Nonmyeloablative bone marrow transplantation: Infectious complications in 65 recipients of HLA-identical and mismatched transplants.

Infections are a common complication of allogeneic bone marrow transplantation and the leading cause of transplantation-related mortality. It had been hypothesized that transplantation following nonmyeloablative preparative regimens would result in fewer infections by causing less mucosal injury, less graft-versus-host disease, and allowing earlier immune reconstitution. We have retrospectively reviewed the infectious complications of 65 consecutive patients with advanced hematologic malignancies who underwent bone marrow transplantation using a novel preparative regimen consisting of cyclophosphamide, thymic irradiation, and in vivo T-cell depletion. Cytomegalovirus (CMV) infection occurred in 52% of cases in which the donor or recipient had evidence of prior CMV exposure. Using a strategy of preemptive therapy and secondary prophylaxis with ganciclovir, no CMV disease occurred. Infections with gram-positive bacteria predominated over the first 100 days after bone marrow transplantation. Thereafter, the relative proportion of gram-negative infections increased without a significant increase in episodes of neutropenia. The rate of bacterial infections was not influenced by relapse of the underlying malignancy. Seven patients developed infections with Aspergillus species, which was the most common infectious cause of death in these patients. Infections with viruses other than CMV (n=10) and with protozoan organisms (n=2) also occurred. The use of HLA-mismatched donors, the occurrence of grade II-IV acute graft-versus-host disease, and treatment with corticosteroids did not influence the risk of CMV or bacterial or fungal infections in patients who underwent transplantation following this preparative regimen. Overall, the incidence and spectrum of infections in this series was similar to the reported incidence of infections following conventional myeloablative allogeneic stem cell transplantation. We conclude that a quantitative T-cell deficiency in these extensively T-cell depleted patients may be a risk factor for infection, even in the absence of graft-versus-host disease.     

Intracellular calcium changes in rat aortic smooth muscle cells in response to fluid flow

Vascular smooth muscle cells (VSM) are normally exposed to transmural fluid flow shear stresses, and after vascular injury, blood flow shear stresses are imposed upon them. Since Ca²⁺ is a ubiquitous intracellular signaling molecule, we examined the effects of fluid flow on intracellular Ca²⁺ concentration in rat aortic smooth muscle cells to assess VSM responsiveness to shear stress. Cells loaded with fura 2 were exposed to steady flow shear stress levels of 0.5–10.0 dyn/cm² in a parallel-plate flow chamber. The percentage of cells displaying a rise in cytosolic Ca²⁺ ion concentration ([Ca²⁺]_i) increased in response to increasing flow, but there was no effect of flow on the ([Ca²⁺]_i) amplitude of responding cells. Addition of Gd³⁺ (10 M) or thapsigargin (50 nM) significantly reduced the percentage of cells responding and the response amplitude, suggesting that influx of Ca²⁺ through ion channels and release from intracellular stores contribute to the rise in ([Ca²⁺]_i) in response to flow. The addition of nifedipine (1 or 10 M) or ryanodine (10 M) also significantly reduced the response amplitude, further defining the role of ion channels and intracellular stores in the Ca²⁺ response. © 2002 Biomedical Engineering Society. PAC2002: 8716Uv, 8719Uv, 8716Dg, 8719Ff     

Craniopharyngiomas in children. Long-term effects of conservative surgical procedures combined with radiation therapy

Thirty-seven patients with craniopharyngioma were treated at Children's Hospital, Boston, between 1972 and 1981, the mean follow-up period now being 10.5 years. Twenty of these patients are old enough to have finished high school and have been queried about their college or job activity. None of the four patients who had undergone radical excision of their tumor and who had reached the age of finishing high school was able to work independently. Among the 16 patients who reached this age and who were treated by more conservative operations and irradiation or irradiation alone, job performance or college attendance varied considerably, indicating that psychosocial impairment occurred in this group, but suggesting that the risk was less. The rate of tumor recurrence or of failure to respond to treatment was 57% (four of a total of seven survivors) following radical surgery and 7% (two of 27 survivors) after conservative operations and irradiation. The overall mortality rate was 8%; the causes of the three deaths were: "hypothalamic crisis" 1 year after radical resection; progressive tumor growth despite two attempts at resection and irradiation; and a brain-stem glioma in the field of irradiation 8 years after treatment.     

Etanidazole as a modulator of combined modality therapy in the rat 9l-gliosarcoma

The use of chemotherapy has led to improved treatment outcome for some pediatric patients with medulloblastoma. We have used a pre-radiation chemotherapy regimen consisting of vincristine and CDDP. The 9L gliosarcoma implanted intracranially and subcutaneously in the same animals was used as a preclinical model system to assess the efficacy of treatment combinations including: vincristine, CDDP, cyclo-phosphamide, etanidazole and radiation. The experimental endpoints were percent increase-in-lifespan, tumor growth delay and tumor cell survival. Both the tumor growth delay and percent increase-in-lifespan improved as the number of agents included in the chemotherapy regimen increased. so that the chemotherapy regimen including all four agents (ETA/VIN/CDDP/CTX) resulted in the greatest tumor growth delay (23.6 +/- 1.5 days) and the greatest increase-in-lifespan (35.8%). When radiation (20 Gray, single dose) was added to the treatment regimens the combinations of ETA/CTX/X-ray and ETA/VIN/CDDP/CTX/X-ray resulted in equivalent tumor growth delays (25.2 +/- 1.3 days and 25.8 +/- 1.7 days, respectively), while the greatest increase-in-lifespan (39.1%) was obtained with the five agent combination. The response of the 9L gliosarcoma to CDDP and cyclophosphamide over a dosage range was very similar to that of the murine FSaII fibrosarcoma. Our results indicate that etanidazole may be an effective chemosensitizer of combination chemotherapy and combined modality treatment regimens for brain tumors.     

Outcomes of a randomized trial of hyperfractionated cranial radiation therapy for treatment of high-risk acute lymphoblastic leukemia: therapeutic efficacy and neurotoxicity.

PURPOSE: We evaluated 8-year survival and late neuropsychologic toxicity in children with acute lymphoblastic leukemia treated in a randomized clinical trial to test whether hyperfractionated (twice daily) cranial radiation therapy (CRT) can reduce incidence and severity of late toxicities associated with 18 Gy of CRT. PATIENTS AND METHODS: Between 1987 and 1995, 369 children treated on two consecutive Dana-Farber Cancer Institute Consortium protocols for high-risk acute lymphoblastic leukemia were randomly assigned to conventionally fractionated CRT (CFX) or hyperfractionated CRT (HFX) to a total dose of 18 Gy. Neuropsychologic testing was completed for 125 of 287 children in continuous complete remission. Event-free and overall survival, as well as neuropsychologic function, were compared for the two arms of the protocol. RESULTS: Eight-year event-free survival (+/- SE) was 80% +/- 3% for children randomly assigned to CFX and 72% +/- 3% for HFX (P =.06). Overall survival was 85% +/- 3% for CFX and 78% +/- 3% for HFX (P =.06). CNS relapses occurred in 2.8% of patients receiving CFX and 2.7% receiving HFX (P =.99). Cognitive function for both groups was solidly in the average range, with no group differences in intelligence, academic achievement, visuospatial reasoning, or verbal learning. Children on the HFX arm exhibited a modest advantage for visual memory (P <.05). CONCLUSION: HFX provides no benefit in terms of cognitive late effects and may compromise antileukemic efficacy. HFX should not be substituted for conventionally dosed CRT in children who require radiation therapy for treatment of acute lymphoblastic leukemia.     

Adult medulloblastoma: prognostic factors and patterns of relapse

OBJECTIVE: To determine the patterns of relapse and the prognostic factors for adult medulloblastomas treated in the magnetic resonance imaging era. METHODS: Between 1986 and 1996, 32 adult patients (age, > or =16 yr) with medulloblastomas confined to the craniospinal axis were treated in our institutions. Twenty cases involved classic histological features and 12 involved the desmoplastic variant. The Chang staging distribution was as follows: T1, 2; T2, 17; T3, 10; T4, 3; M0, 24; M1, 1; M2, 4; M3, 3. Brainstem invasion was present in nine patients. Lesions were midline in 13 cases and lateral in 19. Resection was complete in 17 cases, subtotal in 6, and partial in 5, with biopsy only in 4 cases. All patients received postoperative radiotherapy, with median doses of 36 Gy to the entire craniospinal axis and 55 Gy to the posterior fossa. Twenty-four patients received chemotherapy (20 before radiotherapy, 3 after radiotherapy, and 1 before and after radiotherapy). RESULTS: With a median follow-up period of 5.4 years, 17 patients experienced recurrences. At 5 and 8 years, overall survival rates were 83 and 45% and disease-free survival rates were 57 and 40%, respectively. The 5- and 8-year posterior fossa control rates were 67 and 59%, respectively. Twenty-nine percent of all relapses occurred more than 5 years after treatment. The posterior fossa was the most common site of relapses. In univariate analyses, factors adversely affecting posterior fossa control were less than complete resection (P<0.001), the presence of brainstem invasion (P = 0.02), and the use of chemotherapy (P = 0.03). The overall radiotherapy duration was marginally significant in predicting posterior fossa control, with 5-year posterior fossa control rates of 81 and 49% for durations of less than 48 days and 48 days or more, respectively (P = 0.06). In a multivariate analysis, complete resection was predictive of improved posterior fossa control (P = 0.02) and disease-free survival (P = 0.02) rates. Of the eight low-risk patients who received radiotherapy alone, three experienced recurrences in the bone as the only site of relapse. CONCLUSION: Late relapse is common among adult patients with medulloblastomas, and long-term follow-up monitoring is important. Because of the high risk of systemic failure among the low-risk patients treated with radiotherapy alone, the role of chemotherapy for this group of patients needs to be further investigated. Complete resection, the absence of brainstem invasion, and an overall radiotherapy duration of less than 48 days are important prognostic factors.