Recombinant hematopoietic growth factors fail to induce a proliferative response in precursor B acute lymphoblastic leukemia.

We have tested a panel of recombinant hematopoietic growth factors (HGF) including the interleukins (IL) 1, 2, 3, 4, and 6 and the colony stimulating factors GM-CSF, G-CSF, M-CSF for their ability to induce proliferation of precursor B acute lymphoblastic leukemia cells (ALL) from 19 patients. In Ficoll-Isopaque isolated and T cell-depleted ALL bone marrow samples, IL2 (two cases), IL3 (four cases), and GM-CSF (one case) infrequently stimulated DNA synthesis measured by 3H-thymidine (TdR) uptake, and the other recombinant growth factors completely failed to do so. In repeat experiments with ALL blasts purified by fluorescence activated cell sorting (FACS), IL2, IL3, and GM-CSF responses could not be reproduced, suggesting that nonleukemic contaminant cells, and not the ALL blasts, had been stimulated by these factors. Cocktails containing combinations of IL1-IL4 and IL6 also lacked proliferation inducing potency. Depending on the purity of the incubated ALL cell samples, an impure preparation of B cell growth factors that has been reported to contain a highly effective stimulatory activity for precursor B ALL cells induced proliferation of residual normal cells as well as the ALL cells, as was evident from combined analysis of DNA synthesis and karyotyping. Exposure of the ALL blasts to artificial activators of protein kinase C and Ca2+ mobilization resulted in significant rises in 3H-TdR uptake, suggesting that these intracellular compounds are involved in transducing signals that upregulate proliferation. Although it remains possible that some of the human recombinant growth factors promote the growth of precursor B ALL cells in combination with other stimuli, a dominant role in the regulation of proliferation of these cells cannot be attributed to any of these cytokines at the present time.

Chemotherapy plays a major role in the inhibition of catch-up growth during maintenance therapy for childhood acute lymphoblastic leukemia.

OBJECTIVE: In children treated for acute lymphoblastic leukemia (ALL), catch-up growth occurs after cessation of therapy and not during maintenance therapy. In this study we investigated whether this inhibition of catch-up growth during maintenance treatment is attributable to the influence of chemotherapy or to the influence of corticosteroids. PATIENTS: Forty-six children treated for ALL were included in the study. In 27 patients maintenance therapy comprised vincristine (VCR), prednisone (Pred), or dexamethasone (Dexa) alternated with 6-mercaptopurine (6-MP) and methotrexate (MTX) and 19 patients received maintenance therapy with 6-MP and MTX only. Treatment did not include cranial irradiation. RESULTS: Statural growth during maintenance treatment was comparable in both groups over the study period of 1.5 years. CONCLUSION: Chemotherapy with 6-MP and MTX, and not corticosteroids, is the main factor that prevents catch-up growth from occurring during maintenance therapy for ALL.

Tissue Doppler imaging in detection of myocardial dysfunction in survivors of childhood cancer treated with anthracyclines.

The applicability of tissue Doppler imaging (TDI) was investigated for estimating cardiac function in long-term survivors of childhood cancer treated with anthracyclines. A total of 63 children (age range 7.8-17.3 y) underwent standard echo Doppler cardiographic studies of blood flow velocities, left ventricular dimensions and fractional shortening, followed by measurements of peak myocardial velocities and direction using the noninvasive tissue Doppler imaging (TDI) technique. All 63 were late survivors (median 7.1 y, range 3.5-13.5 y after end of therapy) who had received mean (+/- SD) cumulative dose of 242 (+/- 141) mg/m(2) of anthracyclines. The control group consisted of 160 healthy subjects (age range 4 to 17.9 y). Standard echo-Doppler anatomical parameters that were found significantly (p < 0.01) different for the study group are: RV wall thickness (decreased); LV diameter (increased); and LV fractional shortening (decreased). Studied hemodynamic parameters were not found to be different between the two groups. Quantitative TDI parameters: peak late diastolic myocardial velocities, as well as transmyocardial systolic and diastolic velocity differences, were significantly lower in late survivors than in the healthy pediatric population (p < 0.01). Qualitative local functional impairment of the movement of the left ventricular walls was detected in 20% of the patients. TDI might become a useful noninvasive method for detecting subclinical myocardial damage in apparently healthy children who received moderate doses of anthracyclines for treatment of childhood malignancy. Prospective studies with TDI for the detection of regional myocardial abnormalities are recommended.

Discriminative ability of conventional echocardiography and tissue Doppler imaging techniques for the detection of subclinical cardiotoxic effects of treatment with anthracyclines.

This study investigated improvement of diagnosing myocardial damage caused by anthracyclines using tissue Doppler imaging (TDI). The optimal set of conventional echocardiographic and/or TDI parameters, needed for the discrimination of survivors from healthy controls, was retrospectively assessed. A total of 60 patients and 99 controls, age range 8.5 to 17.6 years, were studied. The survivors received 50 to 400 mg/m(2) cumulative dose of anthracyclines, with a mean follow-up of 7.3 (+/-2.3) years. The parameters used in the discriminant score (S-score) were selected from a large set of 51 echocardiographic parameters, using logistic regression analysis (stepwise selection). The correct classification probability (C-index) and the generalized distance (d) between the distributions of S-scores were used to measure the overall discriminative performance of each echocardiographic technique separately and in combination. The overall discriminative performance of the conventional echo-Doppler parameters (C = 77.3%, d = 1.04) was lower than that of the TDI (C = 84.2%, d = 1.37); the highest C-index was obtained using both techniques (C = 89.2%, d = 1.66). The set of parameters includes: LV fractional shortening and MV early diastolic flow velocity, two long-axis and five apical 4-CV TDI wall velocities (systolic and diastolic). In the patient group, the S-score was positively associated with cumulative dose of anthracyclines (p = 0.05) and duration of treatment (p = 0.01). The diagnostic index S-score, based on a limited number of variables from both techniques simultaneously, could retrospectively discriminate asymptomatic children with anthracycline-induced cardiomyopathy from healthy controls. The potentials of the S-score for serial and prospective studies are further investigated.

[A patient with an immunodeficiency and consecutively 3 primary malignancies]. / Een patiënt met een immunodeficiëntie en achtereenvolgens drie primaire maligniteiten.

Patients with a primary immunodeficiency syndrome have an increased risk of the development of a malignancy. Lymphoreticular malignancies are the most common malignancies in these patients. Patients with ataxia telangiectasia (AT) also appear to be at a high risk for the development of non-lymphoid tumors, in particular carcinomas of the gastrointestinal tract and central nervous system tumors. We describe a child with an immunodeficiency and slight neurologic manifestations. During childhood she developed consecutive three primary malignancies.

Testicular tumor concomitant with von Recklinghausen's disease.

Neurofibromatosis or Von Recklinghausen's disease is an autosomal dominant disorder, associated with an excess of malignant tumors. The most common neurofibromatosis-associated malignancies are derived from neurogenic tissues, although several malignancies that did not originate from neurogenic tissue are also described. This paper provides the first documentation of a patient with neurofibromatosis and a mixed germ cell tumor of the testis.

Response rates in relapsed Wilms' tumor. A need for new effective agents.

Three hundred eighty-one children with Wilms' tumor were treated in the United Kingdom Children's Cancer Study Group WT1 Study (1982 to 1986). Seventy-one patients had relapses during or after treatment with surgery and chemotherapy, and radiation therapy, depending on stage and histologic characteristics. Forty-nine patients were evaluable for disease response to second-line chemotherapy alone. Evaluation of response to chemotherapy was impossible in the remaining patients because either surgery or radiation therapy was used at the time of relapse. With second-line combination chemotherapy (which included ifosfamide, etoposide/VM26, cisplatin/carboplatin, bleomycin, melphalan, and Thiotepa [Lederle Laboratories, Pearl River, NY]), there were five complete responses and 12 partial responses. In patients with favorable histologic findings, six of nine with Stage I, five of ten with Stage II, none of 11 with Stage III, three of 16 with Stage IV, and one of five with Stage V disease survived. Two survivors were treated with chemotherapy alone; the others received combined treatment with chemotherapy, radiation therapy, and/or surgery. For those with unfavorable histologic findings of any stage, only two of 20 survived. The authors conclude that, even for patients with localized disease with favorable histologic findings, the "salvage" rate is little more than 50%, and for all other stages and histologic findings the likelihood of cure after relapse is remote. There is clearly a need for additional effective chemotherapeutic agents for these patients.

How curable is relapsed Wilms' tumour? The United Kingdom Children's Cancer Study Group.

Three hundred and eighty one children with Wilms' tumour were treated on the United Kingdom Children's Cancer Study Group WT1 Study (1980/6). Seventy one patients relapsed during or after treatment, which included surgery and chemotherapy, with irradiation depending on stage and histology. Despite treatment with various combinations of chemotherapy, surgery, and radiotherapy there were only 17 survivors. For unfavourable histology, any stage, only two of 20 survive. We conclude that, after relapse, even for patients who have had localised disease and favourable histology, the 'salvage' rate is little more than 50% and for all others the likelihood of cure is very small. Three of 41 children who relapsed less than 12 months from diagnosis survive, compared with 14 of 30 who relapsed later. It is essential that even with this 'good prognosis' tumour initial treatment is optimal and given by centres experienced in management of children's cancer. Furthermore, there is a clear need for additional effective chemotherapeutic agents for relapsed patients.

Three consecutive primary malignancies in one patient during childhood.

Patients with a primary immunodeficiency syndrome have an increased risk of developing a malignancy. Lymphoreticular malignancies are the most common malignancies in these patients. Patients with ataxia telangiectasia (AT) also appear to be at a high risk for the development of nonlymphoid tumors--in particular, carcinomas of the gastrointestinal tract and central nervous system tumors. We describe a child with an immunodeficiency and slight neurological manifestations. During childhood she developed three consecutive primary malignancies.

Rapid VAC high dose melphalan regimen, a novel chemotherapy approach in childhood soft tissue sarcomas.

Forty-three children with malignant soft tissue sarcomas (IRS Groups II-IV) were treated with rapid dose delivery chemotherapy protocol comprising six courses of vincristine, adriamycin and cyclophosphamide, given in most cases within 8 weeks (Rapid VAC). This was followed in 36 patients by high dose melphalan with autologous bone marrow rescue. Twenty-six patients also received irradiation to the site of primary tumour. The Rapid VAC regimen was well tolerated and largely administered as an out-patient. There was one toxic death which occurred 2 months after high dose melphalan due to a combination of infection and possible anthracycline cardiomyopathy. Stages were, (Intergroup Rhabdomyosarcoma Study (IRS) system) Group, Group II--four patients. Group III--27 patients and Group IV--12 patients; International Society of Paediatric Oncology (SIOP) staging, Stage I--11, Stage II--13, Stage III--7, Stage IV--12. Actuarial survival at 5 years for all stages is 57% and event free survival 44%. For patients with non-metastatic diseases, 62% and 53% respectively. This treatment strategy utilises the philosophy of rapid drug delivery with high dose consolidation and enables all chemotherapy to be finished within a 4 month period. In general, a conservative approach was applied to both radiation and surgery to minimise late sequelae related to these treatment modalities. Although the small number of high risk patients in this study limits conclusions regarding efficacy in these subgroups the overall results with this regimen appear to be comparable to that with other approaches.

Influence of treatment modalities on prepubertal growth in children with acute lymphoblastic leukemia.

The statural growth of 85 prepubertal children treated for acute lymphoblastic leukemia was evaluated in a longitudinal study over 4.5 years. Patients were divided into three groups according to central nervous system prophylaxis: 37 patients received cranial irradiation with a dose of 24 Gy, 15 received a dose of 18 Gy, and 33 were not irradiated. According to the risk of leukemia, patients were divided into normal-risk (n = 74) and high-risk (n = 11) groups. The duration of treatment was 2 years, during which all patients showed growth retardation. The relative standard deviation score for height declined from 0 to -0.7 for the irradiated patients and from 0 to -0.2 for the non-irradiated group (P = 0.0001). There was no difference in growth pattern between cranial irradiation with 18 versus 24 Gy and chemotherapeutic treatment according to high-risk versus normal-risk protocols. However, a negative synergistic effect of more intensive chemotherapy and cranial irradiation on growth was demonstrated.

Influence of treatment modalities on body weight in acute lymphoblastic leukemia.

Weight for height of 92 patients (51 girls and 41 boys) treated for acute lymphoblastic leukemia (ALL) was evaluated in a longitudinal study. Fifty-four patients received cranial irradiation (CI) with a dose of 18 or 24 Gy and 38 patients did not receive CI. Seventy-seven patients were treated according to a normal-risk protocol and 15 patients received more intensive chemotherapy according to a high-risk protocol. In most of the patients the duration of follow-up was 12 years for irradiated patients and 4.5 years for the nonirradiated patients. Thirty of 92 patients were treated according to a protocol without CI, but with a difference in the use of corticosteroids: 19 patients received dexamethasone during the remission-induction and maintenance treatment and 11 patients received prednisone. The influence of dexamethasone vs. prednisone, sex, CI and high-dose vs. low-dose chemotherapy on weight for height was evaluated. Patients who received dexamethasone showed a significant increase in weight for height immediately after the start of therapy. In patients who received CI, weight for height significantly increased after the first year of treatment. The overweight in these patients persisted during the whole follow-up period. The weight for height of patients treated with prednisone and of patients who did not receive CI was below the mean of the normal population during treatment but was not different from normal after cessation of therapy. No difference in weight gain was seen between boys and girls and between patients who were treated with high vs. normal-risk protocols.

Shortened and diminished pubertal growth in boys and girls treated for acute lymphoblastic leukaemia.

Statural growth during puberty was studied longitudinally in 28 patients treated for acute lymphoblastic leukaemia. All patients received prophylactic cranial irradiation. The age at diagnosis was below 7 years, the age at final investigation was above 16 years for girls and above 18 years for boys. Growth was analysed using the Kernel estimation. In girls the onset of puberty and menarche was at a younger age, as compared to reference values, and the duration of the pubertal growth spurt was shorter. Compared to early maturing girls, the growth velocity at peak height velocity was lower. This resulted in a final height which was shorter than expected on the basis of the height standard deviation score before the start of puberty. In boys the duration of the pubertal growth spurt was shorter and the height gain during the growth spurt less than in the reference population. In both sexes the bone age development was accelerated.

Alpha-hemolytic streptococcal septicemia with severe complications during neutropenia in childhood cancer.

After introduction of selective decontamination of the digestive tract (SDD), a change toward an increase of infections by Staphylococcus epidermidis and alpha-hemolytic Streptococci has been noticed in the predominant etiology of infections during neutropenia. During a 27-month study period, 165 positive blood cultures were obtained from 64 neutropenic children. In 26 cases there was septicemia caused by Streptococci. Alpha-hemolytic Streptococci were isolated from blood culture in 25 cases. In 1 case septicemia was caused by beta-hemolytic Streptococcus of group G. In 10 patients, all with hematologic malignancies, septicemia attended with complications. We suggest that patients with hematologic malignancies are at risk of an unusually severe clinical course of streptococcal septicemia.