The relationship of future clinical coronary heart-disease (C.H.D.) to the plasma-high-density-lipoprotein (H.D.L.)-cholesterol concentration has been examined in a 2-year case-control follow-up study of 6595 men aged 20-49 years living in the municipality of Tromsø, Norway. Measurements were also made of the cholesterol concentration in lower-density (i.e., density less than <em>1</em>-603 g/<em>ml</em>) lipoproteins, plasma-triglycerides, systolic and diastolic blood-pressures, relative body-weight, and cigarette consumption. Discriminant-function analysis showed that coronary risk was inversely related to H.D.L.-cholesterol concentration and directly related to density less than <em>1</em>-063 cholesterol. These relationships were independent of each other and of the other measured variables, which showed no significant differences between the cases and controls. H.D.L. cholesterol made a three-fold greater contribution to the prediction of future C.H.D. than did density less than <em>1</em>-063 cholesterol in this cohort of young men. These findings support the proposal that a low H.D.L. concentration is a common antecedent of clinical C.H.D. and is important in accelerating the progression of coronary atherosclerosis.

BACKGROUND

Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined.

RESULTS

A5<em>1</em>64 was a randomized strategy trial of "early ART"--given within <em>1</em>4 days of starting acute OI treatment versus "deferred ART"--given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: <em>1</em>. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL)>>or=50 copies/<em>ml</em>); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/<em>ml</em>). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS. 282 subjects were evaluable; <em>1</em>4<em>1</em> per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis <em>1</em>2%, and bacterial infections <em>1</em>2%. The early and deferred arms started ART a median of <em>1</em>2 and 45 days after start of OI treatment, respectively. THE DIFFERENCE IN THE PRIMARY ENDPOINT DID NOT REACH STATISTICAL SIGNIFICANCE: AIDS progression/death was seen in 20 (<em>1</em>4%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (3<em>1</em>%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.5<em>1</em>; 95% CI = 0.27-0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30-0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/<em>mL</em> (p<0.00<em>1</em>) and no increase in adverse events.

CONCLUSIONS

Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications.

BACKGROUND

ClinicalTrials.gov NCT00055<em>1</em>20.

BACKGROUND

Paclitaxel and carboplatin given every 3 weeks is standard treatment for advanced ovarian carcinoma. Attempts to improve patient survival by including other drugs have yielded disappointing results. We compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer.

METHODS

Patients with stage II to IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this phase 3, open-label, randomised controlled trial at 85 centres in Japan. Patients were randomly assigned by computer-generated randomisation sequence to receive six cycles of either paclitaxel (<em>1</em>80 mg/m(2); 3-h intravenous infusion) plus carboplatin (area under the curve [AUC] 6 mg/<em>mL</em> per min), given on day <em>1</em> of a 2<em>1</em>-day cycle (conventional regimen; n=320), or dose-dense paclitaxel (80 mg/m(2); <em>1</em>-h intravenous infusion) given on days <em>1</em>, 8, and <em>1</em>5 plus carboplatin given on day <em>1</em> of a 2<em>1</em>-day cycle (dose-dense regimen; n=3<em>1</em>7). The primary endpoint was progression-free survival. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT002269<em>1</em>5.

RESULTS

63<em>1</em> of the 637 enrolled patients were eligible for treatment and were included in the ITT population (dose-dense regimen, n=3<em>1</em>2; conventional regimen, n=3<em>1</em>9). Median progression-free survival was longer in the dose-dense treatment group (28.0 months, 95% CI 22.3-35.4) than in the conventional treatment group (<em>1</em>7.2 months, <em>1</em>5.7-2<em>1</em>.<em>1</em>; hazard ratio [HR] 0.7<em>1</em>; 95% CI 0.58-0.88; p=0.00<em>1</em>5). Overall survival at 3 years was higher in the dose-dense regimen group (72.<em>1</em>%) than in the conventional treatment group (65.<em>1</em>%; HR 0.75, 0.57-0.98; p=0.03). <em>1</em>65 patients assigned to the dose-dense regimen and <em>1</em><em>1</em>7 assigned to the conventional regimen discontinued treatment early. Reasons for participant dropout were balanced between the groups, apart from withdrawal because of toxicity, which was higher in the dose-dense regimen group than in the conventional regimen group (n=<em>1</em><em>1</em>3 vs n=69). The most common adverse event was neutropenia (dose-dense regimen, 286 [92%] of 3<em>1</em>2; conventional regimen, 276 [88%] of 3<em>1</em>4). The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group (2<em>1</em>4 [69%]) than in the conventional treatment group (<em>1</em>37 [44%]; p<0.000<em>1</em>). The frequencies of other toxic effects were similar between groups.

CONCLUSIONS

Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer.

BACKGROUND

Bristol-Myers Squibb.

Recent studies have underscored questions about the balance of risk and benefit of RBC transfusion. A better understanding of the nature and timing of molecular and functional changes in stored RBCs may provide strategies to improve the balance of benefit and risk of RBC transfusion. We analyzed changes occurring during RBC storage focusing on RBC deformability, RBC-dependent vasoregulatory function, and S-nitrosohemoglobin (SNO-Hb), through which hemoglobin (Hb) O(2) desaturation is coupled to regional increases in blood flow in vivo (hypoxic vasodilation). Five hundred <em>ml</em> of blood from each of <em>1</em>5 healthy volunteers was processed into leukofiltered, additive solution 3-exposed RBCs and stored at <em>1</em>-6 degrees C according to AABB standards. Blood was subjected to 26 assays at 0, 3, 8, 24 and 96 h, and at <em>1</em>, 2, 3, 4, and 6 weeks. RBC SNO-Hb decreased rapidly (<em>1</em>.2 x <em>1</em>0(-4) at 3 h vs. 6.5 x <em>1</em>0(-4) (fresh) mol S-nitrosothiol (SNO)/mol Hb tetramer (P = 0.032, mercuric-displaced photolysis-chemiluminescence assay), and remained low over the 42-day period. The decline was corroborated by using the carbon monoxide-saturated copper-cysteine assay [3.0 x <em>1</em>0(-5) at 3 h vs. 9.0 x <em>1</em>0(-5) (fresh) mol SNO/mol Hb]. In parallel, vasodilation by stored RBCs was significantly depressed. RBC deformability assayed at a physiological shear stress decreased gradually over the 42-day period (P < 0.00<em>1</em>). Time courses vary for several storage-induced defects that might account for recent observations linking blood transfusion with adverse outcomes. Of clinical concern is that SNO levels, and their physiological correlate, RBC-dependent vasodilation, become depressed soon after collection, suggesting that even "fresh" blood may have developed adverse biological characteristics.

BACKGROUND

Nutritional supplementation may be used to treat muscle loss with aging (sarcopenia). However, if physical activity does not increase, the elderly tend to compensate for the increased energy delivered by the supplements with reduced food intake, which results in a calorie substitution rather than supplementation. Thus, an effective supplement should stimulate muscle anabolism more efficiently than food or common protein supplements. We have shown that balanced amino acids stimulate muscle protein anabolism in the elderly, but it is unknown whether all amino acids are necessary to achieve this effect.

OBJECTIVE

We assessed whether nonessential amino acids are required in a nutritional supplement to stimulate muscle protein anabolism in the elderly.

METHODS

We compared the response of muscle protein metabolism to either <em>1</em>8 g essential amino acids (EAA group: n = 6, age 69 +/- 2 y; +/- SD) or 40 g balanced amino acids (<em>1</em>8 g essential amino acids + 22 g nonessential amino acids, BAA group; n = 8, age 7<em>1</em> +/- 2 y) given orally in small boluses every <em>1</em>0 min for 3 h to healthy elderly volunteers. Muscle protein metabolism was measured in the basal state and during amino acid administration via L-[ring-(2)H(5)]phenylalanine infusion, femoral arterial and venous catheterization, and muscle biopsies.

RESULTS

Phenylalanine net balance (in nmol x min(-<em>1</em>). <em>1</em>00 <em>mL</em> leg volume(-<em>1</em>)) increased from the basal state (P < 0.0<em>1</em>), with no differences between groups (BAA: from -<em>1</em>6 +/- 5 to <em>1</em>6 +/- 4; EAA: from -<em>1</em>8 +/- 5 to <em>1</em>4 +/- <em>1</em>3) because of an increase (P < 0.0<em>1</em>) in muscle protein synthesis and no change in breakdown.

CONCLUSIONS

Essential amino acids are primarily responsible for the amino acid-induced stimulation of muscle protein anabolism in the elderly.

BACKGROUND

Leptin plays a role in fat metabolism and correlates with insulin resistance and other markers of the metabolic syndrome, independent of total adiposity. Therefore, we hypothesized that raised leptin levels may identify men at increased risk of a coronary event in the West of Scotland Coronary Prevention Study (WOSCOPS). Methods and Results- Plasma leptin levels were measured at baseline in 377 men (cases) who subsequently experienced a coronary event and in 783 men (controls) who remained free of an event during the 5-year follow-up period of the study. Controls were matched to cases on the basis of age and smoking history and were representative of the entire WOSCOPS cohort. Leptin levels were significantly higher in cases than controls (5.87+/-2.04 ng/<em>mL</em> versus 5.04+/-2.09 ng/<em>mL</em>, P<0.00<em>1</em>). In univariate analysis, for each <em>1</em> SD increase in leptin, the relative risk (RR) of an event increased by <em>1</em>.25 (95% confidence interval [CI], <em>1</em>.<em>1</em>0 to <em>1</em>.43; P<0.00<em>1</em>). There was minimal change in this RR with correction for body mass index (RR, <em>1</em>.24; 95% CI, <em>1</em>.06 to <em>1</em>.45; P=0.006) or with further correction for classic risk factors, including age, lipids, and systolic blood pressure (RR, <em>1</em>.20; 95% CI, <em>1</em>.02 to <em>1</em>.42; P=0.03). Leptin correlated with C-reactive protein (r=0.24, P<0.00<em>1</em>) and, even with this variable added to the model, leptin retained significance as a predictor of coronary events (RR, <em>1</em>.<em>1</em>8; 95% CI, <em>1</em>.00 to <em>1</em>.39; P=0.05) at the expense of C-reactive protein.

CONCLUSIONS

We show, for the first time, in a large prospective study that leptin is a novel, independent risk factor for coronary heart disease.

BACKGROUND

The relative roles of immunodeficiency, HIV viral load, and combination antiretroviral therapy (cART) in the onset of individual cancers have rarely been examined. We examined the effect of these factors on the risk of specific cancers in patients infected with HIV-<em>1</em>.

METHODS

We investigated the incidence of both AIDS-defining cancers (Kaposi's sarcoma, non-Hodgkin lymphoma, and cervical cancer) and non-AIDS-defining cancers (Hodgkin's lymphoma, lung cancer, liver cancer, and anal cancer) in 52 278 patients followed up in the French Hospital Database on HIV cohort during <em>1</em>998-2006 (median follow-up 4.9 years, IQR 2.<em>1</em>-7.9; 255 353 person-years). We tested 78 models with different classifications of immunodeficiency, viral load, and cART with Poisson regression.

RESULTS

Current CD4 cell count was the most predictive risk factor for all malignancies apart from anal cancer. Compared with patients with CD4 count greater than 500 cells per microL, rate ratios (RR) ranged from <em>1</em>.9 (95% CI <em>1</em>.3-2.7) for CD4 counts 350-499 cells per microL to 25.2 (<em>1</em>7.<em>1</em>-37.0) for counts less than 50 cells per microL for Kaposi's sarcoma (p<0.000<em>1</em>), from <em>1</em>.3 (0.9-2.0) to <em>1</em>4.8 (9.7-22.6) for non-Hodgkin lymphoma (p<0.000<em>1</em>), from <em>1</em>.2 (0.7-2.2) to 5.4 (2.4-<em>1</em>2.<em>1</em>) for Hodgkin's lymphoma (p<0.000<em>1</em>), from 2.2 (<em>1</em>.3-3.6) to 8.5 (4.3-<em>1</em>6.7) for lung cancer (p<0.000<em>1</em>), and from 2.0 (0.9-4.5) to 7.6 (2.7-20.8) for liver cancer (p<0.000<em>1</em>). For cervical cancer, we noted a strong effect of current CD4 (RR 0.7 per log(2), 95% CI 0.6-0.8; p=0.0002). The risk of Kaposi's sarcoma and non-Hodgkin lymphoma increased for current plasma HIV RNA greater than <em>1</em>00 000 copies per mL compared with patients with controlled viral load (RR 3.<em>1</em>, 95% CI 2.3-4.2, p<0.000<em>1</em>; and 2.9, 2.<em>1</em>-3.9, p<0.000<em>1</em>, respectively), whereas cART was independently associated with a decreased incidence (0.3, 0.2-0.4, p<0.000<em>1</em>; and 0.8, 0.6-<em>1</em>.0, p=0.07, respectively). The RR of cervical cancer for those receiving cART was 0.5 (0.3-0.9; p=0.03). The risk of anal cancer increased with the time during which the CD4 count was less than 200 cells per microL (<em>1</em>.3 per year, <em>1</em>.2-<em>1</em>.5; p=0.000<em>1</em>), and viral load was greater than <em>1</em>00 000 copies per mL (<em>1</em>.2 per year, <em>1</em>.<em>1</em>-<em>1</em>.4, p=0.005).

CONCLUSIONS

cART would be most beneficial if it restores or maintains CD4 count above 500 cells per microL, thereby indicating an earlier diagnosis of HIV infection and an earlier treatment initiation. Cancer-specific screening programmes need to be assessed in patients with HIV.

BACKGROUND

Agence Nationale de Recherches sur le SIDA et les hépatites (ANRS), INSERM, and the French Ministry of Health.

BACKGROUND

There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial.

METHODS

Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (<em>1</em>50-220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP <em>1</em>40 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP <em>1</em>80 mm Hg; n=20<em>1</em>). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096.

RESULTS

Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (<em>1</em>2.7 <em>mL</em>, SD <em>1</em><em>1</em>.6) than in the intensive group (<em>1</em>4.2 <em>mL</em>, SD <em>1</em>4.5). From randomisation to <em>1</em> h, mean systolic BP was <em>1</em>53 mm Hg in the intensive group and <em>1</em>67 mm Hg in the guideline group (difference <em>1</em>3.3 mm Hg, 95% CI 8.9-<em>1</em>7.6 mm Hg; p<0.000<em>1</em>); from <em>1</em> h to 24 h, BP was <em>1</em>46 mm Hg in the intensive group and <em>1</em>57 mm Hg in the guideline group (<em>1</em>0.8 mm Hg, 95% CI 7.7-<em>1</em>3.9 mm Hg; p<0.000<em>1</em>). Mean proportional haematoma growth was 36.3% in the guideline group and <em>1</em>3.7% in the intensive group (difference 22.6%, 95% CI 0.6-44.5%; p=0.04) at 24 h. After adjustment for initial haematoma volume and time from onset to CT, median haematoma growth differed between the groups with p=0.06; the absolute difference in volume between groups was <em>1</em>.7 <em>mL</em> (95% CI -0.5 to 3.9, p=0.<em>1</em>3). Relative risk of haematoma growth>>or=33% or>>or=<em>1</em>2.5 <em>mL</em> was 36% lower (95% CI 0-59%, p=0.05) in the intensive group than in the guideline group. The absolute risk reduction was 8% (95% CI -<em>1</em>.0 to <em>1</em>7%, p=0.05). Intensive BP-lowering treatment did not alter the risks of adverse events or secondary clinical outcomes at 90 days.

CONCLUSIONS

Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH.

BACKGROUND

National Health and Medical Research Council of Australia.

Cells within the synovial tissue may recruit mononuclear phagocytes into the synovial fluid and tissues of arthritic patients. We investigated the production of the chemotactic cytokine monocyte chemoattractant protein-<em>1</em> (MCP-<em>1</em>) using sera, synovial fluid, synovial tissue, as well as macrophages and fibroblasts isolated from synovial tissues from 80 arthritic patients. MCP-<em>1</em> levels were significantly higher (P less than 0.05) in synovial fluid from RA patients (mean 25.5 +/- 8.<em>1</em> ng/<em>ml</em> [SE]) compared to synovial fluid from osteoarthritis (OA) patients (0.92 +/- 0.08), or from patients with other arthritides (2.9 +/- <em>1</em>.5). MCP-<em>1</em> levels in RA sera (8.44 +/- 2.33) were significantly greater than MCP-<em>1</em> in normal sera (0.<em>1</em>6 +/- 0.06). The quantities of RA synovial fluid IL-8, which is chemotactic for neutrophils and lymphocytes, and MCP-<em>1</em> were strongly positively correlated (P less than 0.05). To examine the cellular source of MCP-<em>1</em>, RA synovial tissue macrophages and fibroblasts were isolated. Synovial tissue fibroblasts did not express MCP-<em>1</em> mRNA, but could be induced to produce MCP-<em>1</em> by stimulation with either IL-<em>1</em> beta, tumor necrosis factor-alpha (TNF-alpha), or LPS. In contrast, unlike normal peripheral blood monocytes or alveolar macrophages, RA synovial tissue macrophages constitutively expressed MCP-<em>1</em> mRNA and antigen. Immunohistochemical analysis of synovial tissue showed that a significantly greater percentage of RA macrophages (50 +/- 8%) as compared to either OA macrophages (5 +/- 2) or normal macrophages (<em>1</em> +/- 0.3) reacted with anti-MCP-<em>1</em> antibodies. In addition, the synovial lining layer reacted with MCP-<em>1</em> in both RA and OA synovial tissues. In contrast, only a minority of synovial fibroblasts (<em>1</em>8 +/- 8%) from RA synovium were positive for immunolocalization of MCP-<em>1</em>. These results suggest that synovial production of MCP-<em>1</em> may play an important role in the recruitment of mononuclear phagocytes during inflammation associated with RA and that synovial tissue macrophages are the dominant source of this cytokine.

In a search for cosmopolitan phylogenetic clusters of freshwater bacteria, we recovered a total of <em>1</em>90 full and partial <em>1</em>6S ribosomal DNA (rDNA) sequences from three different lakes (Lake Gossenköllesee, Austria; Lake Fuchskuhle, Germany; and Lake Baikal, Russia). The phylogenetic comparison with the currently available rDNA data set showed that our sequences fall into <em>1</em>6 clusters, which otherwise include bacterial rDNA sequences of primarily freshwater and soil, but not marine, origin. Six of the clusters were affiliated with the alpha, four were affiliated with the beta, and one was affiliated with the gamma subclass of the Proteobacteria; four were affiliated with the Cytophaga-Flavobacterium-Bacteroides group; and one was affiliated with the class Actinobacteria (formerly known as the high-G+C gram-positive bacteria). The latter cluster (hgcI) is monophyletic and so far includes only sequences directly retrieved from aquatic environments. Fluorescence in situ hybridization (FISH) with probes specific for the hgcI cluster showed abundances of up to <em>1</em>.7 x <em>1</em>0(5) cells <em>ml</em>(-<em>1</em>) in Lake Gossenköllesee, with strong seasonal fluctuations, and high abundances in the two other lakes investigated. Cell size measurements revealed that Actinobacteria in Lake Gossenköllesee can account for up to 63% of the bacterioplankton biomass. A combination of phylogenetic analysis and FISH was used to reveal <em>1</em>6 globally distributed sequence clusters and to confirm the broad distribution, abundance, and high biomass of members of the class Actinobacteria in freshwater ecosystems.

Previous cross-sectional studies show that puberty is associated with a reduction in insulin sensitivity (S(I)), but no longitudinal studies have examined this change in detail. This study is a longitudinal study in 60 children (33 male and 27 female subjects; 32 Caucasian and 28 African-American) examined at Tanner stage I (age 9.2 +/- <em>1</em>.4 years) and after 2.0 +/- 0.6 years of follow-up, by which time 29 children remained at Tanner stage I and 3<em>1</em> had progressed to Tanner stage III or IV. Tanner stage was assessed by physical examination. S(I), the acute insulin response (AIR), and the disposition index (DI) were determined by the tolbutamide-modified intravenous glucose tolerance test and minimal modeling, body fat mass was assessed by dual-energy X-ray absorptiometry, visceral fat was determined by computed tomography, and fasting blood was analyzed for hormone levels. In children progressing to Tanner stage III, S(I) fell significantly by 32% (4.4 +/- 3.0 to 3.0 +/- <em>1</em>.7 x <em>1</em>0(-4)min(-<em>1</em>)/[microIU/<em>ml</em>]), AIR increased by 30%, DI fell by 27%, and there was a significant increase in fasting glucose (93.5 +/- 5.0 to 97.0 +/- 4.<em>1</em> mg/dl) and insulin (<em>1</em>4.3 +/- 8.<em>1</em> to <em>1</em>8.6 +/- <em>1</em><em>1</em>.0 microIU/<em>ml</em>). In children remaining at Tanner stage I, there was a slight increase in S(I) (6.4 +/- 3.<em>1</em> to 7.4 +/- 3.5 x <em>1</em>0(-4)min(-<em>1</em>)/[microIU/<em>ml</em>]) with no significant change in AIR or fasting glucose and insulin. The pubertal fall in S(I) was more consistent in African-Americans; remained significant after controlling for age, sex, and change in fat mass, visceral fat, and fat-free mass; and was similar in children at low, medium, and high body fat. Change in S(I) was not significantly related to change in fasting hormone levels, but change in AIR was significantly related to change in androstendione (r = 0.39; P = 0.04). Pubertal transition from Tanner stage I to Tanner stage III was associated with a 32% reduction in S(I,) and increases in fasting glucose, insulin, and AIR. These changes were similar across sex, ethnicity, and obesity. The significant fall in DI suggests conservation in beta-cell function or an inadequate beta-cell response to the fall in S(I). The fall in S(I) was not associated with changes in body fat, visceral fat, IGF-I, androgens, or estradiol.

BACKGROUND

Little is known about the long-term efficacy of inhaled corticosteroids in chronic obstructive pulmonary disease (COPD). We investigated the efficacy of inhaled budesonide on decline in lung function and respiratory symptoms in a 3-year placebo-controlled study of patients with COPD.

METHODS

We used a parallel-group, randomised, double-blind, placebo-controlled design in a singlecentre study, nested in a continuing epidemiological survey (the Copenhagen City Heart Study). Inclusion criteria were as follows: no asthma; a ratio of forced expiratory volume in <em>1</em> s (FEV<em>1</em>) and vital capacity of 0.7 or less; FEV<em>1</em> which showed no response ((<em>1</em>5% change) to <em>1</em> mg inhaled terbutaline or prednisolone 37.5 mg orally once daily for <em>1</em>0 days. 290 patients were randomly assigned budesonide, 800 microg plus 400 microg daily for 6 months followed by 400 microg twice daily for 30 months, or placebo for 36 months. The mean age of the participants was 59 years and the mean FEV<em>1</em> 2.37 L or 86% of predicted. The main outcome measure was rate of FEV<em>1</em> decline. Analyses were by intention to treat.

RESULTS

The crude rates of FEV<em>1</em> decline were slightly smaller than expected (placebo group 4<em>1</em>.8 mL per year, budesonide group 45.<em>1</em> mL per year). The estimated rates of decline from the regression model did not differ significantly (49.<em>1</em> mL vs 46.0 mL per year; difference 3.<em>1</em> mL per year [95% CI -<em>1</em>2.8 to <em>1</em>9.0]; p=0.7). Before the study, the minimum relevant difference was defined as 20 mL per year; this difference was outside the 95% CI. No effect of inhaled budesonide was seen on respiratory symptoms. 3<em>1</em>6 exacerbations occurred during the study period, <em>1</em>55 in the budesonide group and <em>1</em>6<em>1</em> in the placebo group. Treatment was well tolerated.

CONCLUSIONS

Inhaled budesonide was of no clinical benefit in COPD patients recruited from the general population by screening. We question the role of long-term inhaled corticosteroids in the treatment of mild to moderate COPD.

OBJECTIVE

Safer and more effective therapies are needed for the treatment of systemic lupus erythematosus (SLE). B lymphocytes have been shown to play fundamental pathogenic roles in SLE, and therefore, elimination of B cells with the use of rituximab may represent a new therapy for SLE.

METHODS

A phase I/II dose-escalation trial of rituximab added to ongoing therapy in SLE was conducted. Rituximab was administered as a single infusion of <em>1</em>00 mg/m2 (low dose), a single infusion of 375 mg/m2 (intermediate dose), or as 4 infusions (<em>1</em> week apart) of 375 mg/m2 (high dose). CD<em>1</em>9+ lymphocytes were measured to determine the effectiveness of B cell depletion. The Systemic Lupus Activity Measure (SLAM) score was used as the primary outcome for clinical efficacy.

RESULTS

Rituximab was well tolerated in this patient population, with most experiencing no significant adverse effects. Only 3 serious adverse events, which were thought to be unrelated to rituximab administration, were noted. A majority of patients (<em>1</em><em>1</em> of <em>1</em>7) had profound B cell depletion (to <5 CD<em>1</em>9+ B cells/microl). In these patients, the SLAM score was significantly improved at 2 and 3 months compared with baseline (P = 0.00<em>1</em>6 and P = 0.0022, respectively, by paired t-test). This improvement persisted for <em>1</em>2 months, despite the absence of a significant change in anti-double-stranded DNA antibody and complement levels. Six patients developed human antichimeric antibodies (HACAs) at a level>> or =<em>1</em>00 ng/ml. These HACA titers were associated with African American ancestry, higher baseline SLAM scores, reduced B cell depletion, and lower levels of rituximab at 2 months after initial infusion.

CONCLUSIONS

Rituximab therapy appears to be safe for the treatment of SLE and holds significant therapeutic promise, at least for the majority of patients experiencing profound B cell depletion. Based on these results, controlled trials of rituximab appear to be warranted.

Since the poor prognosis associated with HER2 amplified breast cancers might be explained by a mechanistic association between p<em>1</em>85HER2 overexpression and therapeutic resistance, we assessed the chemo-endocrine sensitivity of estrogen receptor (ER) containing MCF-7 breast cancer cells transfected with full-length HER2 cDNA. Of the 36 isolated MCF/HER2 subclones, 7 were found to overexpress p<em>1</em>85HER2 surface receptor at levels 3 to 45-fold greater than parental or control transfected cells (MCF/neo). The overexpressing transfectants possessed increased inositol-<em>1</em>,4,5-triphosphate-3'-kinase activity comparable to enzyme activity in the endogenously HER2 amplified breast cancer cell lines SK-Br-3 and BT-474. The anti-p<em>1</em>85HER2 monoclonal antibody and receptor-specific partial agonist, muMAb4D5 (4D5), known to inhibit growth of SK-Br-3 and BT-474 cells, produced no significant growth inhibitory effect on any of the transfectants including the 45-fold overexpressing MCF/HER2-<em>1</em>8 cells which were studied in greater detail. MCF/HER2-<em>1</em>8 cells contained at least partially functioning exogenous receptor since 4D5 (3 micrograms/<em>ml</em>) specifically stimulated phosphorylation of p<em>1</em>85HER2 and its co-precipitating ptyr56 substrate within 5 min, and this was followed at <em>1</em> h by a transient induction of c-myc but not c-fos mRNA. ER content and the in vitro sensitivity of MCF/HER2-<em>1</em>8 cells to 5-fluorouracil and adriamycin were identical to those of control transfectants and parental cells. However, these highly overexpressing transfectants had acquired low level (2 to 4-fold) resistance to cisplatin and were no longer sensitive to the antiestrogen tamoxifen (TAM). To compare the hormone-dependent tumorigenicity of the HER2 transfectants, MCF/HER2-<em>1</em>8 and control cells (MCF, MCF/neo-3) were implanted into ovariectomized athymic nude mice. No tumors were produced in the absence of estradiol (E2) administration. In E2 supplemented mice, MCF/HER2-<em>1</em>8 tumors grew most rapidly. When E2 treatment was stopped and daily TAM injections were initiated, MCF-7 and MCF/neo-3 tumor growth ceased immediately, while MCF/HER2-<em>1</em>8 tumors continued to show an accelerated growth rate lasting weeks. This pattern of hormone-dependent, TAM-resistant growth exhibited by the MCF/HER2-<em>1</em>8 tumors in nude mice supports the possibility that p<em>1</em>85HER2 overexpression in human breast cancers may be linked to therapeutic resistance.

BACKGROUND

Stratum 2 of the Ramipril Efficacy in Nephropathy (REIN) study has already shown that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, angiotensin-converting enzyme (ACE) inhibition reduced the rate of decline in glomerular filtration and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF) found in controls on placebo plus conventional antihypertensives. In REIN stratum <em>1</em>, reported here, 24 h proteinuria was <em>1</em> g or more but less than 3 g per 24 h.

METHODS

In stratum <em>1</em> of this double-blind trial <em>1</em>86 patients were randomised to a ramipril or a control (placebo plus conventional antihypertensive therapy) group targeted at achieving a diastolic blood pressure of less than 90 mm Hg. The primary endpoints were change in glomerular filtration rate (GFR) and time to ESRF or overt proteinuria >> or =53 g/24 h). Median follow-up was 3<em>1</em> months.

RESULTS

The decline in GFR per month was not significantly different (ramipril 0.26 [SE 0.05] mL per min per <em>1</em>.73m2, control 0.29 [0.06]). Progression to ESRF was significantly less common in the ramipril group (9/99 vs <em>1</em>8/87) for a relative risk (RR) of 2.72 (95% CI <em>1</em>.22-6.08); so was progression to overt proteinuria (<em>1</em>5/99 vs 27/87, RR 2.40 [<em>1</em>.27-4.52]). Patients with a baseline GFR of 45 mL/min/<em>1</em>.73 m2 or less and proteinuria of <em>1</em>.5 g/24 h or more had more rapid progression and gained the most from ramipril treatment. Proteinuria decreased by <em>1</em>3% in the ramipril group and increased by <em>1</em>5% in the controls. Cardiovascular events were similar. As expected, the rate of decline in GFR and the frequency of ESRF were much lower in stratum <em>1</em> than they had been in stratum 2.

CONCLUSIONS

In non-diabetic nephropathies, ACE inhibition confers renoprotection even to patients with non-nephrotic proteinuria.

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic peptide with recently identified neurotrophic effects. Because some neurotrophic factors can protect neurons from hypoxic or ischemic injury, we investigated the possibility that VEGF has similar neuroprotective properties. In HN33, an immortalized hippocampal neuronal cell line, VEGF reduced cell death associated with an in vitro model of cerebral ischemia: at a maximally effective concentration of 50 ng/<em>ml</em>, VEGF approximately doubled the number of cells surviving after 24 h of hypoxia and glucose deprivation. To investigate the mechanism of neuroprotection by VEGF, the expression of known target receptors for VEGF was measured by Western blotting, which showed that HN33 cells expressed VEGFR-2 receptors and neuropilin-<em>1</em>, but not VEGFR-<em>1</em> receptors. The neuropilin-<em>1</em> ligand placenta growth factor-2 failed to reproduce the protective effect of VEGF, pointing to VEGFR-2 as the site of VEGF's neuroprotective action. Two phosphatidylinositol 3'-kinase inhibitors, wortmannin and LY294002, reversed the neuroprotective effect of VEGF, implicating the phosphatidylinositol 3'-kinase/Akt signal transduction system in VEGF-mediated neuroprotection. VEGF also protected primary cultures of rat cerebral cortical neurons from hypoxia and glucose deprivation. We conclude that in addition to its known role as an angiogenic factor, VEGF may exert a direct neuroprotective effect in hypoxic-ischemic injury.

The effects of insulin on the renal handling of sodium, potassium, calcium, and phosphate were studied in man while maintaining the blood glucose concentration at the fasting level by negative feedback servocontrol of a variable glucose infusion. In studies on six water-loaded normal subjects in a steady state of water diuresis, insulin was administered i.v. to raise the plasma insulin concentration to between 98 and <em>1</em>93 muU/<em>ml</em> and infused at a constant rate of 2 mU/kg body weight per min over a total period of <em>1</em>20 min. The blood glucose concentration was not significantly altered, and there was no change in the filtered load of glucose; glomerular filtration rate (CIN) and renal plasma flow (CPAH) were unchanged. Urinary sodium excretion (UNaV) decreased from 40<em>1</em> plus or minus 46 (SEM) to 2<em>1</em>3 plus or minus <em>1</em>8 mueq/min during insulin administration, the change becoming significant (P smaller than 0.02) within the 30-60 min collection period. Free water clearance (CH2O) increased from <em>1</em>0.6 plus or minus 0.6 to <em>1</em>3 plus or minus 0.5 <em>ml</em>/min (P smaller than 0.025); osmolar clearance decreased and urine flow was unchanged. There was no change in plasma aldosterone concentration, which was low throughout the studies, and a slight reduction was observed in plasma glucagon concentration. Urinary potassium (UKV) and phosphate (UPV) excretion were also both decreased during insulin administration; UKV decreased from 66 plus or minus 9 to 2<em>1</em> plus or minus <em>1</em> mueq/min (P smaller than 0.005), and tupv decreased from 504 plus or minus 93 to 230 plus or minus 43 mug/min (P smaller than 0.0<em>1</em>). The change in UKV was associated with a significant reduction in plasma potassium concentration. There was also a statistically significant but small reduction in plasma phosphate concentration which was not considered sufficient alone to account for the large reduction in UPV. Urinary calcium excretion (UCaV) increased from <em>1</em>26 plus or minus 24 to 200 plus or minus <em>1</em>7 mug/min (P smaller than 0.0<em>1</em>). These studies demonstrate a reduction in UNaV associated with insulin administration that occurs in the absence of changes in the filtered load of glucose, glomerular filtration rate, renal blood flow, and plasma aldosterone concentration. The effect of insulin on CH2O suggests that insulin's effect on sodium excretion is due to enhancement of sodium reabsorption in the diluting segment of the distal nephron.

BACKGROUND

Abnormal homeostasis of the volume of airway surface liquid in patients with cystic fibrosis is thought to produce defects in mucus clearance and airway defense. Through osmotic forces, hypertonic saline may increase the volume of airway surface liquid, restore mucus clearance, and improve lung function.

METHODS

A total of 24 patients with cystic fibrosis were randomly assigned to receive treatment with inhaled hypertonic saline (5 ml of 7 percent sodium chloride) four times daily with or without pretreatment with amiloride. Mucus clearance and lung function were measured during 14-day baseline and treatment periods.

RESULTS

Long-term inhalation of hypertonic saline without pretreatment with amiloride (i.e., with placebo pretreatment) resulted in a sustained >> or =8 hours) increase in 1-hour rates of mucus clearance, as compared with those with amiloride pretreatment (14.0+/-2.0 vs. 7.0+/-1.5 percent, respectively; P=0.02) and increased 24-hour rates of mucus clearance over baseline. Furthermore, inhalation of hypertonic saline with placebo improved the forced expiratory volume in one second (FEV1) between the baseline period and the treatment period (mean difference, 6.62 percent; 95 percent confidence interval, 1.6 to 11.7; P=0.02), whereas hypertonic saline with amiloride did not improve FEV1 (mean difference, 2.9 percent; 95 percent confidence interval, -2.2 to 8.0; P=0.23). Forced vital capacity (FVC), the forced expiratory flow between 25 and 75 percent of FVC (FEF25-75), and respiratory symptoms also significantly improved in patients treated with hypertonic saline and placebo, whereas the residual volume as a proportion of total lung capacity (RV:TLC) did not change in either group. A comparison of the changes in lung function in the two groups showed no significant difference. In vitro data suggested that sustained hydration of airway surfaces was responsible for the sustained improvement in mucus clearance, whereas inhibition of osmotically driven water transport by amiloride accounted for the observed loss of clinical benefit.

CONCLUSIONS

In patients with cystic fibrosis, inhalation of hypertonic saline produced a sustained acceleration of mucus clearance and improved lung function. This treatment may protect the lung from insults that reduce mucus clearance and produce lung disease.

OBJECTIVE

This study was designed to evaluate prospectively survival after pancreaticoduodenectomy for pancreatic adenocarcinoma, comparing two different postoperative adjuvant chemoradiation protocol to those of no adjuvant therapy.

BACKGROUND

Based on limited data from the Gastrointestinal Tumor Study Group, adjuvant chemoradiation therapy has been recommended after pancreaticoduodenectomy for adenocarcinoma of the head, neck, or uncinate process of the pancrease. However, many patients continue to receive no such therapy.

METHODS

From October <em>1</em>99<em>1</em> through September <em>1</em>995, all patients with resected, pathologically confirmed adenocarcinoma of the head, neck, or uncinate process of the pancreas were reviewed by a multidisciplinary group (surgery, radiation oncology, medical oncology, and pathology) and were offered three options for postoperative treatment after pancreaticoduodenectomy: <em>1</em>) standard therapy: external beam radiation therapy to the pancreatic bed (4000-4500 cGy) given with two 3-day fluorouracil (5-FU) courses and followed by weekly bolus 5-FU (500 mg/m2 per day) for 4 months; 2) intensive therapy: external beam radiation therapy to the pancreatic bed (5040-5760 cGy) with prophylactic hepatic irradiation (2340-2700 cGy) given with and followed by infusional 5-FU (200 mg/m2 per day) plus leucovorin (5 mg/m2 per day) for 5 of 7 days for 4 months; or 3) no therapy: no postoperative radiation therapy or chemotherapy.

RESULTS

Pancreaticoduodenectomy was performed in <em>1</em>74 patients, with <em>1</em> in-hospital death (0.6%). Ninety-nine patients elected standard therapy, 2<em>1</em> elected intensive therapy, and 53 patients declined therapy. The three groups were comparable with respect to race, gender, intraoperative blood loss, tumor differentiation, lymph node status, tumor diameter, and resection margin status. Univariate analyses indicated that tumor diameter < 3 cm, intraoperative blood loss < 700 mL, absence of intraoperative blood transfusions, and use of adjuvant chemoradiation therapy were associated with significantly longer survival (p < 0.05). By Cox proportional hazards survival analysis, the most powerful predictors of outcome were tumor diameter, intraoperative blood loss, status of resection margins, and use of postoperative adjuvant therapy. The use of postoperative adjuvant chemoradiation therapy was a predictor of improved survival (median survival, <em>1</em>9.5 months compared to <em>1</em>3.5 months without therapy; p = 0.003). The intensive therapy group had no survival advantage when compared to that of the standard therapy group (median survival, <em>1</em>7.5 months vs. 2<em>1</em> months, p = not significant).

CONCLUSIONS

Adjuvant chemoradiation therapy significantly improves survival after pancreaticoduodenectomy for adenocarcinoma of the head, neck, or uncinate process of the pancreas. Based on these survival data, standard adjuvant chemoradiation therapy appears to be indicated for patients treated by pancreaticoduodenectomy for adenocarcinoma of the head, neck, or uncinate process of the pancreas. Intensive therapy conferred no survival advantage over standard therapy in this analysis.

BACKGROUND

Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma.

METHODS

In this open-label, phase <em>1</em> dose-escalation trial, patients older than <em>1</em>2 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (<em>1</em>00, <em>1</em>30, <em>1</em>65, 2<em>1</em>5, 280, 365 mg/m(2) per dose) were assessed in the dose-finding phase of the study (part A<em>1</em>), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A<em>1</em>. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials.gov, NCT00939770.

RESULTS

79 patients were enrolled in the study from Oct 2, 2009, to May 3<em>1</em>, 20<em>1</em>2. The median age was <em>1</em>0.<em>1</em> years (range <em>1</em>.<em>1</em>-2<em>1</em>.4); 43 patients were included in the dose escalation phase (A<em>1</em>), 25 patients in part A2, and <em>1</em><em>1</em> patients in part A3. Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m(2) twice daily. Grade 4 adverse events in cycle <em>1</em> were neutropenia (two) and liver enzyme elevation (one). Grade 3 adverse events that occurred in more than one patient in cycle <em>1</em> were lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range <em>1</em>-6). Objective tumour responses were documented in <em>1</em>4 of 79 patients (nine complete responses, five partial responses); and the anti-tumour activity was enriched in patients with known activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of <em>1</em><em>1</em> with neuroblastoma, three of seven with inflammatory myofibroblastic tumour, and one of two with NSCLC).

CONCLUSIONS

The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations, particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours, and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted.

BACKGROUND

Pfizer and National Cancer Institute grant to the Children's Oncology Group.

BACKGROUND

Survival benefit in the management of high-grade clinically localized prostate cancer has been shown for 70 Gy radiation therapy combined with 3 years of androgen suppression therapy (AST), but long-term AST is associated with many adverse events.

OBJECTIVE

To assess the survival benefit of 3-dimensional conformal radiation therapy (3D-CRT) alone or in combination with 6 months of AST in patients with clinically localized prostate cancer.

METHODS

A prospective randomized controlled trial of 206 patients with clinically localized prostate cancer who were randomized to receive 70 Gy 3D-CRT alone (n = <em>1</em>04) or in combination with 6 months of AST (n = <em>1</em>02) from December <em>1</em>, <em>1</em>995, to April <em>1</em>5, 200<em>1</em>. Eligible patients included those with a prostate-specific antigen (PSA) of at least <em>1</em>0 ng/<em>mL</em>, a Gleason score of at least 7, or radiographic evidence of extraprostatic disease.

METHODS

Time to PSA failure (PSA>><em>1</em>.0 ng/<em>mL</em> and increasing >0.2 ng/<em>mL</em> on 2 consecutive visits) and overall survival.

RESULTS

After a median follow-up of 4.52 years, patients randomized to receive 3D-CRT plus AST had a significantly higher survival (P =.04), lower prostate cancer-specific mortality (P =.02), and higher survival free of salvage AST (P =.002). Kaplan-Meier estimates of 5-year survival rates were 88% (95% confidence interval [CI], 80%-95%) in the 3D-CRT plus AST group vs 78% (95% CI, 68%-88%) in the 3D-CRT group. Rates of survival free of salvage AST at 5 years were 82% (95% CI, 73%-90%) in the 3D-CRT plus AST group vs 57% (95% CI, 46%-69%) in the 3D-CRT group.

CONCLUSIONS

The addition of 6 months of AST to 70 Gy 3D-CRT confers an overall survival benefit for patients with clinically localized prostate cancer.

Anthrax lethal toxin, which consists of two proteins, protective antigen and lethal factor, is lethal for experimental animals. This study describes the first in vitro system demonstrating lethality of the toxin. Mouse peritoneal macrophages are killed within <em>1</em> h of exposure to the toxin. Neither protein component alone shows any toxic activity. The minimal effective concentration of protective antigen and lethal factor was approximately equal to <em>1</em>0(-2) and approximately equal to <em>1</em>0(-3) micrograms/<em>ml</em>, respectively. None of the several established cell lines examined was killed. Cells could be completely protected from the toxin by pretreatment with agents, such as amines or monensin, which dissipate intracellular proton gradients and raise the pH of intracellular vesicles. This protection was reversible and could be overcome by lowering the intravesicular pH. Antitoxin added after preincubation with amines was unable to protect cells subsequently exposed to low pH treatment. These results suggest that anthrax lethal toxin requires passage through an acidic endocytic vesicle in order to exert its toxic effect within the cytosol.

The analysis of plasma kinetics of the sympathetic neurotransmitter norepinephrine can be used to estimate sympathetic nervous "activity" (integrated nerve firing rate) for the body as a whole and for individual organs. In <em>1</em>2 patients with cardiac failure (left ventricular ejection fraction <em>1</em>0% to 39%), the mean arterial plasma norepinephrine concentration was 557 +/- 68 pg/<em>ml</em> (mean +/- SE) compared with 2<em>1</em><em>1</em> +/- 2<em>1</em> pg/<em>ml</em> in <em>1</em>5 subjects without heart failure (p less than .002). The difference was due to both increased release of norepinephrine to plasma (indicating increased "total" sympathetic activity) and reduced clearance of norepinephrine from plasma. The increase in sympathetic activity did not involve all organs equally. Cardiac (32 +/- 9 vs 5 +/- <em>1</em> ng/min; p less than .002) and renal (202 +/- 45 vs 66 +/- 9 ng/min; p = .002) norepinephrine spillover were increased by 540% and 206%, respectively, but norepinephrine spillover from the lungs was normal. Adrenomedullary activity was also increased in the patients with heart failure, whose mean arterial plasma epinephrine concentration was <em>1</em>8<em>1</em> +/- 38 pg/<em>ml</em> compared with 7<em>1</em> +/- <em>1</em>2 pg/<em>ml</em> in control subjects (p less than .02). There is marked regional variation, inapparent from measurements of plasma norepinephrine concentration, in sympathetic nerve activity in patients with congestive heart failure. The finding of increased cardiorenal norepinephrine spillover has important pathophysiologic and therapeutic implications.

BACKGROUND

Three fourths of US men older than 50 years have been screened with prostate-specific antigen (PSA) for prostate cancer.

OBJECTIVE

To estimate the receiver operating characteristic (ROC) curve for PSA.

METHODS

Calculation of PSA ROC curves in the placebo group of the Prostate Cancer Prevention Trial, a randomized, prospective study conducted from 1993 to 2003 at 221 US centers. Participants were 18 882 healthy men aged 55 years or older without prostate cancer and with PSA levels less than or equal to 3.0 ng/mL and normal digital rectal examination results, followed up for 7 years with annual PSA measurement and digital rectal examination. If PSA level exceeded 4.0 ng/mL or rectal examination result was abnormal, a prostate biopsy was recommended. After 7 years of study participation, an end-of-study prostate biopsy was recommended in all cancer-free men.

METHODS

Operating characteristics of PSA for prostate cancer detection, including sensitivity, specificity, and ROC curve.

RESULTS

Of 8575 men in the placebo group with at least 1 PSA measurement and digital rectal examination in the same year, 5587 (65.2%) had had at least 1 biopsy; of these, 1225 (21.9%) were diagnosed with prostate cancer. Of 1213 cancers with Gleason grade recorded, 250 (20.6%) were Gleason grade 7 or greater and 57 (4.7%) were Gleason grade 8 or greater. The areas under the ROC curve (AUC) for PSA to discriminate any prostate cancer vs no cancer, Gleason grade 7 or greater cancer vs no or lower-grade cancer, and Gleason grade 8 or greater cancer vs no or lower-grade cancer were 0.678 (95% confidence interval [CI], 0.666-0.689), 0.782 (95% CI, 0.748-0.816), and 0.827 (95% CI, 0.761-0.893), respectively (all P values <.001 for AUC vs 50%). For detecting any prostate cancer, PSA cutoff values of 1.1, 2.1, 3.1, and 4.1 ng/mL yielded sensitivities of 83.4%, 52.6%, 32.2%, and 20.5%, and specificities of 38.9%, 72.5%, 86.7%, and 93.8%, respectively. Age-stratified analyses showed slightly better performance of PSA in men younger than 70 years vs those 70 years or older with AUC values of 0.699 (SD, 0.013) vs 0.663 (SD, 0.013) (P = .03).

CONCLUSIONS

There is no cutpoint of PSA with simultaneous high sensitivity and high specificity for monitoring healthy men for prostate cancer, but rather a continuum of prostate cancer risk at all values of PSA.