Differentiation of lymphoma from histoplasmosis in children with mediastinal masses

The differentiation of mediastinal masses caused by lymphoma from those caused by histoplasmosis may require thoracotomy. We reviewed the medical records of 37 children undergoing initial evaluation for anterior or middle mediastinal masses. Sixteen had biopsy-proved lymphoma, and 21 had histoplasmosis; seven with histoplasmosis underwent thoracotomy. Age, sex, fever, weight loss, duration of illness, anemia, erythrocyte sedimentation rate, nonspecific reactants, and lung infiltrates and calcifications were similar in both groups. Masses were in the middle mediastinum in all patients with histoplasmosis and in 69% with lymphoma. Masses were in the anterior mediastinum in one of 21 (5%) with histoplasmosis and 13 of 16 (81%) with lymphoma. Among patients with lymphoma, histoplasmal complement fixation antibody titers were less than 1:8 in 14 of 15 (93%); a single patient had a titer of 1:16. The CF titers were greater than or equal to 1:32 in 14 of 21 (67%) with histoplasmosis. In children with middle mediastinal masses, a histoplasmal CF yeast or mycelial titer greater than or equal to 1:32 is strongly suggestive of acute histoplasmosis and biopsy is not required. Children not fulfilling these criteria should undergo diagnostic biopsy.     

Histoplasmosis in a pediatric oncology center

OBJECTIVE: To understand the presentation and current management of histoplasmosis in a pediatric oncology center.Study design Retrospective review of clinical features of patients with histoplasmosis at a tertiary-care cancer center in an endemic area. RESULTS: Between 1988 and 2001, 57 patients with cancer had 61 episodes of acute histoplasmosis. Of these, 76% were male, and 64% had acute lymphocytic leukemia (ALL). Most were not neutropenic and had nonspecific febrile illnesses. The most rapid and specific tests for histoplasmosis in patients with cancer were histopathologic examination of lung biopsy specimens in patients with localized pulmonary infection and Histoplasma sp. antigen detection in the urine of patients with disseminated histoplasmosis (DH). The mean times to diagnosis were 20.6+/-15.2 days (pulmonary) and 18.6+/-8.2 days (disseminated) after the onset of symptoms. Most patients were treated with amphotericin B (AmB) followed by azole drugs for a mean of 8.5+/-3.1 weeks (pulmonary) and 10.4+/-7.9 weeks (disseminated). No patient died of histoplasmosis, but cancer therapy often was modified because of the infection. Most received unnecessary antibacterial drugs. CONCLUSIONS: Most readily available diagnostic tests for histoplasmosis lack sensitivity in these patients. Delay in diagnosis of histoplasmosis complicates care. No deaths were attributed to histoplasmosis; outcomes after treatment are good.     

Toxicity of amphotericin b in children with cancer.

The pattern of amphotericin B toxicity was assessed retrospectively in a group of 20 children with cancer who had received one or more courses of the drug for treatment of systemic fungal infection. Azotemia was the most frequent complication, developing during 23 of 24 treatment courses. Other major toxic effects, in decreasing order of frequency, were anemia, hypokalemia, thrombocytopenia, and neutropenia. Infusion side effects, including drug-related fever, chills, and nausea, were also frequently seen. Seventeen of 20 patients were treated for disseminated histoplasmosis. Nineteen of 20 patients had acute leukemia. Although interaction with other agents could not be excluded, amphotericin B appeared to be the major causative agent for the toxic reactions noted. In no patient, however, was administration of amphotericin B stopped because of drug toxicity.     

Evaluation of growth hormone release in children using arginine and L-dopa in combination.

L-Dopa in a dose ranging from 125-500 mg and arginine monochloride in a dose of 0.5 gm/kg were given simultaneously to 56 children with short stature (height less than third percentile). Sixteen of these children were subsequently diagnosed as having growth hormone deficiency. The diagnosis of hyposomatotropism was based on clinical findings and on responses to the combination test and to arginine and L-dopa administered as separate tests. All of the remaining 40 children had a normal GH response of greater than 6 ng/ml to the combination test. However, in this group, nine children were identified who responded to the combination test but who failed to respond to arginine and L-dopa in individual tests. The data suggest that a positive response to arginine and L-dopa in combination in children, who do not respond to the usual provocative tests when administered individually, may fail to identify children with partial GH deficiency who would benefit from treatment. The integrated stimulated GH response in the 31 children in whom a normal GH response to all three tests occurred suggests that the effects of L-dopa and arginine are additive.     

Splenic reticuloendothelial function in children with cancer

We studied splenic function in children with cancer by quantitation of pitted, or pocked, erythrocytes (pocked RBC count), that is, the percentage of erythrocytes containing one or more membrane-bound vesicles, as determined by phase interference microscopy. The mean pocked RBC count in 93 normal children and adults was 0.49% (range 0% to 2.0%), with only 2.4% of normal subjects having values greater than 1.5%. Mean pocked RBC count in 28 children after splenectomy was 37% (range 3.2% to 81%). Among 181 children with cancer (525 specimens), the mean pocked RBC count was 1.06% (range 0% to 12.6%). Fifty-nine (32%) patients had one or more values greater than 1.5%, and 25 (13.8%) children had measurements greater than 3.0%, a level previously suggested to have clinical significance. Elevated pocked RBC counts (greater than 1.5%) occurred in more than one third of children with Wilms tumor and acute lymphoblastic leukemia, and in both patients with juvenile chronic myelogenous leukemia. Elevations in pocked RBC counts were not related to specific chemotherapy regimens or to disease activity. Mild splenic reticuloendothelial hypofunction occurs in many children with cancer and may contribute to the risk of infection in these patients.     

OPPORTUNISTIC INFECTIONS IN PEDIATRIC HIV INFECTION: A study of 74 Autopsy Cases from Latin America

The present report describes opportunistic infections found at 74 autopsies of pediatric HIV AIDS patients performed at several hospitals in Latin American countries. Fungal infections were the most common (53 cases), Candida sp. (39.18 ) and Pneumocystis carinii (20.27 ) being the most frequently recognized. Other fungal diseases included histoplasmosis, aspergillosis, and cryptococcosis. Viral infections were present in 31 cases, 38.7 being due to cytomegalovirus. Other viruses recognized included herpes simplex and adenovirus. Additional opportunistic infections were due to Mycobacterium avium-intracellulare, toxoplasmosis, and tuberculosis. Nonspecific bacterial bronchopneumonia was present in 11 cases. Cytomegalovirus and P. carinii coinfection was the most common association found. In this series patients died at a younger age (72 at or younger than 1 year old) and there was a slightly higher number of cases of histoplasmosis and brain toxoplasmosis than in other previously published series of infants and children.     

Acute myelogenous leukemia in children: a preliminary report of combination chemotherapy.

Twenty-four children (2 to 21 years) diagnosed as having AML from 1969 to 1972 were randomized to receive either a single combination (COMP or PRAVD) or sequential combination chemotherapy (alternating POMP and PRAVD). Seventeen achieved complete remission. Patients who received POMP alone had the longest median duration of remission (1,400 days) compared to PRAVD (395 days) or POMP-PRAVD (270 days); interpretation of this difference is uncertain, since the numbers in each group are small. Fifteen patients have relapsed, four initially with CNS involvement. Successful reinduction was achieved almost exclusively for patients who had initially received POMP. Survival after first relapse was short. Patients less than 16 years had a median survival of 632 days, compared to 285 days for patiens greater than 16 (p less than 0.05). The high initial induction rate in these patients is encouraging, but the duration remission is inferior to that seen in childhood ALL. Moreover, the slope of the relapse curve is continuous over a five-year period with no definite plateau where it might appear that patients are no longer at risk of relapse. Improved methods for the treatment of childhood ALL and adult AML suggest possible new approaches to AML in children, with prophylactic treatment of central nervous system, late intensification, and immunotherapy.     

Disseminated histoplasmosis in infants

BACKGROUND: Disseminated histoplasmosis usually occurs in immunocompromised patients who reside in Histoplasma capsulatum-endemic regions. It has also been described in immunocompetent infants after exposure to a large inoculum of the pathogen resulting in case fatality rates of 40 to 50%. METHODS: From 1983 through 1996 all infants with documented disseminated histoplasmosis were treated with amphotericin B followed by daily ketoconazole for 3 months. Immunologic workups were performed at the time of diagnosis and at 4 to 6 weeks of therapy. Surviving patients were followed for at least 1 year. Time to resolution of signs and symptoms was recorded, as were complications. RESULTS: We managed 40 patients with disseminated histoplasmosis. The age in months at diagnosis was 15.3+/-10.2 (mean +/- SD), and 24 were male. All patients were from endemic regions and they presented with fever, spleen and/or liver enlargement and hematologic abnormalities. Diagnosis was made by histology and culture of bone marrow, spleen, lymph node, bronchoalveolar or liver samples. Twenty patients presented with T cell deficiency that resolved at 4 to 6 weeks of therapy in all of the retested patients, and 10 of 12 tested patients had hyperglobulinemia that resolved. Thirty-five (88%) patients were cured by treatment; 4 died and 1 relapsed. CONCLUSIONS: Disseminated histoplasmosis should be considered in infants from endemic areas who present with fever, hepatosplenomegaly and hematologic abnormalities. These patients develop transient hyperglobulinemia and T cell deficiency that resolve with treatment. Treatment with amphotericin B followed by an oral azole for 3 months is effective in most patients.     

Idiopathic thrombocytopenic purpura in children.

Idiopathic thrombocytopenic purpura in children 10 years of age or younger was observed to have a more favorable prognosis than in older children. Corticosteroid therapy in children judged to be at increased risk of serious hemorrhage resulted in a significantly greater number of patients with an early increase in platelets than was noted in a control group. All patients with chronic disease who responded to administration of a corticosteroid initially and then relapsed had some response to a subsequent course of therapy, although none had a sustained remission. In such patients, splenectomy was a more effective therapeutic measure than treatment with either a corticosteroid or a cytotoxic agent.     

Disseminated histoplasmosis

We describe two cases of disseminated histoplasmosis, which are of interest due to their severity and the infrequency of this infection in our environment. Both children were immunocompromised immigrants from Latin America who developed prolonged fever, weight loss, hepatosplenomegaly and pancytopenia. One patient had respiratory symptoms with associated alterations on x-ray, while no radiological alterations were found in the other patient. Despite administration of broad-spectrum antibiotics and extraction of samples for microbiological analysis, both patients had a rapid and fatal outcome and the diagnosis was made post mortem. Because of its severity, disseminated histoplasmosis should be considered in the differential diagnosis of fever, hepatosplenomegaly and pancytopenia, with or without alterations on chest x-ray, in immunosuppressed children who were born in or have visited endemic regions. In these patients, therapy should be started immediately without waiting for the results of diagnostic tests.     

Intellectual development at 10 years in early treated congenital hypothyroidism.

Fifty nine children born between 1978 and 1981 with congenital hypothyroidism detected by neonatal screening were assessed at 10 years using the Wechsler intelligence scale for children, together with 59 matched classroom controls. Thirty one children with severe hypothyroidism who had pretreatment plasma thyroxine concentrations of 40 nmol/l or less had a mean (SD) full scale IQ score of 104.7 (15.1), compared with a mean (SD) score of 114.6 (16.3) for the 28 less severely affected children who had pretreatment thyroxine levels greater than 40 nmol/l, and mean (SD) scores of 114.5 (12.8) and 114.8 (13.8) respectively for the 31 and 28 control children. In the hypothyroid children the IQ scores at 10 years were closely related to the IQ scores at 5 years and at 3 years. It is concluded that the deficit in IQ score found at 3 and 5 years in children with severe hypothyroidism is still evident at the age of 10 years.     

Second Malignant Neoplasms in Patients Treated for Childhood Leukemia: A Population-based Cohort Study from the Nordic Countries

ABSTRACT. Among a cohort of 981 children who were followed up 4.3–26.5 years after cessation of antileukemic therapy, eight patients in remission of acute lymphoblastic leukemia (ALL) developed a distinctively new malignant disease. The second malignant neoplasms (SMN) included brain tumors, basal cell carcinomas, thyroid cancer, leiomyo-sarcoma and finally rhabdomyosarcoma in a patient who also had suffered from Hodgkin's disease while still on antileukemic treatment. Cranial radiation had been given to 58.4% of the patients in the study group, which consisted of 895 ALL patients who had completed various chemotherapy protocols. With one exception, the SMN appeared after 7.5–16.5 years at a location previously exposed to radiotherapy (RT). The estimated cumulative risk of SMN appearing within 20 years after diagnosis was 2.9%, and the corresponding risk for cases with RT was 8.1% compared to 0.3% for those without ( p = 0.05). In a Cox regression analysis, the incidence rate ratio of SMN between patients with and without RT was 6.7 (95% CI = 0.8, 57.7). Based on age-, year- and sex-specific cancer incidence figures for Norway, the overall standardized incidence rate ratio (SIR) of SMN after treatment for ALL was 5.9 (95% CI = 2.2, 12.9). The number of brain tumors among patients who had received cranial radiation was nearly 27 times greater than expected, whereas no such tumors were seen after chemotherapy. Individuals treated for childhood ALL are at increased risk of a new malignancy, and this seems mainly to be associated with previous irradiation.     

The value of neuroradiology in infantile spasms

The results of neuroradiologic studies of 71 children with infantile spasms treated with ACTH were correlated with the developmental outcome at follow-up (mean 62 months, range 14 to 207 months). Fifty-two (73%) patients had an abnormal NRS on initial evaluation; 49% had cerebral atrophy, 18% had congenital anomalies, and 6% had hydrocephalus. Twenty patients were normal on initial clinical evaluation. At follow-up only the eight (40%) with normal NRS were normal. Twelve (60%) who had unexpected abnormalities on NRS were retarded at follow-up. CAT scanning is necessary to predict the developmental outcome in developmentally normal children with infantile spasm. Eight of nine patients with normal NRS in the early treatment group were developmentally normal at presentation and follow-up. Ten patients who were developmentally normal before spasms began, and had normal NRS but were in the late treatment group, were retarded at initial evaluation and follow-up. This finding suggests that early treatment of children who have a normal NRS and normal development at onset of spasm prevents mental retardation.     

Second malignant neoplasms in patients treated for childhood leukemia. A population-based cohort study from the Nordic countries. The Nordic Society of Pediatric Oncology and Hematology (NOPHO).

Among a cohort of 981 children who were followed up 4.3-26.5 years after cessation of antileukemic therapy, eight patients in remission of acute lymphoblastic leukemia (ALL) developed a distinctively new malignant disease. The second malignant neoplasms (SMN) included brain tumors, basal cell carcinomas, thyroid cancer, leiomyosarcoma and finally rhabdomyosarcoma in a patient who also had suffered from Hodgkin's disease while still on antileukemic treatment. Cranial radiation had been given to 58.4% of the patients in the study group, which consisted of 895 ALL patients who had completed various chemotherapy protocols. With one exception, the SMN appeared after 7.5-16.5 years at a location previously exposed to radiotherapy (RT). The estimated cumulative risk of SMN appearing within 20 years after diagnosis was 2.9%, and the corresponding risk for cases with RT was 8.1% compared to 0.3% for those without (p = 0.05). In a Cox regression analysis, the incidence rate ratio of SMN between patients with and without RT was 6.7 (95% CI = 0.8, 57.7). Based on age-, year- and sex-specific cancer incidence figures for Norway, the overall standardized incidence rate ratio (SIR) of SMN after treatment for ALL was 5.9 (95% CI = 2.2, 12.9). The number of brain tumors among patients who had received cranial radiation was nearly 27 times greater than expected, whereas no such tumors were seen after chemotherapy. Individuals treated for childhood ALL are at increased risk of a new malignancy, and this seems mainly to be associated with previous irradiation.     

A controlled longitudinal study of the social functioning of children who completed treatment of cancer

BACKGROUND: A follow-up assessment of social functioning was performed for children with cancer after completion of treatment. It was hypothesized that children who completed cancer treatment (CCT) would have more social problems than their peers who were not chronically ill (COMP) and that greater treatment intensity would be predictive of increasing social difficulties over time. PATIENTS AND METHODS: Peer, teacher, and self-reports of social functioning were obtained from 69 CCTs and 77 COMPs. Social reputation and social acceptance were evaluated cross-sectionally and longitudinally. RESULTS: Relative to COMPs, CCTs described themselves as more prosocial, were perceived by teachers as less aggressive, and were seen by peers as more sick, more tired, and as missing more school. Longitudinal analyses indicated that self-reported prosocial scores were significantly more stable over time for CCTs relative to COMPs. Children who received more intense treatment were perceived by peers as more prosocial and less aggressive, but as having fewer best friends 2 years after treatment ended. CONCLUSIONS: CCTs had minimal impact on their social functioning as a result of their experience with cancer for those children who have returned to school. These results suggest that routine interventions with regard to social functioning after treatment ends may not be warranted for most CCTs when an integrated program of psychosocial services coordinated by mental health professionals has been provided during treatment. However, children who have undergone especially intense treatment may be at some risk for social problems.     

Isoniazid liver injury during chemoprophylaxis in children.

The incidence of INH-associated liver injury was evaluated in 239 children aged between 9 and 14 years, who were receiving 300 mg INH/day for tuberculosis prophylaxis. Serum SGOT and SGPT levels were determined before INH administration and at 4-weekly intervals thereafter. Levels of both enzymes were raised during the first 3 months of treatment in 18 (7.5%) children, while in 23 (9.6%) children either SGOT or SGPT exceeded normal levels (SGOT greater than 40 units, SGPT greater than 30 units). Only 2 (0.8%) children showed SGOT and SGPT values above 100 units and in them treatment with INH had to be discontinued. In all other children transaminases returned to normal during uninterrupted INH administration. It was noted also that transaminase values in children who did not exhibit a rise above normal, still had significantly higher levels during treatment compared with before. The findings of this study suggest that liver injury in children receiving INH for prophylaxis occurs more often than it had hitherto been believed but that it is usually mild and transient.     

Coagulopathy and platelet activation in Kawasaki syndrome: identification of patients at high risk for development of coronary artery aneurysms

Prospective evaluation of platelet activation and hypercoagulability was performed in 31 patients with Kawasaki syndrome. Most patients had elevated acute-phase reactants when studied during the first 3 weeks of their illness; 17 of 25 (68%) patients had factor VIII activity greater than 150%, 18 of 24 (75%) had fibrinogen greater than 400 mg/dl, and 17 of 31 (55%) had a platelet count greater than 450,000/mm3. Antithrombin III was depressed initially in 17 of 25 (68%) patients. Depleted fibrinolytic activity, as measured by a euglobulin lysis time greater than 300 minutes, was documented in nine of 20 (45%) patients. Plasma beta-thromboglobulin (BTG) measured at 0 to 3 weeks was elevated (greater than 43 ng/ml) in seven of 24 (29%) patients. All patients with coronary artery aneurysms had elevated BTG values. The mean BTG in the group with aneurysms was 72.3 ng/ml when measured during the first 3 weeks after onset of fever, and 87.7 ng/ml at 4 to 7 weeks. The group without aneurysms had mean BTG values of 29.4 and 28.3 ng/ml at 0 to 3 and 4 to 7 weeks, respectively. The difference between the two groups was significant (P less than 0.002) for both the initial and later values. An elevated BTG during the first 3 weeks after onset of fever was highly associated with aneurysm formation in our patients (P less than 0.007). No aneurysms occurred in patients with a normal BTG value.     

Late orthopedic effects in children with Wilms' tumor treated with abdominal irradiation.

Between 1970 and 1984, 31 children with biopsy-proven Wilms' tumor received nephrectomy, chemotherapy, and abdominal irradiation and were followed beyond skeletal maturity. Three patients (10%) developed late orthopedic abnormalities requiring intervention. Ten children received orthovoltage irradiation, and all cases requiring orthopedic intervention or developing a scoliotic curve of greater than 20 degrees were confined to this group, for a complication frequency of 50%. Those children who developed a significant late orthopedic abnormality (SLOA) as defined were treated to a higher median dose (2,890 cGy) and a larger field size (150 cm2) than those who did not (2,580 cGy and 120 cm2). Age at irradiation, sex, and initial stage of disease did not appear to influence the risk of developing an SLOA. No child who received megavoltage irradiation developed an SLOA despite treatment up to 4,000 cGy or to field sizes of 400 cm2. We conclude that modern radiotherapy techniques rarely lead to significant late orthopedic abnormalities previously associated with abdominal irradiation in children with Wilms' tumor.     

Pharmacokinetics and pharmacodynamics of cimetidine and metabolites in critically ill children

Cimetidine and antacids are the mainstays of therapy for the prophylaxis of stress-induced ulceration in critically ill children. Previous cimetidine dosing recommendations have been empiric because of a lack of knowledge about cimetidine disposition kinetics in children. Thirty children, mean age 9 +/- 3.2 years, were admitted to the study with the following primary diagnoses: closed head injury (23 patients), sepsis (four), gunshot wound (two), and bleeding gastric ulceration (one). The mean dose of cimetidine was 26 mg/kg/day, administered intravenously over 15 minutes in four divided doses. Cimetidine disposition was best described by a biphasic elimination curve with t1/2 values for cimetidine, cimetidine sulfoxide, and hydroxymethyl cimetidine of 1.39, 2.6, and 4.7 hours, respectively. Cimetidine plasma concentrations were maintained at greater than or equal to 0.5 microgram/ml for a significantly longer time in patients who received greater than or equal to 20 mg/kg/day. Most patients had a plasma cimetidine concentration below 0.5 to 1.0 microgram/ml 4 hours after infusion. The mean apparent volume of distribution and total body clearance for cimetidine were 1.23 L/kg and 10.4 ml/min/kg, respectively. A significant correlation was found between age and either apparent volume of distribution (r = 0.76, P less than 0.001) or total body clearance (r = 0.75, P less than 0.001). No significant correlation between cimetidine concentrations in either plasma or gastric juice and gastric pH could be determined. However, seven of nine patients who received only cimetidine had a gastric pH of greater than or equal to 4 at 2 hours after infusion when the plasma cimetidine concentration was greater than or equal to 1.0 or the gastric juice concentration was greater than or equal to 2.0 microgram/ml. The mean gastric pH was 2.2 at 6 hours, when plasma and gastric juice concentrations of cimetidine were greater than or equal to 1.0 microgram/ml. On the basis of our data, a cimetidine dosage of 20 to 30 mg/kg/day administered in six divided doses should provide for average steady-state plasma cimetidine concentrations of 1.3 to 2.0 micrograms/ml.     

Serum vascular endothelial growth factor as a significant marker of treatment response in pediatric malignancies

The aim of this pilot study was to determine VEGF serum levels (S-VEGF) at diagnosis and at restaging in children diagnosed with cancer, and to investigate whether this parameter provides prognostic information for remission after induction therapy and response to treatment. S-VEGF levels of 35 consecutive pediatric patients with various types of cancer were assayed at diagnosis and at restaging. Levels of VEGF were determined using a commercially available ELISA anti-human VEGF immunoassay kit. Thirty-one children went into complete remission or had a very good partial response to first-line therapy; 4 patients developed tumor progression. At diagnosis average S-VEGF level was 495 pg/mL (range, 0.89--2220 pg/mL) and at restaging it decreased to 118.36 pg/mL (range, 7.44--487 pg/mL). (p=.0039). The 4 patients with tumor progression had increased S-VEGF levels at restaging. The comparison between the levels of S-VEGF at diagnosis and at restaging showed a significant difference for the patients who responded to treatment with decreased S-VEGF and the patients who developed tumor progression with increased S-VEGF (p=.0019). One child with metastatic Ewing sarcoma developed progressive disease after several weeks, with significantly progressively higher S-VEGF levels. One child with Hodgkin disease, who had a higher level at first restaging and developed progressive disease, responded to reinduction therapy and had a significantly lower level at the second restaging. The child with metastatic hepatoblastoma responded to first-line chemotherapy with concomitant decrease in S-VEGF and alpha-fetoprotein levels, but developed local recurrence with elevation in both parameters. Changes in S-VEGF levels correlated with response to treatment for most of the children diagnosed with cancer. This provides a rationale for exploring clinical interest in S-VEGF measurements of a larger group of children with malignancies, and using the test for clinical trials of antiangiogenic therapies.