YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma.

PURPOSE: YKL-40 is a secreted protein that has been reported to be overexpressed in epithelial cancers and gliomas, although its function is unknown. Previous data in a smaller sample set suggested that YKL-40 was a marker associated with a poorer clinical outcome and a genetically defined subgroup of glioblastoma. Here we test these findings in a larger series of patients with glioblastoma, and in particular, determine if tumor YKL-40 expression is associated with radiation response. EXPERIMENTAL DESIGN: Patients (n=147) with subtotal resections were studied for imaging-assessed changes in tumor size in serial studies following radiation therapy. An additional set (n=140) of glioblastoma patients who underwent a gross-total resection was tested to validate the survival association and extend them to patients with minimal residual disease. RESULTS: In the subtotal resection group, higher YKL-40 expression was significantly associated with poorer radiation response, shorter time to progression and shorter overall survival. The association of higher YKL-40 expression with poorer survival was validated in the gross-total resection group. In multivariate analysis with both groups combined (n = 287), YKL-40 was an independent predictor of survival after adjusting for patient age, performance status, and extent of resection. YKL-40 expression was also compared with genetically defined subsets of glioblastoma by assessing epidermal growth factor receptor amplification and loss at chromosome 10q, two of the common recurring aberrations in these tumors, using fluorescent in situ hybridization. YKL-40 was significantly associated with 10q loss. CONCLUSIONS: The findings implicate YKL-40 as an important marker of therapeutic response and genetic subtype in glioblastomas and suggest that it may play an oncogenic role in these tumors.     

Temozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1.

PURPOSE: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)-dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. EXPERIMENTAL DESIGN: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. RESULTS: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 +/- 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. CONCLUSIONS: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.     

A phase I and pharmacokinetic study of paclitaxel poliglumex (XYOTAX), investigating both 3-weekly and 2-weekly schedules.

PURPOSE: To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. EXPERIMENTAL DESIGN: Nineteen patients were investigated on the 3-weekly phase Ia study and 11 patients on the 2-weekly phase Ib study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. RESULTS: Dose-limiting toxicity of neutropenia was encountered at 266 mg/m(2) (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m(2). Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m(2). Pharmacokinetic investigations indicated a prolonged half-life of >100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m(2) in phase Ia and one in a patient with gastric carcinoma at 175 mg/m(2) in phase Ib. CONCLUSION: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.     

The Variation in Arrestees' Disclosure of Recent Drug Use Across Locations, Drugs, and Demographic Characteristics

This study provides a comprehensive multivariate analysis of drug use disclosure among arrestees interviewed between 2000 and 2001 at 37 sites across the U.S. served by the Arrestee Drug Abuse Monitoring (ADAM) Program. Rates varied widely by drug and across sites. The marijuana disclosure rate varied from 68% in Fort Lauderdale to 93% in Spokane. The cocaine/crack disclosure rate varied from 28% in Chicago to 70% in Kansas City. Moreover, covariates of disclosure differed across drugs. This wide variation in disclosure suggests extreme caution be used when comparing self-reports of prevalence across drugs, locations, and individual characteristics - certainly at least for arrestees.     

Laparoscopic cervical cerclage: a series in women with a history of second trimester miscarriage

We sought to develop a laparoscopic technique for placement of a cervical cerclage in women with a history of failed vaginal cerclage and recurrent miscarriage. This was a case series, design classification III. The study took place at The Recurrent Miscarriage Clinic at National Women's Hospital, Auckland, New Zealand. Ten women with a history of second trimester miscarriage after failed vaginal cerclage, and 1 woman with a history of second trimester miscarriage and findings of a clinically deficient cervix were studied. A laparoscopic cervical cerclage was placed before pregnancy. No intraoperative or postoperative complications were experienced. Ten of 11 women subsequently became pregnant and all delivered live babies by cesarean section in the third trimester. Laparoscopic cervical cerclage is feasible and effective. Outcomes are good in a particularly high-risk group of women with cervical incompetence, who have had failed vaginal cerclage and have a history of recurrent pregnancy loss.     

The effect of uterine fibroids on embryo implantation

Uterine fibroids are common but their role in infertility and effect on embryo implantation is unclear. There is evidence that submucosal fibroids are associated with poor reproductive outcome and that treatment with myomectomy is associated with an improvement in pregnancy rates. Various theories have been proposed to explain this relationship. Fibroids cause a mechanical distortion of the endometrial cavity-their presence may alter gamete and embryo transport (due to blockage of the tubal ostia or by altering uterine contractility and peristalsis) and subsequent embryo implantation (due to compression of the endometrium). They may lead to disruption of the junctional zone within the myometrial layer, affecting general uterine function in the initial stages of embryo invasion and later placentation. Altered vasculature due to the abnormal expression of angiogenic factors by uterine fibroids (such as basic fibroblast growth factor and platelet-derived growth factor) could play a role in a reduced implantation rate in patients with fibroids. Similarly, changes in the endometrium mediated by inflammation and factors involved in the process of fibrosis (such as transforming growth factor) could also have a detrimental effect. In addition, fibroids may affect gene expression pattern in the endometrium (such as HOXA10), disrupting the window of implantation. The supporting evidence for these theories is discussed in this review.     

Midwives and the fetal nuchal cord: a survey of practices and perceptions

A systematic search of studies of intrapartum management of the nuchal umbilical cord at term found no published controlled studies in this area. A postal survey containing both structured and open questions and a request for local protocols and guidelines was sent to all 637 midwives in 7 maternity units in England. There were 401 (63%) responses. There appeared to be no unit guidelines for this area of practice. Midwife approaches to nuchal cord during birth varied, and included clamping and cutting of loose nuchal cords and a hands-off approach to tight nuchal cords. Reasons for specific actions included doing what had been taught during midwifery training and learning from previous personal experiences. Theories of diffusion of innovation and of planned behaviour may provide a conceptual basis for understanding the adoption of specific practices. Future qualitative and controlled studies are needed to explore the nature and consequences of varying approaches to intrapartum nuchal cord management.     

Pulmonary impairment and disability

Respiratory disorders, including occupational and environmental lung diseases, are prevalent. Physicians are frequently called upon to determine impairment and aid in the assessment of disability caused by these conditions, either as the treating physician or as an independent medical examiner. In this article we reviewed the role of physicians in determining the presence and severity of pulmonary disorders. A comprehensive clinical assessment and appropriate standardized tests, to objectively characterize the severity of impairment, are the key elements of the evaluation. This assessment may also include the physician's opinion regarding causative factors. Finally, disability determination is made by nonclinicians, through administrative means, based on the degree of impairment and a review of circumstances specific to the individual. Knowledge of these components of disability evaluation will help physicians to better serve their patients and supply appropriate data to the adjudicating system.     

Progestogens of varying androgenicity and cardiovascular risk factors in postmenopausal women receiving oestrogen replacement therapy

OBJECTIVE: Medroxyprogesterone (MP) was used as the progestogen in randomized clinical trials of postmenopausal hormone replacement on cardiovascular risk. To attempt to understand the lack of benefit in these trials, we have examined the effects of MP and two other progestogens, the less androgenic desogestrel (DG) and the more androgenic norethisterone (NE), on cardiovascular risk factors against a background of oestrogen therapy. DESIGN AND MEASUREMENTS: Thirty-four women were treated with conjugated equine oestrogens (CEE) 0.625 mg daily alone for 12 weeks, followed in random order by each of the three progestogens (DG 75 microg, MP 10 mg and NE 1 mg daily) given sequentially for three 12-week cycles while maintaining the same CEE treatment. We measured serum lipoproteins, paraoxonase activity, C-reactive protein (CRP), fibrinogen, fasting glucose and insulin levels at baseline, at the end of the oestrogen-only phase and at the end of each of the combined oestrogen and progestogen phases. RESULTS: The addition of progestogens to CEE maintained the oestrogen-induced reduction in apolipoprotein B (apo B) and lipoprotein (a) [Lp(a)], and further lowered total cholesterol (P < 0.01) and fibrinogen (P < 0.001). CEE raised serum triglyceride (P < 0.001) and CRP (P < 0.01) concentrations, which reverted towards pre-oestrogen levels with progestogens. Progestogens significantly reduced high density lipoprotein (HDL) cholesterol (P < 0.05). NE was associated with the greatest reduction in HDL cholesterol and apo A1, but was most effective in preserving paraoxonase activity and reducing the potentially unfavourable oestrogen-induced increases in triglycerides and CRP. CONCLUSION: Preconceptions that more androgenic progestogens necessarily have more unfavourable effects on cardiovascular risk factors may require revision.