Joan F. Hilton

Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial

BACKGROUND Minocycline has anti-apoptotic and anti-inflammatory effects in vitro, and extends survival in mouse models of some neurological conditions. Several trials are planned or are in progress to assess whether minocycline slows human neurodegeneration. We aimed to test the efficacy of minocycline as a treatment for amyotrophic lateral sclerosis (ALS). METHODS We did a multicentre, randomised placebo-controlled phase III trial. After a 4-month lead-in phase, 412 patients were randomly assigned to receive placebo or minocycline in escalating doses of up to 400 mg/day for 9 months. The primary outcome measure was the difference in rate of change in the revised ALS functional rating scale (ALSFRS-R). Secondary outcome measures were forced vital capacity (FVC), manual muscle testing (MMT), quality of life, survival, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00047723. FINDINGS ALSFRS-R score deterioration was faster in the minocycline group than in the placebo group (-1.30 vs -1.04 units/month, 95% CI for difference -0.44 to -0.08; p=0.005). Patients on minocycline also had non-significant tendencies towards faster decline in FVC (-3.48 vs -3.01, -1.03 to 0.11; p=0.11) and MMT score (-0.30 vs -0.26, -0.08 to 0.01; p=0.11), and greater mortality during the 9-month treatment phase (hazard ratio=1.32, 95% CI 0.83 to 2.10; p=0.23) than did patients on placebo. Quality-of-life scores did not differ between the treatment groups. Non-serious gastrointestinal and neurological adverse events were more common in the minocycline group than in the placebo group, but these events were not significantly related to the decline in ALSFRS-R score. INTERPRETATION Our finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocycline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in patients with ALS.

Outcomes of Active Surveillance for Men With Intermediate-Risk Prostate Cancer

PURPOSE Active surveillance (AS) is an option for the initial management of early-stage prostate cancer. Current risk stratification schema identify patients with low-risk disease who are presumed to be most suitable for AS. However, some men with higher risk disease also elect AS; outcomes for such men have not been widely reported. PATIENTS AND METHODS Men managed with AS at University of California, San Francisco, were classified as low- or intermediate-risk based on serum prostate-specific antigen (PSA), Gleason grade, extent of biopsy involvement, and T stage. Clinical and demographic characteristics, and progression in terms of Gleason score, PSA kinetics, and active treatment were compared between men with low- and intermediate-risk tumors. RESULTS Compared to men with low-risk tumors, those with intermediate-risk tumors were older (mean, 64.9 v 62.3 years) with higher mean PSA values (10.9 v 5.1 ng/mL), and more tumor involvement (mean, 20.4% v 15.3% positive biopsy cores; all P < .01). Within 4 years of the first positive biopsy, the clinical risk group did not differ in terms of the proportions experiencing progression-free survival, (low [54%] v intermediate [61%]; log-rank P = .22) or the proportions who underwent active treatment (low [30%] v intermediate [35%]; log-rank P = .88). Among men undergoing surgery, none were node positive and none had biochemical recurrence within 3 years. CONCLUSION Selected men with intermediate-risk features be appropriate candidates for AS, and are not necessarily more likely to progress. AS for these men may provide an opportunity to further reduce overtreatment of disease that is unlikely to progress to advanced cancer.

The CAPRA-S score: a straightforward tool for improved prediction of outcomes after radical prostatectomy

The authors previously developed and validated the Cancer of the Prostate Risk Assessment (CAPRA) score to predict prostate cancer recurrence based on pretreatment clinical data. They aimed to develop a similar postsurgical score with improved accuracy via incorporation of pathologic data.

Does Treatment (Nonoperative and Operative) Improve the Two-Year Quality of Life in Patients With Adult Symptomatic Lumbar Scoliosis: A Prospective Multicenter Evidence-Based Medicine Study

Study Design. Prospective observational cohort study with matched and unmatched comparisons. Level II evidence. Objective. The purpose of this study is to compare results of adult symptomatic lumbar scoliosis (ASLS) patients treated nonoperatively and operatively. This is an evidence-based prospective multicenter study to answer the question of whether nonoperative and operative treatment improves the quality of life (QOL) in these patients at 2-year follow-up. Summary of Background Data. Only 1 paper in the peer-reviewed published data directly addresses this question. That paper suggested that operative treatment was more beneficial than nonoperative care, but the limitations relate to historical context (all patients treated with Harrington implants) and the absence of validated patient-reported QOL (QOL) data. Methods. This study assesses 160 consecutively enrolled patients (ages 40–80 years) with baseline and 2-year follow-up data from 5 centers. Lumbar scoliosis without prior surgical treatment was defined as a minimum Cobb angle of 30° (mean: 54° for patients in this study). All patients had either an Oswestry Disability Index (ODI) score of 20 or more (mean: 33) or Scoliosis Research Society (SRS) domain scores of 4 or less in pain, function, and self-image (mean: 3.2) at baseline. Pretreatment and 2-year follow-up data collected prospectively included basic radiographic parameters, complications and SRS QOL, ODI, and Numerical Rating Scale back and leg pain scores. Results. At 2 years, follow-up on the operative patients was 95% and for the nonoperative patients it was 45%.The demographics for the nonoperative patients who were followed up for 2 years versus those who were lost to follow-up were identical. The operative cohort significantly improved in all QOL measures. The nonoperativecohort did not improve and nonsignificant decline in QOL scores was common. At minimum 2-year follow-up, operative patients outperformed nonoperative patients by all measures. Conclusion. It would appear from this study that common nonoperative treatments do not change the QOL in patients with ASLS at 2-year follow-up. However, operative treatment does significantly improve the QOL for this group of patients. Our conclusions are limited by the fact that we were only able to follow-up 45% of the nonoperative group to 2-year follow-up, in spite of extensive efforts on our part to accomplish such.

The influence of the dentin smear layer on adhesion: a self-etching primer vs. a total-etch system

OBJECTIVE To determine the effect of dentin smear layers created by various abrasives on the adhesion of a self-etching primer (SE) and total-etch (SB) bonding systems. METHODS Polished human dentin disks were further abraded with 0.05 micro m alumina slurry, 240-, 320- or 600-grit abrasive papers, # 245 carbide, # 250.9 F diamond or # 250.9 C diamond burs. Shear bond strength (SBS) was evaluated by single-plane lap shear, after bonding with SE or SB and with a restorative composite. Smear layers were characterized by thickness, using SEM; surface roughness using AFM; and reaction to the conditioners, based on the percentage of open tubules, using SEM. RESULTS Overall, SBS was lower when SB was used than when SE was used. SBS decreased with increasing coarseness of the abrasive in the SE group. Among burs, the carbide group had the highest SBS, and 320- and 240-grit papers had SBS close to the carbide group. Surface roughness and smear layer thickness varied strongly with coarseness. After conditioning with SE primer, the tubule openness of specimens abraded by carbide bur did not differ from 240- or 320-grit paper, but did differ from the 600-grit. SIGNIFICANCE Even though affected by different surface preparation methods, SE yielded higher SBS than SB. The higher SBS and thin smear layer of the carbide bur group, suggests its use when self-etching materials are used in vivo. Overall, the 320-grit abrasive paper surface finish yielded results closer to that of the carbide bur and its use is recommended in vitro as a clinical simulator when using the SE material.

Microfluidic-Based Multiplex qRT-PCR Identifies Diagnostic and Prognostic microRNA Signatures in the Sera of Prostate Cancer Patients

Recent prostate-specific antigen-based screening trials indicate an urgent need for novel and noninvasive biomarker identification strategies to improve the prediction of prostate cancer behavior. Noncoding microRNAs (miRNA) in the serum and plasma have been shown to have potential as noninvasive markers for physiologic and pathologic conditions. To identify serum miRNAs that diagnose and correlate with the prognosis of prostate cancer, we developed a multiplex quantitative reverse transcription PCR method involving the purification of multiplex PCR products followed by uniplex analysis on a microfluidics chip to evaluate 384 human miRNAs. Using Dgcr8 and Dicer knockout (small RNA-deficient) mouse ES cells as the benchmark, we confirmed the validity of our technique and uncovered a considerable lack of accuracy in previously published methods. Profiling 48 sera from healthy men and untreated prostate cancer patients with differing CAPRA scores, we identified miRNA signatures that allow us to diagnose cancer patients and correlate with a prognosis. These serum signatures include oncogenic and tumor-suppressive miRNAs, suggesting functional roles in prostate cancer progression.

Significant reductions in mortality for children with burn injuries through the use of prompt eschar excision.

During the past 19 years, mortality due to burn injuries has markedly declined for children at the Boston Unit of the Shriners Burns Institute (SBI), dropping from an average of 9% of SBI admissions during 1968–1970 to an average of 1% during 1981–1986. Detailed statistical analysis using logistic regression was necessary for determining whether this decline in mortality was explained by changes in patient characteristics, such as age or burn size, which are known to strongly influence the outcome of burn injuries. This dramatic decline in mortality during the past 19 years was not the result of change in the age of the patients or their burn sizes; rather, it may be attributed to improvements in burn care. Results of this statistical analysis indicated that, for burn injury patients whose ages ranged from 11 days to 19 years, age had no demonstrable effect on survival from a burn injury. Children survived burn injuries at least as well if not better than the young adult (20–29 years of age). Also, infants (less than 1 year old) survived as well as other children (2–19 years old). Dramatic improvement in survival occurred in patients with burns covering more than 50% of the body surface area. Since 1979, mortality has been essentially eliminated for patients with burn sizes less than 70% of the total body surface area (of 296 patients with burns covering 15–69% of the total body surface area, only two patients died). During the period 1979–1986, 29 of 37 patients (78%) survived an 80% or greater total body surface area thermal injury.

Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis

Objective To examine the risk of treatment emergent, cardiovascular serious adverse events associated with varenicline use for tobacco cessation. Design Meta-analysis comparing study effects using four summary estimates. Data sources Medline, Cochrane Library, online clinical trials registries, and reference lists of identified articles. Review methods We included randomised controlled trials of current tobacco users of adult age comparing use of varenicline with an inactive control and reporting adverse events. We defined treatment emergent, cardiovascular serious adverse events as occurring during drug treatment or within 30 days of discontinuation, and included any ischaemic or arrhythmic adverse cardiovascular event (myocardial infarction, unstable angina, coronary revascularisation, coronary artery disease, arrhythmias, transient ischaemic attacks, stroke, sudden death or cardiovascular related death, or congestive heart failure). Results We identified 22 trials; all were double blinded and placebo controlled; two included participants with active cardiovascular disease and 11 enrolled participants with a history of cardiovascular disease. Rates of treatment emergent, cardiovascular serious adverse events were 0.63% (34/5431) in the varenicline groups and 0.47% (18/3801) in the placebo groups. The summary estimate for the risk difference, 0.27% (95% confidence interval −0.10 to 0.63; P=0.15), based on all 22 trials, was neither clinically nor statistically significant. For comparison, the relative risk (1.40, 0.82 to 2.39; P=0.22), Mantel-Haenszel odds ratio (1.41, 0.82 to 2.42; P=0.22), and Peto odds ratio (1.58, 0.90 to 2.76; P=0.11), all based on 14 trials with at least one event, also indicated a non-significant difference between varenicline and placebo groups. Conclusions This meta-analysis—which included all trials published to date, focused on events occurring during drug exposure, and analysed findings using four summary estimates—found no significant increase in cardiovascular serious adverse events associated with varenicline use. For rare outcomes, summary estimates based on absolute effects are recommended and estimates based on the Peto odds ratio should be avoided.

Effect of hypercarbia and isoflurane on brain cell death and neurocognitive dysfunction in 7-day-old rats.

Background:Millions of neonates undergo anesthesia each year. Certain anesthetic agents cause brain cell death and long-term neurocognitive dysfunction in postnatal day (P)7 rats. Despite its intuitive appeal, a causal link between cell death and neurocognitive decline after anesthesia has not been established. If one existed, the degree of cell death would be expected to correlate with the degree of neurocognitive dysfunction caused by anesthesia. The authors therefore tested if cell death caused by various durations of isoflurane at 1 minimum alveolar concentration causes duration-dependent long-term neurocognitive dysfunction. Methods:Isoflurane was administered to P7 rats at 1 minimum alveolar concentration for 0, 1, 2, or 4 h. To control for the respiratory depressant effects of anesthesia, a group of rats was treated with 4 h of carbon dioxide. Cell death was assessed by FluoroJade staining 12 h after the end of each intervention, and neurocognitive outcome was assessed 8 weeks later by using fear conditioning, spatial reference memory, and spatial working memory tasks. Results:Widespread brain cell death was caused by 2 h and 4 h of isoflurane and by 4 h of carbon dioxide. The degree and distribution of thalamic cell death was similar in 4 h isoflurane-treated and 4-h carbon dioxide–treated rats. Only 4 h of isoflurane caused a long-term neurocognitive deficit affecting both spatial reference memory and spatial working memory. Working memory was improved in carbon dioxide–treated rats. Conclusion:Isoflurane-induced brain cell death may be partly caused by hypercarbia. The inconsistencies between cell death and neurocognitive outcome suggest that additional or alternative mechanisms may mediate anesthesia-induced long-term neurocognitive dysfunction.

Hepatoma in the noncirrhotic liver.

The pathologic features, clinical presentation and natural history of hepatocellular carcinoma (HCC) developing in the noncirrhotic liver were studied in 61 patients against a background of 63 patients seen concurrently with HCC complicating cirrhosis. Noncirrhotic HCC had a bimodal age distribution, with females predominating the first age‐clustering (10–50 years) and males predominating the second age‐clustering (50–90 years). Cirrhotic HCC had a unimodal age distribution (40–90 years) with male dominance throughout. Estrogen exposure was noted in 57% of the noncirrhotic HCC women overall and in 80% of those in the younger age‐clustering. The majority of noncirrhotic HCC presented with a single hepatic mass or a dominant primary with satellite lesions in contrast to the usual multinodular or diffuse disease seen with cirrhosis. Twenty‐nine noncirrhotic patients survived complete resection of disease limited to the liver and exhibited a median survival of 2.7 years with a 5‐year survival of 25%. Low histologic grade, minimal necrosis, and the absence of hemoperitoneum, hepatomegaly, and adjacent organ involvement were all favorable prognostic variables. Patients with metastatic or locally unresectable noncirrhotic HCC had a median survival of 9 months, and 24% survived in excess of 2 years. This survival experience is significantly more favorable than cirrhotic HCC patients, who had only a 1.2‐month median and a 3% 2‐year survival. Low histologic grade, mild mitotic activity and the presence of some fibrosis within the specimen were associated with a favorable outcome in advanced noncirrhotic HCC. The favorable prognosis and heterogeneous composition of the noncirrhotic, when compared to the cirrhotic HCC cohort, may be important considerations in the design and evaluation of future clinical trials.