Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers.

OBJECTIVE: To assess the safety/tolerability and perform a preliminary efficacy evaluation of a multiple-dosing regimen of recombinant human vascular endothelial growth factor (VEGF165 or rhVEGF; telbermin) applied topically to chronic diabetic neuropathic foot ulcers. METHOD: Subjects with type 1 or 2 diabetes mellitus were randomised to receive either topical applied telbermin (72 microg/cm2) (n=29) or placebo (n=26) treatment to the foot ulcer surface in conjunction with standard ulcer care. Subjects received treatment every 48 hours (maximum three doses per week) for up to six weeks. Weekly 35mm photography, quantitative planimetry and physical examinations documented the ulcer appearance, surface area and stage. Safety endpoints included incidence of clinically significant hypotension, adverse events and ulcer infection. Exploratory efficacy endpoints included percentage reduction in total ulcer surface area, incidence of complete ulcer healing and time to complete ulcer healing. RESULTS: Incidence of adverse events was comparable in the two treatment groups. None of the adverse events were attributed to study drug, and no hypotension was observed as a result of telbermin treatment. Occurrence of infected study ulcers appeared to be balanced between the treatment groups. Positive trends suggestive of potential signals of biological activity were observed for incidence of complete ulcer healing (41.4% telbermin versus 26.9% placebo at day 43 [P=0.39]) and time to complete ulcer healing (25th percentile of 32.5 days telbermin versus 43.0 days placebo [log-rank P=0.13]). CONCLUSION: The topical application of telbermin 72 microg/cm2 three times a week for up to six weeks appeared to be well tolerated. Further studies are required to characterise the safety/efficacy of telbermin more completely.

Estimating effectiveness in an observational study: a case study of dornase alfa in cystic fibrosis. The Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis.

Patients with cystic fibrosis (CF) receiving dornase-alfa had improved pulmonary function relative to a control group in a large randomized phase III controlled study. We reviewed data from a large observational phase IV study to estimate the observed drug effect in patients receiving dornase alfa as part of their routine care. Patients 6 years or older and with a baseline forced expiratory volume in 1 second (FEV1) of at least 40% predicted who had been enrolled for at least 18 months were included (n = 283). The control group consisted of 2382 patients who had never received dornase alfa. Patients in the study had a baseline spirometry and a second spirometry recorded 12 months later; a baseline observation period of 6 months preceded the initial spirometry, and dornase alfa had to have been started after the baseline spirometry (within 3 months) and to have continued through the 12-month follow-up spirometry. Patients treated with dornase alfa had lower pulmonary functions, more bacterial colonization, and more exacerbations at baseline (FEV1 : 76.0% vs 87.6%, Pseudomonas aeruginosa : 64.1% vs 46.7%, pulmonary exacerbations during the previous 6 months: 56.4% vs 22. 2%). Mean values of FEV1 for patients treated with dornase alfa improved by 3.9% of predicted compared with a decline of 1.6% in the untreated cohort. Covariate adjustment provided an estimated benefit of dornase alfa of 4.3% predicted FEV1 (SE = 0.9, P <.0001). This analysis provides evidence for the effectiveness of dornase alfa therapy in clinical practice.

Response to growth hormone in attention deficit hyperactivity disorder: effects of methylphenidate and pemoline therapy.

OBJECTIVE: To determine whether treatment of attention deficit hyperactivity disorder (ADHD) with methylphenidate hydrochloride or pemoline diminishes the response to growth hormone (GH) therapy in patients with idiopathic GH deficiency (IGHD) or idiopathic short stature (ISS). METHODS: The National Cooperative Growth Study database was used to identify patients between 3 and 20 years of age with IGHD or ISS and those within these groups who were treated with methylphenidate or pemoline for ADHD. Their growth in response to GH treatment (change in height standard deviation score [SDS]) was compared with that of patients with IGHD or ISS who were not treated for ADHD, by using a stepwise multiple regression analysis. RESULTS: In the IGHD cohort, there were 184 patients who were being treated for ADHD and 2313 who were not. In the ISS cohort there were 117 patients who were being treated for ADHD and 1283 who were not. There was a higher percentage of males being treated for ADHD in both cohorts. In the IGHD cohort, the change in height SDS was positively associated with the number of years of GH treatment, parents' heights, body mass index, and GH injection schedule, and was negatively associated with height SDS at the initiation of GH therapy, age, and maximum stimulated GH level. The use of methylphenidate or pemoline had a negative effect on the change in height SDS, but the magnitude of the effect was small. Similar effects were noted in the ISS cohort, but body mass index and the use of methylphenidate or pemoline had no effect on the change in height SDS. CONCLUSIONS: Concurrent ADHD therapy is associated with a slight decrease in the change in height SDS during GH treatment in patients with IGHD but not in those with ISS. Even in IGHD, the magnitude of the effect is small and should not deter the use of such concurrent therapy.

Treatment of glucocorticoid-induced growth suppression with growth hormone. National Cooperative Growth Study.

Growth failure is common during long term treatment with glucocorticoids (GC) due to blunting of GH release, insulin-like growth factor I (IGF-I) bioactivity, and collagen synthesis. These effects could theoretically be reversed with GH therapy. The National Cooperative Growth Study database (n = 22,005) was searched for children meeting the following criteria: 1) pharmacological treatment with GC and GH for more than 12 months, 2) known type and dose of GC, and 3) height measurements for more than 12 months. A total of 83 patients were identified. Monitoring of glucose, insulin, IGF-I, IGF-binding protein-3, type 1 procollagen, osteocalcin, and glycosylated hemoglobin levels was performed in a subset of patients. Stimulated endogenous GH levels were less than 10 microg/L in 51% of patients and less than 7 microg/L in 37% of patients. The mean GC dose, expressed as prednisone equivalents, was 0.5 +/- 0.6 mg/kg day. Baseline evaluation revealed extreme short stature (mean height SD score = -3.7 +/- 1.2), delayed skeletal maturation (mean delay, 3.1 yr), and slowed growth rates (mean, 3.0 +/- 2.5 cm/yr). After 12 months of GH therapy (mean dose, 0.29 mg/kg x weeks), mean growth rate increased to 6.3 +/- 2.6 cm/yr, and height SD score improved by 0.21 +/- 0.4 (P < 0.01). During the second year of GH therapy (n = 44), the mean growth rate was 6.3 +/- 2.0 cm/yr. Prednisone equivalent dose and growth response to GH therapy were negatively correlated (r = -0.264; P < 0.05). Plasma concentrations of IGF-I, IGF-binding protein-3, procollagen, osteocalcin, and glycosylated hemoglobin increased with GH therapy, whereas glucose and insulin levels did not change. The following conclusions were reached. The growth-suppressing effects of GC are counterbalanced by GH therapy; the mean response is a doubling of baseline growth rate. Responsiveness to GH is negatively correlated with GC dose. Glycosylated hemoglobin levels increased slightly, but glucose and insulin levels were not altered by GH therapy.

Growth-hormone treatment of renal transplant recipients: the National Cooperative Growth Study experience--a report of the National Cooperative Growth Study and the North American Pediatric Renal Transplant Cooperative Study.

OBJECTIVE: To evaluate growth response and renal allograft measures after recombinant human growth-hormone (GH) treatment in pediatric renal transplant recipients. STUDY DESIGN: Data on GH-treated children in the National Cooperative Growth Study (NCGS) database were linked to the database of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Data were analyzed for growth rate, graft survival, graft function, acute rejection, and adverse events. Data on 2390 transplant recipients in the NAPRTCS who had at least 24 months of graft function were used in the comparisons. RESULTS: Fifty-nine patients were treated with GH after renal transplantation. One-year growth data were available for 42 of these; 2-year, for 31; and 3-year, for 13. Growth velocity increased from 2.47 +/- 1.83 cm/yr to 7.17 +/- 2.97 cm/yr after 1 year. Year-2 and -3 growth rates were 5.93 +/- 2.29 cm/yr and 6.31 +/- 2.32 cm/yr. Height standard deviation score immediately after transplantation was -3.26 +/- 1.44 and at the initiation of GH was -3.59 +/- 1.15; it increased to -3.18 +/- 1.06 at year 1 and to -3.16 +/- 0.92 at year 2 and was -3.31 +/- 1.00 at year 3. Five-year graft survival was 80% in the GH cohort and 85% in the NAPRTCS cohort. Acute rejection ratio was 1.44 and 1.43 episodes per patient in the GH and NAPRTCS cohorts, respectively. Calculated creatinine clearance at 6 years was 68 and 63 ml/min per 1.73 m2, respectively. CONCLUSIONS: Growth hormone increase growth velocity for up to 3 years without an apparent decrease in graft survival or renal function, and no relation between GH therapy and acute rejection is seen. A randomized, prospective study to evaluate further the safety and efficacy of this promising therapy is required.

When perfectly HLA-matched kidneys are refused for transplant: implications for a national cooperative sharing system.

BACKGROUND: The transplant community attempts to maximize overall renal graft survival rates through nationwide sharing of perfectly-matched cadaveric kidneys. Although the number of such transplants is determined annually, the number available but not transplanted has never been assessed. There has also been no verification of the widespread claim that kidneys transplanted as paybacks for perfect matches are inferior. STUDY DESIGN: From records of the United Network for Organ Sharing, a complete accounting of six-antigen-matched kidney disposition was obtained, including a frequency distribution of reasons for refusal given when kidneys were refused for matched patients. Actuarial graft survival (GS) rates for matched, payback, and other cadaveric renal transplants were determined. RESULTS: Of the six-antigen-matched kidneys available, 97 percent were transplanted; 71 percent of those were accepted for matched patients. The two-year GS rate for matched patients was 84 percent, significantly higher than that for kidneys available for matched patients but transplanted into other patients (71.3 percent) and that for all other cadaveric kidneys (75.5 percent). Most reasons for refusal were related to donor quality. Kidneys refused for such reasons showed a 67.7 percent two-year GS rate in nonmatched patients and the highest rates of acute and chronic rejection and primary failure. The two-year GS rate for kidneys accepted as paybacks for matched kidneys (75.7 percent) was equivalent to that for all non-matched cadaveric kidneys (75.5 percent). CONCLUSIONS: If all normal-quality grafts refused for perfectly matched patients during 1990 through 1992 had been accepted for those patients, the number of transplants with typically superior survival rates could have increased by 25 percent, from 1,365 to 1,704. The payback requirement of the United Network for Organ Sharing does not seem to reduce the overall benefits of sharing perfectly matched kidneys nationwide.

Linear growth in response to growth hormone treatment in children with short stature associated with intrauterine growth retardation: the National Cooperative Growth Study experience.

Short stature commonly follows intrauterine growth retardation (IUGR). Most patients are not growth hormone (GH)-deficient, but GH therapy has been used in IUGR. Early studies found a heterogeneous increase in initial growth rate that could not be maintained. Results of more recent studies with higher doses are more encouraging but do not establish whether final height is increased. Data from a large number of patients in the National Cooperative Growth Study were reviewed to evaluate the response to GH treatment in patients with IUGR-associated short stature. Two hundred seventy such patients were identified and were categorized as those with unclassified IUGR and those with Russell-Silver syndrome/primordial short stature (RSS/PSS). Patients were treated with standard doses of recombinant human GH (approximately 0.3 mg/kg per week) and were assessed periodically for up to 4 years. The height SD score at baseline in patients with unclassified IUGR was -3.49 +/- 1.16, and their relative height improved with each year of therapy. Patients who completed 4 years of treatment reached a height SD score of -1.32 +/- 0.79. Results were similar in patients with RSS/PSS; their baseline height SD score was -3.83 +/- 1.05 and improved to -2.10 +/- 0.99 by year 4. Despite these encouraging results, no change occurred in predicted adult heights. Furthermore the number of patients who remained in treatment for 4 years decreased substantially, thus limiting the interpretation of the data. These data suggest that a beneficial response to GH occurs in some patients with IUGR-associated short stature and that little difference exists in the responses in patients with RSS/PSS compared with those in patients with unclassified IUGR.

Growth hormone treatment of children with myelomeningocele.

From the National Cooperative Growth Study database 106 patients (53 boys) with myelomeningocele who were treated with recombinant human growth hormone (GH) at 56 centers were identified. Eighty-one patients (41 boys) were prepubertal at enrollment. The mean pretreatment growth rate (GR) in these prepubertal patients was 4.5 +/- 3.7 cm/yr, and the mean height SD score was -4.0 +/- 1.2. The maximal stimulated GH level was less than 10 micrograms/L in 71% of these patients and less than 7 micrograms/L in 49%. The mean chronologic age was 6.5 +/- 2.9 years, and the mean height age was 3.7 +/- 1.7 years. After GH treatment the year 1 GR in those who remained prepubertal was 8.5 +/- 3.3 cm/yr, a significant increase over baseline (p < 0.01). This increase was sustained through year 4 and remained significant through year 3 (p < 0.01). The height SD score showed sustained significant improvement through year 4, to -2.2 +/- 1.4 (p < 0.001). The GR and SD score for stature improve with GH treatment in children with myelomeningocele.

Overview of the National Cooperative Growth Study substudy of serial growth hormone measurements.

For the National Cooperative Growth Study II substudy, data on spontaneous growth hormone (GH) secretion were collected from 5106 children with short stature. Of these, 2123 with complete 12-hour samples were subsequently enrolled in the NCGS. Compared with NCGS enrollees who were not in the NCGS II substudy, these children were significantly older (11.3 +/- 3.3 years vs 9.9 +/- 4.2 years), had a higher maximum reported GH level (13.3 +/- 10.5 micrograms/L vs 9.2 +/- 8.7 micrograms/L), and were more likely to be male (71% vs 62%) and pubertal (27.3% vs 21.9%) (p<0.001) for all). Height deficit, bone age delay, and pretreatment growth rates were similar. Children who were classified as having GH deficiency on the basis of their response to standard pharmacologic tests had lower spontaneous GH secretion than those who were classified as having idiopathic short stature, but considerable overlap was seen between the two groups on all indexes of spontaneous GH secretion. This finding suggests that the investigators were using serial sampling studies in examining children with short stature who were not growing well but had "normal" GH responses to standard pharmacologic testing.

National Cooperative Growth Study substudy. II: Do growth hormone levels from serial sampling add important diagnostic information?

The National Cooperative Growth Study includes growth data on more the 24,000 children in the United States and Canada who have been treated with growth hormone (GH). To determine whether dysregulation of GH release causes growth failure in children, we initiated the National Cooperative Growth Study substudy II to evaluate the diagnostic utility of serially sampled GH levels and to determine whether those patterns were responsible for the low growth rates in certain subsets of short children and whether children in any of the diagnostic categories would respond to GH therapy. A total of 3744 subjects whose mean height standardized for their chronological age was -2.8 SD and whose pretreatment growth rate was 4.2 cm/yr had complete 12-hour data sets-- serial samples obtained in a 12-hour overnight period. Pulsatile characteristics of GH release were assessed with the cluster algorithm. There was a virtually complete overlap of the GH pulsatile characteristics between control subjects and short children, but the insulin-like growth factor I (IGF-I) levels were markedly lower in the short children, suggesting impairment in the GH-IGF-I axis. THe growth response to administered GH showed only very weak correlations with the various cluster-derived parameters. Our results indicate that one must look beyond the release of GH to find an explanation for the short statures and low IGF-I levels in the subsets of children with idiopathic short stature.

Heart transplantation in dilated heart muscle disease and myocarditis.

A detailed analysis of outcome with reference to pre-transplant diagnosis was performed in 14 055 cardiac transplant recipients to determine whether the diagnosis of dilated heart muscle disease predicted survival. Overall survival at one year was greater than 80% in all patients. In general, those with dilated heart muscle disease had a small but significantly improved survival compared to those with other diagnoses. Outcome in women, which is significantly poorer than men, showed similar diagnosis-specific results. Multivariate analysis confirmed the significant difference (P = 0.02) with a minimal reduction in risk (relative risk 0.927). In conclusion, carefully selected patients with dilated heart muscle disease are excellent candidates for cardiac transplantation.

The effect of transplant center volume on cardiac transplant outcome. A report of the United Network for Organ Sharing Scientific Registry.

OBJECTIVE: The number of cardiac transplant programs continues to increase despite no increase in the number of hearts available for transplantation. As a result, the majority of heart transplant centers perform extremely small numbers of transplant operations annually. To determine the effect of small transplantation volume on transplant outcome, the following study was performed. DESIGN: Using the Scientific Registry of the United Network for Organ Sharing, all cardiac transplant procedures from October 1987 through December 1991 were analyzed to determine whether center volumes affected cardiac transplant outcome. Patient survival rates for each center were determined, and the survival rates were modeled for the following patient variables: first transplantation or retransplantation, patient condition at the time of transplantation, patient underlying cardiac disease (congenital vs all others), and time. SETTING: All cardiac transplant centers in the United States were included in the analysis. PATIENTS: All patients undergoing cardiac transplantation in the United States from October 1987 through December 1991 were included in the analysis. MAIN OUTCOME MEASURE: The primary end point in this analysis was mortality. RESULTS: Throughout the entire study, of the 150 cardiac transplant centers, 35.3% of the centers were performing fewer than five cardiac transplantations per year, 53.3% were performing fewer than nine transplantations per year, and 61.3% were performing fewer than 12 transplantations per year, the minimum required for Medicare payment eligibility. Using the modeled survival rates, the risk of mortality decreased to a basal level in those centers performing between eight and 10 transplant operations per year. In centers performing fewer than nine transplantations, mortality increased sharply and exponentially. Dividing centers into those that performed nine or more transplantations per year (70 centers) and fewer than nine transplantations per year (80 centers), the increased risk of mortality at 1 month and 12 months was 40.3% and 33.1%, respectively, in centers performing fewer than nine cardiac transplantations per year (P < .001). Once the threshold of nine transplant procedures was met, those centers that were eligible for Medicare payment did not have significantly better survival than those centers not eligible for Medicare coverage. CONCLUSIONS: These data demonstrate that the risk of mortality at early and intermediate time points is substantially higher in low-volume cardiac transplant centers, which make up more than half of the centers performing cardiac transplantation in the United States.

Effect of donor age on outcome of kidney transplantation. A two-year analysis of transplants reported to the United Network for Organ Sharing Registry.

The shortage of cadaveric donors coupled with a rapidly growing number of potential recipients has resulted in an increased use of older donors. In 1992, 10.7% of all cadaveric kidney transplants were from donors above the age of 55 compared with 5.4% in 1988. The present investigation serves as a follow-up of a prior study of the effect of donor age on outcome with a 2-year analysis of more than 30,000 cadaveric kidney transplants performed in the United States between October 1, 1987, and December 31, 1991, that were reported to the United Network for Organ Sharing. There was no difference between the graft survival at 1 and 2 years comparing donors aged 56-65 versus 65 and older, but the older donors (aged 56 and greater) had a 1- and 2-year graft survival that was approximately 10% and 14% less than that for recipients from the ideal age group of donors (16-45 years). There was no practical adverse interaction between donor age and recipient age, gender, diabetic status, peak PRA (panel reactive antibody activity) level of mismatch, cold ischemia time, or recipient race on outcome. The kidneys from older donors had poorer graft survival than the kidneys from younger donors when transplanted into recipients of repeat transplants, though the impact of repeat transplant and donor age on graft survival are independent of one another. These data suggest that kidneys from donors over the age of 55 overall have reduced functional reserve, which has an adverse effect on long-term function. Thus, attempts should be made to better estimate functional reserve among the older age group, but age alone should not be the sole factor for exclusion of a potential donor. The use of older donors appears to present an increased but acceptable risk of graft loss 2 years after transplant.

Thoracic organ transplants in the United States: a report from the UNOS/ISHLT Scientific Registry for Organ Transplants. United Network for Organ Sharing. International Society for Heart and Lung Transplantation.

1. The frequency of heart and lung transplantation has increased dramatically over time. The number of heart transplants increased 170% between 1968 and 1981. Exponential increases began in 1982 and increased through 1990, as evidenced by a 1,835% growth in the number of procedures performed during those years. In more recent years, heart transplant numbers have leveled off, with only an 8% increase in the last 3 years. Lung transplant procedures have grown significantly in the short period of time between 1987 (n = 18) and 1993 (n = 669). 2. Since the beginning of the ISHLT Registry in 1968 the number of thoracic transplant programs has increased 7,767%, from 3 to 236. 3. The most frequently reported indications for thoracic transplantation include: coronary artery disease (43.4%) for heart, cystic fibrosis (39.5%) for double-lung, emphysema/COPD (40.2%) for single-lung and primary pulmonary hypertension (38.3%) for heart-lung. 4. The majority of heart transplant recipients are at least 18 years old (89.5%), male (78.2%), and White (83.8%). The majority of lung transplant recipients are at least 18 years old (93.7%), female (53.2%), and White (91.3%). 5. One-year survival over time has almost doubled for all types of thoracic transplantation, with increases from 47.7% in 1968-79 to 81.6% in 1993 for heart; 35.3% in 1987 to 67.1% in 1993 for lung; and 40% in the early 1980s to 73% in 1993 for heart-lung. 6. Long-term 10-year survival rates were 33.5% for heart and 5.6% for heart-lung transplant recipients. Five-year survival for lung recipients was 37%. 7. Male-to-male donor-to-recipient gender-match heart transplant patients exhibited slightly higher survival (4-5%) than other match pairs from one to 5 years posttransplant. Female-to-male combinations in lung transplant recipients exhibited slightly higher survival (4-8%) at 3 years than other match pairs. 8. There was no significant difference in 5-year survival for donor hearts procured from local, intraregional, or interregional sources. Lungs procured from interregional sources exhibited an 8-10% advantage over local and intraregionally procured organs at 3 years posttransplant.