Negative effect of DNA hypermethylation on the outcome of intensive chemotherapy in older patients with high-risk myelodysplastic syndromes and acute myeloid leukemia following myelodysplastic syndrome.

PURPOSE: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy. EXPERIMENTAL DESIGN: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-beta-d-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15(ink4b) (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment. RESULTS: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile. CONCLUSIONS: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.     

Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2

LAT1 and LAT2 are heterodimeric large amino acid transporters that are expressed in various tissues, including the intestinal wall, blood-brain barrier, and kidney. These transporters consist of membrane spanning light chain and heavy chain, and they act as 1:1 exchangers in concert with other amino acid transporters. Only a few drugs (less than 10) are substrates of LAT1 and LAT2, including l-DOPA, alpha-methyldopa, melphalan, and gabapentin. The mechanisms and substrates have been mostly elucidated using mammalian cells and Xenopus oocytes. The in vivo relevance of LAT1 and LAT2 in pharmacokinetics is obscure, because contradictory findings have been reported. It is difficult to make quantitative pharmacokinetic conclusions about LAT1 and LAT2. This is due to the possible involvement of other transporters (including cross-linked heterodimers of light chain with different heavy chains, other overlapping transporters, for example TAT1), competing endogenous amino acids, and saturation phenomena. This review presents the current functional knowledge on LAT1 and LAT2 with emphasis on their potential involvement in pharmacokinetics.     

Autoreactivity against matrilin-1 in a patient with relapsing polychondritis

Relapsing polychondritis (RP) is a rare inflammatory disease of cartilage. Chondritis of the auricular, nasal, and tracheal cartilages predominates in this disease, suggesting a response to a tissue-specific antigen. One potential antigen is matrilin-1, a cartilage matrix protein found uniquely in the tracheal, auricular, and nasal cartilage of adults. We describe herein a patient with RP who had both a humoral and a cellular immune response directed toward the cartilage matrix protein matrilin-1.     

Human papillomavirus types and cervical squamous intraepithelial lesions that recur after cold-knife conization

The purpose of this study was to analyze the HPV types and histological margins of cervical squamous intraepithelial lesions (SILs) treated by cold-knife conization and to correlate this with recurrent disease. Of 203 cone biopsies done for SILs primarily because the entire lesion could not be visualized at colposcopy, follow-up information was available for 85 cases. Of these 85 cases, biopsy-proven recurrences were documented for 10 (12%) women. In the SILs which recurred after conization, the lesion was noted on the surgical margin in 7/10 (70%) cases. In contrast, SILs that did not recur after cold-knife conization were detected on the surgical margin in only 12% of cases. In 7 of the recurrences, the HPV type detected in the pretreatment SIL was the same as that detected in the SIL that occurred after conization. In the other 3 recurrences, one of either the primary or recurrent SILs was HPV positive and the other corresponding lesion HPV negative. It is concluded that detection of a SIL on the surgical margin is a marker for recurrent disease and that recurrences are often associated with the same HPV type as that noted in the pretreatment SIL.     

UPPP for habitual snoring: A 5-year follow-up with respiratory sleep recordings

Fifty-six men who underwent uvulopalatopha-ryngoplasty (UPPP) because of habitual snoring without preoperative obstructive sleep apnea (OSA), according to respiratory sleep recordings, were interviewed concerning persistent snoring and excessive daytime sleepiness (EDS). Renewed recordings were made in 53 of them at a median time of 63 months postoperatively. Median preoperative oxygen desaturation index (ODI) was 0; the median postoperative index was 1. Median duration of the preoperative obstructive respiratory pattern was 8% of total sleeping time, and the median duration postoperatively was 17%. (Significant individual increases were P=.0005 and P=.004, respectively.) Six patients answered to OSA criteria postoperatively. Weight increases were significantly correlated to increases in both ODI and obstructive respiratory pattern and to persistent snoring. Preoperatively 51 of 56 patients reported EDS, and 73% of the patients were improved or cured. From snoring, 87% reported improvement or cure. No patient had any serious sequelae of UPPP. Uvulopalatopharyngoplasty is a safe and effective treatment for habitual snoring, but it does not give absolute protection from development of OSA.     

PRIMARY CARE FOR WOMEN: Comprehensive Assessment of the Neurologic System

This article reviews the essential neuroanatomy and neurophysiology, and summarizes the components of the health history, physical exam, and laboratory tests required for an assessment of the neurologic system within the primary care setting. Brief case studies illustrate the wide range of symptoms associated with neurologic disorders in women and the manner in which the pattern of symptoms can be used to locate the site of pathology and indicate the need for referral and follow-up.     

Targeting of Teniposide to the Mononuclear Phagocytic System (MPS) by Incorporation in Liposomes and Submicron Lipid Particles; An Autoradiographic Study in Mice

Liposomes are concentrated in the mononuclear phagocytic system in vivo and may therefore be of value as carriers of drugs when treating diseases involving phagocytic cells. Teniposide (VM-26) is a potent and lipophilic cytotoxic drug. Teniposide was incorporated in large unilamellar liposomes (LUVs) consisting of egg phosphatidylcholine and dioleoyl phosphatidic acid and into the novel submicron lipid particles containing cholesteryl oleate, cholesteryl palmitate and soybean lecithin, in order to evaluate the drug targeting effect. Radiolabelled teniposide and lipids were used and the organ distribution in mice was studied with whole-body autoradiography 20 and 90 min post i.v. injection. When the commercial formulation of teniposide (Vumon) was administered, teniposide accumulated in the liver where the drug is metabolized. Biliary excretion was rapid and considerable already after 20 min. The liposomal formulation enhanced liver uptake of teniposide slightly. The distribution of radiolabelled phosphatidyl choline differed from that of teniposide indicating instability of the liposomes in circulation. Despite this, the splenic uptake of the drug was significantly enhanced by administration in liposomes. In the red pulp of the spleen the teniposide level was 23 times higher 90 min post injection, using the liposomal formulation as compared to free drug. The submicron lipid particles were mainly accumulated in the liver and to a lesser extent in the spleen. The study shows that liposomes and lipid particles enhance splenic and liver uptake and can be used to target teniposide to the MPS.