Clinical and in vitro resistance to bexarotene in adult T-cell leukemia: loss of RXR-alpha receptor.

The oral rexinoid bexarotene (Targretin) is widely used for treatment of cutaneous T-cell lymphomas (CTCL). We recently reported the first case of adult T-cell leukemia/lymphoma (ATLL) that responded rapidly to combination therapy of bexarotene and interferon (IFN)-alpha2b with complete clinical response. We demonstrated that bexarotene induced apoptosis of the patient's malignant peripheral blood T-cells in vitro. However, our patient developed skin and nodal relapse 180 days after starting treatment. We now demonstrate that his peripheral blood malignant T cells became resistant to bexarotene-induced apoptosis. We investigated potential mechanisms that may cause aberrations in the retinoid X receptor (RXR) subunits, RXR-alpha and RXR-beta, to account for these findings. Sequence analysis did not reveal acquisition of mutations in the genes encoding RXR-alpha and RXR-beta by resistant cells. We assessed RXR-alpha and RXR-beta expression by Western blot analysis and found that resistant cells had significantly decreased RXR-alpha expression compared with pretherapy bexarotene-sensitive cells. Our findings indicate that reduced expression of the RXR-alpha receptor subunit may represent a mechanism for resistance to bexarotene in T-cell malignancies.

Multiple eccrine poromas in the setting of total body irradiation and immunosuppression.

Eccrine poromas are benign, adnexal tumors that most often occur as a solitary lesion on the palm or sole. The occurrence of multiple eccrine poromas is extremely rare. In this report, we describe the development of several eccrine poromas in an acral distribution in a 42-year-old man. Before the appearance of these tumors, the patient had received total body irradiation and allogeneic bone marrow transplantation for treatment of acute lymphocytic leukemia. As a complication of the bone marrow transplant, the patient developed chronic graft-versus-host disease, which was treated with immunosuppressive therapy. We discuss this patient and review the available literature regarding multiple eccrine poromas.

Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria.

Trimethylaminuria is a rare metabolic disorder that is associated with abnormal amounts of the dietary-derived trimethylamine. Excess unmetabolized trimethylamine in the urine, sweat and other body secretions confers a strong, foul body odor that can affect the individual's ability to work or engage in social activities. This review summarizes the biochemical aspects of the condition and the classification of the disorder into: 1) primary genetic form, 2) acquired form, 3) childhood forms, 4) transient form associated with menstruation, 5) precursor overload and 6) disease states. The genetic variability of the flavin-containing monooxygenase (form 3) that is responsible for detoxication and deodoration of trimethylamine is discussed and put in context with other variant forms of the flavin-containing monooxygenase (forms 1-5). The temporal-selective expression of flavin-containing monooxygenase forms 1 and 3 is discussed in terms of an explanation for childhood trimethylaminuria. Information as to whether variants of the flavin-containing monooxygenase form 3 contributes to hypertension and/or other diseases are presented. Discussion is provided outlining recent bioanalytical approaches to quantify urinary trimethylamine and trimethylamine N-oxide and plasma choline as well as data on self-reporting individuals tested for trimethylaminuria. Finally, trimethylaminuria treatment strategies and nutritional support are described including dietary sources of trimethylamine, vitamin supplementation and drug treatment and issues related to trimethylaminuria in pregnancy and lactation are discussed. The remarkable progress in the biochemical, genetic, clinical basis for understanding the trimethylaminuria condition is summarized and points to needs in the treatment of individuals suffering from trimethylaminuria.

Volatile biomarkers from human melanoma cells.

Dogs can identify, by olfaction, melanoma on the skin of patients or melanoma samples hidden on healthy subjects, suggesting that volatile organic compounds (VOCs) from melanoma differ from those of normal skin. Studies employing gas chromatography-mass spectrometry (GC-MS) and gas sensors reported that melanoma-related VOCs differed from VOCs from normal skin sources. However, the identities of the VOCs that discriminate melanoma from normal skin were either unknown or likely derived from exogenous sources. We employed solid-phase micro-extraction, GC-MS and single-stranded DNA-coated nanotube (DNACNT) sensors to examine VOCs from melanoma and normal melanocytes. GC-MS revealed dozens of VOCs, but further analyses focused on compounds most likely of endogenous origin. Several compounds differed between cancer and normal cells, e.g., isoamyl alcohol was higher in melanoma cells than in normal melanocytes but isovaleric acid was lower in melanoma cells. These two compounds share the same precursor, viz., leucine. Melanoma cells produce dimethyldi- and trisulfide, compounds not detected in VOCs from normal melanocytes. Furthermore, analyses of the total volatile metabolome from both melanoma cells and normal melanocytes by DNACNT sensors, coupled with the GC-MS results, demonstrate clear differences between these cell systems. Consequently, monitoring of melanoma VOCs has potential as a useful screening methodology.

Evaluation of reliability, validity, and responsiveness of the CDASI and the CAT-BM.

To properly evaluate therapies for cutaneous dermatomyositis (DM), it is essential to administer an outcome instrument that is reliable, valid, and responsive to clinical change, particularly when measuring disease activity. The purpose of this study was to compare two skin severity DM outcome measures, the Cutaneous Disease and Activity Severity Index (CDASI) and the Cutaneous Assessment Tool-Binary Method (CAT-BM), with the Physician Global Assessment (PGA) as the "gold standard". Ten dermatologists evaluated 14 patients with DM using the CDASI, CAT-BM, and PGA scales. Inter- and intra-rater reliability, validity, responsiveness, and completion time were compared for each outcome instrument. Responsiveness was assessed from a different study population, where one physician evaluated 35 patients with 110 visits. The CDASI was found to have a higher inter- and intra-rater reliability. Regarding construct validity, both the CDASI and the CAT-BM were significant predictors of the PGA scales. The CDASI had the best responsiveness among the three outcome instruments examined. The CDASI had a statistically longer completion time than the CAT-BM by about 1.5 minutes. The small patient population may limit the external validity of the findings observed. The CDASI is a better clinical tool to assess skin severity in DM.

Characterization CSMD1 in a large set of primary lung, head and neck, breast and skin cancer tissues.

The Cub and Sushi Multiple Domains-1 (CSMD1) is a tumor suppressor gene on 8p23.2, where allelic loss is both frequent and associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). To understand the extent of CSMD1 aberrations in vivo, we characterized 184 primary tumors from the head and neck, lung, breast and skin for gene copy number and analyzed expression in our HNSCCs and lung squamous cell carcinomas (SCCs). We detected loss of CSMD1 in a large proportion of HNSCCs (50%), lung (46%) and breast cancers (55%), and to a lesser extent in cutaneous SCCs (29%) and basal cell carcinomas (BCCs, 17%) using array-based comparative genomic hybridization (aCGH). Studying the region more closely with quantitative real-time PCR (qPCR), the loss of CSMD1 increased to 80% in HNSCCs and 93% in lung SCCs. CSMD1 expression was decreased in tumors compared to adjacent benign tissue (65%, 13/20) and was likely due to gene loss in 45% of cases (9/20). We also identified truncated transcripts lacking exons due to DNA copy number loss (30%, 5/17) or aberrant splicing (24%, 4/17). We show loss of CSMD1 in primary HNSCC tissues, and document for the first time that CSMD1 is lost in breast, lung and cutaneous SCCs. We also show that deletions of CSMD1 and aberrant splicing contribute to altered CSMD1 function in vivo.