Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia.

BACKGROUND: Pediatric patients receiving induction chemotherapy for newly diagnosed acute lymphoblastic leukemia (ALL) are at high risk of developing life-threatening infections. We investigated whether uniform antibacterial guidelines, including mandatory antibacterial prophylaxis in afebrile patients during induction, decreases the incidence of microbiologically documented bacteremia. METHODS: Between 2012 and 2015, 230 patients with newly diagnosed ALL (aged 1-21) were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 11-001 (DFCI 11-001). Induction therapy, regardless of risk group, included vincristine, prednisone, doxorubicin, methotrexate, and PEG-asparaginase. Afebrile patients received fluoroquinolone prophylaxis at the initiation of induction and those presenting with fever received broad-spectrum antibiotics; antibiotics were continued until blood count recovery. Rates of documented bacteremias and fungal infections on DFCI 11-001 were compared to those on the predecessor protocol (DFCI 05-001), which included the same induction phase without antibiotic prophylaxis guidelines. RESULTS: Sixty-six (28.7%) patients received fluoroquinolone prophylaxis, the remaining patients received broad-spectrum antibiotics. Twenty-four (36.4%) patients on prophylaxis developed fever and seven (10.6%) developed bacteremia. The overall rate of infection during induction on DFCI 11-001 was lower than on DFCl 05-001 (14.3% vs. 26.3%, P < 0.0001) due to a decreased rate of bacteremia (10.9% vs. 24.4%, P < 0.0001). The rate of fungal infections (4.8% vs. 3.6%) and induction death (0.9% vs. 2%) was not significantly different. CONCLUSION: For children with newly diagnosed ALL, uniform antibiotic administration until blood count recovery, including fluoroquinolone prophylaxis for afebrile patients, reduced the incidence of bacteremia during the induction phase. Larger, randomized studies should be performed to confirm these findings.

γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate.

BACKGROUND: γ-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect. METHODS: We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo. RESULTS: Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increased as folate concentration increased. CONCLUSION: Modulation of GGH affects chemosensitivity of cancer cells to 5FU and MTX, and exogenous folate levels can further modify the effects.

Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000).

The Dana-Farber Cancer Institute (DFCI) acute lymphoblastic leukemia (ALL) Consortium has been conducting multi-institutional clinical trials in childhood ALL since 1981. The treatment backbone has included 20-30 consecutive weeks of asparaginase during intensification and frequent vincristine/corticosteroid pulses during the continuation phase. Between 1985 and 2000, 1457 children aged 0-18 years were treated on four consecutive protocols: 85-01 (1985-1987), 87-01 (1987-1991), 91-01 (1991-1955) and 95-01 (1996-2000). The 10-year event-free survival (EFS)+/-s.e. by protocol was 77.9+/-2.8% (85-01), 74.2+/-2.3% (87-01), 80.8+/-2.1% (91-01) and 80.5+/-1.8% (95-01). Approximately 82% of patients treated in the 1980s and 88% treated in the 1990s were long-term survivors. Both EFS and overall survival (OS) rates were significantly higher for patients treated in the 1990s compared with the 1980s (P=0.05 and 0.01, respectively). On the two protocols conducted in the 1990s, EFS was 79-85% for T-cell ALL patients and 75-78% for adolescents (age 10-18 years). Results of randomized studies revealed that dexrazoxane prevented acute cardiac injury without adversely affecting EFS or OS in high-risk (HR) patients, and frequently dosed intrathecal chemotherapy was an effective substitute for cranial radiation in standard-risk (SR) patients. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.

Benign outcome of RSV infection in children with cancer.

BACKGROUND: High case-fatality rates have been reported among adults who develop respiratory syncytial virus (RSV) infection while being treated for oncologic diseases, particularly after bone marrow transplantation. Previous reports of RSV infection among children with primary and acquired immunodeficiencies describe increased morbidity compared with that seen in immunocompetent children, but there have been few reports describing the outcome of RSV infection specifically among pediatric oncology patients. METHODS: We retrospectively reviewed the charts of all children being treated by the Pediatric Oncology Service at Memorial Sloan-Kettering Cancer Center who had positive tests for RSV between the Fall of 1994 and the Spring of 1998. Patients on the BMT Service were excluded from this analysis. RESULTS: Eighteen RSV infections were identified among pediatric oncology patients, who were being treated with aggressive, predominantly alkylator-based chemotherapy for a variety of oncologic diagnoses. Nine episodes of RSV infection (50%) were treated with specific antiviral therapy. Only one death less than 100 days from the diagnosis of RSV infection occurred among these 18 patients and was attributed to progressive leukemia. The remaining patients recovered fully, although three were readmitted with respiratory symptoms within two weeks of discharge. Seven patients had concurrent infection with other pathogenic organisms. CONCLUSIONS: In striking contrast with the outcome of RSV infection in adult oncology patients, there may be low mortality associated with RSV infection in pediatric oncology patients. It is possible that scheduled anti-neoplastic therapy need not be delayed for these patients when the diagnosis of RSV infection is made.

Effects of overexpression of gamma-Glutamyl hydrolase on methotrexate metabolism and resistance.

Intracellular metabolism of methotrexate (MTX) to MTX-polyglutamates (MTXPG) is one determinant of cytotoxicity. Steady-state accumulation of MTXPG seems to depend on the activity of two enzymes: folylpolyglutamate synthetase (FPGS), which adds glutamate residues, and gamma-glutamyl hydrolase (GGH), which removes them. Overexpression of GGH would be expected to decrease intracellular MTXPG, thereby increasing efflux of MTX and decreasing cytotoxicity. Increased expression of GGH has been shown to be associated with resistance to MTX in human sarcoma cell lines and a rat hepatoma cell line. To clarify the specific role of GGH in determining MTX sensitivity, we investigated the phenotype produced by forced GGH overexpression in two cell types. Furthermore, because MTX and folic acid share metabolic pathways, we measured the effects of GGH overexpression on folic acid metabolism. The full-length cDNA for GGH, subcloned into a constitutive expression vector, was transfected into a human fibrosarcoma (HT-1080) and a human breast carcinoma (MCF-7) cell line. Compared with the clones containing an empty vector, the GGH-overexpressing cells express 15- to 30-fold more GGH mRNA, more GGH protein, and 15- to 90-fold more GGH enzyme activity. GGH overexpression altered MTX accumulation and metabolism to long-chain polyglutamates. In contrast to expectations, however, GGH overexpression did not confer resistance to short MTX exposures in either cell line. Changes in MTX metabolism were found to be balanced by alterations in accumulation and metabolism of folic acid. The ratio of MTX:folate accumulation may be a better predictor of MTX cytotoxicity than the accumulation of either alone. We conclude that, at least for these two cell lines, GGH overexpression alone is insufficient to produce clinical resistance to MTX.

Prevention of hypothyroidism related to mantle irradiation for Hodgkin's disease: preparative phantom study.

To decrease the incidence of hypothyroidism related to mantle irradiation for Hodgkin's disease, we initiated a study designed to protect the thyroid gland using a phantom. A thyroid phantom was filled with technetium-99m. The thyroid phantom was placed inside of its corresponding anterior neck position in a whole body phantom. An anterior scintiscan of the head and neck region demonstrated the radioactivity in the simulated thyroid. A mantle port included a focused block that would shield the thyroid from the anterior port. The phantom was exposed (4 MeV) to 180 cGy (AP-PA) at midplane with lithium fluoride dosimeters in the position of the thyroid. The thyroid received an average of 12 cGy from the anterior field and 48 cGy from the posterior field for a total of 60 cGy per treatment or 30% of the prescribed dose. A complete mantle field course of radiation of 4000 cGy would lead to a thyroid dose of 1200 cGy at a daily fractional dose of 60 cGy. We elected not to block the thyroid from the posterior field to prevent shielding and potential underdosage of involved nodal sites. The present study suggests a method of safe and effective thyroid shielding which needs to be tested clinically to determine whether it would reduce the incidence of chemical and clinical hypothyroidism or simply extend the period until occurrence.

Identification of N-epsilon-(2-propenal)lysine as a major urinary metabolite of malondialdehyde.

N-epsilon-(2-propenal)lysine (epsilon-PL) was identified as one of two major metabolites of malondialdehyde (MDA) excreted in rat and human urine. This compound is derived mainly but not exclusively from the diet, where it arises from a reaction between free MDA generated in the oxidative decomposition of polyunsaturated fatty acids and the epsilon-amino of the lysine residues of food proteins. It is released during protein digestion and represents the main form in which MDA is absorbed. It is excreted partially in unchanged form and partially as the acetylated derivative N-alpha-acetyl-N-epsilon-(2-propenal)lysine. Its administration to rats did not result in an increase in the excretion of free MDA in the urine. The findings that MDA in foods is absorbed mainly as epsilon-PL, and that this compound is not metabolized to free MDA in vivo, mitigate concern over the possible mutagenicity and carcinogenicity of MDA in the diet.

Malondialdehyde excretion by subjects consuming cod liver oil vs a concentrate of n-3 fatty acids.

Urinary malondialdehyde (MDA), an indicator of lipid peroxidation in the diet and in the tissues, was determined in human adults consuming a supplement of n-3 fatty acids derived from a pharmaceutical grade of cod liver oil (CLO) without added antioxidants vs a concentrate of n-3 acids containing dodecyl gallate and vitamin E. MDA excretion increased immediately in the subjects consuming CLO but remained unchanged in those ingesting the concentrate for 50 days. The increase in the subjects taking CLO was attributable to MDA in the oil. The results indicate that consuming unstabilized fish oils as a source of n-3 fatty acids may entail exposure to potentially toxic products of lipid peroxidation.

Identification of N-epsilon-(2-propenal)lysine as the main form of malondialdehyde in food digesta.

The form(s) in which malondialdehyde (MDA), a mutagenic product of the oxidative decomposition of polyunsaturated fatty acids (PUFA), occurs in foods was investigated. Several foods of animal origin (ground beef, smoked fish, chicken, sausages) were digested in vitro using pepsin and porcine intestinal fluid and the occurrence of MDA derivatives in the digesta was investigated by thin-layer, column and high-performance liquid chromatography. The predominant form of MDA was shown to be identical to synthetic N-epsilon-propenal lysine. This compound is apparently formed by a reaction between free MDA generated as a product of the oxidative rancidity of PUFA in foods and the free epsilon-amino groups of proteins, from which it is released in the course of digestion. It has been shown to be excreted in rat and human urine partially in the unchanged form and partially as the N-alpha-acetyl derivative. The results of this study serve to mitigate concern over the possible carcinogenicity of MDA in the diet, since less than 10% of the MDA in several foods containing highly unsaturated fatty acids was found in the free form.