Pamela Waber

Impact of alendronate on quality of life in children with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a debilitating clinical condition characterized by fragile bone and skeletal deformity. Over the past decade frequent reports have suggested that the cyclical administration of intravenous pamidronate has a positive impact on bone density and skeletal fractures; however, the impact of such therapy on the quality of life (QOL) has rarely been reported. Alendronate, an oral bisphosphonate, is widely used to treat osteoporosis. The purpose of this study was to evaluate the impact of daily alendronate on QOL and bone parameters in children with OI. A prospective double-blind crossover study was designed in which placebo was alternated with daily alendronate. Twenty children with types I, III, and IV OI were recruited. Seventeen patients completed the study. Markers of QOL were measured in children with type III and IV OI (n = 15) using total mobility (PEDI), self-care (WeeFIM), well-being, pain, and use of analgesic scores. After 1 year of alendronate therapy, vertebral bone mineral density (BMD) improved from a change in standard deviation score (z-score) of 0.89 ± 0.19 to −0.12 ± 0.14 after 1 year of placebo (P < 0.001). All QOL markers, except for mobility score, improved in response to alendronate therapy. Change in height z-score also improved in response to 1 year of alendronate therapy (0.41 ± 0.21 vs. −0.09 ± 0.11, P < 0.05). Alendronate therapy did not alter serum levels of calcium, osteocalcin, parathyroid hormone (PTH), 1, 5 (OH)2 vitamin D, cholesterol, or urinary hydroxyproline or any other biochemical marker evaluated. Alendronate decreased by 56% urinary cross-linked N-telopeptide of type 1 collagen divided by urinary creatinine (uNTX/uCr). Daily alendronate therapy was well tolerated. Only two patients had mild gastrointestinal discomfort, responding to minor adjustments in alendronate intake. Daily alendronate therapy is safe and effective in improving QOL in children with OI.

Recurrence of focal segmental glomerulosclerosis in renal allograft: An in-depth review

Vinai M, Waber P, Seikaly MG. Recurrence of focal segmental glomerulosclerosis in renal allograft: An in‐depth review.
Pediatr Transplantation 2010: 14: 314–325.

Genetic alterations of chromosome band 9p21-22 in head and neck cancer are not restricted to p16INK4a

Although genetic alterations of chromosome band 9p21 – 22 occur frequently in head and neck squamous cell carcinoma (HNSCC) cell lines, alterations of the cyclin-dependent kinase inhibitor p16INK4a located in this region are less common in corresponding primary tumors. To further investigate genetic alterations at 9p21 – 22 and p16INK4a in primary HNSCC, a paired set of 21 tumors and blood specimens that were shown previously to exhibit allelic loss at 3p and elsewhere, were tested for LOH at 9p21 – 22 using eight different highly polymorphic marker. Sixteen of the samples (81%) exhibited LOH for at least one marker. Frequent LOH was found surrounding p16INK4a and at three additional non-contiguous regions of 9p21 – 22. No homozygous deletions were identified. SSCP screening and direct sequence analysis led to the identification of mutations the p16INK4a gene in two tumors. p16INK4a was not hypermethylated in any of the samples studied. Furthermore, there was no correlation between LOH at 9p21 – 22 and the RB1 tumor suppressor gene. These findings indicate that in the set of tumors that we tested, LOH at 9p21 – 22 is common in primary HNSCC but that genetic alterations of p16INK4a located in this region are unusual. Additional tumor suppressor genes at 9p21 – 22 may therefore be involved in the pathogenesis of this tumor.

p53 mutations, O6-alkylguanine DNA alkyltransferase activity, and sensitivity to procarbazine in human brain tumors

Background. In human brain tumors, sensitivity to procarbazine as measured by sensitivity in a xenograft tumor model correlated inversely with amounts of the DNA repair enzyme O6‐alkylguanine DNA alkyltransferase(AT).

Infrequency of BRCA2 alterations in head and neck squamous cell carcinoma

Alterations of BRCA2 result in increased susceptibility to breast cancer in both men and women (relative lifetime risks of 0.06 and 0.8 respectively). BRCA2 maps to 13q12-q13 and encodes a transcript of 10 157 bp. Other cancers that have been described in BRCA2 mutation carriers include those of the larynx. Human chromosome 13q has been shown previously by LOH studies to harbor several tumor suppressor genes for head and neck squamous cell carcinoma (HNSCCs). We therefore examined the role of BRCA2 in the development of these cancers. Only 6/22 (27%) of the laryngeal cancers we examined demonstrated LOH of the BRCA2-containing region. These and 10 other HNSCCs of different origins that were demonstrated by LOH studies to have lost the region of chromosome 13 containing BRCA2 were examined for alterations in this gene. SSCP analysis failed to reveal any alterations leading us to conclude that BRCA2 alterations are not frequently involved in the pathogenesis of HNSCCs and that the observed LOH of chromosome 13 loci is due to other, as yet, unidentified tumor suppressor gene(s). Interestingly tumors with LOH in this region (proximal to D13S118) were far more likely to be derived from women than men. This is unusual since HNSCCs are usually fourfold more common in men than in women.

Bisphosphonate use in children with bone disease.

Bisphosphonates are widely used to manage osteoporosis in adults. In children, however, bisphosphonate use has been limited because of scarce data regarding its long-term effects on statural growth. In the pediatric literature, clinical data supporting the use of bisphosphonates in managing metabolic bone disease in children are sparse and largely anecdotal. Although more studies are available on conditions such as osteogenesis imperfecta and osteoporosis, additional studies are needed for fibrodysplasia ossificans progressiva, fibrous dysplasia, mucolipidosis type III, and Legg-Calvé-Perthes disease.

Urinary prostaglandins and the effect of indomethacin on phosphate excretion in children with hypophosphatemic rickets.

We recently reported the urinary prostaglandin E2/creatinine ratio (PGE2/Cr) was markedly elevated in Hyp mice, the animal model for X-linked hypophosphatemia, compared with control mice. We provided evidence for altered prostaglandin production mediating the phosphaturia and that indomethacin decreases urinary phosphate excretion in Hyp mice but not control mice. To determine the levels of urinary PGE2/Cr, the safety and efficacy of indomethacin on phosphate excretion in children with hypophosphatemic rickets (HPR), a prospective clinical trial was performed in 16 children with HPR and 16 age- and gender-matched healthy controls. Urinary PGE2/Cr excretion was determined on a 24 h timed urine collection. A randomized cross over, placebo versus indomethacin, clinical trial was performed in the 16 children with HPR. There was no difference in urinary PGE2/Cr excretion between controls and patients with HPR. In children with HPR, indomethacin treatment for 3 mo had no significant effect on serum phosphorus or urinary phosphate excretion. In conclusion, urinary prostaglandin excretion is similar in children with HPR compared with controls. Indomethacin had no significant effect on serum phosphorus or urinary phosphate excretion in children with HPR.