Simpson Golabi Behmel syndrome: progress toward understanding the molecular basis for overgrowth, malformation, and cancer predisposition.

Simpson Golabi Behmel syndrome (SGBS) is a complex congenital overgrowth syndrome with features that include macroglossia, macrosomia, and renal and skeletal abnormalities as well as an increased risk of embryonal cancers. Most cases of SGBS appear to arise as a result of either deletions or point mutations within the glypican-3 (GPC3) gene at Xq26, one member of a multigene family encoding for at least six distinct glycosylphophatidylinositol-linked cell surface heparan sulfate proteoglycans. As a class of molecules, heparan sulfate proteoglycans have been found to play essential roles in development by modulating cellular responses to growth factors and morphogens. Specifically, mutations in both the murine GPC3 gene and the Drosophila glypican, dally, have been found to modify cellular responses to bone morphogenetic proteins, providing important clues to the molecular basis of SGBS in humans. Despite these advances, there remains a paucity of information about the natural history of SGBS and optimal medical management strategies, and whether select mutations influence the SGBS phenotype and risk of cancer. To this end, an International SGBS Registry has been created and is being maintained to improve the clinical care and understanding of the pathogenesis of SGBS. Using an integrated approach employing epidemiology, molecular genetic characterization of specific GPC3 mutations, and the use of model organisms should rapidly expand the understanding of this complex disorder.

Protean clinical manifestations in children with leukemias containing MLL-AF10 fusion.

Translocations involving the MLL gene on chromosome 11q23 occur in 5-10% of human leukemias, and involve fusion with more than 30 different partner genes. The MLL-AF10 fusion produced by the t(10;11)(p12;q23) or ins(10;11)(p12;q23q13) occurs in a small percentage of acute leukemias, most commonly acute myelogenous leukemia (AML) of the M5 FAB subtype. We report two cases of AML (M5a and M0) and one case of acute lymphoblastic leukemia containing MLL-AF10 fusion. Each case had varied clinical characteristics, despite expressing similar MLL-AF10 fusion transcripts. Including the three cases described in this report, we identified a total of 38 cases of leukemia with MLL-AF10 fusion. Approximately one-third of these are not M5 AML. Taken together, these findings emphasize that while the sentinel molecular event may be identical in a disease, the clinical presentation and outcome can vary widely.

Single-dose half-body irradiation for palliation of multiple bone metastases from solid tumors. Final Radiation Therapy Oncology Group report.

This is the final analysis of Protocol #78-10 which explored increasing single-doses of half-body irradiation (HBI) in patients with multiple (symptomatic) osseous metastases. When given as palliation, HBI was found to relieve pain in 73% of the patients. In 20% of the patients the pain relief was complete; over two thirds of all patients achieved better than 50% pain relief. The HBI pain relief was dramatic with nearly 50% of all responding patients doing so within 48 hours and 80% within one week from HBI treatment. Furthermore, the pain relief was long-lasting and continued without need of retreatment for at least 50% of the remaining patient's life. These results compare favorably with those obtained by the Radiation Therapy Oncology Group (RTOG) using several conventional daily fractionated schemes on similar patients in a prior study (RTOG #74-02). HBI achieves pain relief sooner and with less evidence of pain recurrence in the irradiated area than conventionally treated patients. The most effective and safest of the HBI doses tested were 600 rad for the upper HBI and 800 rad for the lower or mid-HBI. Increasing doses beyond these levels did not increase pain relief, duration of relief, or achieved a faster response; however, the increase in dose was associated with a definite increase in toxicity. Single-dose HBI was well tolerated with no fatalities seen among 168 treated patients. A comprehensive premedication program has proven to decrease the acute radiation syndrome to very acceptable levels. There were excellent responses found in practically all tumors treated, but especially breast and prostate among which over 80% of all patients experienced pain relief, 30% in a complete fashion. Single-dose HBI emerges as one of the safest, fastest, and more effective palliative tools for intractable cancer pain in modern radiation oncology.

Systemic hemibody irradiation for overt and occult metastases.

Hemibody irradiation was initially employed as a palliative technique to treat diffuse metastatic disease in one session as opposed to multiple fields over an extended period. It provides a radiation treatment for disseminated cancer and therefore has been termed "systemic" therapy. Since it is possible to treat both halves of the body sequentially, it allows radiation treatment to the whole body in larger doses than could be accomplished with total-body irradiation. Because of the success in terms of dramatic rapid pain relief and the objective response on metastatic disease, it has been explored in the treatment of occult disease and as consolidation therapy in patients with tumors that have responded to chemotherapy. When hemibody irradiation is combined with chemotherapy, responses have been shown in metastases for several primaries, particularly small cell carcinoma, which is perhaps the most encouraging, and supports further research in the treatment of micrometastatic disease for this tumor type. As the technique moves from its current research phase into more general clinical use, radiation oncologists should become more familiar with the treatment, and the hospitalization originally required may be able to be avoided. An intensive premedication program has been developed to facilitate this. Innovative approaches using radiosensitizers, radioprotectors, hyperthermia, and hyperfractionation are ideas that are starting to be tested and will be further explored in the near future.

Alpha-1 antitrypsin in childhood asthma.

Alpha-1 antitrypsin (AAT) phenotypes and serum levels were studied in two childhood perennial asthmatic populations. The first was an ambulatory, mostly mild nonsteroid-dependent group living in Rochester, N.Y. The second was a more severe mostly steroid-dependent group residing at an asthma residential treatment center in Denver, Colo. The prevalences of alpha-1 antitrypsin protease inhibitor (Pi) tyes were the same for bothe groups and similar to prevalences in a random population. Alpha-1 antitrypsin serum levels were significantly elevated for the mild nonsteroid-dependent group when compared to the more severe steroid-dependent group. The steroid-dependent group had serum levels similar to a group of nonasthmatic control children. These findings indicate that there is not a strong association of alpha-1 antitrypsin Pi variants such as Pi MZ or Pi MS with more severe asthma. Elevated serum levels in the milk perennial asthmatic group may be the result of chronic inflammatory processes. Normal levels in the sterioid-dependent group may be the result of corticosteroid control of inflammation associated with asthma.

Third component of complement in cystic fibrosis.

In a study of C3 levels and phenotypes in 64 cystic fibrosis (CF) patients, 92 CF parents, 64 normal siblings, and 126 healthy controls, significant elevations of mean C3 levels were found in CF patients, their parents, and in one genetic sub-group of their siblins (SS females). C3 concentration in CF patients correlated with the degree of clinical impairment as measured by Shwachman-Kulczycki (S-K) score. No significant differences were found in the prevalences of C3 phenotypes or the S and F gene frequencies among the groups studied.