Progressive multifocal leukoencephalopathy post ibrutinib therapy in relapsed chronic lymphocytic leukaemia.

Progressive multifocal leukoencephalopathy (PML) is a generally fatal infection of the cerebrum by the JC virus. It occurs in a range of primary and secondary immunosuppressed states and has become more common with AIDS and increasing the use of immunosuppressive therapies. Recently, Ibrutinib, a Bruton's Tyrosine Kinase Inhibitor (BTKi), has also been associated with PML. Here, we describe the case of a 77-year-old man treated for relapsed Chronic Lymphocytic Leukemia (CLL) with Ibrutinib, who eventually developed a fatal cerebellar granule cell variant of PML confirmed on autopsy. The case adds to the growing body of literature finding such an association with BTKis and highlights the importance of clinical vigilance in patients receiving such therapy.

Urological complications in renal transplantation.

INTRODUCTION: Renal transplantation has gained much wider acceptance as a treatment option for local patients with end-stage renal failure in the last three decades. However, there are no local reports regarding the associated urological complications and their management. This paper aims to explore these complications in the local setting. METHODS: This is a retrospective review of 440 consecutive renal transplantations performed in Singapore General Hospital over a ten-year period. From the retrieved clinical records of transplant recipients, the occurrence of various urological complications and their management were studied. RESULTS: The overall incidence of urological complications among transplant recipients was 7.7 percent. Urological complications included urinary leakage, ureteric strictures, symptomatic lymphocoeles, malignancies, urolithiasis, double-J stent fragmentation as well as haemorrhagic cystitis, and their incidences were 1.4 percent, 2.0 percent, 1.8 percent, 2.3 percent, 0.2 percent, 0.2 percent and 0.2 percent, respectively. Among the malignancies, 70 percent were renal cell carcinomas in the native kidneys. CONCLUSION: The incidence of urological complications in our series was comparable to those in the various major centres. However, there was a significantly higher incidence of native renal cell carcinoma in our series, which was likely to be secondary to the prolonged period of dialysis prior to renal transplantation.

A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities.

OBJECTIVE: Our objective was to determine whether long-term treatment of young patients with cystic fibrosis (CF) with dornase alfa maintains lung function and reduces respiratory tract exacerbations. STUDY DESIGN: This was a 96-week, randomized, double-blind, placebo-controlled trial involving 49 CF centers. Inclusion criteria were age 6 to 10 years and forced vital capacity > or = 85% predicted. Patients were excluded for hospitalization for complications of CF within 2 months and use of dornase alfa within 6 months. Patients were treated with dornase alfa 2.5 mg or placebo once daily with a jet nebulizer and a compressor. RESULTS: Patients were randomized, 239 to dornase alfa and 235 to placebo. At baseline the mean age was 8.4 years, the mean forced expiratory volume in 1 second 95% predicted, the mean forced expiratory flow, midexpiratory phase 85% predicted, and the mean forced vital capacity 102% predicted. At 96 weeks the treatment benefit for dornase alfa compared with placebo in percent predicted (mean +/- SE) was 3.2 +/- 1.2 for forced expiratory volume in 1 second (P =.006), 7.9 +/- 2.3 for forced expiratory flow between 25% and 75% of vital capacity (P =.0008), and 0.7 +/- 1.0 for forced vital capacity (P =.51). The risk of respiratory tract exacerbation was reduced by 34% in patients who received dornase alfa (relative risk 0.66, P =.048). There was no statistically significant difference between the groups in changes in weight-for-age percentile. Adverse event profiles for the treatment groups were similar. CONCLUSIONS: Treatment of young patients with CF with dornase alfa maintains lung function and reduces the risk of exacerbations over a 96-week period.

Estimation in a Cox proportional hazards cure model.

Some failure time data come from a population that consists of some subjects who are susceptible to and others who are nonsusceptible to the event of interest. The data typically have heavy censoring at the end of the follow-up period, and a standard survival analysis would not always be appropriate. In such situations where there is good scientific or empirical evidence of a nonsusceptible population, the mixture or cure model can be used (Farewell, 1982, Biometrics 38, 1041-1046). It assumes a binary distribution to model the incidence probability and a parametric failure time distribution to model the latency. Kuk and Chen (1992, Biometrika 79, 531-541) extended the model by using Cox's proportional hazards regression for the latency. We develop maximum likelihood techniques for the joint estimation of the incidence and latency regression parameters in this model using the nonparametric form of the likelihood and an EM algorithm. A zero-tail constraint is used to reduce the near nonidentifiability of the problem. The inverse of the observed information matrix is used to compute the standard errors. A simulation study shows that the methods are competitive to the parametric methods under ideal conditions and are generally better when censoring from loss to follow-up is heavy. The methods are applied to a data set of tonsil cancer patients treated with radiation therapy.

Regular monitoring of bone age is useful in children treated with growth hormone.

Objective. This study was undertaken to determine whether serial bone age (BA) radiographs were obtained in patients with growth hormone deficiency and to assess whether there were differences in outcome between subjects with and without monitoring of BA radiographs. Research Design and Methods. Data were collected from the National Cooperative Growth Study database on growth hormone-deficient subjects who were treated for at least 3 years. Comparisons were made among three groups of subjects: 1) those with BAs at entry versus those without; 2) those with BA values in the first year of follow-up if an entry radiograph had not been done versus those with no first-year examination; and 3) those with a BA at entry and yearly for 3 years versus those with no radiographs during the same period. Differences in the change in height standard deviation score (SDS); change in height age, age, pubertal progression, number of visits, growth hormone dosage; and number of growth hormone injections per week were compared. Results. Of the 6191 subjects assessed, 93% had at least one BA radiograph obtained; there was a mean of 3.6 +/- 2.6 total number of BA radiographs per patient during the 5.2 +/- 1.9 years of follow-up. Subjects with BA values at entry were older and had slightly higher cumulative height SDS and height age change compared with those without BA values at entry. Subjects with BA assessment during the first year were older and had shorter growth hormone treatment time and slightly better cumulative change in height SDS and height age than did those without BA in the first year. Comparing those with serial BA determination for the first 3 years of treatment versus those with no BA values, those with BA were older, more pubertal, seen more often, had more growth hormone injections per week of a comparable growth hormone dosage, and had slightly larger cumulative change in height SDS and height age than those without x-rays. Conclusions. These data suggest that National Cooperative Growth Study investigators find it of benefit to obtain baseline and follow-up measurements of BA in most subjects treated with growth hormone. Subjects with BA monitoring do slightly better than do those whose skeletal maturation is not measured. BA assessment should be considered part of the follow-up of patients treated with growth hormone therapy.

Analysis of bone age data from national cooperative growth study substudy VII.

National Cooperative Growth Study substudy VII was conducted 1) to compare standardized hand-wrist and knee bone age determinations in pubertal children treated with growth hormone (GH); 2) to compare local determinations of bone ages with centrally determined bone ages; 3) to relate the response to GH therapy to the bone age determinations; and 4) to ascertain the predictive value of each type of bone age determination. Eligible subjects were those in the National Cooperative Growth Study who were at Tanner pubertal stage 2 or greater for breasts (girls) or genitals (boys). Radiographs of the hand-wrist were taken annually, and radiographs of the knee were taken at the beginning and the end of the study. Separate bone age determinations were made from these radiographs. A combined hand-wrist and knee bone age determination also was derived. There were 990 patients in the study; in 925 (677 boys), there were both hand-wrist and knee bone age determinations from the baseline pubertal radiographs. There was only one radiographic assessment in 496 patients, two in 205 patients, and three to eight in the remaining patients. The strongest correlation was between the hand-wrist bone age and the hand-wrist plus knee bone age (r =.995). Also strongly correlated were knee with hand-wrist (r =.872) and knee with hand-wrist plus knee (r =.914). For none of these bone age methods was any statistically significant difference found between the methods. The locally determined bone ages correlated strongly with the centrally determined bone ages for knee (r =.850), hand-wrist (r =.928), and hand-wrist plus knee (r =.930); however, the locally determined knee and hand-wrist values were less (by approximately 0.3 year) than the centrally determined values. These differences, however, do not appear to be clinically significant.

The effect of growth hormone treatment on stature in Aarskog syndrome.

We describe 19 males with Aarskog syndrome who were treated with growth hormone (GH) and enrolled in the National Cooperative Growth Study (NCGS). There was a significant increase in both growth rate (3.9 +/- 1.9 cm/yr vs 8.9 +/- 1.7 cm/yr, p < 0.001) and height SD score (change in HtSDS = 1.0 +/- 0.8). The increase in HtSDS was dependent on treatment duration, frequency of injections, weight-for-height SDS, and HtSDS at enrollment. The results of our study suggest a positive effect of GH treatment on growth and adult height in Aarskog syndrome patients.

Effects of recombinant human growth hormone on height and skeletal maturation in growth hormone-deficient children with and without severe pretreatment bone age delay.

UNLABELLED: The relative effects of growth hormone (GH) on GH-deficient (GHD) children with and without severely delayed skeletal maturation prior to treatment are unclear. METHODS: Pre-pubertal GHD children enrolled in the National Cooperative Growth Study were divided into two groups: severe pretreatment BA delay (BA Z-score

Growth hormone treatment of girls with Turner syndrome: the National Cooperative Growth Study experience.

OBJECTIVE: To evaluate growth rate and adult height with recombinant growth hormone (GH) treatment in girls with Turner syndrome (TS) and predictors of their growth response. METHODS: Data on girls with TS who were treated with GH in the National Cooperative Growth Study (NCGS) were evaluated. As of January 1997, there were 2798 girls with TS in the NCGS database, 2652 of whom had not previously received GH. Follow-up data on growth were available for 2475 subjects, and data on adult height were available for 622. RESULTS: The average age of girls with TS at enrollment in the NCGS was 10.1 +/- 3.6 years. These patients had severely short stature compared with that of unaffected American girls (height, 118.5 +/- 16.5 cm; height standard deviation score [SDS], -3.1 +/- 0.9), but their heights were typical of those of American girls with TS (TS-specific height SDS, 0.01 +/- 0.9). Treatment with GH for an average duration of 3.2 +/- 2.0 years resulted in an increase in height SDS of 0.8 +/- 0.7 compared with unaffected girls and of 1.2 +/- 0.8 compared with TS standards. Growth rates increased from 4.0 +/- 2.3 cm/year before treatment to 7.5 +/- 2.0 cm/year after 1 year of treatment. Duration of treatment with GH was the strongest predictor of change in height SDS. After 6 to 7 years of treatment with GH, there was a cumulative change of 2.0 in mean height SDS. The 622 girls who reached adult height were older when they began taking GH. Their mean height gain over pre-GH projected height was 6.4 +/- 4.9 cm after 3.7 +/- 1.9 years of treatment. Their adult height was 148.3 +/- 5.6 cm. CONCLUSIONS: Although the response to treatment with GH varied, it was associated with highly significant gains in growth and adult height in girls with TS. Duration of treatment with GH was the most important variable predicting adult height.

Optimizing estrogen replacement treatment in Turner syndrome.

Estrogen has a biphasic effect on growth, stimulatory at low doses but inhibitory at higher doses. Therefore, designing optimal sex hormone replacement treatment in girls with Turner syndrome (TS) who are being treated with growth hormone (GH) involves considering the dose and form of the estrogen as well as the route and timing of its administration. We report here a preliminary analysis of a study to test the concept that an optimal estrogen replacement regimen should consist of estradiol administered in a low dose by a systemic route. The study population consisted of 9 girls with TS who had been treated with GH for 6 or more months. When the girls were 12 to 15 years old, we added depot estradiol at a monthly intramuscular dose of 0.2 mg and increased the dose at 6-month intervals to 0.4, 0.6, and, in 7 of the girls, 0.8 mg. We compared the results in these subjects with those in a matched group of 37 patients with TS in whom routine estrogen treatment had been started at similar ages and who were treated with a similar course of GH therapy. The gain in height at 2 years was 2.6 cm greater in those who were treated with depot estradiol than in those who were treated with routine estrogen. The bone age in the patients who were treated with depot estradiol increased in proportion to their chronologic age, suggesting that this difference indicates an increase in their predicted adult height. We conclude that using very low doses of systemic estradiol to induce puberty before the age of 15 years in girls with TS who are treated with GH, instead of using routine estrogen therapy, can result in increased final heights.

The role of serial sampling in the diagnosis of growth hormone deficiency.

We analyzed 12-hour serial sampling of growth hormone (GH) levels in two cohorts of short children: 96 children referred to a university endocrine clinic or studied on a research protocol and 825 children in the National Cooperative Growth Study of children treated with exogenous GH. The mean 12-hour GH levels correlated with growth velocity in 60 children with normal height and growth velocity in the university study, and this correlation was stronger in the boys. The testosterone levels also correlated with growth velocity and mean 12-hour GH levels in the boys. The mean 12-hour GH levels were lower in a group of 36 children with idiopathic short stature than in the control subjects, as were the peak GH levels within 1 hour after the onset of sleep and the insulin-like growth factor I levels. In the National Cooperative Growth Study cohort, pooled 12-hour GH levels were lower in the group with idiopathic GH deficiency (n = 300) than in the group with idiopathic short stature (n = 525), but the difference was not significant. The duration of GH treatment was the most significant predictor of change in the height SD score in both groups. Indices of spontaneous secretion of GH were not predictive of the response to GH treatment, nor were the results of provocative GH testing, the responses to GH treatment being similar in both groups over time. We conclude that the results of GH testing must be interpreted for each patient and that several testing modalities may be helpful in finding GH insufficiency that originates at various levels of the somatotropic axis.

Effects of growth hormone treatment in children with cystic fibrosis: the National Cooperative Growth Study experience.

Poor longitudinal growth and low body weight affect many persons with cystic fibrosis (CF). The Cystic Fibrosis Foundation reports that 28% of all persons with CF are below the 10th percentile for height and that 34% are below the 10th percentile for weight. Intensive nutritional supplementation has not resulted in sustained improvement in the poor linear growth and low weight in CF. Because of the significant impact of nutrition in CF, the anabolic effects of growth hormone (GH) may make the agent useful as adjunctive treatment for malnutrition and poor linear growth. To date, 24 patients with CF (16 boys; 87% Tanner stage 1) have been enrolled in the National Cooperative Growth Study. The average age at enrollment was 10.3 years, and there was significant delay in height in all patients (mean height age, 7.1 years). Bone age was also significantly delayed (mean delay, 3.0 years). The mean maximum stimulated GH level was 12.3 micrograms/L and the mean GH dose given was 0.291 +/- 0.038 mg/kg per week. After 1 and 2 years of treatment with GH the growth rate increased in all patients with available growth rate data. The growth rates in these children were slightly lower than in children who were treated with GH for idiopathic GH deficiency. The weight-for-height standard deviation scores improved significantly after 2 years of GH treatment. There were adverse reactions (glucose intolerance) to GH in only two patients; treatment was suspended in one of these patients but was continued in the other. National Cooperative Growth Study data indicate that treatment with GH increases linear growth and weight in prepubertal patients with CF. These data suggest that GH may be useful for treating malnutrition in CF.

A stochastic model for the analysis of bivariate longitudinal AIDS data.

We present a model for multivariate repeated measures that incorporates random effects, correlated stochastic processes, and measurement errors. The model is a multivariate generalization of the model for univariate longitudinal data given by Taylor, Cumberland, and Sy (1994, Journal of the American Statistical Association 89, 727-736). The stochastic process used in this paper is the multivariate integrated Ornstein-Uhlenbeck (OU) process, which includes Brownian motion and a random effects model as special limiting cases. This process is an underlying continuous-time autoregressive order [AR(1)] process for the derivatives of the multivariate observations. The model allows unequally spaced observations and missing values for some of the variables. We analyze CD4 T-cell and beta-2-microglobulin measurements of the seroconverters at multiple time points from the Los Angeles section of the Multicenter AIDS Cohort Study. The model allows us to investigate the relationship between CD4 and beta-2-microglobulin through the correlations between their random effects and their serial correlation. The data suggest that CD4 and beta-2-microglobulin follow a bivariate Brownian motion process. The fit of the model implies that an increase in beta-2-microglobulin is associated with a decrease in future CD4 but not vice versa, agreeing with immunologic postulates about the relationship between these two variables.

Hospitalized congestive heart failure patients with preserved versus abnormal left ventricular systolic function: clinical characteristics and drug therapy.

PURPOSE: To compare clinical characteristics of and pharmacologic therapy for hospitalized patients with congestive heart failure (CHF) and left ventricular systolic dysfunction or normal left ventricular systolic function. PATIENTS AND METHODS: Medical records were reviewed for all patients discharged with a principal diagnosis of CHF from a university hospital and a community hospital between September 1, 1991 and August 31, 1992. Pertinent medical history items and prescribed drug therapies at discharge were recorded for each patient's first calendar year admission. Patients were categorized as having either normal left ventricular systolic function or systolic dysfunction based on the results of echocardiography and radionuclide angiography or contrast ventriculogram. RESULTS: Of 298 patients with CHF, 92 (31%) had normal left ventricular systolic function. Patients with normal systolic function were older, were more often women, were less likely to have a history of coronary artery disease, and were more likely to have a history of hypothyroidism than patients with systolic dysfunction. However, the prevalence of clinical characteristics overlapped considerably between the two groups. Among patients with systolic dysfunction, 79% were discharged on a therapeutic regimen of digoxin, 65% on an angiotensin-converting enzyme inhibitor, and 26% on either a beta-blocker or a calcium channel blocker. Among patients with normal systolic function, 50% were discharged on a regimen of a beta-blocker or a calcium channel blocker and 38% were discharged on digoxin. Twenty-six percent of patients with normal systolic function and without a history of atrial fibrillation were discharged on a digoxin regimen. CONCLUSION: Hospitalized CHF patients with normal left ventricular systolic function and those with diminished left ventricular systolic function share many clinical features. Since recommended drug therapy and prognosis differ, our data underscore the importance of diagnostic testing to assess left ventricular systolic function. Drug therapy for CHF patients provides a major challenge for quality-of-care improvement.

CD4+ T-cell number at the time of acquired immunodeficiency syndrome.

In this article, the authors adapt and extend the methodology of Phillips (Phillips et al. J Acquir Immune Defic Syndr 1992;5:148-52) to estimate the distribution of CD4+ T-cell number at the time of acquired immunodeficiency syndrome (AIDS) and to estimate the correlation between CD4+ T-cell number at AIDS and CD4+ T-cell number prior to human immunodeficiency virus infection. Using data from the Los Angeles portion of the Multicenter AIDS Cohort Study, the authors find that the median CD4+ T-cell count at the time of AIDS is 67 cells/mm3 with a 95% confidence interval of 58-84. The 5th and 95th percentiles of the distribution are 8 and 284, respectively. The authors estimate the correlation between the CD4+ T-cell number at the time of AIDS and the CD4+ T-cell number prior to human immunodeficiency virus infection to be 0.71 with a 95% confidence interval of 0.21-0.94. This very high correlation is suggestive of biologic hypotheses concerning possible control of the circulating CD4+ T-cell number. The high correlation can also be useful in determining when to start prophylactic treatment.

Identification of intraocular lens-adsorbed proteins in mammalian in vitro and in vivo systems.

OBJECTIVE: Mammalian in vitro and in vivo systems were used to study the protein-adsorbing potential of intraocular lenses (IOLs). METHODS: Intraocular lenses composed of polymethyl methacrylate optics with polypropylene haptics were incubated in rabbit plasma for 3 hours (in vitro grouping) or implanted in rabbit eyes for 48 hours (in vivo grouping). Lens-adsorbed proteins from both experimental groupings were eluted with sodium dodecyl sulfate and identified by Western Blot analyses. RESULTS: The adsorbed protein layer was composed of at least six different proteins: albumin, complement C3 fragments, IgG, fibrinogen/fibrin (as a fibrin clot in vivo), fibronectin, and transferrin. Of the identified components, albumin, IgG, fibronectin, and fibrinogen were the predominant protein species on the in vitro IOLs, while fibronectin and fibrin were on the in vivo IOLs. CONCLUSIONS: The composition of the protein layer has the potential to alter the biological property of IOLs.

Nicardipine in heart failure: distinguishing its acute beneficial from its chronic effects.

Concern over negative inotropic effects has limited the use of calcium blockers in patients with congestive heart failure. Nicardipine, a second generation dihydropyridine calcium channel blocker, has demonstrated positive hemodynamic effects in short-term therapy in patients with congestive heart failure. Prolonged use of calcium channel blockers remains contraindicated in patients with congestive heart failure due to the potential for activation of the renin-angiotensin system. However, acute intravenous nicardipine administration has important clinical applications (as in the management of surgical hypertension or hypertensive emergencies). Nicardipine may be safely used for these indications even in the presence of congestive heart failure.

Dipeptide inhibitors of ubiquitin-mediated protein turnover prevent growth factor-induced neurite outgrowth in rat pheochromocytoma PC12 cells.

Dipeptide inhibitors of the ubiquitin-dependent proteolysis pathway governed by N-terminal recognition (N-end rule) in reticulocyte lysates significantly suppress NGF- and bFGF-induced neurite outgrowth in rat pheochromocytoma PC12 cells, but do not cause retraction of already formed neurites. Peptides which do not inhibit proteolysis are also without effect on PC12 cell differentiation. Suppression of neurite outgrowth is readily reversible upon removal of the inhibitors. These data demonstrate a requirement for specific protein turnover in the process of neuron-like differentiation in PC12 cells and provide the first demonstration of a physiological role for the N-end rule.