Richard M. Shore

Treatment of High-Risk Neuroblastoma With Triple-Tandem High-Dose Therapy and Stem-Cell Rescue: Results of the Chicago Pilot II Study

PURPOSE To investigate whether intensive induction therapy followed by triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue and local irradiation will improve event-free survival for patients with high-risk neuroblastoma. PATIENTS AND METHODS From August 1995 to January 2000, 25 consecutive newly diagnosed high-risk neuroblastoma patients and one child with recurrent MYCN-amplified disease were enrolled onto the Chicago Pilot II Protocol. After induction therapy and surgery, peripheral-blood stem cells were mobilized with three cycles of high-dose cyclophosphamide and granulocyte colony-stimulating factor. Patients then underwent triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue followed by radiation to the primary site. RESULTS Twenty-two of the 26 patients successfully completed induction therapy and were eligible for the triple-tandem consolidation high-dose therapy. Sufficient numbers of peripheral-blood stem cells were collected in all but one patient. Seventeen patients were able to complete all three cycles of high-dose therapy and peripheral-blood stem-cell rescue, two patients completed two cycles, and three patients completed one cycle. There was one toxic death, and one patient died from complications of treatment for graft failure. With a median follow-up of 38 months, the 3-year event-free survival and survival rates are 57% +/- 11% and 79% +/- 10%, respectively. CONCLUSION The results of this pilot study demonstrate that it is feasible to intensify consolidation with triple-tandem high-dose chemotherapy and peripheral-blood stem-cell rescue and local irradiation, and suggest that this treatment strategy may lead to improved survival for patients with high-risk neuroblastoma.

Bone mineral status in growth hormone deficiency

Bone mineral status was monitored by photon absorptiometry in 18 children with growth hormone deficiency. Before exogenous growth hormone therapy, bone mineral content, bone width, and BMC/BW were below predicted values. Delayed maturation, as assessed by skeletal age, accounted for approximately 35% of the deficit for these values. Height velocity doubled during therapy, and BMC, BW, and BMC/BW increased commensurate with height and weight increases so that the relative deficit was unchanged. The pathogenesis of relative osteopenia in growth hormone deficiency was not determined.

Osteopenia in juvenile diabetes.

SummaryThe bone mineral status of fifty-one children with diabetes mellitus was studied by single photon absorptiometry. The mean bone mineral content was 13% below values predicted by age, sex, height, and weight. Those children whose diabetes was one year or less in duration were as osteopenic as those whose diabetes was of longer duration. The demineralized children received a higher daily insulin dose than the others. No association was noted between the degree of skeletal demineralization and sex, statural growth, renal function, and serum calcium and phosphorus. No significant changes in bone mineral content were noted longitudinally.

Skeletal demineralization in Turner's syndrome.

SummaryThe bone mineral status of 17 girls with Turners syndrome was evaluated by single photon absorptiometry. Bone mineral content (BMC) was 25.4% below that predicted by normalization for age, sex, height, weight, and bone width. Only 25% of this demineralization could be attributed to delayed skeletal maturation. Bones of girls who received estrogen replacement therapy were less demineralized than those of the others. The bone mineral deficit became less pronounced with advancing age. It could not be determined if the apparent effect of estrogens was related to age or if the apparent improvement with age was really due to an effect of estrogen treatment. For 8 subjects followed longitudinally there was no significant change in the BMC deficit.

Pathophysiology of Ureteropelvic Junction Obstruction: Experimental and Clinical Observations

We compared experimental ligature-induced ureteropelvic junction obstruction in the dog with naturally occurring ureteropelvic junction obstruction in children to determine if clinical behavior and difficulties in diagnosis could be related to different types or components of obstruction at the ureteropelvic junction. Measurements of flow rate out of the ligature-obstructed canine renal pelvis demonstrated a pressure-dependent pattern in which flow increased linearly in response to increasing pressures. In 5 human kidneys with intrinsic ureteropelvic junction obstruction a similar pressure-dependent pattern was demonstrated. This was in contrast to 6 human kidneys with extrinsic mechanical ureteropelvic junction obstruction in which a volume-dependent pressure flow pattern occurred, such that urinary flow rate did not keep pace with increases in pelvic pressure. In some cases flow actually decreased at high pressures because the ureteropelvic junction became self-obstructing as the pelvis enlarged. These findings indicate that the precise pathological anatomy of the ureteropelvic junction defines the pattern of flow across the obstruction. The 2 different types of obstruction, pressure-dependent and volume-dependent flow restrictions, which exist are important determinants of the clinical behavior of the obstructed kidney insofar as its potential for progressive hydronephrosis. They also help to explain why diagnostic tests for assessing obstruction in hydronephrosis are inaccurate at times.

Rickets: Part I

Rickets is characterized by impaired mineralization and ossification of the growth plates of growing children caused by a variety of disorders, the most frequent of which is nutritional deficiency of vitamin D. Despite ample knowledge of its etiology and the availability of cost-effective methods of preventing it, vitamin D deficiency rickets remains a significant problem in developing and developed countries. This two-part review covers the history, etiology, pathophysiology and clinical and radiographical findings of vitamin D deficiency rickets. Other less frequent causes of rickets and some of the disorders entering into the differential diagnoses of rickets are also considered. Controversial issues surrounding vitamin D deficiency include determination of what constitutes vitamin D sufficiency and the potential relationship between low levels of vitamin D metabolites in many individuals and unexplained fractures in infants.

Diuretic radionuclide urography

Diuretic radionuclide urography is a modification of conventional renography which utilizes the administration of intravenous furosemide to distinguish dilated, non-obstructed, hydronephrotic systems from those with significant mechanical obstruction. Diagnostic patterns are derived from computer generated time-activity histograms that depict the accumulation and washout of radiotracer before and after diuretic injection. In dilated but non-obstructed systems, diuresis produces a decline in activity. In obstructed systems, there is a failure of radiotracer washout in response to diuresis and no decline in activity is observed. The procedure is applicable to patients of all ages with suspected upper urinary tract obstruction. Clinical and experimental data support the accuracy and utility of this methodology and define its limitations and pitfalls.

Hyperphosphatemic familial tumoral calcinosis: Response to acetazolamide and postulated mechanisms

Hyperphosphatemic familial tumoral calcinosis (HFTC) is characterized by enhanced renal phosphate absorption, hyperphosphatemia, and tumor‐like extraosseous calcifications due to inactivating mutations in FGF23 or associated proteins. Surgical excision is needed when low phosphate diet and phosphate binders are ineffective. Sporadic reports have supported acetazolamide use. We report on a 7‐year‐old African American boy who presented with severe HFTC requiring numerous surgical excisions. Tumors continued to appear and others reoccurred despite phosphate restriction and sevelamer carbonate. At the age of 9.5 years, acetazolamide (40 mg/kg/day) was added and resulted in mild metabolic acidosis (bicarbonate 25.3 mEq/L vs. 21.4 mEq/L, P < 0.001; serum pH 7.38 vs. 7.31, P = 0.013, pre‐ and post‐acetazolamide, respectively) but no change in tubular reabsorption of phosphate (TRP) (96.9% vs. 95.9%, P = 0.34) or serum phosphate (6.6 mg/dl vs. 6.9 mg/dl, P = 0.52 pre‐ and post‐acetazolamide, respectively). Following the initiation of acetazolamide therapy, the patient experienced significant improvement in disease course as indicated by resolution of localized bone pain, cessation of tumor formation, and no tumor recurrence. Despite mild metabolic acidosis, our patient had improved linear growth and did not develop any other side effects related to therapy. Intact FGF23 remained abnormally low throughout disease course, while C‐terminal FGF23 increased with acetazolamide. We conclude that acetazolamide can control severe HFTC by inducing mild metabolic acidosis despite no change in serum phosphate or TRP. This effect may be exerted though improved calcium–phosphate complex solubility and increased FGF23 locally.

Lumbar and radial bone mineral density in children and adolescents with X-linked hypophosphatemia : evaluation with dual X-ray absorptiometry

Abstract  Objective. To evaluate the bone mineral status of children being treated for X-linked hypophosphatemia, including potential differences between cortical bone in the radial diaphysis and combined cortical and trabecular bone in the lumbar spine. Design and patients. Forty-four bone mineral evaluations were performed in 11 children and adolescents with X-linked hypophosphatemia. Bone mineral density (BMD) of the lumbar spine and the radial diaphysis were measured by dual X-ray absorptiometry (DXA), second metacarpal cortical thickness was measured on hand radiographs, and these results were expressed as Z-scores (standard deviations from the mean). Results. For the 11 initial examinations, Z-scores (mean±SD) were: radial BMD, –2.73±1.15, lumbar BMD, +1.28±1.53; and cortical thickness, –2.21±0.95. Lumbar BMD Z-scores were significantly greater than those for radial BMD and cortical thickness. On follow-up examinations there was a mild increase in radial BMD and decrease in lumbar BMD. Although these changes were statistically significant, they were quite small and the discordance between radial and lumbar BMD was not corrected. Conclusions. Children and adolescents who are being treated for X-linked hypophosphatemia manifest a bone mineral disorder characterized by decreased BMD in the appendicular skeleton and increased BMD in the lumbar spine. Although current therapy is successful in its anti-rachitic effects, it does not correct this bone mineral disorder and additional therapeutic trials should be considered.

Newborn society of fetal urology grade 3 hydronephrosis is equivalent to preserved percentage differential function

PURPOSE In newborn hydronephrosis (HN), the level of differential function (%df) measured by diuretic renography (DR) is used to judge the need for pyeloplasty. As DR testing is complex, we sought to determine if grading the level of HN (Society of Fetal Urology grade, SFU Gr) by a simple ultrasound correlates with percentage differential function (%df) and thereby obviates the need to perform DR. MATERIALS AND METHODS Between 1990 and 2003 our institution prospectively enrolled all cases of fetal HN who showed unilateral newborn SFU Gr HN > or =3. The cases underwent standardized testing. DR was done using the method of Well-Tempered Renography which was then followed by ultrasound (US). The US studies were performed while the hydration induced by DR was in effect. The level of %df was categorized as preserved (> or =40%) or reduced (<40%). Cases were excluded if there was an additional urological abnormality (e.g. ureterocele). RESULTS There were 71 cases that met our study criteria. The SFU Gr HN was 3 (n=33) or 4 (n=38). Kidneys with SFU Gr 3 HN showed preserved %df (33/33,100%) (mean=50.1+/-3.6) significantly more often than kidneys with SFU Gr 4 HN (27/38, 71%) (mean=42.2+/-13.9) (RR=1.41, 95% CI (1.15-1.72), p<0.001). CONCLUSION In newborns with a history of fetal HN, the postnatal finding of SFU Gr 3 HN uniformly correlates with preserved %df. Standardized hydration prior to US study is done to assure consistency in measurement of the SFU Gr HN. Determining the duration of the relationship between SFU Gr 3 HN and preserved %df will require prospective, longitudinal studies.