Summary Background Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this ...treatment combination provided greater survival benefit than did chlorambucil or fludarabine. Methods 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. Findings There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38% vs 15%, respectively; overall response rate 94% vs 80%, respectively; p<0·0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0·006 and 0·04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0·00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (VH ) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. Interpretation Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.
Background There is a need for additional effective treatments for acne vulgaris. Laser therapy has been explored as a therapeutic option for acne, but rigorously designed studies in this area have ...been limited. Objective We sought to examine the efficacy of an infrared laser in the treatment of acne. Methods We conducted a randomized, controlled, single-blind, split-face clinical trial of 46 patients with facial acne. Patients received a series of 3 nonablative laser treatments using a novel neodymium:yttrium-aluminum-garnet (Nd:YAG) laser to half of the face. Serial blinded lesion counts and global acne severity rating of standardized bilateral patient photographs were performed. Sebum production was measured, and patient self-assessment surveys were administered. Results A transient but statistically significant improvement in lesion counts of open comedones was demonstrated in treated skin as compared with untreated skin. There were no significant differences between treated and control sides of the face in terms of changes in mean papule or pustule counts. Grading of serial photographs revealed no significant differences between treated and untreated skin. Patient surveys indicated that the majority of patients found the treatments to be at least mildly effective for both acne and oiliness. Limitations The current study only addresses the efficacy of a single laser system employing a specific treatment regimen. Conclusions Infrared laser therapy may improve comedonal acne. Additional work is needed to better define the degree and duration of the effect. Patients appear to positively view such therapy for both acne and oily skin.
Background The cytochrome P450 (CYP) enzyme CYP26 (retinoic acid RA 4-hydroxylase) initiates the catabolism of all- trans RA ( t RA) and limits the effects of t RA. The CYP26 enzyme acts specifically ...on t RA, but not 13- cis RA (isotretinoin), a retinoid used to treat severe acne. However, 13- cis RA can isomerize to t RA, which can then be metabolized by CYP26. Objective In healthy individuals, we assessed the variability of CYP26 enzymatic activity. We then investigated whether response to oral 13- cis RA among patients with acne correlates with variability in CYP26 expression. Methods In healthy individuals, we isolated microsomal fractions from the epidermis of keratome biopsy specimens and measured CYP26 enzymatic activity in untreated skin and skin treated with t RA. Enzymatic activity was determined based on rate of formation of 4-hydroxy RA (pg/min/mg microsomal protein). Using real-time polymerase chain reaction we quantified CYP26 messenger RNA induction after t RA application in patients with acne who responded or did not respond to one course of 13- cis RA. Results In normal-appearing skin (N = 118), CYP26 enzymatic activity was widely variable (1-180 pg/min/mg microsomal fraction; mean 42.7 ± 3.5). Furthermore, CYP26 enzymatic activity was inducible in a dose-dependent manner in normal-appearing skin after t RA application, but not correlated with age or sex (N = 29). In patients with acne, CYP26 messenger RNA induction after 0.1% t RA application did not differ ( P > .05) between patients who responded (N = 8, 587 ± 325-fold) or did not respond (N = 8, 657 ± 227-fold) to one course of 13- cis RA. Limitations The small number of patients with acne treated with 13- cis RA was a major limitation. Conclusion Factors other than CYP26 activity may determine response to isotretinoin in acne.
Intraepidermal erbium:YAG laser resurfacing Orringer, Jeffrey S., MD; Rittié, Laure, PhD; Hamilton, Ted, MS ...
Journal of the American Academy of Dermatology,
2011, Volume:
64, Issue:
1
Journal Article
Peer reviewed
Background Various minimally invasive treatments enhance the skin's appearance. Little is known about the molecular mechanisms whereby treatments working at the epidermal level might alter the ...dermis. Objective We sought to quantify the molecular changes that result from erbium:yttrium-aluminium-garnet (Er:YAG) laser microablative resurfacing. Methods We performed biochemical analyses after intraepidermal Er:YAG laser resurfacing of 10 patients. Immunohistochemical analysis and polymerase chain reaction technology were utilized to measure key biomarkers. Results The basement membrane remained intact after intraepidermal microablation, as demonstrated by laminin γ2 immunostaining. Epidermal injury was demonstrated with acute up-regulation of keratin 16. An inflammatory response ensued as indicated by increases in cytokines interleukin 1 beta (IL-1β) and IL-8 as well as a substantial neutrophil infiltrate. Levels of cJun and JunB proteins, components of the transcription factor AP-1 complex, were also elevated. Up-regulation of extracellular matrix degrading proteinases matrix metalloproteinase 1 (MMP-1), MMP-3, and MMP-9 was noted. A transient increase in keratinocyte proliferation, as indicated by staining for Ki67, was observed. Increased expression of type I and type III procollagen was demonstrated. Limitations The data presented are those that resulted from a single treatment session. Conclusions Although microablation was confined to the uppermost epidermis, marked changes in epidermal and dermal structure and function were demonstrated after Er:YAG laser microablative resurfacing. We demonstrated substantial dermal matrix remodeling, including a degree of collagen production that compares favorably with some more invasive interventions. Dermal remodeling and stimulation of collagen production are associated with wrinkle reduction. Thus these results suggest that the skin's appearance may be enhanced by creating dermal changes through the use of superficially acting treatments.
PDF