Long-term Follow-up Data from Pivotal Studies of Adjuvant Trastuzumab in Early Breast Cancer

The addition of adjuvant trastuzumab therapy for 1 year to standard chemotherapy significantly improved disease-free survival and overall survival versus chemotherapy alone in a number of pivotal early breast cancer studies. Here we review long-term follow-up data on the efficacy, cardiac safety, and general safety of trastuzumab in these pivotal studies. We also evaluate ongoing phase II/III adjuvant trials with newer HER2-targeted agents and the efficacy and safety of the recently developed subcutaneous (SC) formulation of trastuzumab in early breast cancer. Long-term follow-up data confirm the significant survival benefit afforded by the addition of trastuzumab to chemotherapy in patients with HER2-positive disease, with an acceptable safety profile. Long-term cardiac safety data suggest that the incidence of cardiac adverse events is maintained at a relatively low level with continued follow-up. At this present time, 1 year of trastuzumab treatment remains the standard of care in HER2-positive early breast cancer. Future adjuvant trastuzumab treatment strategies should focus on reducing cardiotoxicity, particularly in elderly patients, by identifying potential predictive biomarkers of cardiac dysfunction. Clinicians must also decide whether to omit trastuzumab in women who would achieve little benefit from treatment to avoid cardiotoxicity.

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Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity

Burren CP, Wanek D, Mohan S, Cohen P, Guevara-Aguirre J, Rosenfeld RG. Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity. Acta Pædiatr 1999; Suppl 428: 185–91. Stockholm. ISSN 0803–5326
Although insulin-like growth factor binding proteins (IGFBPs) are known to be important modulators of the action of insulin-like growth factors (IGFs), regulation of their production in vivo is not completely understood. Serum concentrations of IGFBP-3, -4 and -5 and acid-labile subunit (ALS) were therefore examined in 20 children with growth hormone (GH) insensitivity before and after 6 months of therapy with recombinant human IGF-I (80 or 120 ug/kg twice daily). The IGFBP concentrations in these children were compared with those in 62 GH-deficient children receiving GH therapy for 3 months. Serum levels of IGFBP-3, -4 and -5 and ALS all increased significantly ( p < 0.0001) in GH-deficient children in response to GH therapy, whereas no significant increases occurred in the children with GH insensitivity. These findings indicate that GH is responsible for the regulation of serum levels of IGFBP-3, -4 and -5 and ALS, and that IGF-I does not directly regulate the concentrations of these circulating IGFBPs. □ Growth hormone, growth hormone insensitivity, insulin-like growth factor I, insulin-like growth factor binding protein     

Insulin-like growth factor binding proteins: a proposed superfamily

Hwa V, Oh Y, Rosenfeld RG. Insulin-like growth factor binding proteins: a proposed superfamily. Acta Pzdiatr 1999; Suppl 428:37-45. Stockholm. ISSN 0803-5326
The conventional concept is that the insulin-like growth factor binding proteins (IGFBPs) are cysteine-rich proteins, with conserved N- and C-domains, that are capable of binding insulin-like growth factors (IGFs) with high affinity. This dogma was recently challenged by the discovery of a group of cysteine-rich proteins that share important structural similarities with the IGFBPs, but have demonstrably lower affinity for IGFs. It is therefore proposed that these IGFBP-related proteins (IGFBP-rPs) and the IGFBPs constitute an IGFBP superfamily. We speculate that the IGFBP superfamily is derived from an ancestral gene/protein that was critically involved in the regulation of cell growth and was capable of binding IGF peptides. Over the course of evolution, some members (IGFBPs) evolved into high-affinity IGF binders and others (IGFBP-rPs) into low-affinity IGF binders, thereby conferring on the IGFBP superfamily the ability to influence cell growth by both IGF-dependent and IGF-independent means. 0 Insulin-like growth factor binding protein, insulin-like growth factor binding protein-related protein, superfamily     

Fibre composition in the interosseous nerve of the pigeon

The interosseous nerve of birds innervates a string of Herbst corpuscles located near the interosseous membrane between the tibia and fibula. Fibre composition of this nerve was assessed including both myelinated and unmyelinated axons. The diameter of the whole nerve is ∼100 μm. Complete data were obtained for 3 nerves. The mean total number of myelinated fibres and unmyelinated axons was 2872±53. The mean number of myelinated fibres was 280±20 and that for unmyelinated axons was 2600±47. There was a broad distribution of diameters for myelinated fibres ranging from ∼2 μm to 10 μm with a distinct peak at ∼3–5 μm and a less prominent second peak at 6–8 μm. Similarly, myelin sheath thickness distribution showed 2 peaks, one at 0.6–0.8 μm and another at 1.4–1.6 μm. It is suggested that the group represented by the second peak innervates the Herbst corpuscles. The group of smaller myelinated fibres and the unmyelinated axons are assumed to innervate other types of receptors, some of which may be nociceptors.     

The discovery of phthalazinone-based human H1 and H3 single-ligand antagonists suitable for intranasal administration for the treatment of allergic rhinitis

A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.1 and 8.9, respectively, vs 9.7 for the clinical gold-standard azelastine, and H(3) potency (pK(i) 9.6 and 9.5, respectively, vs 6.8 for azelastine). Compound 56a had longer duration of action than azelastine, low brain penetration, and low oral bioavailability, which coupled with the predicted low clinical dose, should limit the potential of engaging CNS-related side-effects associated with H(1) or H(3) antagonism.     

Clinical and pathological heterogeneity in late-onset partial merosin deficiency

Mutations in the LAMA2 gene result in a complete loss of merosin and underlie a severe congenital type of muscular dystrophy (MDC1A).We investigated the clinical, genetic, and histological basis of late-onset muscular dystrophy in one family. The proband and her affected brother exhibited late-onset predominantly proximal muscle weakness. In addition, the proband experienced seizures. Magnetic resonance imaging of her brain demonstrated white-matter abnormalities. Sequencing of LAMA2 identified two new heterozygous point mutations in the two affected members. Muscle histology demonstrated dystrophic features, rimmed vacuoles, and partial loss of laminin α immunoreactivity. Partial merosin deficiency can present with a mild, late-onset limb-girdle-type pattern of weakness, with or without epilepsy, and pathologically may exhibit features observed in inclusion-body myopathy.