Treatment of hepatosplenic candidiasis with liposomal-amphotericin B.

Nine patients with hematologic malignancies developed fungal infections, predominantly involving the liver and spleen. Eight patients had biopsy-documented progressive candidiasis and one had an unclassified fungus. The patients were treated with liposomal-amphotericin B (L-AmpB) after their fungal infection progressed during treatment with standard intravenous (IV) AmpB (Fungizone; E. R. Squibb & Son, Princeton, NJ) and/or other antifungals. Eight patients (88.8%) were cured of their fungal infection, and one showed improvement after treatment. Minor acute toxicity and no chronic toxicity were associated with the administration of L-AmpB. L-AmpB is a safe and effective therapeutic method for treating fungal infections that have invaded the liver and spleen even when they are refractory to conventional anti-fungal therapy.

High-dose methotrexate as part of remission maintenance therapy for childhood acute lymphocytic leukemia: a Pediatric Oncology Group pilot study.

Seventeen children with acute lymphocytic leukemia (ALL) in remission were treated with parenteral high-dose methotrexate (HDM) pulses every eight weeks during standard 6-mercaptopurine and methotrexate (MTX) oral maintenance therapy. MTX (1,000 mg/m2) was infused over one hour followed by one hour of intravenous hydration for the purpose of achieving plasma and cerebrospinal fluid (CSF) levels greater than 10(-6) M for a period of 24 hours. Leucovorin (15 mg/m2) was administered orally six, 12, and 18 hours after completion of the HDM. Plasma and CSF concentrations of MTX were evaluated serially in the first 48 hours. During the first 24 hours, the plasma MTX level was maintained at greater than 10(-6) M. The patients receiving intrathecal MTX at a dose of 15 mg/m2 had an adequate, sustained MTX level in the CSF, but when no intrathecal MTX was administered, the CSF levels were less than 10(-6) M. For that reason, intrathecal MTX in a low dose (6 mg/m2) was injected intrathecally one hour after the HDM infusion, allowing the MTX level in CSF to approximate 10(-6) M over the 24 hours. The toxicity of this therapy was minimal. Due to the facts that the plasma and CSF MTX levels could be sustained above the desired concentrations and this regimen could be given in the outpatient clinic, this program has been incorporated into an ongoing study in an effort to prolong complete remissions.

Lack of ETV6 (TEL) gene rearrangements or p16INK4A/p15INK4B homozygous gene deletions in infant acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) occurring in infants less than 1 year of age differs clinically and biologically from that observed in older children. Cytogenetically, 11q23 translocations are detected in approximately 50% of infant ALLs and fuse the 11q23 gene HRX with a variety of partner chromosomal loci. Overall, HRX rearrangements are detected molecularly in 70-80% of infant ALLs as compared to 5-7% of ALLs arising in older children. Two recently described molecular abnormalities in childhood ALL are ETV6 gene rearrangements and homozygous deletions of p16(INK4A) and/or p15(INK4B). Each of these abnormalities occurs in 15-20% of all childhood ALLs, and neither can be accurately identified by routine cytogenetic analyses. The incidence of these genetic abnormalities and their potential relationship to HRX gene status in infant ALL is unknown. Using Southern blot analyses, we determined ETV6 and p16(INK4A)/p15(INK4B) gene status in a cohort of infant ALLs. No ETV6 rearrangements or homozygous deletions (n=69) or homozygous p16(INK4A) and/or p15(INK4B) gene deletions (n=54) were detected in any of the infant ALLs. Therefore, ETV6 and p16(INK4A)/p15(INK4B) do not play a significant role in the pathogenesis of infant ALL, further emphasizing the distinctive biology of this subset of leukemias.

Treatment of systemic fungal infections with liposomal amphotericin B.

Forty-six patients with systemic fungal infections were treated with liposomal amphotericin B. Twenty-one patients had disseminated candidiasis, 19 had aspergillosis, and the rest had a variety of other fungal infections. Forty patients failed to respond to conventional amphotericin B therapy, and 6 patients were given liposomal amphotericin B because conventional amphotericin B caused severe side effects. Twenty-four patients had a complete response, and 22 patients failed to respond. No short- or long-term toxic reactions were observed. The acute side effects such as fever, chills, and potassium loss were infrequent and milder than those commonly observed with conventional amphotericin B. No chronic renal, hematologic, or central nervous system side effects were observed. Liposomal amphotericin B therapy was effective and less toxic than conventional amphotericin B therapy.

Multiple-dose amikacin kinetics in pediatric oncology patients.

Amikacin kinetics was studied in 8 pediatric oncology patients who received the drug by intravenous infusion over 30 or 60 min at a dose of 5 mg/kg every 6 or 8 hr. This regimen is recommended but, due to patient variability, patients should be monitored. Dosing intervals during 1 or 2 and 3 or 4 days of therapy were studied with serum samples collected before and at the end of the infusion and serially to the end of the dosing interval. The data appeared consistent with and were analyzed according to 1-compartment model. An equation describing serum concentration with time for the multiple-dose case was fit to each patient's multiple-interval data with nonlinear regression. Half-life averaged 1.2 hr. volume of distribution 0.24 l/kg, and total body clearance 109 ml/min/1.73 m2 or 2.51 ml/min/kg. The volume of distribution and the clearance are greater than reported for adults and probably account for the larger dose needed to achieve and maintain therapeutic levels. Although the total daily dose was greater than previously reported, there were no signs of toxicity, although therapuetic concentrations were maintained.

Neuropsychological effects of childhood cancer treatment.

The potential neuropsychological effects of treatment were investigated in 124 childhood cancer patients. Children were classified into groups on the basis of treatment modality and treatment status. All patients received systemic chemotherapy. Other treatment modalities included intrathecal chemotherapy and intrathecal chemotherapy plus central nervous system radiation therapy. Treatment status was determined by whether children were newly diagnosed patients in active treatment or long-term survivors of cancer. This classification resulted in five groups; group 1 (n = 29)--children with newly diagnosed disease who were receiving intrathecal chemotherapy; group 2 (n = 21)--children with newly diagnosed disease who were receiving systemic chemotherapy without central nervous system treatment; group 3 (n = 24)--long-term survivors who had received intrathecal chemotherapy; group 4 (n = 25)--long-term survivors who had received intrathecal chemotherapy plus cranial radiotherapy; and group 5 (n = 25)--long-term survivors who had received systemic chemotherapy only (no specific central nervous system treatment). Groups were compared by using multivariate analysis of variance on sets of neuropsychological test variables that represent major cognitive domains. Results of comparisons indicated significant group differences for most dependent-variable sets. Follow-up pairwise comparisons showed that the group of long-term survivors who had received intrathecal chemotherapy plus cranial radiotherapy consistently obtained lower test scores than the other four groups. These findings are consistent with results of previous studies, thus indicating that intrathecal chemotherapy plus cranial radiotherapy is associated with significant effects on neuropsychological performance. Comparisons among newly diagnosed and long-term groups of patients who did not receive cranial radiotherapy yielded null results on measures of higher-order cognitive functions. However, significant group differences were observed on measures of fine-motor and visual-motor skills; newly diagnosed groups obtained lower scores than the nonirradiated long-term survivor groups. Findings were attributed to chemotherapy-induced peripheral neuropathy that differentially affected the newly diagnosed groups.

Factor XIII deficiency and intracranial hemorrhages in infancy.

We report an infant with Factor XIII deficiency who had 2 seemingly spontaneous intracranial hemorrhages. It is important to consider Factor XIII deficiency as a possible cause of unexplained intracranial hemorrhages in infancy. Ongoing factor replacement therapy is recommended to prevent further bleeding episodes.

Incidence of childhood and adolescent cancer in Texas.

Population-based data from the Texas Cancer Registry were used to describe the incidence of cancer in 1990 among Texas residents younger than 20 years. A total of 788 primary malignant neoplasms were diagnosed. Higher incidence of all cancers was observed among Texas Anglo children compared with Hispanics or African-Americans, and lower rates of central nervous system (CNS) neoplasms were seen among Hispanics. Compared with national data, significantly fewer cases of all cancers combined, non-Hodgkin's lymphoma, neuroblastoma, and CNS neoplasms were seen in Texas Hispanics. The overall incidence of leukemia and acute nonlymphocytic leukemia (ANLL) was highest in Hispanics compared with other Texas children, and a three-fold statistically significant excess of ANLL was evident in Hispanic females compared with national whites. In summary, the incidence of cancer in Texas Hispanic children and adolescents differs from that seen in other racial and ethnic groups. Incidence data for Texas provide additional insight into the descriptive nature of childhood and adolescent cancers.

Diagnosis of leukemic relapse in the pelvic soft tissues of juvenile females.

Five females with childhood acute lymphocytic leukemia whose disease relapsed in the pelvis were studied. In all five patients, relapse occurred late in the disease process, and all patients had been in complete continuous remission before relapse. Intravenous pyelogram and barium enema revealed hydronephrosis or a mass effect on the bladder or rectosigmoid colon. In three patients, sonography established the presence of a clinically palpable mass with involvement of the uterus, ovaries, and pelvic side walls. In one patient there was infiltration of the bladder and in another, infiltration of the appendix, both confirmed by biopsy.

Soft tissue ameloblastoma in a 92-year-old woman.

Ameloblastoma is a rare epithelial neoplasm that most commonly is found within the bony structure of the jaw. Soft tissue ameloblastomas are rarer. Only nine well-documented cases are found in the reviewed world's literature. It is our purpose to report the clinical and morphological features of a gingival ameloblastoma in a 92-year-old woman.

Pelvic and ovarian extramedullary leukemic relapse in young girls: a report of four cases and review of the literature.

Currently attention is focused on the testicle as a site of leukemic relapse. Leukemic involvement of the ovary has been described in several autopsy series with an incidence of 11-50% in patients with bone marrow relapse, but has rarely been reported during the clinical course of leukemia. In this report, four girls with childhood acute lymphocyte leukemia (ALL) who relapsed with a pelvic mass are presented. Three had marked ovarian infiltrates and the fourth had a presacral mass without ovarian disease. Involvement was also present in abdominal and pelvic lymph nodes, mesentery, omentum, and serosal surfaces. Two patients had infiltrates of the fallopian tubes and one had uterine involvement. Two patients had central nervous system disease and one patient has renal involvement at the time of relapse. Relapse occurred late in the course of disease. All patients had been in complete continuous remission prior to relapse. Retreatment was instituted in all patients and follow-up ranges from 18-135 months from the time of pelvic relapse. All patients have maintained continuous bone marrow remission from the time of initial diagnosis, and one patient died 18 months after ovarian relapse with significant extramedullary disease but no marrow involvement. This represents the first series of pelvic extramedullary leukemic relapse in females, an area of involvement that may be encountered more frequently in the future.

Severe hypertensive reactions to teniposide (VM-26) in infants with congenital leukemia.

Two cases of infants with congenital leukemia who had severe, refractory hypertensive reactions to teniposide (VM-26) are described. Patients on a 5 mg/kg twice weekly schedule of teniposide had hypertensive reactions in which their systolic blood pressure was greater than 200 mm Hg after the second dose of teniposide. Hypertension combined with myelosuppression resulted in the patient's death in one case. Although the exact mechanism of this unusual toxicity of teniposide remains unknown, it might be an age-specific problem, considering the very young age of our patients. Meticulous monitoring of vital signs, including blood pressure, is mandatory in leukemic infants receiving teniposide.

Diagnostic value of surgical testicular biopsy after therapy for acute lymphocytic leukemia.

Inasmuch as several cooperative research groups currently require routine testicular biopsy in boys with acute lymphocytic leukemia before cessation of therapy, we performed bilateral open wedge biopsies in 38 boys aged 4 1/2 to 18 years, all of whom were completing 3 years of therapy, were apparently in complete remission, and had palpably normal testes. Biopsy specimens from two other patients were examined during therapy for specific clinical indications. Among the 40 patients, one biopsy revealed leukemia bilaterally; 39 patients had negative biopsy results, three of whom had overt, biopsy-proved testicular relapse 6 weeks to 17 months after normal biopsy. All four patients with testicular relapse are in complete remission six to 50 months after testicular irradiation. We conclude that random sampling during routine testicular biopsies may fail to demonstrate occult leukemia, and that the high rate of complete remissions following retrieval therapy after overt testicular relapse makes routine biopsies before cessation of therapy unnecessary.

Mezlocillin pharmacokinetics in pediatric oncology patients.

The pharmacokinetics of mezlocillin were studied in 31 children (age, 2 to 19 years) with malignancies and normal renal and hepatic functions. Mezlocillin was administered intravenously over 30 min every 4 h at doses ranging from 12.2 to 125 mg/kg. Blood samples were obtained over one dosage interval at steady state. For all patients, the mean clearance was 0.21 +/- 0.11 liter/h per kg, the mean distribution volume was 0.26 +/- 0.13 liter/kg, and the mean elimination half-life was 0.97 +/- 0.51 h. Trough concentrations were 23.0 +/- 29.9 mg/liter before the dose was administered and 20.4 +/- 27.5 mg/liter at the end of the dosing interval. Peak concentrations averaged 245 +/- 90.4 mg/liter, and average concentrations for the dosing interval were 83.7 +/- 40.4 mg/liter. There were no apparent effects of sex, malignancy, age, or dose on either the kinetic parameters or plasma concentrations. Overall, the disposition parameters for mezlocillin in this patient group were comparable to those reported in adults.

Ag-NOR staining in human chromosomes: differential staining in normal and leukemic bone-marrow samples.

A silver staining technique developed by Goodpasture and Bloom (1975) stains a specific protein associated with the activity of ribosomal cistrons during the preceding interphase. By counting the number of chromosomes with darkly stained nucleolus organizer regions (NORs), the number of active NORs per metaphase can be determined. A comparison of NOR activity in bone-marrow cells from leukemic patients in different stages of disease with that of bone marrow from normal, healthy individuals was conducted and differential NOR activity was detected. The control group showed significantly lower NOR activity when compared with a group of patients with acute lymphocytic leukemia (ALL). These preliminary data indicate that this simple cytochemical technique can be effectively used to differentiate between normal and ALL bone-marrow samples.

Aplastic crisis in occult hereditary spherocytosis caused by human parvovirus (HPV B19).

We have reported a case of aplastic crisis occurring in an 11-year-old black boy with occult hereditary spherocytosis. An etiologic diagnosis of human parvovirus (HPV) B19 infection was confirmed serologically. The Coulter Model S + IV proved useful for both diagnosis and treatment monitoring through serial histograms. The relationship of HPV infection and aplastic crisis is discussed.

Bioavailability of allopurinol oral and rectal dosage forms.

The bioavailability of allopurinol from orally administered tablets and rectally administered suppositories is reported. Two types of rectal suppositories (cocoa butter and polyethylene glycol) were compounded and contained 300 mg allopurinol (from oral tablets). Five healthy volunteers received 300 mg allopurinol orally from tablets or rectally from suppositories in a randomized, three-way crossover design. Serial blood samples were drawn for 72 hours following administration and were analyzed by high-pressure liquid chromatography for allopurinol and its metabolite, oxipurinol. The interaction between allopurinol and PEG was studied in vitro using a dialysis method. Serum allopurinol levels following oral administration of tablets peaked at 1.5 +/- 0.23 microgram/ml at 5.20 +/- 0.65 hours. Allopurinol was not detectable after administration of cocoa butter/allopurinol suppositories; oxipurinol peaked at 0.34 +/- 0.14 microgram/ml at 13 +/- 11 hours. The bioavailability of allopurinol from the cocoa butter suppository, relative to the tablet, was 5.77 +/- 2.5%. Neither allopurinol nor oxipurinol was detectable (less than 0.1 microgram/ml) in the sera of persons following administration of PEG suppositories. Dialysis studies showed decreased loss of allopurinol from the dialysis sac as PEG concentration increased. The rectal suppositories of allopurinol used in this study did not appear to be an efficient means of administering this drug.