Bony morbidity in children treated for acute lymphoblastic leukemia.

PURPOSE: Corticosteroids are widely used in the treatment of acute lymphoblastic leukemia (ALL). To determine the frequency of corticosteroid-associated bony morbidity in children with ALL, we retrospectively evaluated the incidence of fractures and osteonecrosis (ON) on two consecutive pediatric ALL protocols. PATIENTS AND METHODS: One hundred seventy-six consecutive children were treated for ALL between 1987 and 1995 at the Dana-Farber Cancer Institute and Children's Hospital. Prednisone was used as the corticosteroid during postremission therapy from 1987 to 1991, and dexamethasone was used from 1991 to 1995. Medical records for all patients were reviewed to assess the occurrence of fractures and ON. RESULTS: With a median follow-up of 7.6 years, the 5-year cumulative incidence (CI) +/- SE of any bony morbidity for the 176 patients was 30% +/- 4%, with a 5-year CI of fractures of 28% +/- 3% and of ON of 7% +/- 2%. With multivariate analysis, independent predictors of bony morbidity included age 9 to 18 years at diagnosis (P <.01), male sex (P <.01), and treatment with dexamethasone (P =.01). Dexamethasone was associated with a higher risk of fractures (5-year CI, 36% +/- 5% v 20% +/- 4% with prednisone; P =.04), but not ON (P =.40). The 5-year event-free survival for the 176 patients was 79% +/- 3%. CONCLUSION: Children treated for ALL had a high incidence of fractures and ON. Older children, boys, and patients receiving dexamethasone were at increased risk for the development of bony morbidity. Future studies should attempt to minimize corticosteroid-associated bony morbidity without compromising clinical efficacy.

Apg7p/Cvt2p is required for the cytoplasm-to-vacuole targeting, macroautophagy, and peroxisome degradation pathways.

Proper functioning of organelles necessitates efficient protein targeting to the appropriate subcellular locations. For example, degradation in the fungal vacuole relies on an array of targeting mechanisms for both resident hydrolases and their substrates. The particular processes that are used vary depending on the available nutrients. Under starvation conditions, macroautophagy is the primary method by which bulk cytosol is sequestered into autophagic vesicles (autophagosomes) destined for this organelle. Molecular genetic, morphological, and biochemical evidence indicates that macroautophagy shares much of the same cellular machinery as a biosynthetic pathway for the delivery of the vacuolar hydrolase, aminopeptidase I, via the cytoplasm-to-vacuole targeting (Cvt) pathway. The machinery required in both pathways includes a novel protein modification system involving the conjugation of two autophagy proteins, Apg12p and Apg5p. The conjugation reaction was demonstrated to be dependent on Apg7p, which shares homology with the E1 family of ubiquitin-activating enzymes. In this study, we demonstrate that Apg7p functions at the sequestration step in the formation of Cvt vesicles and autophagosomes. The subcellular localization of Apg7p fused to green fluorescent protein (GFP) indicates that a subpopulation of Apg7pGFP becomes membrane associated in an Apg12p-dependent manner. Subcellular fractionation experiments also indicate that a portion of the Apg7p pool is pelletable under starvation conditions. Finally, we demonstrate that the Pichia pastoris homologue Gsa7p that is required for peroxisome degradation is functionally similar to Apg7p, indicating that this novel conjugation system may represent a general nonclassical targeting mechanism that is conserved across species.

Second malignancies in patients treated for childhood acute lymphoblastic leukemia.

PURPOSE: Second malignant neoplasms (SMN) are devastating late complications of childhood acute lymphoblastic leukemia (ALL) and its treatment. We evaluated the incidence and type of SMN diagnosed before leukemic relapse in a large series of patients with ALL. PATIENTS AND METHODS: We reviewed the outcome of all patients treated for childhood ALL between 1972 and 1995 on Dana-Farber Cancer Institute (DFCI) and DFCI ALL Consortium protocols. The follow-up time from diagnosis of ALL to induction failure, relapse, remission death, or SMN, whichever occurred first, ranged from 0 to 24.0 years (median, 7.6 years; mean, 6.7 years). RESULTS: Thirteen SMNs were diagnosed among 1,597 patients. Eight tumors occurred in a radiation field (five in the CNS and three in the head and neck), two occurred outside of a radiation field (one adenocarcinoma of the sigmoid colon and one epithelioid sarcoma of the chest wall), and three were hematopoietic malignancies. The median time to occurrence was 6.7 years (range, 1.0 to 17.2 years) and the cumulative incidence of second malignancy before another first event was 2.7% (95% confidence interval, 0.7 to 4.7). The risk of a first event, which included induction failure, relapse, or remission death, was 31.0% (95% confidence interval, 28.5 to 33.5). CONCLUSION: We found a more than 10-fold risk of other first events when compared with SMN. Thus, we conclude that SMN before first relapse is a relatively uncommon occurrence among survivors of childhood ALL. Future therapeutic regimens must focus on reducing leukemia relapse and enhancing quality of life, as well as preventing SMNs.

Ion regulation in ion-poor acidic water by the blackskirt tetra (Gymnocorymbus ternetzi), a fish native to the Amazon River.

We examined the ionoregulatory capabilities of the blackskirt tetra (Gymnocorymbus ternetzi), which is native to ion-poor acidic waters of the Amazon River. Examination of Na+ uptake, which was only slightly sensitive to the uptake blocker amiloride, revealed several specializations for uptake in these waters. Kinetic analysis of Na+ uptake (at pH 6.5) revealed a high maximum rate of uptake and a low Michaelis-Menten constant, which allows the tetras to take up Na+ at high rates even at very low water levels. At pH 4.5, a pH where they experience sizable ion disturbances, they displayed several mechanisms to restore balance. Kinetic analysis at pH 4.5 revealed that the maximum uptake rate rose 67% while the Michaelis-Menten constant remained unchanged. Further tests showed that the upregulation of Na+ uptake occurred within 12 h in response to a doubling of Na+ efflux. Despite these specializations of the Na+ uptake mechanism, blackskirt tetras were not especially tolerant of low pH. Upon exposure to pH 4.0, they experienced a massive loss of Na+ due to a fourfold increase of Na+ efflux (relative to pH 5.0) and an 80% inhibition of uptake. Measurement of Na+ efflux in waters with different Ca2+ levels and in the presence of LaCl, a strong Ca2+ competitor, correlated the stimulation of Na+ efflux at low pH with a low branchial affinity for Ca2+. These tests indicate that blackskirt tetras possess abilities to resist the disruptive effects of moderately low pH but cannot survive in waters with a pH of 4.0 or less because of leaching of Ca2+ from branchial tight junctions, which stimulates ion losses.