Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Phase 1 and Randomized Phase 2 Trial.

Importance: ERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life. Objective: To determine maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine in patients with previously treated ERBB2-positive mBC and locally advanced/metastatic gastric cancer (LA/mGC) (phase 1) and the efficacy and safety of this combination vs T-DM1 alone in patients with mBC (phase 2). Design, Setting, and Participants: The MTD in phase 1 was assessed using a 3 + 3 design with capecitabine dose modification. Phase 2 was an open-label, randomized, international multicenter study of patients with mBC treated with T-DM1 plus capecitabine or T-DM1 alone. Eligible patients had previously treated ERBB2-positive mBC or LA/mGC with no prior chemotherapy treatment for advanced disease. Interventions: Patients in the phase 1 mBC cohort received capecitabine (750 mg/m2, 700 mg/m2, or 650 mg/m2 twice daily, days 1-14 of a 3-week cycle) plus T-DM1 3.6 mg/kg every 3 weeks. Patients with LA/mGC received capecitabine at the mBC phase 1 MTD, de-escalating as needed, plus T-DM1 2.4 mg/kg weekly. In phase 2, patients with mBC were randomized (1:1) to receive capecitabine (at the phase 1 MTD) plus T-DM1 or T-DM1 alone. Main Outcomes and Measures: The phase 1 primary objective was to identify the MTD of capecitabine plus T-DM1. The phase 2 primary outcome was investigator-assessed overall response rate (ORR). Results: In phase 1, the median (range) age was 54.0 (37-71) and 57.5 (53-70) years for patients with mBC and patients with LA/mGC, respectively. The capecitabine MTD was identified as 700 mg/m2 in 11 patients with mBC and 6 patients with LA/mGC evaluable for dose-limiting toxic effects. In phase 2, between October 2014 and April 2016, patients with mBC (median [range] age, 52.0 [28-80] years) were randomized to receive combination therapy (n = 81) or T-DM1 (n = 80). The ORR was 44% (36 of 81 patients) and 36% (29 of 80 patients) in the combination and T-DM1 groups, respectively (difference, 8.2%; 90% CI, -4.5 to 20.9; P = .34; clinical cutoff, May 31, 2017). Adverse events (AEs) were reported in 78 of 82 patients (95%) in the combination group, with 36 (44%) experiencing grade 3-4 AEs, and 69 of 78 patients (88%) in the T-DM1 group, with 32 (41%) experiencing grade 3-4 AEs. No grade 5 AEs were reported. Conclusions and Relevance: Adding capecitabine to T-DM1 did not statistically increase ORR associated with T-DM1 in patients with previously treated ERBB2-positive mBC. The combination group reported more AEs, but with no unexpected toxic effects. Trial Registration: ClinicalTrials.gov Identifier: NCT01702558.

Diagnostic performance of bilateral false profile radiographs in early hip osteoarthritis.

OBJECTIVES: 1. To show that the anterior hip joint space is profiled only on the contralateral false profile radiograph. 2. To provide normal values of hip joint space width on anteroposterior and false profile radiographs. 3. To identify the best sites for joint space radiographic measurements to depict early hip osteoarthritis. METHODS: Anteroposterior and bilateral false profile radiographs of a cadaveric pelvis with markers around the anterior part of the hip joint were obtained. Joint space width was measured at ten sites on anteroposterior pelvis and bilateral hip false profile radiographs in 37 patients without hip pain (mean age, 59 years) and 65 patients with hip pain (mean age, 57.5 years), including 30 with and 35 without radiographic osteoarthritic subchondral bone changes. Between-groups differences in joint space width at each site were evaluated using ANOVA. The ability of joint space width at each site to discriminate between patients groups was investigated using logistic regression. RESULTS: The anterior joint space was only profiled on a contralateral false profile radiograph. Presumably, normal joint space widths were obtained in the group without hip pain. Joint space widths measured on the false profile radiographs differed significantly between the patient groups while measurements on the anteroposterior pelvis radiograph did not. CONCLUSIONS: Bilateral false profile radiographs profile the entire hip joint space, including its anterior part, and discriminate better between patients with and without hip pain than the anteroposterior pelvis radiograph. The AS/P joint space width ratio (anterosuperior/posterior) was the best parameter.

Efficacy of octreotide long-acting repeatable in neuroendocrine tumors: RADIANT-2 placebo arm post hoc analysis.

Somatostatin analogues (SSA) have demonstrated antiproliferative activity in addition to efficacy for carcinoid symptom control in functional neuroendocrine tumors (NET). A post hoc analysis of the placebo arm of the RAD001 In Advanced Neuroendocrine Tumors-2 (RADIANT-2) study was conducted to assess the efficacy of octreotide long-acting repeatable (LAR) on progression-free survival (PFS) and overall survival (OS) estimated using the Kaplan-Meier method. Out of 213 patients randomized to placebo plus octreotide LAR in RADIANT-2, 196 patients with foregut, midgut, or hindgut NET were considered for present analysis. Of these, 41 patients were SSA-treatment naïve and 155 had received SSA therapy before study entry. For SSA-naïve patients, median PFS by adjudicated central review was 13.6 (95% CI 8.2-22.7) months. For SSA-naïve patients with midgut NET (n=24), median PFS was 22.2 (95% CI 8.3-29.5) months. For patients who had received SSA previously, the median PFS was 11.1 (95% CI 8.4-14.3) months. Among the SSA-pretreated patients who had midgut NET (n=119), the median PFS was 12.0 (95% CI 8.4-19.3) months. Median OS was 35.8 (95% CI 32.5-48.9) months for patients in the placebo plus octreotide LAR arm; 50.6 (36.4 - not reached) months for SSA-naïve patients and 33.5 (95% CI 27.5-44.7) months for those who had received prior SSA. This post hoc analysis of the placebo arm of the large phase 3 RADIANT-2 study provides data on PFS and OS among patients with progressive NET treated with octreotide therapy.

Effect of dynamic humeral centring (DHC) treatment on painful active elevation of the arm in subacromial impingement syndrome. Secondary analysis of data from an RCT.

BACKGROUND: The physiotherapy dynamic humeral centring (DHC) aims to prevent subacromial impingement of rotator cuff tendons during elevation of the arm. The objective of the study was to determine whether DHC acts via an effect on subacromial impingement mechanism by assessing its effect on painful elevation of the arm in subacromial impingement syndrome. METHODS: This is a secondary analysis of results of a randomised controlled trial of the effectiveness of DHC. Sixty-nine patients with subacromial impingement syndrome were prospectively included. Patients and the assessor were blinded to the study hypothesis and treatment, respectively. Patients underwent DHC or non-specific mobilisation as a control for 6 weeks in 15 supervised individual outpatient sessions with home exercises. Outcomes were pain-free range of motion and presence of painful arc of the shoulder, both in active flexion and abduction of the arm at 3 months. RESULTS: At 3 months, pain-free range of motion, both flexion and abduction, was greater in the DHC group than in the mobilisation group. The number of patients with painful arc during flexion was decreased in the DHC group. CONCLUSIONS: DHC improves painful active elevation of the arm. We suggest that DHC may act via a specific effect on subacromial impingement mechanism.

Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial.

BACKGROUND: Many patients with acromegaly do not achieve biochemical control despite receiving high doses of the first-generation somatostatin analogues octreotide or lanreotide. In the PAOLA trial, we aimed to assess the efficacy and safety of two different doses of the somatostatin analogue pasireotide long-acting release compared with active control (octreotide or lanreotide) in patients with inadequately controlled acromegaly. METHODS: In a multicentre, randomised, phase 3 trial, we enrolled eligible patients aged 18 years or older with acromegaly who were inadequately controlled (5-point, 2 h mean growth hormone concentration >2·5 µg/L and insulin-like growth factor 1 [IGF-1] concentration >1·3 times the upper normal limit) and had received 30 mg octreotide long-acting repeatable or 120 mg lanreotide (Somatuline Autogel; Ipsen, UK) as monotherapy for 6 months or longer. We randomly assigned patients in a 1:1:1 ratio with an interactive voice-web response system to receive 40 mg pasireotide long-acting release once every 28 days for 24 weeks, 60 mg pasireotide long-acting release once every 28 days for 24 weeks, or continued treatment with octreotide or lanreotide (active control). Patients were stratified according to previous treatment (octreotide or lanreotide) and growth hormone concentrations at screening (2·5-10 µg/L and >10 µg/L). Patients and study investigators were not masked to study drug assignment but were masked to pasireotide dose allocation. The primary endpoint was number of patients achieving biochemical control, defined as mean growth hormone concentration less than 2·5 µg/L and normalised IGF-1 concentration. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01137682. FINDINGS: Between Dec 17, 2010, and Aug 6, 2012, 198 patients were enrolled and randomly assigned to pasireotide 40 mg (n=65), pasireotide 60 mg (n=65), or active control (n=68) groups. At 24 weeks, ten (15%) patients in the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group achieved biochemical control, compared with no patients in the active control group (absolute difference from control group 15·4%, 95% CI 7·6-26·5, p=0·0006 for pasireotide 40 mg group, 20·0%, 11·1-31·8, p<0·0001 for pasireotide 60 mg group). The most common adverse events were hyperglycaemia (21 [33%] for treatment with 40 mg pasireotide, 19 [31%] with 60 mg pasireotide, and nine [14%] with active control), diabetes (13 [21%], 16 [26%], and five [8%]), and diarrhoea (ten [16%], 12 [19%], and three [5%]); most were grade 1 or 2 in severity. Serious adverse events were reported in six (10%) patients in the pasireotide 40 mg group, two (3%) in the pasireotide 60 mg group, and three (5%) in the active control group. INTERPRETATION: Pasireotide provides superior efficacy compared with continued treatment with octreotide or lanreotide, and could become the new standard pituitary-directed treatment in patients with acromegaly who are inadequately controlled using first-generation somatostatin analogues. FUNDING: Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.

A direct comparison of intravenous enoxaparin with unfractionated heparin in primary percutaneous coronary intervention (from the ATOLL trial).

Intravenous enoxaparin did not reduce significantly the primary end point (p = 0.06) compared with unfractionated heparin (UFH) in the randomized Acute Myocardial Infarction Treated with primary angioplasty and intravenous enoxaparin Or unfractionated heparin to Lower ischemic and bleeding events at short- and Long-term follow-up (ATOLL) trial. We present the results of the prespecified per-protocol analysis excluding patients who did not receive the treatment allocated by randomization or received both enoxaparin and UFH. We evaluated all-cause mortality, complication of myocardial infarction, procedural failure, or major bleeding (primary end point) and all-cause mortality, recurrent acute coronary syndrome, or urgent revascularization (main secondary end point). Baseline and procedural characteristics were well balanced between the 2 treatment groups. Of 910 randomized patients, 795 patients (87.4%) were treated according to the protocol with consistent anticoagulation using intravenous enoxaparin (n = 400) or UFH (n = 395). Enoxaparin reduced significantly the rates of the primary end point (relative risk [RR] 0.76, 95% confidence interval [CI] 0.62 to 0.94, p = 0.012) and the main secondary end point (RR 0.37, 95% CI 0.22 to 0.63, p <0.0001). There was less major bleeding with enoxaparin (RR 0.46, 95% CI 0.21 to 1.01, p = 0.050) contributing to the significant improvement of the net clinical benefit (RR 0.46, 95% CI 0.3 to 0.74, p = 0.0002). All-cause mortality was also reduced with enoxaparin (RR 0.36, 95% CI 0.18 to 0.74, p = 0.003). In conclusion, in the per-protocol analysis of the ATOLL trial, pertinent to >87% of the study population, enoxaparin was superior to UFH in reducing ischemic end points and mortality.

ESM-1 expression in stromal cells is predictive of recurrence after radiofrequency ablation in early hepatocellular carcinoma.

BACKGROUND & AIMS: The prognosis of hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA) is mainly linked to tumor recurrence. So far, no tissue biomarker of recurrence has been validated in biopsy samples. We aimed at investigating the prognostic value of tissue biomarkers in HCC biopsy samples of patients treated with RFA. METHODS: All consecutive naive patients from 3 university hospitals, with compensated cirrhosis, early-stage (BCLC 0/A) uninodular HCC treated with RFA, and available tumor biopsy, were included. Edmondson's grade, and the expression of cytokeratin 19, glutamine synthase, beta-catenin, epithelial cell adhesion molecule (EpCAM), and endothelial cell-specific molecule 1 (ESM-1) were assessed. Main clinical end points were overall and early recurrence. Statistical analyses were performed using Kaplan Meier, Log-rank test, and Cox models. RESULTS: 150 patients were included. Recurrence, death or liver transplantation occurred in 85, 51, and 12 patients, respectively. Median follow-up was 27months. ESM-1 expression by HCC stromal endothelial cells was observed in 58 patients (40%) and was associated with higher serum AFP levels, larger tumor, and more frequent expression of EpCAM and surrogate markers of activation of the Wnt-ß-catenin pathway. The 2 independent predictive factors of overall recurrence were serum AFP (HR 1.11 [1.002; 1.22], p=0.045) and ESM-1 expression (HR 1.56 [1.004; 2.43], p=0.048). ESM-1 expression was also an independent predictive factor of early recurrence (HR 1.81 [1.02; 3.21], p=0.042). CONCLUSIONS: ESM-1 expression by stromal endothelial cells, in tumor biopsy samples, has an independent predictive value of early recurrence after RFA.

Safety and efficacy of adjuvant glycoprotein IIb/IIIa inhibitors during primary percutaneous coronary intervention performed from the radial approach for acute ST segment elevation myocardial infarction.

The use of glycoprotein IIb/IIIa receptor inhibitors (GPIs) in high-risk patients with acute coronary syndromes has been associated with reductions in ischemic events but increases in bleeding complications. The role of GPIs in patients who undergo primary percutaneous coronary intervention (PCI) by the transradial approach (TRA) is not well studied. The aim of this post hoc analysis from the randomized prospective Acute Myocardial Infarction Treated With Primary Angioplasty and Intravenous Enoxaparin or Unfractionated Heparin to Lower Ischemic and Bleeding Events at Short- and Long-Term Follow-Up (ATOLL) trial was to assess the safety and efficacy of GPIs in primary PCI performed using the TRA. A total of 910 patients were enrolled in ATOLL; 522 patients (67%) underwent PCI using the TRA. Two comparative analyses were performed. First, patients who underwent PCI using the TRA who received GPIs were compared with those who did not receive GPIs. Second, patients who underwent PCI using the TRA who received GPIs were compared with those who underwent PCI using a nonradial route and received GPIs. Composite end points of net clinical benefit, ischemic outcomes, and safety consisting of bleeding and transfusion at 1 month were analyzed. A propensity score was constructed, and weight adjustment were made for variables, including but not limited to age, weight, gender, renal function, concomitant use of other medications, Killip class, and medical history, when analyzing the end points. There was no significant difference in net clinical benefit or ischemic outcomes between either TRA patients with versus without GPIs or TRA patients with GPIs versus non-TRA patients with GPIs. Additionally, there were significantly fewer major bleeding events and blood transfusions in TRA patients with GPIs compared with non-TRA patients with GPIs. In conclusion, the addition of GPIs in the setting of primary PCI using the TRA was not associated with bleeding liability. The use of GPIs with TRA was associated with safer outcomes than using GPIs with a nontransradial approach. This study was limited in that it was a nonrandomized retrospective analysis.

Management of lower urinary tract symptoms related to benign prostatic hyperplasia in real-life practice in france: a comprehensive population study.

BACKGROUND: Male lower urinary tract symptoms (LUTS) are one of the most treated diseases, but little is known about patient trajectories in current clinical practice. OBJECTIVE: To describe the dynamic treatment patterns of LUTS presumably due to benign prostatic obstruction (BPO). DESIGN, SETTINGS, AND PARTICIPANTS: All prescriptions of α1-adrenergic receptor blocking agents (α1-blockers), 5α-reductase inhibitors (5-ARIs), and phytotherapy, and all surgeries related to BPO performed in France from 2004 to 2008 were identified using two distinct administrative claim databases maintained by the National Health Insurance system that covers the entire population. After linking the two data sets, all consecutive treatment events were analyzed for each patient. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Drug prescription details were assessed for each year, region, and prescriber qualification. Medical treatment initiation, interruption, evolution, and events after surgical management (hospital stay, reoperation, complication rates, and subsequent medical prescriptions) were also investigated. RESULTS AND LIMITATIONS: Overall, 2 620 269 patients were treated within 5 yr, with important geographic variations. Medical treatment was interrupted for approximately 16% of patients. The α1-blockers were prescribed most frequently, but phytotherapy surprisingly accounted for 27% of all monotherapies and 54% of all combination therapies. General practitioners and urologists (92% and 3.7% of overall prescribers, respectively) exhibited a similar prescription profile. Treatment initiation was medical in 95.4% of cases, consisting primarily of monotherapy using α1-blockers (60.3%), phytotherapy (31.8%), or 5-ARIs (7.9%). Treatment was modified at extremely high rates within 12 mo of initiation (8.7%, 14.6%, and 12.9%, respectively). The median hospital stay for surgical management was far higher than in clinical trials. Long-term surgical complications and reoperation rates favored open prostatectomy. Incidence of pharmacologic treatment after surgery was as high as 13.8% at 12 mo. CONCLUSIONS: This unique dynamic evaluation of clinical practice revealed unexpected results that contrast with previously published evidence from clinical trials. This approach may merit monitored and targeted measures to improve the level of care in the field.

Helical CT-enteroclysis in the detection of small-bowel tumours: a meta-analysis.

OBJECTIVE: To perform a meta-analysis to determine sensitivity and specificity estimates of helical CT-enteroclysis in the detection of small-bowel tumours. METHODS: A search for relevant articles published from January 1992 to November 2010 was performed. Study design, patient characteristics and 2 × 2 contingency tables were recorded for eligible studies. Heterogeneity was assessed with the I (2) statistic. A bivariate generalised linear random-effects model was used to summarise sensitivity and specificity estimates for small-bowel tumour detection on a per-patient basis. Sensitivity and specificity estimates were compared in different subgroups. RESULTS: Twelve studies (696 patients) were eligible. The mean small-bowel tumour prevalence was 22.6 % (range 7.7-45.8 %). Inter-study heterogeneity was substantial for sensitivity (I (2) = 66.9 %; 95 % CI 28.7-88.5 %) and low for specificity (I (2) = 10.6 %; 95 % CI 0.0-55.0 %). On a per-patient basis, pooled sensitivity was 92.8 % (95 % CI 71.3-98.5 %) and pooled specificity 99.2 % (95 % CI 94.2-99.9 %) for the diagnosis of small-bowel tumour. Subgroup analysis revealed that small-bowel preparation, more than one imaging pass and large volumes (≥2 L) of enteral contrast agent did not improve tumour detection. CONCLUSION: Our meta-analysis confirms that helical CT-enteroclysis has high degrees of sensitivity and specificity for small-bowel tumour detection. However, our findings reinforce the need for more standardised individual studies.

Prospective short-term evaluation of transurethral needle ablation procedure in an ambulatory setting.

OBJECTIVE: To assess the results of transurethral needle ablation (TUNA) (Prostiva®, Medtronic, France) performed in an ambulatory setting in men with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A multicenter open-label study was conducted. Short-term success was defined by ability to leave the hospital on the evening of the intervention, and absence of rehospitalization due to complications during the first postoperative month. Sexual and urinary functions were evaluated by validated questionnaires. RESULTS: The procedure was successful in 44/49 patients. Sexual and ejaculatory function was not affected or slightly improved in the majority of patients. Urinary parameters improved with a 32% decrease in the International Prostate Symptom Score. At 1 month postoperation, more than 80% of patients were satisfied, and 36/41 patients were prepared to undergo the procedure again if needed. Our study was limited by the short follow-up duration. CONCLUSIONS: TUNA can be successfully performed in an ambulatory setting under local and/or general anesthesia with a high level of patient satisfaction and a low short-term morbidity, especially on sexual function. Thus, the procedure is a suitable mini-invasive option for patients who cannot/do not want to take medical therapy or undergo invasive surgical procedures, or want to preserve their sexual function.

Malignancy and chronic leg ulcers: the value of systematic wound biopsies: a prospective, multicenter, cross-sectional study.

OBJECTIVE: To determine the frequency of skin cancers associated with chronic leg ulcers (CLUs) presumably of vascular origin and failing to heal (ie, increased wound area or depth) despite 3 months or more of appropriate treatment. DESIGN: Prospective cross-sectional study. SETTING: Ambulatory or hospitalized patients from 17 dermatology departments. PATIENTS: Between January 1, 2006, and May 31, 2008, a total of 144 patients consulted for CLUs, attributed to venous and/or peripheral arterial disease(s), increasing in wound size, that is, larger area and/or depth, despite appropriate standard treatment for at least 3 months. MAIN OUTCOME MEASURES: At inclusion, at least two 6-mm punch biopsies, 1 at the wound edge and 1 in the wound bed, in the most clinically suspicious areas, were systematically performed. The primary end point was the skin cancer frequency diagnosed in at least 1 wound biopsy specimen obtained at inclusion. RESULTS: The 144 patients included had 154 CLUs. The overall skin cancer frequency in the CLUs was 10.4%: 9 squamous cell and 5 basal cell carcinomas, 1 melanoma, and 1 leiomyosarcoma; 56.3% had persisted for at least 3 years. Univariate analyses retained older age, abnormal excessive granulation tissue at wound edges, high clinical suspicion of cancer, and number of biopsies, but not wound area or duration, as being significantly associated with skin cancer in 1 or more biopsy specimens. CONCLUSIONS: The combined primary ulcerated cancer or malignant transformation frequency was sufficiently high in CLUs referred to tertiary care centers to consider systematic biopsy of a wound refractory to 3 months or more of appropriate treatment.

Effect of long-term propranolol treatment on hepatocellular carcinoma incidence in patients with HCV-associated cirrhosis.

UNLABELLED: Propranolol bears antioxidant, anti-inflammatory, and antiangiogenic properties and antitumoral effects and therefore is potentially active in the prevention of hepatocellular carcinoma (HCC). We retrospectively assessed the impact of propranolol treatment on HCC occurrence in a cohort of 291 patients with compensated viral C (HCV) cirrhosis, prospectively followed and screened for HCC detection. Of the 291 patients included in the cohort, 93 patients [50 males: mean age, 59.5 ± 12 years; body mass index (BMI), 25.7 ± 4.4 kg/m(2); and platelet count, 111 ± 53 Giga/L] developed esophageal varices (OV) or had OV at inclusion and 198 patients (111 males: mean age, 55.8 ± 13 years; BMI, 25.7 ± 5 kg/m(2); platelet count, 137 ± 59 Giga/L) did not. Among patients with OV, 50 received treatment by propranolol. During a median follow-up of 54 months interquartile range (32-82), 61 patients developed an HCC. The 3- and 5-year HCC incidence was 4% and 4%, and 10% and 20% for patients treated and not treated by propranolol, respectively (Gray test, P = 0.03). In multivariate analysis, propranolol treatment was associated with a decrease risk of HCC occurrence [HR, 0.25; 95% confidence interval (CI), 0.09-0.65; P = 0.004], and was the only independent predictive factor of HCC occurrence in patients with OV (HR, 0.16; CI, 0.06-0.45; P = 0.0005). The benefit of propranolol was further supported by propensity scores analyses. CONCLUSION: This retrospective long-term observational study suggests that propranolol treatment may decrease HCC occurrence in patients with HCV cirrhosis. These findings need to be verified by prospective clinical trial.

Photoselective vaporization of the prostate with GreenLight 120-W laser compared with monopolar transurethral resection of the prostate: a multicenter randomized controlled trial.

BACKGROUND: Evidence supporting the widespread use of GreenLight High Performance System (HPS) 120-W photoselective vaporization of the prostate (PVP) is lacking. OBJECTIVE: To assess the noninferiority of PVP compared with transurethral resection of the prostate (TURP) on urinary symptoms and the superiority of PVP over TURP on length of hospital stay. DESIGN, SETTING, AND PARTICIPANTS: A multicenter randomized controlled trial was conducted. INTERVENTION: Patients underwent monopolar TURP or PVP with the GreenLight HPS 120-W laser. MEASUREMENTS: International Prostate Symptom Score (IPSS), Euro-QOL questionnaire, uroflowmetry, Danish Prostate Symptom Score Sexual Function Questionnaire, sexual satisfaction, and adverse events were collected at 1, 3, 6, and 12 mo. The two groups were compared using the 95% confidence interval (CI) of median difference for testing noninferiority of the IPSS at 12 mo and the student t test for testing the difference in length of hospital stay. RESULTS AND LIMITATIONS: A total of 139 patients (70 vs 69 men in each group) were randomized. Median IPSS scores at 12-mo follow-up were 5 (interquartile range [IQR]: 3-8) for TURP versus 6 (IQR: 3-9) for PVP, and the 95% CI of the difference of the median was equal to -2 to 3. Because the upper limit of the 95% CI was >2 (the noninferiority margin), the hypothesis of noninferiority could not be considered demonstrated. Median length of stay was significantly shorter in the PVP group than in the TURP group, with a median of 1 (IQR: 1-2) versus 2.5 (IQR: 2-3.5), respectively (p<0.0001). Uroflowmetry parameters and complications were comparable in both groups. Sexual outcomes were slightly better in the PVP group without reaching statistical significance. CONCLUSIONS: The present study failed to demonstrate the noninferiority of 120-W GreenLight PVP versus TURP on prostate symptoms at 1 yr but showed that PVP was associated with a shorter length of stay in the hospital. TRIAL REGISTRATION: NCT01043588.

Tuberculosis in the intensive care unit: A retrospective descriptive cohort study with determination of a predictive fatality score.

BACKGROUND: Despite effective treatments, tuberculosis-related mortality remains high among patients requiring admission to the intensive care unit (ICU). OBJECTIVE: To determine prognostic factors of death in tuberculosis patients admitted to the ICU, and to develop a simple predictive scoring system. METHODS: A 10-year, retrospective study of 53 patients admitted consecutively to the Hôpitaux de Paris, Hôpital Lariboisière (Paris, France) ICU with confirmed tuberculosis, was conducted. A multivariate analysis was performed to identify risk factors for death. A predictive fatality score was determined. RESULTS: Diagnoses included pulmonary tuberculosis (96%) and tuberculous encephalomeningitis (26%). Patients required mechanical ventilation (45%) and vasopressor infusion (28%) on admission. Twenty patients (38%) died, related to direct tuberculosis-induced organ failure (n=5), pulmonary bacterial coinfections (n=14) and pulmonary embolism (n=1). Using a multivariate analysis, three independent factors on ICU admission were predictive of fatality: miliary pulmonary tuberculosis (OR 9.04 [95% CI 1.25 to 65.30]), mechanical ventilation (OR 11.36 [95% CI 1.55 to 83.48]) and vasopressor requirement (OR 8.45 [95% CI 1.29 to 55.18]). A score generated by summing these three independent variables was effective at predicting fatality with an area under the ROC curve of 0.92 (95% CI 0.85 to 0.98). CONCLUSIONS: Fatalities remain high in patients admitted to the ICU with tuberculosis. Miliary pulmonary tuberculosis, mechanical ventilation and vasopressor requirement on admission were predictive of death.

HISTORIQUE: Malgré des traitements efficaces, la mortalité liée à la tuberculose demeure élevée chez les patients qui doivent être hospitalisés à l'unité de soins intensifs (USI). OBJECTIF: Déterminer les facteurs pronostiques de décès chez les patients tuberculeux admis à l'USI et élaborer un système d'indice prédictif simple. MÉTHODOLOGIE: Les chercheurs ont mené une étude rétrospective d'une durée de dix ans auprès de 53 patients hospitalisés consécutivement à l'USI de l'Hôpital Lariboisière des Hôpitaux de Paris, en France, en raison d'une tuberculose confirmée. Ils ont procédé à une analyse multivariée pour déterminer les facteurs de risque de décès et ont établi un indice prédictif de fatalité. RÉSULTATS: Les diagnostics incluaient une tuberculose pulmonaire (96 %) et une encéphaloméningite tuberculeuse (26 %). Les patients avaient besoin d'une ventilation mécanique (45 %) et d'une perfusion de vasopresseur (28 %) à l'admission. Vingt patients (38 %) sont décédés en raison d'une insuffisance organique liée directement à la tuberculose (n=5), de co-infections bactériennes pulmonaires (n=14) et d'une embolie pulmonaire (n=1). Selon l'analyse multivariée, trois facteurs indépendants à l'admission à l'USI étaient prédictifs d'une fatalité : une tuberculose miliaire (RRR 9,04 [95 % IC 1,25 à 65,30]), une ventilation mécanique (RRR 11,36 [95 % IC 1,55 à 83,48]) et des besoins vasopressifs (RRR 8,45 [95 % IC 1,29 à 55,18]). Un indice conforme à la somme de ces trois variables indépendantes était efficace pour prévenir la fatalité, avec une zone sous la courbe ROC de 0,92 (95 % IC 0,85 à 0,98). CONCLUSIONS: Les décès demeurent élevés chez les patients tuberculeux admis à l'USI. La tuberculose miliaire, la ventilation mécanique et les besoins vasopressifs à l'admission sont prédictifs d'un décès.

Survival after radiofrequency ablation and salvage transplantation in patients with hepatocellular carcinoma and Child-Pugh A cirrhosis.

BACKGROUND & AIMS: In patients with hepatocellular carcinoma (HCC) within the Milan criteria, liver transplantation (LT) may be the best therapeutic option. However, the shortage of grafts, leads to attempt liver resection (LR) or radiofrequency ablation (RFA) as a first-line treatment for patients with Child-Pugh A cirrhosis. METHODS: We report results, obtained between 2000 and 2007 from a single center, involving 67 patients (mean age: 57 years) eligible for LT, who were treated with RFA, followed by LT if there was recurrence or liver failure. RESULTS: Eighty three tumors were treated (mean size: 29±9 mm; 16 binodular forms). RFA achieved complete ablation in 96% of nodules. No mortality occurred. During a post-RFA median follow-up of 48 months, 38 patients experienced recurrence, corresponding to a 5-year recurrence rate of 58%. Of these, 14 patients did not receive a transplant because they fell outside the Milan criteria, 21 were transplanted, and 3 were treated by RFA after refusing LT. Binodularity (95% CI HR=2, 1.0-4.0; p=0.049) was the unique risk factor for recurrence. By the study's end-point, 24 patients had undergone LT (21 for HCC recurrence and three for liver failure). No HCC recurrence occurred after LT. Among the 43 non-transplant patients, 12 died due to HCC progression, and 27 were alive without detectable viable tumor. The probability rates for 5-year overall and tumor-free survival were 74% and 69%, respectively. CONCLUSIONS: First line RFA followed by salvage LT allows survival figures that are at least as good as a first-line LT, while limiting the number of grafts.

Atorvastatin decreases computed tomography and S100-assessed brain ischemia after subarachnoid aneurysmal hemorrhage: a comparative study.

OBJECTIVE: Statins, which improve the bioavailability of endogenous nitric oxide and upregulate endothelial nitric oxide synthase, have been used to prevent cerebral vasospasm after aneurysmal subarachnoid hemorrhage. The objective of this study was to determine whether statin therapy diminished vasospasm-induced ischemia as assessed using daily measurements of serum S100B, a biomarker for cerebral ischemia, and computed tomography measurement of ischemic lesion volume. DESIGN: Single-center study of cases and historical controls. SETTING: Neurointensive care unit in a university hospital. PATIENTS: Consecutive patients with aneurysmal subarachnoid hemorrhage treated with clipping or coiling within 96 hrs of symptom onset (n = 278) were included from April 2004 to October 2007. INTERVENTION: Oral atorvastatin, 40 mg/day for 21 days, was used routinely starting on December 1, 2005, in 142 patients, who were compared with the 136 patients managed earlier. MEASUREMENTS AND MAIN RESULTS: Ischemic lesion size was measured using computed tomography on the last available scan and serum S100B was assayed daily for 15 days after admission. Angiographic narrowing was semiquantitatively assessed in patients with vasospasm. In the overall population, cerebral vasospasm was significantly less common in the statin-treated group. Severity of vasospasm, as assessed on the most severe angiogram, was lowered with statin. Statins significantly reduced volume of ischemia in patients with vasospasm and an uncomplicated coiling procedure. S100B levels were significantly lower in statin-treated patients, and the decrease was greatest among high-grade patients (World Federation of Neurological Surgeons 3-5). No differences were found between statin-treated and untreated groups regarding rescue therapy intensity or 1-yr clinical outcomes. CONCLUSIONS: Atorvastatin reduces the incidence, the severity and the ischemic consequences of vasospasm as assessed on computed tomography. In high-grade World Federation of Neurological Surgeons patients, atorvastatin decreases serum levels of S100B, a biomarker of brain ischemia. Despite these positive effects on biomarkers, no improvement of outcome was seen in the overall population, although there was a tendency for a better clinical outcome in high-grade patients.

Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial.

BACKGROUND: Primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction has traditionally been supported by unfractionated heparin, which has never been directly compared with a new anticoagulant using consistent anticoagulation and similar antiplatelet strategies in both groups. We compared traditional heparin treatment with intravenous enoxaparin in primary PCI. METHODS: In a randomised open-label trial, patients presenting with ST-elevation myocardial infarction were randomly assigned (1:1) to receive an intravenous bolus of 0·5 mg/kg of enoxaparin or unfractionated heparin before primary PCI. Wherever possible, medical teams travelling in mobile intensive care units (ambulances) selected, randomly assigned (using an interactive voice response system at the central randomisation centre), and treated patients. Patients who had received any anticoagulant before randomisation were excluded. Patients and caregivers were not masked to treatment allocation. The primary endpoint was 30-day incidence of death, complication of myocardial infarction, procedure failure, or major bleeding. The main secondary endpoint was the composite of death, recurrent acute coronary syndrome, or urgent revascularisation. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00718471. FINDINGS: 910 patients were assigned to treatment with enoxaparin (n=450) or unfractionated heparin (n=460). The primary endpoint occurred in 126 (28%) patients after anticoagulation with enoxaparin versus 155 (34%) patients on unfractionated heparin (relative risk [RR] 0·83, 95% CI 0·68-1·01, p=0·06). The incidence of death (enoxaparin, 17 [4%] vs heparin, 29 [6%] patients; p=0·08), complication of myocardial infarction (20 [4%] vs 29 [6%]; p=0·21), procedure failure (100 [26%] vs 109 [28%]; p=0·61), and major bleeding (20 [5%] vs 22 [5%]; p=0·79) did not differ between groups. Enoxaparin resulted in a significantly reduced rate of the main secondary endpoint (30 [7%] vs 52 [11%] patients; RR 0·59, 95% CI 0·38-0·91, p=0·015). Death, complication of myocardial infarction, or major bleeding (46 [10%] vs 69 [15%] patients; p=0·03), death or complication of myocardial infarction (35 [8%] vs 57 [12%]; p=0·02), and death, recurrent myocardial infarction, or urgent revascularisation (23 [5%] vs 39 [8%]; p=0·04) were all reduced with enoxaparin. INTERPRETATION: Intravenous enoxaparin compared with unfractionated heparin significantly reduced clinical ischaemic outcomes without differences in bleeding and procedural success. Therefore, enoxaparin provided an improvement in net clinical benefit in patients undergoing primary PCI. FUNDING: Direction de la Recherche Clinique, Assistance Publique-Hôpitaux de Paris; Sanofi-Aventis.

Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients.

CONTEXT: Insulin resistance plays a role in hepatocarcinogenesis and is decreased by metformin treatment. OBJECTIVE: The aim of the study was to assess the influence of metformin treatment on the prognosis of compensated hepatitis C virus (HCV) cirrhosis in patients with type 2 diabetes. DESIGN AND SETTING: We studied an observational prospective cohort (1988-2007) at a university hospital referral center. PATIENTS: A total of 100 consecutive diabetic patients (53 men, age 61 ± 11 yr) with ongoing HCV cirrhosis and no contraindication for metformin were included in a screening program for hepatocellular carcinoma (HCC). MAIN OUTCOMES: The patients were prospectively followed up for HCC incidence, liver-related death, or hepatic transplantation. RESULTS: The level of platelet count was significantly lower in patients treated with metformin (n = 26) compared with those not treated with metformin (n = 74) [117 (interquartile range, 83-166) vs. 149 (105-192) Giga/liter, P = 0.045]. During a median follow-up of 5.7 (3.8-9.5) yr, one patient was lost to follow-up, 39 developed a HCC, and 33 died from liver causes or were transplanted. The 5-yr incidence of HCC was 9.5 and 31.2% (P = 0.001) and of liver-related death/transplantation, 5.9 and 17.4% (P = 0.013), in patients who received metformin treatment and in those who did not, respectively. In multivariate analysis, metformin treatment was independently associated with a decrease in HCC occurrence [hazard ratio, 0.19 (95% confidence interval, 0.04-0.79); P = 0.023] and liver-related death or transplantation [hazard ratio, 0.22 (95% confidence interval, 0.05-0.99); P = 0.049]. CONCLUSIONS: In patients with type 2 diabetes and HCV cirrhosis, use of metformin is independently associated with reduced incidence of HCC and liver-related death/transplantation.