Biomedical subjects
Publications and source records attributed to J Blatt.
Pyoderma gangrenosum is an uncommon skin lesion often associated with autoimmune diseases. A clear association between leukemia and pyoderma gangrenosum in adults has been established. Two cases of pyoderma gangrenosum in children with leukemia in whom it may be an initial finding are presented.
That ferritin, an iron storage protein, can be produced by neuroblastoma cells raises the possibility that iron may have some role in promoting tumor cell growth. To explore this possibility, we studied the effects of desferoxamine, a compound which chelates iron, on viability of CHP 126 and CHP 100, two human neuroblastoma cell lines. Cells (5 X 10(4)) were incubated with graded amounts of desferoxamine or ferrioxamine, an iron-saturated analogue of desferoxamine. Within 5 days of exposure to 60 microM desferoxamine, approximately 90% of cells from each of these cell lines were dead. This effect was dose dependent, was not seen with ferrioxamine, and could be prevented by coincubation with greater than stoichiometric amounts of ferric citrate. As determined by binding of OK-T9, desferoxamine also resulted in increased expression of receptors for transferrin, an iron transport protein. Desferoxamine had only minimal effects on viability of several non-neuroblastoma cell lines. These results suggest that iron is required for growth of neuroblastoma and that desferoxamine has potent, specific, antineuroblastoma activity in vitro.
To examine the effects of "low-dose" cranial irradiation on growth and to determine if one can predict patients in whom growth will be most affected, we studied 47 children with acute lymphocytic leukemia who had been treated with 2400 rad (24 Gy), 1800 rad (18 Gy), or no whole-brain irradiation. Serial measurements of height, weight, and weight for height were obtained by retrospective chart review. The effects of 1800 rad (18 Gy) and 2400 rad (24 Gy) treatment were indistinguishable. Height percentiles among irradiated patients decreased by a mean of 12% six months after diagnosis, and growth generally did not catch up. Moreover, although 33 irradiated patients maintained heights within the normal range, In 11 patients (33%) a dramatic falloff occurred such that by three years following diagnosis their height for age was more than 30 percentiles below the original value. These patients were all identifiable at six months since their height percentiles had already decreased by more than 15%. Although weight percentiles did not change following irradiation, the weight-for-height ratio increased and patients were relatively stockier three years after therapy than they had been at diagnosis. In patients who had received chemotherapy alone, the weight-for-height ratio also increased, but this appeared to be due to a disproportionate increase in weight. Longer follow-up and evaluation of larger cohorts of patients treated with 1800 rad (18 Gy) will be needed to confirm these results.
To determine whether human growth hormone (HGH) can cause proliferation of human leukemic lymphoblasts, we studied colony formation in semi-solid medium of MOLT 4, a cell line derived from an adolescent with acute lymphoblastic leukemia (ALL). Although exposure to single doses of HGH in supraphysiologic concentrations resulted in almost two-fold increases in number of colonies compared with control samples, physiologic concentrations had no effect. Similarly, physiologic concentrations of HGH had no effect on thymidine incorporation in short-term cultures of fresh lymphoblasts from children with ALL. In addition, total white blood cell and differential counts in 14 children with isolated growth hormone deficiency were reviewed pre- and post-treatment with HGH. In no case was there evidence of in vivo lymphocytosis or blastogenesis.
To document the incidence and severity of symptomatic hepatomegaly in patients with Stage IV-S neuroblastoma, we reviewed the charts of children with neuroblastoma seen at Children's Hospital of Pittsburgh between 1951 and 1985. Sixteen met the criteria for IV-S disease, and 11 of these (69%) had massive hepatomegaly. Five children had symptoms referable to their liver size including respiratory distress, gastroesophageal reflux, or decreased urine output. Liver function appeared to be normal or only mildly abnormal in the 9 patients where data were available. Because therapy was so variable, it was not possible to correlate treatment regimen with outcome. However, 3 symptomatic patients who received less than or equal to 600 rad without chemotherapy had prompt subjective responses. Follow-up was available on 10 children 6 months-18 years (median 18 years) from diagnosis. Eight were alive with resolved or resolving hepatomegaly. High dose (greater than or equal to 3,300 rad) radiation-related side effects included multiple rib chondromas, chest- and pelvic-wall hypoplasia in one patient, and radiation nephritis with hepatic fibrosis resulting in death of a second patient. Our results support prior recommendations that for symptomatic hepatomegaly, low doses of radiation be considered.
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Although tumors are a known complication of von Recklinghausen's neurofibromatosis (NF), they often develop after the second decade and their characteristics in the pediatric population are unclear. To define the frequency and distribution of tumor types in children with NF, the authors reviewed the experience at Children's Hospital of Pittsburgh between 1953 and 1984. During that time, 121 children younger than 18 years with documented NF were seen. Three patients (2.5%) developed locally extensive, unresectable sarcomas, two of which were clearly neural in origin. Two other children died from complications of highly cellular but not histologically malignant neurofibromas. Seventeen patients (14%) had brain tumors, of which 3 (2.5%) were malignant astrocytomas and 9 were optic gliomas. Two children had acute myelogenous leukemia. Although it has been said that patients with NF are particularly susceptible to the oncogenic effects of radiation, 12 children were treated with a median of 5000 rad to their tumor bed. Follow-up after radiation in that small cohort of patients ranged from 6 months to 12 years (mean, 6 years). Eleven of 12 patients experienced adequate local control. During the follow-up period, none developed a second tumor outside or within the radiation port that could be related to radiation. The authors conclude that clinically significant tumors in children with NF, not all of which are histologically malignant, are not rare. Although more prospective information is needed on response to and sequelae from therapy, the data in this report suggest no contraindication to aggressive therapy.
Rhabdoid sarcoma is a tumor of unknown etiology that usually occurs in the kidneys of infants and small children. We report an adolescent with a rhabdoid sarcoma of the chest wall. In addition to the patient's age and the site of the tumor, other unusual features of this case were as follows: positive staining of tumor cells with neuron-specific enolase, the presence of chronic, active, hepatitis that apparently developed coincident with the sarcoma, and the presence of widespread hemosiderosis. Two of the patient's siblings died in infancy with degenerative neurologic disease, hepatomegaly, and multiple congenital anomalies. The histochemical findings and family history lend support to previous suggestions that some rhabdoid sarcomas may be of neural crest origin and may be heritable lesions.
Metoclopramide (MCP) was used as an antiemetic agent in 11 pediatric oncology patients during 22 courses of cancer therapy including cisplatin, doxorubicin, and other agents. Initial MCP regimens used 2 mg/kg/dose iv prior to and at 1.5, 3.5, 5.5, and 8.5 hours post-chemotherapy. Subsequent dose reduction to 1 mg/kg and addition of diphenhydramine to all regimens has been made to decrease adverse drug effects. Seven of 11 children reported subjective benefit, defined by comparison with previous antiemetic response, comfort, and willingness to continue MCP therapy. MCP effectively reduced the volume of emesis per 24-hour period as compared with volume of emesis recorded following other antiemetics, an observation that should be confirmed in controlled studies of efficacy. Acute dystonic reactions developed in five children, occurring most frequently in those who received 2 mg/kg/dose regimens or consecutive day dosing. These reactions were rapidly reversible with diphenhydramine, but limited patient acceptance of further MCP use.
Avascular necrosis of bone (AVNB) is a known complication of systemic adrenocorticosteroid therapy, and one which is thought to be dose-related. However, despite the large amounts of prednisone which have been used in the standard treatment of acute lymphocytic leukemia (ALL), AVNB rarely has been reported in children with that disease. We described our experience with one adolescent with ALL who developed multifocal AVNB presenting as bone pain after aggressive chemotherapy that included a high cumulative dose of corticosteroids as well as other antitumor agents, some of which also have been associated with AVNB. Four similar cases from the literature are reviewed. Because the bone pain of AVNB can mimic that of leukemic relapse, this is an important entity to be aware of, and one which may become more common with increasingly aggressive combination chemotherapy.
Current practice for achieving local control of testicular relapse in males with acute lymphoblastic leukemia (ALL) includes the use of 2,400-rad testicular radiation. Although this therapy is known to cause germ cell depletion, it has been assumed that it does not alter testicular secretion of testosterone. To test this assumption, we measured gonadotropin and testosterone levels in seven boys with ALL who had been treated with radiation for clinically apparent testicular relapse. In four of seven boys, testicular relapse was bilateral with overt involvement of one testicle and microscopic involvement of the other. Three of these four boys demonstrated delayed sexual maturation, and in addition to elevated follicle-stimulating hormone (FSH) concentrations, testosterone levels were low and luteinizing hormone levels were elevated compared with controls. These data indicate that boys with overt testicular leukemia who are treated with 2,400-rad testicular radiation are at risk for Leydig cell dysfunction. However, the relative contributions of radiation, prior chemotherapy, and leukemic infiltration to this dysfunction remain to be clarified.
To test the possibility that osteosarcoma cells produce their own growth factors, we measured levels of insulin and somatomedin C (SMC), an insulin-like growth factor, in culture media of two cell lines derived from patients with that disease. SMC but not insulin levels increased three- to ten-fold over a period of 7 days paralleling the increases in cell number. Production of SMC was inhibited by cycloheximide.
From a group of 28 patients with biopsy-proven testicular leukemia seen at our institution since 1979, we describe two boys with lymphoid malignancy who, subsequent to 1,800 rad and 2,400 rad testicular radiation, had second overt testicular relapses. This experience suggests that these patients need careful follow-up physical examinations, that higher doses may be needed for prolonged local control, and that there may be a role for follow-up testicular biopsies.
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Basal growth hormone levels were measured every 20 minutes over 24 hours in eight long-term survivors of acute lymphoblastic leukemia and in 13 age- and pubertal stage-matched normal children. Among the patients, the median total basal growth hormone output (AUC) was 43 units, compared with 341 units in the normal control group (P less than 0.001). In the patients, mean pulse amplitude (6.9 ng/ml) and frequency (4.6) over 24 hours also were reduced, compared with the control values (32 ng/ml and 8.5, P less than 0.001 and P less than 0.05, respectively). In addition, normal children secreted more GH at night (median AUC 280) than during the day (113, P less than 0.001). However, this diurnal pattern was absent in three of the patients studied. These data suggest that perturbations of spontaneous pulsatile GH secretion are common after standard therapy for ALL and may be a sensitive means of detecting therapy-related neuroendocrine damage. Blunting of spontaneous pulsatile GH secretion may contribute to the abnormalities in growth seen in children with ALL.
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The activities of three purine pathway enzymes--adenosine deaminase (ADA), 5'-nucleotidase (5'N) and purine nucleoside phosphorylase (PNP)--were examined in the circulating malignant cells (Sezary cells) of eight patients with cutaneous T-cell lymphoma (CTCL). Cell lines derived from two other patients with CTCL were also studied. These were compared with enzyme activities in peripheral blood T-lymphocytes from 11 normal donors and six samples of human thymocytes. ADA activities were similar in the Sezary cells and peripheral blood T-cells (medians 7 U and 15 U, P = 0.14), and both of these groups demonstrated significantly lower activity than did the thymocytes (median 100 U, P = 0.002). 5'N activity in the Sezary cells was also similar to that of the T-lymphocytes (median 0.022 U and 0.030 U, P greater than 0.05) and both of these groups had significantly greater activity than did the thymocytes (median 0.002 U, P = 0.001). Median PNP activity in the Sezary cell population was also comparable to that measured in normal T-cells. These findings suggest there is a characteristic purine pathway enzyme pattern in Sezary cells that is similar to that seen in normal T-lymphocytes. This pattern is clearly distinguishable from that of thymocytes and from that previously described in lymphoblasts from patients with T-cell acute lymphoblastic leukaemia. These results support the concept that Sezary cells are well-differentiated with respect to the T-cell axis. Quantitation of purine pathway enzymes may be useful in defining subsets of T-cell malignancy.