Showing papers by "Rob Knight published in 2001"

Safety and Efficacy of Bisphosphonates Beyond 24 Months in Cancer Patients

Abstract: PURPOSE: Bisphosphonate therapy has decreased the risk of skeletal complications associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma. The large prospective studies have used 21 to 24 months of treatment. We studied the safety and efficacy of bisphosphonates in a subset of patients who received therapy for more than 24 months. PATIENTS AND METHODS: Patients who received bisphosphonates (pamidronate or zoledronic acid) were identified. Data on skeletal events and laboratory parameters were gathered by chart review. RESULTS: We studied 22 patients who received intravenous pamidronate or zoledronic acid for a duration of 3.6 years (range, 2.2 to 6.0 years). Prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were encountered. There was a clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine in these patients. The fracture rate beyond 2 years was no greater than durin...

Origins of anteroposterior patterning and Hox gene regulation during chordate evolution.

Abstract: All chordates share a basic body plan and many common features of early development. Anteroposterior (AP) regions of the vertebrate neural tube are specified by a combinatorial pattern of Hox gene expression that is conserved in urochordates and cephalochordates. Another primitive feature of Hox gene regulation in all chordates is a sensitivity to retinoic acid during embryogenesis, and recent developmental genetic studies have demonstrated the essential role for retinoid signalling in vertebrates. Two AP regions develop within the chordate neural tube during gastrulation: an anterior 'forebrain-midbrain' region specified by Otx genes and a posterior 'hindbrain-spinal cord' region specified by Hox genes. A third, intermediate region corresponding to the midbrain or midbrain-hindbrain boundary develops at around the same time in vertebrates, and comparative data suggest that this was also present in the chordate ancestor. Within the anterior part of the Hox-expressing domain, however, vertebrates appear to have evolved unique roles for segmentation genes, such as Krox-20, in patterning the hindbrain. Genetic approaches in mammals and zebrafish, coupled with molecular phylogenetic studies in ascidians, amphioxus and lampreys, promise to reveal how the complex mechanisms that specify the vertebrate body plan may have arisen from a relatively simple set of ancestral developmental components.

Identification of conserved C2H2 zinc-finger gene families in the Bilateria

Abstract: Identification of orthologous relationships between genes from widely divergent taxa allows partial reconstruction of the gene complement of ancestral genomes. C2H2 zinc-finger genes are one of the largest and most complex gene superfamilies in metazoan genomes, with hundreds of members in the human genome. Here we analyze C2H2 zinc-finger genes from three taxa - Drosophila, Caenorhabditis elegans and human - from which near-complete genome sequence data are available. Our analyses conclusively identify 39 families of genes, of which 38 can be defined as orthology groups in that they are descended from single ancestral genes in the common ancestor of Drosophila, C. elegans and humans. On the basis of current metazoan phylogeny, these 39 groups represent the minimum complement of C2H2 zinc-finger genes present in the genome of the bilaterian common ancestor.

Safety a nd E fficacy o f B isphosphonates B eyond 2 4 M onths in C ancer P atients

Abstract: Purpose: Bisphosphonate therapy has decreased the risk of skeletal complications associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma. The large prospective studies have used 21 to 24 months of treatment. We studied the safety and efficacy of bisphosphonates in a subset of patients who received therapy for more than 24 months. Patients and Methods: Patients who received bisphosphonates (pamidronate or zoledronic acid) were identified. Data on skeletal events and laboratory parameters were gathered by chart review. Results: We studied 22 patients who received intravenous pamidronate or zoledronic acid for a duration of 3.6 years (range, 2.2 to 6.0 years). Prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were encountered. There was a clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine in these patients. The fracture rate beyond 2 years was no greater than during the first 2 years of treatment. There were no stress fractures of long bones with prolonged therapy. Conclusion: Prolonged treatment with the potent bisphosphonates pamidronate and zoledronic acid seems to be well tolerated and should be studied in prospective, randomized studies to document prolonged skeletal efficacy. J Clin Oncol 19:3434-3437. © 2001 by American Society of Clinical Oncology. REATMENT WITH bisphosphonates has been shown to decrease the risk of skeletal complications and pain associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma. Two multicenter, randomized, double-blind, placebo-controlled trials of pamidronate have been reported in patients with stage IV breast cancer. Patients received either 90 mg of pamidronate or placebo given as a 2-hour intravenous (IV) infusion every 3 to 4 weeks for 2 years. The study population consisted of 754 patients, 367 in the pamidronate group and 387 in the placebo group. Overall, 31.3% of the pamidronate and 25.8% of placebo patients completed the 24 months of treatment. The number of skeletal complications over time was reduced by 35% in the pamidronate group compared with the placebo group, and 20% fewer pamidronate-treated patients experienced any of the skeletal complications commonly associated with metastatic bone disease. 1-3 Furthermore, the time to a first skeletal complication was significantly longer in the pamidronate-treated group than in the placebo-treated group. Similar results have been obtained in patients with Durie-Salmon stage III multiple myeloma in whom 21 months of IV pamidronate resulted in a one-third reduction in the number of skeletal-related events. 4