)/I at diagnosis; in the allo-BMT group 9/10 survived, as opposed to 8/20 of the matched controls (P = 0.03). We conclude that allo-BMT in 1CR should be seriously considered for children with a matched sibling donor and a VHR-ALL with WBC of > or = 100 and other established VHR criteria.

Opportunistic osteomyelitis in the jaws of children on immunosuppressive chemotherapy.

PURPOSE: Four children with an osteomyelitic process in the jaw bones while on cytotoxic chemotherapy were treated by radical surgery and antimicrobial chemotherapy. PATIENTS AND METHODS: Symptoms (local swelling and pain in the jaw, necrotic gingivitis, and spontaneous loss of teeth) appeared 3 weeks, 4 weeks, and 8 months after diagnosis of leukemia, and 8 days posttransplant in a patient with severe aplastic anemia. Three had the process in the mandible and one in the maxilla. Specific diagnoses of Aspergillus flavus, Saccharomyces cerevisiae, and Actinomyces species were obtained histologically from surgical samples. Treatment was radical surgery to remove all infected and necrotic tissue: removal of a substantial part of the mandible and loss of seven to eight permanent teeth in those with mandibular lesions. Actinomycosis was treated with penicillin for 2 years. The patients with fungal lesions received amphotericin B for 2, 5, and 6 months, with adjuvant itraconazole, fluconazole, or 5-fluorocytosine for 9-12 months. Anti-cancer chemotherapy was continued. RESULTS: All the bony lesions healed. The patient with acute myeloid leukemia died in relapse 1 year postdiagnosis; her aspergillus osteomyelitis had been inactive for 8 months. The other three patients are alive and well 1.9, 2.1, and 1.9 years after termination of antimicrobial therapy. CONCLUSIONS: We emphasize the necessity of specific diagnosis from appropriate surgical samples and conclude that in patients undergoing chemotherapy bony lesions caused by opportunistic microorganisms may be curable with aggressive surgery and prolonged medication.

Chemotherapy with the "8 in 1" protocol for malignant brain tumors in children: a population-based study in Finland.

We evaluated the outcome of 68 children with malignant brain tumors treated with the "8 in 1" chemotherapy protocol in Finland from 1986 to 1993, comparing 5-year survival rates with those for a historical control group (from 1975 to 1985). For all malignant brain tumors, overall survival was 43% (vs 28% in the control group; P <0.05), and progression-free survival (PFS) was 43% (vs 23%; P <0.05). For medulloblastoma and primitive neuroectodermal tumor, survival was 63% (vs 35%; P <0.05), and the corresponding PFS was 59% (vs 35%; P = 0.15). For high-grade glioma, both the survival rate and the PFS were 27% (vs 17%; P = NS). Thus the outcome was significantly better for our "8 in 1" -treated patients than for the historical controls, especially among the children with primitive neuroectodermal tumor and medulloblastoma. In contrast, those with high-grade gliomas and brain stem tumors seem to have received little benefit; different, more effective treatments are needed for these patients.

Myocardial function in children and adolescents after therapy with anthracyclines and chest irradiation.

Cardiotoxicity is a potential adverse effect of anthracycline (A) therapy. Radiotherapy (XRT) may also cause a variety of cardiac complications. The purpose of the present study was to evaluate these cardiac side-effects in children and adolescents treated for cancer. We assessed the cardiac status of 91 patients, divided into three groups: Group A (n = 53) had anthracyclines at a mean cumulative dose of 410 mg/m2, group A+XRT (n = 26) had both chest irradiation (XRT) and A (mean 360 mg/m2), and group XRT (n = 12) had XRT alone. The patients differed from the controls in both systolic and diastolic indices of myocardial function. In echocardiography, the left ventricular (LV) contractility was abnormal in 32% in group A, in 50% in group A+XRT, and in 8% in group XRT. In radionuclide cineangiography, the LV ejection fraction was subnormal in 19% in group A, in 24% in group A+XRT, and in 1 patient in group XRT. A higher cumulative dose of A predicted decreased contractility. Treatment with A and/or XRT often leads to cardiotoxicity. Although in most cases this cardiotoxicity seems to be mild and subclinical, the long-term clinical sequelae merit further evaluation.

Impaired response to hepatitis B vaccine in children receiving anticancer chemotherapy.

Serologic responses to hepatitis B vaccine were investigated in 197 pediatric cancer patients. The patients, ages 1 to 21 years, comprised 66 with solid tumors, 101 with hematologic malignancies and 30 with various benign conditions. Of them 51 were receiving cytotoxic chemotherapy and 114 had not received chemotherapy for 0.2 to 11 years. Three doses of plasma-derived hepatitis B vaccine (20 micrograms) were given at 0, 1 and 6 months; and antibody concentrations to hepatitis B surface antigen were determined at 3, 6 and 8 months. The geometric mean antibody concentration after 3 vaccine doses was 1076 mIU/ml in cancer patients receiving chemotherapy and 18,833 mIU/ml in cancer patients not receiving chemotherapy. The protective titer of antibody (> or = 10 mIU/ml) was reached after 3 doses of vaccine by 67% of patients receiving chemotherapy and by 97% of those not receiving chemotherapy. The patients being treated for solid tumors had weaker responses than those being treated for hematologic malignancies: after 3 vaccine doses no response was observed in 6 of 11 patients with solid tumors compared with 3 of 25 of patients with hematologic malignancies. Children receiving anticancer chemotherapy have essentially weaker responses to hepatitis B vaccine than children not receiving chemotherapy or those with benign conditions. This reflects the profound immunosuppression during chemotherapy. The effect of more intensive immunization schedules should be investigated.

Breastfeeding as prophylaxis against atopic disease: prospective follow-up study until 17 years old.

Atopic diseases constitute a common health problem. For infants at hereditary risk, prophylaxis of atopy has been sought in elimination diets and other preventive measures. We followed up healthy infants during their first year, and then at ages 1, 3, 5, 10, and 17 years to determine the effect on atopic disease of breastfeeding. Of the initial 236 infants, 150 completed the follow-up, which included history taking, physical examination, and laboratory tests for allergy. The subjects were divided into three groups: prolonged (> 6 months), intermediate (1-6 months), and short or no (< 1 month) breastfeeding. The prevalence of manifest atopy throughout follow-up was highest in the group who had little or no breastfeeding (p < 0.05, analysis of variance and covariance with repeated measures [ANOVA]). Prevalence of eczema at ages 1 and 3 years was lowest (p = 0.03, ANOVA) in the prolonged breastfeeding group, prevalence of food allergy was highest in the little or no groups (p = 0.02, ANOVA) at 1-3 years, and respiratory allergy was also most prevalent in the latter group (p = 0.01, ANOVA) having risen to 65% at 17 years of age. Prevalences in the prolonged, intermediate, and little or no groups at age 17 were 42 (95% CI 31-52)%, 36 (28-44)%, and 65 (56-74)% (p = 0.02, trend test) for atopy, respectively, and 8 (6-10)%, 23 (21-25)%, and 54 (52-56)% (p = 0.0001, trend test) for substantial atopy. We conclude that breastfeeding is prophylactic against atopic disease--including atopic eczema, food allergy, and respiratory allergy--throughout childhood and adolescence.

Allogeneic bone marrow transplantation in children: single institution experience from 1974 to 1992.

At the Children's Hospital, University of Helsinki, Finland, bone marrow transplantations have been performed since 1974. Between 1974 and 1992, 62 children received allogeneic bone marrow grafts. Median patient age was 9.3 years. Thirty-two patients had ALL, 13 AML and 11 had severe aplastic anemia (SAA). Graft failure occurred in 4 of the 62 patients. The overall long-term survival rate was 47%. Relapse of leukemia was the most common cause of death, especially in patients with ALL transplanted in second or later remission. Deaths during the first 2 months after transplant have decreased with time. In a small country such as Finland, it is important to centralize the experience of allogeneic BMTs, particularly for pediatric patients.

Cardiopulmonary evaluation of exercise tolerance after chest irradiation and anticancer chemotherapy in children and adolescents.

OBJECTIVE: The aim of the study was to evaluate the cardiopulmonary exercise tolerance in children and adolescents after chest irradiation and anticancer chemotherapy. METHODS: We studied 30 subjectively asymptomatic patients aged 8 to 25 years treated for pediatric malignancies with chest irradiation (XRT) +/- chemotherapy. The median interval since XRT was 7 (range, 2 to 13) years. The median XRT dose for mediastinum and/or lungs was 2550 (range, 1000 to 5100) cGy. The median cumulative dose of anthracyclines was 250 (range, 0 to 480) mg/m2. Cardiac function and exercise tolerance were evaluated by electrocardiography, echocardiography, radionuclide cineangiography, and exercise test with gas exchange analysis. RESULTS: The patients differed from normal controls in systolic indices of myocardial function. In echocardiography, the left ventricular contractility was abnormal in 14/30 patients. In radionuclide cineangiography, the left ventricular ejection fraction was subnormal in 6/30 patients, and in 9/30 patients the rise in ejection fraction during exercise was inadequate (< 5%). In exercise testing, the mean (+/- SD) maximum workload attained was 2.7 (+/- 0.7) watts/kg, and the mean (+/- SD) maximum oxygen consumption was 35.4 (+/- 9.7) mL/min/kg. Both variables were < 80% of predicted values in 11 patients. CONCLUSIONS: XRT and anticancer chemotherapy very often lead to late cardiopulmonary toxicity and impaired exercise tolerance. Although in most cases this toxicity seemed to be mild and subclinical, the long-term clinical sequels merit further evaluation.