Rare diseases Xagena

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Lymphangioleiomyomatosis: Sirolimus reduces circulating LAM cells

Lymphangioleiomyomatosis ( LAM ), sporadic or in women with tuberous sclerosis complex ( TSC ), is characterized by cystic lung destruction, lymphatic involvement ( eg, chylous pleural effusions, lymphangioleiomyomas ), and renal angiomyolipomas ( AMLs ).

The multisystem manifestations of lymphangioleiomyomatosis appear to result from metastatic dissemination of LAM cells bearing inactivating mutations or having loss of heterozygosity ( LOH ) of the tumor suppressor genes TSC1 or TSC2, which leads to hyperactivation of the mammalian target of rapamycin.
Sirolimus slows the decline of lung function, reduces chylous effusions, and shrinks the size of angiomyolipomas.

The aim of a study was to determine the effect of Sirolimus on circulating LAM cells.

Cells from blood were isolated by a density-gradient fractionation system and from urine and chylous effusions by centrifugation.
Blood cells were incubated with anti-CD45-fluorescein isothiocyanate ( FITC ) and anti-CD235a-R-phycoerythrin ( PE ) antibodies, and urine and chylous effusion cells were incubated with anti-CD44v6-FITC and anti-CD9-R-PE antibodies.
Cells were sorted and analyzed for TSC2 LOH.

LAM cells with TSC2 LOH were identified in 100% of blood specimens and 75% of urine samples from patients before therapy.
Over a mean duration of 2.2 years of Sirolimus therapy, detection rates of LAM cells were significantly decreased to 25% in blood ( P less than 0.001 ) and 8% in urine ( P=0.003 ).

Following therapy, a greater loss of circulating LAM cells was seen in postmenopausal patients ( P=0.025 ).

In conclusion, patients receiving Sirolimus had a progressive loss of circulating LAM cells that depended on time of treatment and menopausal status. ( Xagena )

Cai X et al, Chest 2014;145:108-112