No abstract

Over a period of seven years, 15 patients (aged from birth to 15 years; median 22 months) with lymphangioma were treated with OK-432; they received a mean of three injections each. Ten received OK-432 as first line treatment; five were treated after surgery (three had a residual lymphangioma after incomplete removal and two had a late recurrence). OK-432 proved to be eVective for primitive as well as for residual and recurrent lymphangioma. Seven cases were macrocystic; complete regression was obtained in all. Five cases were microcystic: two had more than 50% regression, and three less than 50%. Three cases were mixed, with both large and microscopic cysts: one had more than 50% regression, and two less than 50%. These last two cases underwent surgery after the sclerosing treatment. The results obtained were excellent in 100% of macrocystic cases; a shrinkage in size was obtained in all microcystic cases. OK-432 is therefore proposed as a first line option for treatment of lymphangiomas. (Arch Dis Child 2000;82:316-318)

Traditionally, local invasiveness and size have been considered prognostic factors. In our experience, both patients with local invasiveness and the patient with a tumor larger than 2 cm had good outcomes. Ileocolectomy performed in the patient with a 2-cm tumor and in another two patients with smaller tumors did not demonstrate residual disease. Although the need for right hemicolectomy still remains controversial for tumors measuring more than 2 cm, the approach may be nonaggressive in case of tumors invading the serosa and the periappendiceal fat. Nonaggressive treatment has been suggested by some authors in cases of tumors larger than 2 cm; however, larger series need to be evaluated.

Primary lymphedema is caused by developmental and functional defects of the lymphatic vascular system that result in accumulation of protein-rich fluid in tissues, resulting in edema. The 28 currently known genes causing primary lymphedema can explain <30% of cases. Angiopoietin 1 (ANGPT1) and ANGPT2 function via the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor–like domains 1 and 2) receptor complex and α5β1 integrin to form an endothelial cell signaling pathway that is critical for blood and lymphatic vessel formation and remodeling during embryonic development, as well as for homeostasis of the mature vasculature. By screening a cohort of 543 individuals affected by primary lymphedema, we identified one heterozygous de novo ANGPT2 whole-gene deletion and four heterozygous ANGPT2 missense mutations. Functional analyses revealed three missense mutations that resulted in decreased ANGPT2 secretion and inhibited the secretion of wild-type (WT)–ANGPT2, suggesting that they have a dominant-negative effect on ANGPT2 signaling. WT-ANGPT2 and soluble mutants T299M and N304K activated TIE1 and TIE2 in an autocrine assay in human lymphatic endothelial cells. Molecular modeling and biophysical studies showed that amino-terminally truncated ANGPT subunits formed asymmetrical homodimers that bound TIE2 in a 2:1 ratio. The T299M mutant, located in the dimerization interphase, showed reduced integrin α5 binding, and its expression in mouse skin promoted hyperplasia and dilation of cutaneous lymphatic vessels. These results demonstrate that primary lymphedema can be associated with ANGPT2 mutations and provide insights into TIE1 and TIE2 activation mechanisms.