Membrane type matrix metalloproteinases (MMPs) show differential expression in non-small cell lung cancer (NSCLC) compared to normal lung: correlation of MMP-14 mRNA expression and proteolytic activity

Improved understanding of the involvement of matrix metalloproteinases (MMPs), including membrane-type MMPs (MT-MMPs), in human tumours has potential diagnostic, prognostic and therapeutic implications. We assessed the relationship between MT-MMP expression and clinicopathological parameters in human non-small cell lung cancer (NSCLC) and histologically normal lung tissue by quantitative Real Time PCR (qRT-PCR). All MT-MMPs (MMPs 14-17, 24 and 25) were detected by qRT-PCR with significantly higher MMP-14, -15 and -17 expression observed in tumour relative to normal lung specimens. MMP-16 was undetectable in normal lung but expressed in 8% tumours. MMP-15 demonstrated significant overexpression in adenocarcinomas relative to squamous cell carcinomas and normal lung tissue. MMP-14 mRNA expression strongly correlated to MMP-14 proteolytic activity in preclinical tumour models, indicating that qRT-PCR may predict MMP-14 activity levels in NSCLC. These data suggest that MMP-14, -15 and -17 may be good markers of disease, or therapeutic targets for treatment of human NSCLC.     

Efficacy and safety of every-2-week darbepoetin alfa in patients with anemia of cancer: a controlled, randomized, open-label phase II trial

This randomized, controlled trial evaluated the effect of darbepoetin alfa on hospitalization days, transfusion requirements, hemoglobin levels, and fatigue in patients with anemia of cancer (AOC). Eligible patients were anemic (hemoglobin or=18 years old, and had not received chemotherapy or radiotherapy within 4 weeks of study screening. Patients were randomized 4:1 to receive darbepoetin alfa, 3.0 microg/kg every 2 weeks (Q2W) (n = 226), or observation only for 12 weeks (n = 59), followed by an optional 9 weeks of darbepoetin alfa, 3.0 microg/kg Q2W. Endpoints were compared between the two treatment arms at week 13. A planned interim analysis indicated that assumptions regarding hospitalization in the study design were incorrect, so the study was terminated early. Therefore, results for the primary endpoint should be interpreted cautiously. The hospitalization rate was similar (0.5 days) for both the darbepoetin alfa and observation groups (p = .73). Transfusion incidence (weeks 5-12) was significantly lower for darbepoetin alfa patients (8%) than for observation patients (22%) (p = .0092). By week 13, hemoglobin increased by 2.1 g/dl in patients receiving darbepoetin alfa, compared with 0.1 g/dl in the observation group p < .0001. Hemoglobin improvements were paralleled by an increase in Functional Assessment of Cancer Therapy-Fatigue score (mean change in score at week 13: darbepoetin alfa, 6.0; observation, 2.2; p < .05). Darbepoetin alfa Q2W can significantly improve hemoglobin levels and reduce transfusion requirements in patients with AOC, resulting in significant improvements in health-related quality of life.     

The importance of transitions between dialysis and transplantation in the care of end-stage renal disease patients

Analyses describing outcomes of kidney transplantation usually exclude the survival of wait-listed patients and dialysis patients with failed kidney transplants, and thus reflect only a portion of the typical transplant process. We determined death rates during the continuum of wait-listing, transplantation, and after allograft failure among adult end-stage renal disease patients in the United States between 1995 and 2003. Before transplantation, death rates increased with longer waiting times. Death rates were lowest during the period of allograft function and highest after allograft failure. Patients were at particularly high risk during periods of transition between dialysis and transplantation (death rates during the peri-transplant period and during the re-initiation of dialysis after transplant failure were 8.2/100 patient-years (95% confidence interval (CI) 7.7, 8.8) and 17.9/100 patient-years (95% CI 15.7, 20.3), respectively compared to 6.4/100 patient-years (95% CI 6.25, 6.51) during the period of wait-listing. Diabetic patients and older patients were at increased risk at all time points. The most common known cause of death in all age subgroups was cardiovascular disease. The proportion of death owing to sepsis was greatest after allograft failure (16.8% of all deaths were due to sepsis compared to 14.0% during wait-listing, and 12.7% during the period of allograft function). Consideration of the entire transplant experience as a whole should help to focus patient care on periods of particularly high risk, and emphasizes opportunities to improve outcomes by strategies aimed at preventing death owing to cardiovascular and infectious causes.     

A preoperative prognostic nomogram for solid enhancing renal tumors 7 cm or less amenable to partial nephrectomy

PURPOSE: Small renal masses are increasing in incidence. Most tumors 7 cm or less are treated with radical or partial nephrectomy but clinicians are increasingly relying on ablative therapies and observation for some small renal masses. We present novel nomograms that predict the likelihood of benign, likely indolent or potentially aggressive pathological findings based only on readily identifiable preoperative factors. MATERIALS AND METHODS: Information on all partial nephrectomies performed at a single institution was collected in an institutional review board approved registry. Using retrospectively collected data on all 862 patients who underwent partial nephrectomy for a single, solid, enhancing, clinical T1 (7 cm or less) tumor between 1999 and 2005 tumors were classified as benign or malignant. Grade 3 clear cell renal cell carcinoma, grade 4 renal cell carcinoma of any type and any renal cell carcinoma with vascular, fat or collecting system invasion were considered potentially aggressive. The likelihood of benign, likely indolent or potentially aggressive pathological findings was modeled using multivariable logistic regression models based on age, gender, radiographic tumor size, symptoms at presentation and smoking history. RESULTS: Of 862 small renal masses 20% were benign and 80% were malignant but only 30% of cancers (24% of small renal masses) were potentially aggressive. All 11 patients with systemic symptoms had cancer. The remaining 851 patients underwent further analysis. Factors that were most strongly associated with the likelihood of benign pathology were age, gender, tumor size and smoking history. A nomogram constructed to predict benign histology proved to be relatively accurate and discriminating (bootstrap corrected concordance index 0.644) and calibrated. Small renal masses in older men and younger women were more likely to be benign. With regard to differentiating indolent from potentially aggressive cancers, only advanced age was independently significant on multivariate analysis (p <0.005). The nomogram for this outcome performed with limited ability (concordance index 0.557). CONCLUSIONS: Clinical factors provide substantial predictive ability to predict benign vs malignant pathology for small renal masses amenable to partial nephrectomy. Although most of these small renal masses are benign or indolent, our ability to predict potentially aggressive cancer in this population remains limited.     

Endothelial NO/cGMP-dependent vascular relaxation of cornuside isolated from the fruit of Cornus officinalis

Cornuside is a bisiridoid glucoside compound isolated from the fruit of CORNUS OFFICINALIS Sieb. et Zucc. (Cornaceae). In the present study, we investigated the effect of cornuside on vascular tone in rat aortic tissue. Cornuside induced a concentration-dependent relaxation of the phenylephrine-precontracted rat aorta, which was abolished by removal of the endothelial layer. Pretreatment of the aortic tissues with either N(G)-nitro- L-arginine methyl ester (L-NAME) or 1 H- -oxadiazole-[4,3-alpha]-quinoxalin-1-one (ODQ) completely inhibited the relaxation induced by cornuside. However, the relaxant effect of cornuside was not blocked by pretreatment with verapamil, diltiazem, tetraethylammonium (TEA), glibenclamide, indomethacin, atropine, or propranolol. In addition, incubation of human umbilical vein endothelial cells (HUVECs) with cornuside increased the production of cGMP in a dose-dependent manner, but this effect was blocked by pretreatment with L-NAME and ODQ, respectively. Taken together, the present study suggests that cornuside dilates vascular smooth muscle via endothelium-dependent nitric oxide (NO)/cGMP signaling.     

The Hong Kong Society of Rheumatology consensus recommendations for the management of gout

Clinical Rheumatology - Gout is one of the most common noncommunicable diseases in Hong Kong. Although effective treatment options are readily available, the management of gout in Hong Kong remains...     

Recent trends in HIV and other STIs in the United Kingdom: data to the end of 2002

Sexual health in the United Kingdom has deteriorated in recent years with further increases in HIV and other sexually transmitted infections (STIs) reported in 2002. This paper describes results from the available surveillance data in the United Kingdom from the Health Protection Agency and its national collaborators. The data sources range from voluntary reports of HIV/AIDS from clinicians, CD4 cell count monitoring, a national census of individuals living with HIV, and the Unlinked Anonymous Programme, to statutory reports of STIs from genitourinary medicine (GUM) clinics and enhanced STI surveillance systems. In 2002, an estimated 49500 adults aged over 15 years were living with HIV in the United Kingdom, of whom 31% were unaware of their infection. Diagnoses of new HIV infections have doubled from 1997 to 2002, mainly driven by heterosexuals who acquired their infection abroad. HIV transmission also continues within the United Kingdom, particularly among homo/bisexual men who, in 2002, accounted for 80% of all newly diagnosed HIV infections acquired in the United Kingdom. New diagnoses of syphilis have increased eightfold, and diagnoses of chlamydia and gonorrhoea have doubled from 1997 to 2002 overall; STI rates disproportionately affect homo/bisexual men and young people. Effective surveillance is essential in the provision of timely information on the changing epidemiology of HIV and other STIs; this information is necessary for the targeting of prevention efforts and through providing baseline information against which progress towards targets can be monitored.