Long-term trastuzumab (Herceptin®) treatment in a continuation study of patients with HER2-positive breast cancer or HER2-positive gastric cancer.

BACKGROUND: Trastuzumab (Herceptin® [H]) is the standard of care for HER2-positive locally advanced/metastatic breast cancer and gastric/gastroesophageal junction (GEJ) cancer. However, there is a paucity of data available on long-term H treatment of patients. The Rollover Protocol (ROP) Study was conducted to report safety data for patients with HER2-positive locally advanced/metastatic breast and gastric/GEJ cancer who have received long-term H therapy (≥ 5 years and ≥ 3 years for breast and gastric/GEJ cancer, respectively). METHODS: The ROP Study was a single-arm, multicenter, international continuation trial of H in patients who had previously completed a global Roche-sponsored trial with H therapy, had stable disease, and were receiving H at the end of the lead-in trial. Patients with chronic heart failure during the lead-in trial could be included following a risk-benefit analysis. The primary objectives were to provide H therapy to patients with HER2-overexpressing locally advanced/metastatic breast or gastric/GEJ cancer at the end of the lead-in study, and to follow the long-term outcomes and long-term overall safety in these patients. RESULTS: Twenty-five of 69 patients enrolled in the ROP Study received long-term H therapy (19 breast cancer and 6 gastric/GEJ cancer). The median duration of H treatment for patients with breast cancer was 8 years 7 months, and 5 years 2 months for patients with gastric/GEJ cancer. The cardiac status of the patients remained stable over time, with no serious cardiac adverse events or marked changes in left ventricular ejection fraction (LVEF). The median overall worst LVEF measurement was 57.0%, and no patients experienced an LVEF of < 45% (range 47-63%). There were no serious adverse events related to study treatment. CONCLUSIONS: These results suggest that H has an acceptable safety profile and was well tolerated in patients who received long-term H therapy (≥ 5 years and ≥ 3 years for breast and gastric/GEJ cancer, respectively). Further investigation and reporting of long-term H therapy would be valuable. TRIAL REGISTRATION: This study was retrospectively registered on March 24, 2016 with Clinicaltrials.gov, number NCT02721641 .

Fractional flow reserve-guided PCI for stable coronary artery disease.

BACKGROUND: We hypothesized that in patients with stable coronary artery disease and stenosis, percutaneous coronary intervention (PCI) performed on the basis of the fractional flow reserve (FFR) would be superior to medical therapy. METHODS: In 1220 patients with stable coronary artery disease, we assessed the FFR in all stenoses that were visible on angiography. Patients who had at least one stenosis with an FFR of 0.80 or less were randomly assigned to undergo FFR-guided PCI plus medical therapy or to receive medical therapy alone. Patients in whom all stenoses had an FFR of more than 0.80 received medical therapy alone and were included in a registry. The primary end point was a composite of death from any cause, nonfatal myocardial infarction, or urgent revascularization within 2 years. RESULTS: The rate of the primary end point was significantly lower in the PCI group than in the medical-therapy group (8.1% vs. 19.5%; hazard ratio, 0.39; 95% confidence interval [CI], 0.26 to 0.57; P<0.001). This reduction was driven by a lower rate of urgent revascularization in the PCI group (4.0% vs. 16.3%; hazard ratio, 0.23; 95% CI, 0.14 to 0.38; P<0.001), with no significant between-group differences in the rates of death and myocardial infarction. Urgent revascularizations that were triggered by myocardial infarction or ischemic changes on electrocardiography were less frequent in the PCI group (3.4% vs. 7.0%, P=0.01). In a landmark analysis, the rate of death or myocardial infarction from 8 days to 2 years was lower in the PCI group than in the medical-therapy group (4.6% vs. 8.0%, P=0.04). Among registry patients, the rate of the primary end point was 9.0% at 2 years. CONCLUSIONS: In patients with stable coronary artery disease, FFR-guided PCI, as compared with medical therapy alone, improved the outcome. Patients without ischemia had a favorable outcome with medical therapy alone. (Funded by St. Jude Medical; FAME 2 ClinicalTrials.gov number, NCT01132495.).

Incident disability in older adults: prediction models based on two British prospective cohort studies.

OBJECTIVE: To develop and validate a prediction model for incident locomotor disability after 7 years in older adults. SETTING: Prospective British cohort studies: British Women's Heart and Health Study (BWHHS) for development and the English Longitudinal Study of Ageing (ELSA) for validation. SUBJECTS: Community-dwelling older adults. METHODS: Multivariable logistic regression models after selection of predictors with backward elimination. Model performance was assessed using metrics of discrimination and calibration. Models were internally and externally validated. RESULTS: Locomotor disability was reported in BWHHS by 861 of 1,786 (48%) women after 7 years. Age, a history of arthritis and low physical activity levels were the most important predictors of locomotor disability. Models using routine measures as predictors had satisfactory calibration and discrimination (c-index 0.73). Addition of 31 blood markers did not increase the predictive performance. External validation in ELSA showed reduced discrimination (c-index 0.65) and an underestimation of disability risks. A web-based calculator for locomotor disability is available (http://www.sealedenvelope.com/trials/bwhhsmodel/). CONCLUSIONS: We developed and externally validated a prediction model for incident locomotor disability in older adults based on routine measures available to general practitioners, patients and public health workers, and showed an adequate discrimination. Addition of blood markers from major biological pathways did not improve the performance of the model. Further replication in additional data sets may lead to further enhancement of the current model.

Oral or transdermal opioids for osteoarthritis of the knee or hip.

BACKGROUND: Osteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in older people. Opioids may be a viable treatment option if people have severe pain or if other analgesics are contraindicated. However, the evidence about their effectiveness and safety is contradictory. This is an update of a Cochrane review first published in 2009. OBJECTIVES: To determine the effects on pain, function, safety, and addiction of oral or transdermal opioids compared with placebo or no intervention in people with knee or hip osteoarthritis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL (up to 28 July 2008, with an update performed on 15 August 2012), checked conference proceedings, reference lists, and contacted authors. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials that compared oral or transdermal opioids with placebo or no treatment in people with knee or hip osteoarthritis. We excluded studies of tramadol. We applied no language restrictions. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate. We calculated standardised mean differences (SMDs) and 95% confidence intervals (CI) for pain and function, and risk ratios for safety outcomes. We combined trials using an inverse-variance random-effects meta-analysis. MAIN RESULTS: We identified 12 additional trials and included 22 trials with 8275 participants in this update. Oral oxycodone was studied in 10 trials, transdermal buprenorphine and oral tapentadol in four, oral codeine in three, oral morphine and oral oxymorphone in two, and transdermal fentanyl and oral hydromorphone in one trial each. All trials were described as double-blind, but the risk of bias for other domains was unclear in several trials due to incomplete reporting. Opioids were more beneficial in pain reduction than control interventions (SMD -0.28, 95% CI -0.35 to -0.20), which corresponds to a difference in pain scores of 0.7 cm on a 10-cm visual analogue scale (VAS) between opioids and placebo. This corresponds to a difference in improvement of 12% (95% CI 9% to 15%) between opioids (41% mean improvement from baseline) and placebo (29% mean improvement from baseline), which translates into a number needed to treat (NNTB) to cause one additional treatment response on pain of 10 (95% CI 8 to 14). Improvement of function was larger in opioid-treated participants compared with control groups (SMD -0.26, 95% CI -0.35 to -0.17), which corresponds to a difference in function scores of 0.6 units between opioids and placebo on a standardised Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability scale ranging from 0 to 10. This corresponds to a difference in improvement of 11% (95% CI 7% to 14%) between opioids (32% mean improvement from baseline) and placebo (21% mean improvement from baseline), which translates into an NNTB to cause one additional treatment response on function of 11 (95% CI 7 to 14). We did not find substantial differences in effects according to type of opioid, analgesic potency, route of administration, daily dose, methodological quality of trials, and type of funding. Trials with treatment durations of four weeks or less showed larger pain relief than trials with longer treatment duration (P value for interaction = 0.001) and there was evidence for funnel plot asymmetry (P value = 0.054 for pain and P value = 0.011 for function). Adverse events were more frequent in participants receiving opioids compared with control. The pooled risk ratio was 1.49 (95% CI 1.35 to 1.63) for any adverse event (9 trials; 22% of participants in opioid and 15% of participants in control treatment experienced side effects), 3.76 (95% CI 2.93 to 4.82) for drop-outs due to adverse events (19 trials; 6.4% of participants in opioid and 1.7% of participants in control treatment dropped out due to adverse events), and 3.35 (95% CI 0.83 to 13.56) for serious adverse events (2 trials; 1.3% of participants in opioid and 0.4% of participants in control treatment experienced serious adverse events). Withdrawal symptoms occurred more often in opioid compared with control treatment (odds ratio (OR) 2.76, 95% CI 2.02 to 3.77; 3 trials; 2.4% of participants in opioid and 0.9% of participants control treatment experienced withdrawal symptoms). AUTHORS' CONCLUSIONS: The small mean benefit of non-tramadol opioids are contrasted by significant increases in the risk of adverse events. For the pain outcome in particular, observed effects were of questionable clinical relevance since the 95% CI did not include the minimal clinically important difference of 0.37 SMDs, which corresponds to 0.9 cm on a 10-cm VAS.

Comparative efficacy of seven psychotherapeutic interventions for patients with depression: a network meta-analysis.

BACKGROUND: Previous meta-analyses comparing the efficacy of psychotherapeutic interventions for depression were clouded by a limited number of within-study treatment comparisons. This study used network meta-analysis, a novel methodological approach that integrates direct and indirect evidence from randomised controlled studies, to re-examine the comparative efficacy of seven psychotherapeutic interventions for adult depression. METHODS AND FINDINGS: We conducted systematic literature searches in PubMed, PsycINFO, and Embase up to November 2012, and identified additional studies through earlier meta-analyses and the references of included studies. We identified 198 studies, including 15,118 adult patients with depression, and coded moderator variables. Each of the seven psychotherapeutic interventions was superior to a waitlist control condition with moderate to large effects (range d = -0.62 to d = -0.92). Relative effects of different psychotherapeutic interventions on depressive symptoms were absent to small (range d = 0.01 to d = -0.30). Interpersonal therapy was significantly more effective than supportive therapy (d = -0.30, 95% credibility interval [CrI] [-0.54 to -0.05]). Moderator analysis showed that patient characteristics had no influence on treatment effects, but identified aspects of study quality and sample size as effect modifiers. Smaller effects were found in studies of at least moderate (Δd = 0.29 [-0.01 to 0.58]; p = 0.063) and large size (Δd = 0.33 [0.08 to 0.61]; p = 0.012) and those that had adequate outcome assessment (Δd = 0.38 [-0.06 to 0.87]; p = 0.100). Stepwise restriction of analyses by sample size showed robust effects for cognitive-behavioural therapy, interpersonal therapy, and problem-solving therapy (all d>0.46) compared to waitlist. Empirical evidence from large studies was unavailable or limited for other psychotherapeutic interventions. CONCLUSIONS: Overall our results are consistent with the notion that different psychotherapeutic interventions for depression have comparable benefits. However, the robustness of the evidence varies considerably between different psychotherapeutic treatments.

Comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia syndrome: network meta-analysis.

OBJECTIVES: To synthesise the available evidence on pharmacological and non-pharmacological interventions recommended for fibromyalgia syndrome (FMS). METHODS: Electronic databases including MEDLINE, PsycINFO, Scopus, the Cochrane Controlled Trials Registry and the Cochrane Library were searched for randomised controlled trials comparing any therapeutic approach as recommended in FMS guidelines (except complementary and alternative medicine) with control interventions in patients with FMS. Primary outcomes were pain and quality of life. Data extraction was done using standardised forms. RESULTS: 102 trials in 14 982 patients and eight active interventions (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors (SNRIs), the gamma-amino butyric acid analogue pregabalin, aerobic exercise, balneotherapy, cognitive behavioural therapy (CBT), multicomponent therapy) were included. Most of the trials were small and hampered by methodological quality, introducing heterogeneity and inconsistency in the network. When restricted to large trials with ≥100 patients per group, heterogeneity was low and benefits for SNRIs and pregabalin compared with placebo were statistically significant, but small and not clinically relevant. For non-pharmacological interventions, only one large trial of CBT was available. In medium-sized trials with ≥50 patients per group, multicomponent therapy showed small to moderate benefits over placebo, followed by aerobic exercise and CBT. CONCLUSIONS: Benefits of pharmacological treatments in FMS are of questionable clinical relevance and evidence for benefits of non-pharmacological interventions is limited. A combination of pregabalin or SNRIs as pharmacological interventions and multicomponent therapy, aerobic exercise and CBT as non-pharmacological interventions seems most promising for the management of FMS.

Predictors of patterns of change in health-related quality of life in older women over 7 years: evidence from a prospective cohort study.

BACKGROUND: the evaluation of the determinants of change over time in health-related quality of life (HR-QoL) in older people is limited. This study aims to identify patterns of change in HR-QoL over 7 years and their determinants using data from the British Women's Heart and Health Study, a representative sample of older women (n = 4286). METHODS: longitudinal latent class analysis was used to identify subpopulations of women with similar HR-QoL trajectories from 1999-2000 to 2007. HR-QoL was measured using the EQ-5D. Multivariate multinomial logistic regression was used to model the association of identified trajectories with baseline predictors after multiple imputation of missing data. RESULTS: four distinct EQ-5D trajectories were suggested: high (19% of women), high decline (22%), intermediate (42%) and low decline (16%). Prevalent arthritis (OR = 13.4; 95% CI: 8.8, 20.5), diabetes (OR = 4.6; 95% CI: 1.5, 14.2) and obesity (OR = 3.9; 95% CI: 2.5, 6.0) were the strongest predicting health conditions of adverse changes in HR-QoL and physical activity the strongest predicting lifestyle factor (OR = 2.8; 95% CI: 2.0, 3.9). CONCLUSIONS: findings suggest that older women without obesity or pre-existing health conditions who undertake more physical activity are more likely to experience high HR-QoL, reinforcing the importance of these factors for healthy ageing.

Effect of changes in moderate or vigorous physical activity on changes in health-related quality of life of elderly British women over seven years.

PURPOSE: This study investigates the effect of changes in moderate or vigorous physical activity (MVPA) on trajectories in health-related quality of life (HR-QoL) over 7 years in British elderly women. METHODS: A total of 1,926 women from the British Women's Heart and Health Study with information on MVPA and HR-QoL [measured using Euro quality of life 5 dimension (EQ-5D)] at baseline and at 7 years of follow-up were included in the analysis. Baseline and 7-year follow-up MVPA values were categorised into 3 groups, generating 9 categories of change in MVPA. Logistic regression was used to obtain odds ratios (ORs) of maintaining or improving HR-QoL according to different patterns of change in MVPA level. RESULTS: Women who remained inactive over the 7 years of follow-up had the largest reduction in their EQ-5D scores. Compared to these women, women that increased their MPVA level from "inactive" to "low" or to "moderate-high" were more likely to maintain or improve their HR-QoL over 7 years (ORs 1.65 or 2.70, respectively, p value for trend <0.001). After adjustment for baseline EQ-5D score and a wide range of potential confounders, results remained largely unchanged, though precision of the estimates generally decreased. CONCLUSIONS: Our findings suggest that relatively regular MVPA, even taken up later in life, can help older women prevent a decline in HR-QoL and even improve their enjoyment of life.

Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis.

BACKGROUND: Viscosupplementation, the intra-articular injection of hyaluronic acid, is widely used for symptomatic knee osteoarthritis. PURPOSE: To assess the benefits and risks of viscosupplementation for adults with symptomatic knee osteoarthritis. DATA SOURCES: MEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), the Cochrane Central Register of Controlled Trials (1970 to January 2012), and other sources. STUDY SELECTION: Randomized trials in any language that compared viscosupplementation with sham or nonintervention control in adults with knee osteoarthritis. DATA EXTRACTION: Primary outcomes were pain intensity and flare-ups. Secondary outcomes included function and serious adverse events. Reviewers used duplicate abstractions, assessed study quality, pooled data by using a random-effects model, examined funnel plots, and explored heterogeneity by using meta-regression. DATA SYNTHESIS: Eighty-nine trials involving 12 667 adults met inclusion criteria. Sixty-eight had a sham control, 40 had a follow-up duration greater than 3 months, and 22 used cross-linked forms of hyaluronic acid. Overall, 71 trials (9617 patients) showed that viscosupplementation moderately reduced pain (effect size, -0.37 [95% CI, -0.46 to -0.28]). There was important between-trial heterogeneity and an asymmetrical funnel plot: Trial size, blinded outcome assessment, and publication status were associated with effect size. Five unpublished trials (1149 patients) showed an effect size of -0.03 (CI, -0.14 to 0.09). Eighteen large trials with blinded outcome assessment (5094 patients) showed a clinically irrelevant effect size of -0.11 (CI, -0.18 to -0.04). Six trials (811 patients) showed that viscosupplementation increased, although not statistically significantly, the risk for flare-ups (relative risk, 1.51 [CI, 0.84 to 2.72]). Fourteen trials (3667 patients) showed that viscosupplementation increased the risk for serious adverse events (relative risk, 1.41 [CI, 1.02 to 1.97]). LIMITATIONS: Trial quality was generally low. Safety data were often not reported. CONCLUSION: In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events. PRIMARY FUNDING SOURCE: Arco Foundation.

A first-in-human study of the fibroblast activation protein-targeted, 4-1BB agonist RO7122290 in patients with advanced solid tumors.

This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent (n = 65) or in combination with a 1200-milligram fixed dose of the anti-programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab given every 3 weeks (n = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8+ and Ki67+CD8+ T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors.

Delayed coverage in malapposed and side-branch struts with respect to well-apposed struts in drug-eluting stents: in vivo assessment with optical coherence tomography.

BACKGROUND: Pathology studies on fatal cases of very late stent thrombosis have described incomplete neointimal coverage as common substrate, in some cases appearing at side-branch struts. Intravascular ultrasound studies have described the association between incomplete stent apposition (ISA) and stent thrombosis, but the mechanism explaining this association remains unclear. Whether the neointimal coverage of nonapposed side-branch and ISA struts is delayed with respect to well-apposed struts is unknown. METHODS AND RESULTS: Optical coherence tomography studies from 178 stents implanted in 99 patients from 2 randomized trials were analyzed at 9 to 13 months of follow-up. The sample included 38 sirolimus-eluting, 33 biolimus-eluting, 57 everolimus-eluting, and 50 zotarolimus-eluting stents. Optical coherence tomography coverage of nonapposed side-branch and ISA struts was compared with well-apposed struts of the same stent by statistical pooled analysis with a random-effects model. A total of 34 120 struts were analyzed. The risk ratio of delayed coverage was 9.00 (95% confidence interval, 6.58 to 12.32) for nonapposed side-branch versus well-apposed struts, 9.10 (95% confidence interval, 7.34 to 11.28) for ISA versus well-apposed struts, and 1.73 (95% confidence interval, 1.34 to 2.23) for ISA versus nonapposed side-branch struts. Heterogeneity of the effect was observed in the comparison of ISA versus well-apposed struts (H=1.27; I(2)=38.40) but not in the other comparisons. CONCLUSIONS: Coverage of ISA and nonapposed side-branch struts is delayed with respect to well-apposed struts in drug-eluting stents, as assessed by optical coherence tomography. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique identifier: NCT00389220, NCT00617084.

Gender is an independent risk factor for distribution pattern and lesion morphology in chronic critical limb ischemia.

BACKGROUND: The aim of this study was to determine gender differences in atherosclerotic lesion morphology and distribution pattern of patients with critical limb ischemia (CLI). METHODS: In this prospective cohort study, 233 patients, including 134 men (58%) and 99 women (43%) presenting with critically ischemic limbs were consecutively enrolled. Lesions of the entire lower limb arterial tree were evaluated and grouped into iliac, femoropopliteal, and below-the-knee (BTK) arterial disease. To elucidate whether gender is an independent risk factor for distribution pattern, we performed multivariable logistic regression models adjusted for cardiovascular risk factors. RESULTS: At time of diagnosis, women with CLI presented with higher mean age (78 ±10 vs 74 ±10, P = .01), suffered more often from hypertension (83% vs 71%, P = .04), and fewer were current or former smokers (25% vs 70%, P < .001). After multivariate analysis, women with CLI showed a 2.5-fold higher risk for femoropopliteal lesions (odds ratio [OR], 2.53; 95% confidence interval [CI], 1.05-6.11, P = .04), with a threefold higher risk for occlusions compared with men (OR, 3.81; 95% CI, 1.45-10.0; P = .01). Moreover, in women a higher risk for multilevel disease was observed (OR, 3.81; 95% CI, 1.45-10.0; P = .01). In contrast, men presented more often with isolated BTK lesions compared with women (OR, 0.15; 95% CI, 0.05-0.70; P = .03). CONCLUSIONS: The finding that female gender may be an independent predictor for pronounced femoropopliteal involvement and more severe and diffuse atherosclerotic disease in CLI may be of particular relevance for early detection and for choosing distinct treatment strategies in women compared with men. Further studies are warranted, especially on confounding risk factors that might be different in men and women and their possible association with lesion morphology in patients with critical limb ischemia.

Association between cam-type deformities and magnetic resonance imaging-detected structural hip damage: a cross-sectional study in young men.

OBJECTIVE: Femoroacetabular impingement may be a risk factor for hip osteoarthritis in men. An underlying hip deformity of the cam type is common in asymptomatic men with nondysplastic hips. This study was undertaken to examine whether hip deformities of the cam type are associated with signs of hip abnormality, including labral lesions and articular cartilage damage, detectable on magnetic resonance imaging (MRI). METHODS: In this cross-sectional, population-based study in asymptomatic young men, 1,080 subjects underwent clinical examination and completed a self-report questionnaire. Of these subjects, 244 asymptomatic men with a mean age of 19.9 years underwent MRI. All MRIs were read for cam-type deformities, labral lesions, cartilage thickness, and impingement pits. The relationship between cam-type deformities and signs of joint damage were examined using logistic regression models adjusted for age and body mass index. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined. RESULTS: Sixty-seven definite cam-type deformities were detected. These deformities were associated with labral lesions (adjusted OR 2.77 [95% CI 1.31, 5.87]), impingement pits (adjusted OR 2.9 [95% CI 1.43, 5.93]), and labral deformities (adjusted OR 2.45 [95% CI 1.06, 5.66]). The adjusted mean difference in combined anterosuperior femoral and acetabular cartilage thickness was -0.19 mm (95% CI -0.41, 0.02) lower in those with cam-type deformities compared to those without. CONCLUSION: Our findings indicate that the presence of a cam-type deformity is associated with MRI-detected hip damage in asymptomatic young men.

Inflammation, coagulation and risk of locomotor disability in elderly women: findings from the British Women's Heart and Health Study.

This study investigated associations between chronic inflammation and coagulation and incident locomotor disability using prospective data from the British Women's Heart and Health Study. Locomotor disability was assessed using self-reported questionnaires in 1999/2000, and 3 and 7 years later. Scores for inflammation and coagulation were obtained from summation of quartile categories of all available biomarkers from blood samples taken at baseline. 534 women developed locomotor disability after 3 years, 260 women after 7 years, while 871 women remained free of locomotor disability over the whole study period. After adjustment for demographic characteristics, lifestyle factors and health conditions, we found associations between inflammation and incident locomotor disability after three (OR per unit increase in score = 1.08, 95 % confidence interval (CI): 1.03, 1.13) and 7 years (OR = 1.10, 95 % CI: 1.03, 1.18) and between coagulation and incident locomotor disability after 3 (OR = 1.06, 95 % CI: 0.98, 1.14) and 7 years (OR = 1.09, 95 % CI: 1.00, 1.18). This corresponds to ORs between 1.8 and 2.4 comparing women with highest to lowest inflammation or coagulation scores. These results support the role of inflammation and coagulation in the development of locomotor disability in elderly women irrespective of their lifestyle factors and underlying age-related chronic diseases.

Doxycycline for osteoarthritis of the knee or hip.

BACKGROUND: Osteoarthritis is a chronic joint disease that involves degeneration of articular cartilage. Pre-clinical data suggest that doxycycline might act as a disease-modifying agent for the treatment of osteoarthritis, with the potential to slow cartilage degeneration. This is an update of a Cochrane review first published in 2009. OBJECTIVES: To examine the effects of doxycycline compared with placebo or no intervention on pain and function in people with osteoarthritis of the hip or knee. SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2008, issue 3), MEDLINE, EMBASE and CINAHL up to 28 July 2008, with an update performed at 16 March 2012. In addition, we checked conference proceedings, reference lists, and contacted authors. SELECTION CRITERIA: We included studies if they were randomised or quasi-randomised controlled trials that compared doxycycline at any dosage and any formulation with placebo or no intervention in people with osteoarthritis of the knee or hip. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate. We contacted investigators to obtain missing outcome information. We calculated differences in means at follow-up between experimental and control groups for continuous outcomes and risk ratios (RR) for binary outcomes. MAIN RESULTS: We identified one additional trial (232 participants) and included two trials (663 participants) in this update. The methodological quality and the quality of reporting were considered moderate. At end of treatment, clinical outcomes were similar between the two treatment groups, with an effect size of -0.05 (95% confidence interval (CI) -0.22 to 0.13), corresponding to a difference in pain scores between doxycycline and control of -0.1 cm (95% CI -0.6 to 0.3 cm) on a 10-cm visual analogue scale, or 32% versus 29% improvement from baseline (difference 3%; 95% CI -5% to 10%). The effect size for function was -0.07 (95% CI -0.25 to 0.10), corresponding to a difference between doxycycline and control of -0.2 (95% CI -0.5 to 0.2) on the Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability subscale with a range of 0 to 10, or 24% versus 21% improvement (difference 3%; 95% CI -3% to 10%). The difference in changes in minimum joint space narrowing assessed in one trial was in favour of doxycycline (-0.15 mm; 95% CI -0.28 to -0.02 mm), which corresponds to a small effect size of -0.23 standard deviation units (95% CI -0.44 to -0.02). More participants withdrew from the doxycycline group compared with placebo due to adverse events (RR 2.28; 95% CI 1.06 to 4.90). There was no evidence that participants in the doxycycline group experienced more serious adverse events than those in the placebo group, but the estimate was imprecise (RR 1.07; 95% CI 0.68 to 1.68). AUTHORS' CONCLUSIONS: In this update, the strength of evidence for effectiveness outcomes was improved from low to moderate and we confirmed that the symptomatic benefit of doxycycline is minimal to non-existent, while the small benefit in terms of joint space narrowing is of questionable clinical relevance and outweighed by safety problems. The CIs of the summary estimates now exclude any clinically relevant difference in improvement of symptoms and the small benefit in terms of joint space narrowing does not outweigh the harms.

Tissue coverage of a hydrophilic polymer-coated zotarolimus-eluting stent vs. a fluoropolymer-coated everolimus-eluting stent at 13-month follow-up: an optical coherence tomography substudy from the RESOLUTE All Comers trial.

AIMS: To compare the tissue coverage of a hydrophilic polymer-coated zotarolimus-eluting stent (ZES) vs. a fluoropolymer-coated everolimus-eluting stent (EES) at 13 months, using optical coherence tomography (OCT) in an 'all-comers' population of patients, in order to clarify the mechanism of eventual differences in the biocompatibility and thrombogenicity of the devices. METHODS AND RESULTS: Patients randomized to angiographic follow-up in the RESOLUTE All Comers trial (NCT00617084) at pre-specified OCT sites underwent OCT follow-up at 13 months. Tissue coverage and apposition were assessed strut by strut, and the results in both treatment groups were compared using multilevel logistic or linear regression, as appropriate, with clustering at three different levels: patient, lesion, and stent. Fifty-eight patients (30 ZES and 28 EES), 72 lesions, 107 stents, and 23 197 struts were analysed. Eight hundred and eighty-seven and 654 uncovered struts (7.4 and 5.8%, P= 0.378), and 216 and 161 malapposed struts (1.8 and 1.4%, P= 0.569) were found in the ZES and EES groups, respectively. The mean thickness of coverage was 116 ± 99 µm in ZES and 142 ± 113 µm in EES (P= 0.466). No differences in per cent neointimal volume obstruction (12.5 ± 7.9 vs. 15.0 ± 10.7%) or other areas-volumetric parameters were found between ZES and EES, respectively. CONCLUSION: No significant differences in tissue coverage, malapposition, or lumen/stent areas and volumes were detected by OCT between the hydrophilic polymer-coated ZES and the fluoropolymer-coated EES at 13-month follow-up.

T-Cell Heterogeneity in Baseline Tumor Samples: Implications for Early Clinical Trial Design and Analysis.

Background: In early stage clinical trials, changes to levels of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) are critical biomarkers of the mechanism of action of novel immunotherapies. However, baseline heterogeneity of tumor samples, both between and within patients, and the resultant impact on the validity of clinical trial data is not well defined. Here we identify and quantify the impact of baseline variables on the heterogeneity of FoxP3+ and proliferating CD8+ T-cells levels (MKi67+CD8A+) in the TME both between and within patients for the purpose of informing clinical trial design and analysis. Methods: We compared levels of FoxP3+ and MKi67+CD8+ cell densities (counts/mm2) from >1000 baseline tumor samples from clinical trials and commercially available sources. Using multivariate hierarchical regression techniques, we investigated whether inter-person heterogeneity of activated or regulatory T-cells could be attributed to baseline characteristics including demographics, indication, lesion type, tissue of excision, biopsy method, prior cancer treatment, and tissue type i.e., "fresh" or "archival" status. We also sought to characterize within-patient heterogeneity by lesion type and tissue type. Results: Prior cancer treatment with hormone therapy or chemotherapy that induces immunogenic cell death may alter the TME. Archival tissue is an unreliable substitute for fresh tissue for determining baseline TIL levels. Baseline and on treatment biopsies should be matched by lesion type to avoid bias.

Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials.

Pathological complete response (pCR) to neoadjuvant treatment correlates with outcome in breast cancer. We determined whether characteristics of neoadjuvant therapy are associated with pCR. We used multi-level models, which accounted for heterogeneity in pCR across trials and trial arms, to analyze individual patient data from 3332 women included in 7 German neoadjuvant trials with uniform protocols. PCR was associated with an increase in number of chemotherapy cycles (odds ratio [OR] 1.2 for every two additional cycles; P = 0.009), with higher cumulative anthracycline doses (OR 1.6; P = 0.002), higher cumulative taxane doses (OR 1.6; P = 0.009), and with capecitabine containing regimens (OR 1.62; P = 0.022). Association of pCR with increase in number of cycles appeared more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; P for interaction = 0.046). Effect of anthracycline dose was particularly pronounced in HER2-negative tumors (OR 1.61), compared to HER2-positive tumors (OR 0.83; P for interaction = 0.14). Simultaneous trastuzumab treatment in HER2-positive tumors increased odds of pCR 3.2-fold (P < 0.001). No association of pCR and number of trastuzumab cycles was found (OR 1.20, P = 0.39). Dosing characteristics appear important for successful treatment of breast cancer. Longer treatment, higher cumulative doses of anthracyclines and taxanes, and the addition of capecitabine and trastuzumab are associated with better response. Tailoring according to breast cancer phenotype might be possible: longer treatment in HR-positive tumors, higher cumulative anthracycline doses for HER2-negative tumors, shorter treatment at higher cumulative doses for triple-negative tumors, and limited number of preoperative trastuzumab cycles in HER2-positive tumors.

Long-term tissue coverage of a biodegradable polylactide polymer-coated biolimus-eluting stent: comparative sequential assessment with optical coherence tomography until complete resorption of the polymer.

BACKGROUND: Biolimus-eluting stents (BESs) with a biodegradable polymer in abluminal coating achieve more complete coverage at 9 months compared with sirolimus-eluting stents (SESs) with a durable polymer, as assessed by optical coherence tomography (OCT). Whether this advantage persists or augments after complete resorption of the polymer (>12 months) is unknown. METHODS: The LEADERS trial compared the performance of BES with that of SES. Patients were randomly allocated to a sequential angiographic follow-up, including OCT in selected sites, at 9 and 24 months. Struts coverage was compared using Bayesian hierarchical models as the primary outcome for the OCT substudy. RESULTS: Fifty-six patients (26 BES, 30 SES) were enrolled in the OCT substudy. Twenty-one patients (10 BES, 11 SES) agreed to perform a second OCT follow-up at 24 months. Eleven lesions and 12 stents were analyzed sequentially in the BES group (2,455 struts at 9 months, 2,131 struts at 24 months) and 11 lesions and 18 stents in the SES group (3,421 struts at 9 months, 4,170 struts at 24 months). The previously reported advantage of BES over SES in terms of better strut coverage at 9 months was followed by improvement in coverage of the SES, resulting in identical coverage in both BES and SES at 24 months: 1.5% versus 1.8% uncovered struts, difference -0.2%, 95% credibility interval, -3.2% to 2.6%, P = .84. CONCLUSIONS: More complete strut coverage of BES as compared with SES at 9 months was followed by improvement of coverage in SES between 9 and 24 months and a similar long-term coverage in both stent types at 24 months.

Association of bone attrition with knee pain, stiffness and disability: a cross-sectional study.

OBJECTIVES: Bone pathologies as detected on MRI are associated with the presence of pain in knee osteoarthritis (OA). The authors examined whether bone attrition assessed on x-rays was associated with pain, stiffness and disability. METHODS: The authors analysed x-rays of 1326 knees with OA from 783 individuals participating in the cross-sectional population-based Somerset and Avon Survey of Health. The diagnosis of OA was defined by the presence of osteophytes in anteroposterior (AP) or lateral views. Bone attrition was graded from 0 (no attrition) to 3 (severe attrition >10 mm) and Kellgren and Lawrence (K/L) scores were assigned on AP views. Logistic regression models adjusted for gender, age, body mass index, effusion and K/L scores were used to determine whether bone attrition was associated with pain, stiffness and disability. RESULTS: Pain was reported in 84 knees (74%) with radiographic bone attrition compared with 505 (42%) without bone attrition (adjusted OR 2.22, 95% CI 1.29 to 3.80). The adjusted OR was increased for day pain but not for night pain (p for interaction <0.001). Stiffness was reported for 85 knees with bone attrition (75%) and 437 knees without (36%) (adjusted OR 3.23, 95% CI 1.85 to 5.64). Disability was reported by 40 individuals with bone attrition (50%) and 140 individuals without (24%) (adjusted OR 2.09, 95% CI 1.19 to 3.68). CONCLUSIONS: Bone attrition detected on conventional x-rays using a simple cheap technique is strongly associated with the presence of day pain, stiffness and disability in knee OA.