Application of intensity-modulated radiation therapy for pediatric malignancies

Novel radiation therapy delivery techniques have moved very slowly in the field of pediatric oncology. Some collaborative groups allow new radiation therapy delivery techniques in their trials. In many instances, the option of using these techniques is not addressed. These newer techniques of radiation delivery have the potential to reduce the probability of the common late effects of radiation and at the same time, potentially improve upon control and survival. The purpose of this study is to show the feasibility of IMRT in pediatric patients. No treatment results or toxicities will be presented. Five patients with a variety of pediatric malignancies received intensity-modulated radiation therapy (IMRT) at our institution as part of their disease management. A rigid immobilization device was developed for each patient and a computed tomography (CT) simulation was performed in the treatment position. In 3 of the patients, magnetic resonance imaging (MRI) scans were coregistered with the planning CT to facilitate target and critical structure delineation. In all but 1 patient, coplanar beam arrangements were used in the IMRT planning process. All IMRT plans exhibited a high degree of conformality. Dose homogeneity inside the tumor and rapid dose falloff outside the target volume is characteristic of IMRT plans, which allows for improved normal tissue sparing. Dose distributions were obtained for all plans, as well as dose and volume relationship histograms, to evaluate the fitness of the plans. IMRT is a viable alternative to conventional treatment techniques for pediatric cancer patients. The improved dose distributions coupled with the ease of delivery of the IMRT fields make this technique very attractive, especially in view of the potential to increase local control and possibly improve on survival.     

The role of micro-inflammation in the pathogenesis of uraemic pruritus in haemodialysis patients.

BACKGROUND: Uraemic pruritus (UP) is still one of the most vexing and disabling symptoms in chronic renal failure. The pathogenesis of UP is obscure and effective therapeutic strategies are elusive. Deduced from partial successful treatment modalities, there is evidence that an alteration of the immune system with a pro-inflammatory pattern along with a deranged T-helper-cell differentiation may be involved in the pathogenesis of UP. We, therefore, investigated whether UP is related to an augmented Th1-differentiation as measured by determination of intracytoplasmatic (i.c.) cytokines and expression of chemokine receptors. Additionally, pro-inflammatory cytokines were determined in serum. METHODS: In a multicentre study, 171 patients on haemodialysis (HD) were screened for UP. Finally, 13 HD patients with and 13 HD patients without UP, as well as 15 healthy controls were enrolled in the study. Peripheral blood mononuclear cells were isolated and the proportion of Th1- and Th2-cells was determined by flow cytometry. The expression of chemokine receptors on CD4 cells (CXCR3 preferentially on Th1 and CCR4 on Th2) and i.c. cytokines (IFNgamma for Th1 and IL4 for Th2) were measured after in vitro stimulation. Serum cytokine levels (IL6 and TNFalpha) and CRP were measured by ELISA. RESULTS: Compared to HD patients without UP, those complaining of UP showed a significantly enhanced proportion of Th1-cells as measured by both techniques. Additionally, serum CRP and IL6 levels were significantly higher in HD patients with UP, compared to HD patients without UP. CONCLUSIONS: These results point to a central role of inflammation in the pathogenesis of UP in HD patients.     

HLA typing and primary cadaver graft survival.

Analysis of 463 consecutive primary cadaver renal transplants showed no influence of HLA match grade on renal allograft survival. Additional categorization according to HLA match grade and degree of presensitization again showed no correlation between match grade and graft survival. Mismatches and matches of specific antigens, cross-reacting groups of antigens, and effect of matching at both locus A and B were also evaluated. There was no significant effect on graft survival except when mismatches against donor A2 and cross-reacting group A2, A28 occurred. A trend toward better graft survival was suggested in recipients matched for A9 and cross-reacting group A9, Aw 23, Aw 24. Although HLA match grade did not influence ultimate graft survival, HLA typing remains important, especially to avoid mismatch against donor A2 antigen. In addition, subsequent detection of new specificities, particularly in other than the A and B loci, may provide significance in the future.     

The importance of eosinophil cells in kidney allograft rejection

The composition of the intragraft cellular infiltrate was studied in 83 renal allograft recipients with the technique of fine-needle aspiration cytology in the first four weeks following kidney transplantation. We found a significantly (P less than 0.05) higher mean tissue eosinophil percentage in patients who had irreversible rejections with transplant loss than in those who had reversible rejections (12.54 +/- 2.31 versus 3.79 +/- 1.14, mean +/- SEM). Patients who had serious, dialysis-requiring rejections also showed a significantly (P less than 0.05) higher mean tissue eosinophil percentage than those who had reversible rejections (21.40 +/- 5.98 versus 3.79 +/- 1.14, mean +/- SEM). The frequency of the HLA B8 antigen was 46.2% in patients who had excessive tissue eosinophilia, whereas its frequency in all the studied patients was 18.3%. Based on our observations, the presence of more than 4% eosinophils in the tissue inflammatory exudate is a specific (91%) and fairly sensitive (78%) indicator of irreversible and severe acute rejections.     

Results and significance of angiography in potential kidney donors.

Multiple renal arteries originating from the aortoiliac vessels were identified angiographically in 44% of 444 prospective renal donors. Bilateral multiple renal arteries were identified in 12%. With good immunological donor-recipient matching, 17 kidneys with multiple renal arteries were transplanted with excellent results; therefore, presence of multiple renal arteries should not be considered a contraindication to kidney transplantation. A high proportion (17%) of the prospective donors, acceptable by all other means of evaluation, had abnormmal angiographic findings that led to reconsideration of their acceptance. In addition to multiple renal arteries, neither renovascular atherosclerosis nor fibromuscular dysplasia proved to be an absolute contraindication to transplantation.     

Analysis of costs and outcomes of renal transplantation at one center. Its implications.

A cost increase of more than 900% for medical services to dialysis patients and transplant recipients has been projected during the decade 1974 to 1984. To evaluate the role of renal transplantation in the End-Stage Renal Disease Program, we analyzed direct costs and patient outcomes in 466 consecutive transplants at our center. A successful transplant from either a living related or cadaver donor cost less than +7,000 per year for two years of graft function. The cost of transplants rejected during the second year also proved cost-effective when compared with the yearly costs of maintenance-facility hemodialysis. Patient survival was 100% at two years for recipients of a transplant from a living related donor and 84% at two years for recipients of a transplant from a cadaver. Renal transplantation can reduce the rising costs for end-stage renal disease patient care, without reducing life expectancy.     

Stereotactic body radiation therapy for centrally located lung lesions

Presentation of outcomes of patients treated by stereotactic body radiation therapy (SBRT) for lung lesions located within or touching a 2 cm zone around major airways. Serial tomotherapeutic SBRT has been planned and delivered at our institution since August 2001. Of 108 patients treated for primary and secondary lung tumors, nine harbored tumors (8 metastases, 1 recurrent NSCLC) located in close proximity to carina, right and left main bronchi, right and left upper lobe bronchi, intermedius, right middle lobe, lingular, or right and left lower lobe bronchi. SBRT was delivered to total doses of 36 Gy in 3 fractions (n = 8) or 6 fractions (n = 1), using a serial tomotherapy system (Nomos Peacock). We assessed local tumor control, clinical toxicity, normal tissue imaging changes, and overall survival. Median tumor volume was 26 cm³ (range 1.7 to 135 cm³). Tumor locations were hilar (n = 3), and parenchymal in six cases. Hilar lesions accounted for the three largest tumor volumes in the series. During a median follow-up of 10.6 months (range 2.5 to 41.5 months), all lesions treated were locally controlled as confirmed by CT or CT/PET imaging. Parenchymal imaging changes included focal lung fibrosis and major airway wall thickening. One occurrence of major airway occlusion (right lower lobe bronchus) was observed. This event was diagnosed by chest x-ray at 36 months, following treatment of the second largest hilar lesion in the present series. Based on the outcomes observed in this small sample series, SBRT for centrally located lung lesions appears feasible, was associated with low incidence of toxicities, and provided sustained local tumor control. However, long-term survival may be associated with major airway injury. As long-term follow-up in larger numbers of patients is lacking at this time, exclusion of patients with centrally located lesions may be considered when patients are treated in curative intent.     

Effect of zoledronic acid on incorporation of a bioceramic bone graft substitute

Many osteoporotic fracture patients are candidates for concurrent treatment with bisphosphonates and bioceramic bone graft substitutes. Osteopromotive silica-based bioactive glasses are known to induce accelerated local bone turnover and adjunct antiresorptive agents, such as zoledronic acid, may affect the process. The current study examined the effect of adjunct zoledronic acid therapy on bioactive glass incorporation. In Harlan Sprague-Dawley rats (n = 80), a standardized region of the proximal tibia was subjected to ablation of local bone marrow and filled with bioactive glass (BG) microspheres. Experimental animals received zoledronic acid (1.5 mug/kg, s.c., once a week, started 1 week before surgery) or doxycycline (a metalloproteinase inhibitor) (33 mg/kg, daily gavage) as a control agent. BG incorporation and geometric bone properties were followed by sequential pQCT imaging. The final outcome at 8 weeks was analyzed by digital radiography, histomorphometry, BEI-SEM, EDXA and muCT. The mRNA levels of markers for bone resorption (cathepsin K, TRACP, MMP-9, MMP-13) and synthesis (type I, II, III collagens, osteocalcin, osteonectin, osteopontin) were measured for determination of local bone turnover. Bones filled with BG microspheres produced 2.5-fold more intramedullary new bone than controls with bone marrow ablation only, but the BG filling delayed the recovery of pQCT strength strain index (SSI) of the bones. Adjunct therapy with zoledronic acid enhanced new bone formation on BG microspheres and particularly improved the SSI values of the BG-filled bones (P < 0.05). The zoledronic acid therapy alone (without BG filling) produced the highest amount of intramedullary new bone (6-fold more than in unfilled controls, P < 0.001) but did not show a similar benefit in SSI. The analyses of mRNA expression confirmed high local bone turnover in all bones with BG filling. At the 9th week of zoledronic acid treatment, bones with and without BG filling showed increased mRNA levels of bone resorption markers and decreased mRNA levels of markers for synthesis, indicating that a corrective resorption process was already in progress in response to massive accumulation of medullary new bone at earlier stages of the therapy. Adjunct antiresorptive therapy seems to be beneficial for incorporation of bioactive glass microspheres and does not block local natural remodeling processes. In the current model, the therapy even resulted in favorable remodeling of the tubular bone structure.