ABSTRACT
BACKGROUND: Malignant melanoma is an exceptionally aggressive, drug-resistant and heterogeneous cancer. Recently it has been shown that melanoma cells with high clonogenic and tumourigenic abilities are common, but markers distinguishing such cells from cells lacking these abilities have not been identified. There is therefore no definite evidence that an exclusive cell subpopulation, i.e. cancer stem cells (CSC), exists in malignant melanoma. Rather, it is suggested that multiple cell populations are implicated in initiation and progression of the disease, making it of importance to identify subpopulations with elevated aggressive properties. METHODS AND FINDINGS: In several other cancer forms, Aldehyde Dehydrogenase (ALDH), which plays a role in stem cell biology and resistance, is a valuable functional marker for identification of cells that show enhanced aggressiveness and drug-resistance. Furthermore, the presence of ALDH(+) cells is linked to poor clinical prognosis in these cancers. By analyzing cell cultures, xenografts and patient biopsies, we showed that aggressive melanoma harboured a large, distinguishable ALDH(+) subpopulation. In vivo, ALDH(+) cells gave rise to ALDH(-) cells, while the opposite conversion was rare, indicating a higher abilities of ALDH(+) cells to reestablish tumour heterogeneity with respect to the ALDH phenotype. However, both ALDH(+) and ALDH(-) cells demonstrated similarly high abilities for clone formation in vitro and tumour initiation in vivo. Furthermore, both subpopulations showed similar sensitivity to the anti-melanoma drugs, dacarbazine and lexatumumab. CONCLUSIONS: These findings suggest that ALDH does not distinguish tumour-initiating and/or therapy-resistant cells, implying that the ALDH phenotype is not associated with more-aggressive subpopulations in malignant melanoma, and arguing against ALDH as a "universal" marker. Besides, it was shown that the ability to reestablish tumour heterogeneity is not necessarily linked to the more aggressive phenotype.
Subject(s)
Aldehyde Dehydrogenase/metabolism , Melanoma/enzymology , Melanoma/pathology , Animals , Biopsy , Cell Line, Tumor , Cell Proliferation , Cell Separation , Clone Cells , Humans , Melanoma/drug therapy , Mice , Phenotype , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Xenograft Model Antitumor AssaysABSTRACT
The timing of repair of a cleft lip continues to be debated. One of the reasons for delaying operation has been the belief that there is an increased risk of anaesthesia during the neonatal period. As a contribution to this debate we have analysed the anaesthetic and surgical complications of neonatal cleft lip repair undertaken at a single centre. We made a retrospective study of 99 babies consecutively referred for repair of cleft lip over a five-year period (January 1995-December 1999). In contrast to other series, all babies were considered for neonatal surgery and no exclusion criteria were set. All repairs were undertaken within 28 days of birth (median 4); the median gestational age was 40 weeks (range 34-42) and median birth weight of 3300 g (range 1500-4600 g). Perianaesthetic complications included one case of hypoxia presumably as a result of transitional circulation, one reintubation for poor respiratory effort in a premature baby, and five cases of nasal obstruction, three of which required a nasal stent. All recovered without long-term effects. There were significantly more surgical complications with bilateral repairs than with unilateral (p < 0.03). Breast feeding was achieved in 54 babies by the time of discharge. We found no evidence that neonatal repair of cleft lip is unsafe. Paediatric anaesthetic and intensive care support within a specialised centre are necessary, and close postoperative monitoring is required, with attention to the nasal airway.
