Evaluation of treatment outcome in 175 patients with Hodgkin lymphoma aged 60 years or over: the SHIELD study.

The SHIELD program for Hodgkin lymphoma in patients 60 years of age or older, prospectively evaluated clinical features and outcome in a large patient cohort (n = 175). The central element was a phase 2 study of VEPEMB chemotherapy (n = 103, median age 73 years) incorporating comorbidity assessment. A total of 72 other patients were treated off-study but registered prospectively and treated concurrently with: ABVD (n = 35); CLVPP (n = 19), or other (n = 18). Of VEPEMB patients, 31 had early-stage disease (stage 1A/2A) and received VEPEMB 3 times plus radiotherapy. Median follow-up was 36 months. Complete remission (CR) rate (intention-to-treat) was 74% and 3-year overall survival (OS) and progression-free survival (PFS) were 81% and 74%, respectively. A total of 72 patients had advanced-stage disease (stage 1B/2B/3 or 4) and received VEPEMB 6 times. CR rate was 61% with 3-year OS and PFS of 66% and 58%, respectively. Of patients achieving CR, 13% with early-stage and 5% with advanced-stage disease progressed. Overall treatment-related mortality was 7%. In patients treated with curative intent with VEPEMB, ABVD, and CLVPP (n = 157), CR linked to several factors in univariate analysis. In a Cox regression model only, obtaining CR remained significant for OS and CR plus comorbidity and age for PFS. RS-EBV status had no significant effect on outcome.

Use of proton pump inhibitors to treat persistent throat symptoms: multicentre, double blind, randomised, placebo controlled trial.

OBJECTIVE: To assess the use of proton pump inhibitors (PPIs) to treat persistent throat symptoms. DESIGN: Pragmatic, double blind, placebo controlled, randomised trial. SETTING: Eight ear, nose, and throat outpatient clinics, United Kingdom. PARTICIPANTS: 346 patients aged 18 years or older with persistent throat symptoms who were randomised according to recruiting centre and baseline severity of symptoms (mild or severe): 172 to lansoprazole and 174 to placebo. INTERVENTION: Random blinded allocation (1:1) to either 30 mg lansoprazole twice daily or matched placebo twice daily for 16 weeks. MAIN OUTCOME MEASURES: Primary outcome was symptomatic response at 16 weeks measured using the total reflux symptom index (RSI) score. Secondary outcomes included symptom response at 12 months, quality of life, and throat appearances. RESULTS: Of 1427 patients initially screened for eligibility, 346 were recruited. The mean age of the study sample was 52.2 (SD 13.7) years, 196 (57%) were women, and 162 (47%) had severe symptoms at presentation; these characteristics were balanced across treatment arms. The primary analysis was performed on 220 patients who completed the primary outcome measure within a window of 14-20 weeks. Mean RSI scores were similar between treatment arms at baseline: lansoprazole 22.0 (95% confidence interval 20.4 to 23.6) and placebo 21.7 (20.5 to 23.0). Improvements (reduction in RSI score) were observed in both groups-score at 16 weeks: lansoprazole 17.4 (15.5 to19.4) and placebo 15.6 (13.8 to 17.3). No statistically significant difference was found between the treatment arms: estimated difference 1.9 points (95% confidence interval -0.3 to 4.2 points; P=0.096) adjusted for site and baseline symptom severity. Lansoprazole showed no benefits over placebo for any secondary outcome measure, including RSI scores at 12 months: lansoprazole 16.0 (13.6 to 18.4) and placebo 13.6 (11.7 to 15.5): estimated difference 2.4 points (-0.6 to 5.4 points). CONCLUSIONS: No evidence was found of benefit from PPI treatment in patients with persistent throat symptoms. RSI scores were similar between the lansoprazole and placebo groups after 16 weeks of treatment and at the 12 month follow-up. TRIAL REGISTRATION: ISRCTN Registry ISRCTN38578686 and EudraCT 2013-004249-17.

Lansoprazole for persistent throat symptoms in secondary care: the TOPPITS RCT.

BACKGROUND: Persistent throat symptoms are commonly attributed to 'laryngopharyngeal reflux'. Despite a limited evidence base, these symptoms are increasingly being treated in primary care with proton pump inhibitors. OBJECTIVE: To assess the value of proton pump inhibitor therapy in patients with persistent throat symptoms. DESIGN: This was a double-blind, placebo-controlled, randomised Phase III trial. SETTING: This was a multicentre UK trial in eight UK ear, nose and throat departments. PARTICIPANTS: A total of 346 participants aged ≥ 18 years with persistent throat symptoms and a Reflux Symptom Index score of ≥ 10, exclusive of the dyspepsia item, were recruited. INTERVENTION: Random allocation (1 : 1 ratio) to either 30 mg of lansoprazole twice daily or matched placebo for 16 weeks. MAIN OUTCOME MEASURE: Symptomatic response (i.e. total Reflux Symptom Index score after 16 weeks of therapy). RESULTS: A total of 1427 patients were screened and 346 were randomised. The mean age was 52 years (standard deviation 13.7 years, range 20-84 years); 150 (43%) participants were male and 196 (57%) were female; 184 (53%) participants had a mild Reflux Symptom Index minus the heartburn/dyspepsia item and 162 (47%) had a severe Reflux Symptom Index minus the heartburn/dyspepsia item. A total of 172 patients were randomised to lansoprazole and 174 were randomised to placebo. MAIN OUTCOMES: A total of 267 participants completed the primary end-point visit (lansoprazole, n = 127; placebo, n = 140), of whom 220 did so between 14 and 20 weeks post randomisation ('compliant' group); 102 received lansoprazole and 118 received placebo. The mean Reflux Symptom Index scores at baseline were similar [lansoprazole 22.0 (standard deviation 8.0), placebo 21.7 (standard deviation 7.1), overall 21.9 (standard deviation 7.5)]. The mean Reflux Symptom Index scores at 16 weeks reduced from baseline in both groups [overall 17.4 (standard deviation 9.9), lansoprazole 17.4 (standard deviation 9.9), placebo 15.6 (standard deviation 9.8)]. Lansoprazole participants had estimated Reflux Symptom Index scores at 16 weeks that were 1.9 points higher (worse) than those of placebo participants (95% confidence interval -0.3 to 4.2; padj = 0.096), adjusted for site and baseline severity. SECONDARY OUTCOMES: Ninety-five (43%) participants achieved a Reflux Symptom Index score in the normal range (< 12) at 16 weeks: 42 (41%) in the lansoprazole group and 53 (45%) in the placebo group. A total of 226 participants completed the end-of-trial follow-up visit (lansoprazole, n = 109; placebo, n = 117), of whom 181 were 'compliant'. The mean Reflux Symptom Index scores at 12 months reduced from baseline in both groups [lansoprazole 16.0 (standard deviation 10.8), placebo 13.6 (standard deviation 9.6), overall 14.7 (standard deviation 10.2)]. A total of 87 (48%) participants achieved a Reflux Symptom Index score in the normal range at 12 months: 33 (40%) in the lansoprazole group and 54 (55%) in the placebo group. Likewise, the Comprehensive Reflux Symptom Score and Laryngopharyngeal Reflux - Health Related Quality of Life total scores and subscales all showed very similar changes in the lansoprazole and placebo cohorts at both 16 weeks and 12 months. LIMITATIONS: Drop-out rate and compliance are issues in pragmatic clinical trials. The Trial Of Proton Pump Inhibitors in Throat Symptoms (TOPPITS) aimed to detect clinically relevant difference with 90% power. The 346 randomised participants reduced to 283 at the primary end point; 267 completed the primary outcome measure, 220 within the protocol time scale. Despite this, the powers to detect the clinically relevant difference in Reflux Symptom Index score at 16 weeks were 82% (compliant comparison) and 89% (pragmatic comparison). The lack of difference between lansoprazole and placebo is generalisable across NHS clinics. CONCLUSIONS: Participants on lansoprazole did not report significantly better outcomes than participants on placebo on any of the three patient-reported outcome tools (Reflux Symptom Index, Comprehensive Reflux Symptom Score and Laryngopharyngeal Reflux - Health Related Quality of Life). This multicentre, pragmatic, powered, definitive Phase III trial found no evidence of benefit for patients by treating persistent throat symptoms with lansoprazole. TRIAL REGISTRATION: Current Controlled Trials ISRCTN38578686 and EudraCT number 2013-004249-17. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 3. See the NIHR Journals Library website for further project information.

BACKGROUND: One of the commonest reasons for patients attending hospital throat or voice clinics is persistent throat symptoms, which include a feeling of a lump in the throat, a cough or a hoarse voice. Over time, more of these patients are being treated with proton pump inhibitors to suppress stomach acid in the belief that stomach acid entering the throat causes the symptoms, but there is little evidence that these medications work. STUDY AIM: The aim of this study is to explore whether or not having a 16-week course of proton pump inhibitors has any impact on throat symptoms. We also tested the usefulness of three different questionnaires in measuring throat symptoms, explored side effects and whether or not patients adhere to treatment, and measured patients' quality of life. METHODS: Patients with persistent (lasting for more than 6 weeks) throat symptoms who agreed to participate were randomised to receive either the proton pump inhibitor lansoprazole or a placebo. Participants took lansoprazole or placebo for 16 weeks. Symptoms and quality of life were measured before patients were randomised and at 4 and 12 months after randomisation. RESULTS: The total number of participants was 346. The mean Reflux Symptom Index outcome score (higher scores meaning worse symptoms) was 22 before the 4-month course of capsules, 16 after 4 months and 15 after 12 months. Participant-reported throat symptoms and quality of life in all participants improved over the 12 months of the study. There was no difference in the symptom improvement experienced by proton pump inhibitor and placebo participants. CONCLUSIONS: This study shows that proton pump inhibitors do not benefit patients with persistent throat symptoms. Future research should focus on other available therapies.

Uncoupling proteins in human heart.

Abnormal energetic activity in heart failure correlates inversely with plasma free-fatty-acid concentrations. However, the link between energetic and metabolic abnormalities is unknown. To investigate this association, we obtained blood samples from 39 patients undergoing coronary artery bypass graft surgery. Patients fasted overnight before samples were taken. When plasma free-fatty-acid concentrations were raised, cardiac mitochondrial uncoupling proteins (UCP) increased (isoform UCP2, p<0.0001; isoform UCP3, p=0.0036) and those of glucose transporter (GLUT4) protein decreased (cardiac, p=0.0001; skeletal muscle, p=0.0006). Consequently, energy deficiency in heart failure might result from increased mitochondrial UCPs (ie, less efficient ATP synthesis) and depleted GLUT4 (ie, reduced glucose uptake). New treatment to correct these energy defects would be to simultaneously lower plasma free fatty acids and provide an alternative energy source.