Robert F. Gagel

Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: Comparison of 30-, 60-, and 90-mg dosages

PURPOSEnTo determine the efficacy, dose-response relationship, and safety of 30, 60, and 90 mg of a single intravenous dose of an aminobisphosphonate, pamidronate (APD), for the treatment of moderate to severe hypercalcemia of malignancy.nnnPATIENTS AND METHODSnPatients with histologically proven cancer and a corrected serum calcium level of at least 12.0 mg/dL after 48 hours of normal saline hydration were enrolled in a double-blind, multicenter, randomized clinical trial. Pamidronate in 30-, 60-, or 90-mg doses was administered as a single 24-hour infusion. Serum calcium corrected for albumin, urine hydroxyproline, and calcium excretion, and serum parathyroid hormone (PTH) (1-84) were determined before and after pamidronate therapy.nnnRESULTSnThirty-two men and 18 women entered the study. A dose-response relationship for normalization of corrected serum calcium was seen after pamidronate administration. Corrected serum calcium normalized in 40% of patients who received 30 mg, in 61% of patients who received 60 mg, and in 100% of patients who received 90 mg of pamidronate. The decline in the serum calcium level was associated with decreased osteoclastic skeletal resorption evidenced by a decrease in urine calcium and hydroxyproline excretion. Among those with a normalized corrected serum calcium level, the mean (median) duration of normalization of the corrected serum calcium value was 9.2 (4), 13.3 (5), and 10.8 (6) days in the 30-, 60-, and 90-mg treatment groups, respectively. The response of hypercalcemia to pamidronate was not significantly influenced by the presence of skeletal metastases. PTH 1-84, suppressed in patients on entry into this study, increased to a greater extent in those patients with osteolytic skeletal metastases compared with those with humoral hypercalcemia of malignancy. Clinical improvement, including improved mental status and decreased anorexia, accompanied the decline in the corrected serum calcium level in all three treatment groups. Side effects included low-grade fever, asymptomatic hypocalcemia, hypomagnesemia, and hypophosphatemia.nnnCONCLUSIONSnA single-dose infusion of 60 to 90 mg of pamidronate was highly effective and well tolerated and normalized corrected serum calcium in nearly all patients (61% to 100%) with hypercalcemia of malignancy.

Inhibition of growth hormone receptor activation by pegvisomant may increase bone density in acromegaly.

Treatment of acromegaly with pegvisomant lowers serum IGF-1 and raises serum growth hormone. As both IGF-1 and GH are important for bone growth and remodeling, we were concerned that lowering of IGF-1 could cause loss of bone. To evaluate the effects of treatment of acromegaly with pegvisomant on bone mineral density (BMD) we developed an observational, prospective study. 7 acromegaly patients participated in the study. Male and female subjects aged 18 years or more were eligible to participate. Patients were eugonadal or on adequate gonadal replacement therapy for at least 3 years before participating in the study. These patients were treated with a mean dosage of 20 mg of pegvisomant daily for up to 7 years. Bone mineral density (BMD) was evaluated by dual X-ray absorbtiometry (DXA) at baseline, 8, and 18 months as a part of a prospective trial and periodically thereafter. Baseline mean serum insulin-like growth factor-1 (IGF-1) concentration±SD was elevated in all patients (679.86±138.21 ng/ml). The IGF-1 concentrations at 18 months decreased significantly from baseline (p=0.016). Wilcoxon signed-rank tests showed significant increases in the spine BMD from baseline to 18 months (p=0.016) and significant increases in the right hip BMD from baseline to 18 months (p=0.032). The range of the increases was 4.3-17.8% at 7 years. It is concluded that successful treatment of acromegaly with pegvisomant increases BMD.

The Ret Signaling System and Its Role in Hereditary Medullary Thyroid Carcinoma

The identification of mutations of the rearranged during transfection (c-ret) proto-oncogene causative for multiple endocrine neoplasia type 2 (MEN2) in 1993 was the first in a series of remarkable discoveries that have provided insight not only into the cause of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid neoplasia, but also the development of the neurologic and urogenital systems. It also illustrates one example of the frenetic and sometimes illogical process by which scientific knowledge has progressed over the past decade, mixing the use of molecular genetics, molecular biology, and animal model systems to identify and characterize a unique signaling system.

MOLECULAR MECHANISMS OF CALCITONIN GENE TRANSCRIPTION AND POST-TRANSCRIPTIONAL RNA PROCESSING

Publisher Summary This chapter discusses the molecular mechanisms of calcitonin (CT) gene transcription and posttranscriptional RNA processing. The primary site of CT production in mammals is the parafollicular cell or C cell of the thyroid gland. This cell type originates in the neural crest and migrates, during embryonic life, to the fourth pharyngeal pouch. A mass of the C-cell precursors, collectively known as the ultimobranchial body, fuses with the thyroid gland as it migrates caudally during neck morphogenesis. Transcription of protein-encoding genes by eukaryotic RNA polymerase II is regulated by interaction of trans -acting factors with specific DNA sequences, cis elements. The cell-restricted transcription of a gene is mediated by one or a combination of cis elements that function to enhance or repress transcription. The removal of intronic sequence between adjacent exons occurs in two steps. Exon sequence is first defined by recognition processing signals and then splicing proceeds by removal of sequence between defined exons These elements are located in regions flanking the transcription unit or within the transcription unit itself. The key event in the processing of the CT pre-mRNA is the inclusion or exclusion of exon four.

Molecular Mechanisms of Disease: The RET Proto-oncogene

Multiple endocrine neoplasia type 2 (MEN2 ) is a rare disorder with distinct clinical features that were key to the elucidation of its underlying molecular cause. Oncogenic transformation of the thyroid C-cell in MEN2 is highly penetrant and progresses through a hyperplastic process prior to malignancy. Tumor burden is assessed by the measurement of serum calcitonin levels, and thyroidectomy is the primary treatment. Clearly defined kindreds with MEN2 were used to map the causative gene to chromosome 10 and to identify mutations in the RET proto-oncogene. The discovery that MEN2 is caused by activating mutations of the RET gene has served to guide an evolving strategy of prophylactic thyroidectomy for the treatment of hereditary MTC and therapeutic strategies for sporadic MTC, where RET activation in the most commonly observed genetic defect. Thyroid C cells are known to express RET at high levels relative to most other cell types; therefore, aberrant activation of the receptor is thought to preferentially sensitize these cells to transformation. A role of RET in medullary thyroid carcinoma has also served to highlight the importance of the MAPK and PI3K signaling pathways in its initiation and progression. Newly published studies demonstrate equally important functions of RET to prevent apoptosis, perhaps allowing the survival of tumor-initiating cell populations. A growing understanding of how RET interacts with growth and death pathways in normal C-cell function, during oncogenic transformation, and finally in tumor progression has helped drive the development of molecular-targeted therapies for the treatment of metastatic medullary thyroid carcinoma.

Molecular Mechanisms of Hypoglycemia Associated with Increased Insulin Production

The differential diagnosis of hypoglycemia in the pediatric age group is broad (Table 55-1). In the neonatal period, transient hypoglycemia caused by hyperinsulinemia is common. It is, however, the rare newborn who presents with profound and prolonged hypoglycemia requiring substantial glucose replacement. When this is detected, it most commonly is caused by hyperinsulinism.