Effect of Pantoprazole on the Absorption of Hydroxychloroquinea A Randomized Drug-Drug Interaction Trial in Healthy Adults.

Hydroxychloroquine as a weak basic compound with two amines is strongly enriched in cell compartments with low pH, suggesting that modification of gastric pH by coadministered proton pump inhibitors might reduce its solubility and absorption and thus its efficacy in patients. We addressed this question in a single-center, open-label, randomized, parallel drug-drug interaction trial in healthy adults (EudraCT No. 2020-001470-30). All participants received a single oral dose of 400-mg hydroxychloroquine, and one group additionally received 40 mg of pantoprazole once daily for 9 days dosed to steady state. Whole-blood samples were collected for 72 hours, and hydroxychloroquine was quantified by liquid chromatography-tandem mass spectrometry. Primary endpoints were whole-blood hydroxychloroquine areas under the concentration-time curve from 0 to 72 hours (AUC0-72h ) and peak concentrations (Cmax ). Unpaired 2-sided t-tests of the log transformed pharmacokinetic parameters were performed to compare both groups. Twenty-four participants (12 per group) were included. Hydroxychloroquine AUC0-72h and Cmax did not differ between groups without and with pantoprazole (arithmetic mean; AUC0-72h , 7649 ng/ml • h, and 8429 ng/ml • h, P = .50; Cmax , 448 ng/mL and 451.5 ng/mL, P = .96, respectively). Pantoprazole did not alter hydroxychloroquine absorption, indicating that proton pump inhibitors do not affect its bioavailability.

Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial.

BACKGROUND: Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo-controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting. FINDINGS: Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0·043); the result was similar when the model was stratified by diagnostic group (p=0·042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint. The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1·69 FVC % predicted (95% CI -0·65 to 4·03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3·53 FVC % predicted (95% CI 0·21 to 6·86) with imputation of deaths as prespecified, or 2·79 FVC % predicted (95% CI 0·03 to 5·54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed. INTERPRETATION: In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC. FUNDING: German Center for Lung Research, Roche Pharma.

Comprehensive serial biobanking in advanced NSCLC: feasibility, challenges and perspectives.

BACKGROUND: Availability of tumor material at baseline and disease progression is increasingly important for patient management in non-small-cell lung cancer (NSCLC), especially for the application of targeted therapies like tyrosine kinase inhibitors and for immune checkpoint inhibitor treatment. Here we report the experience of prospective biomaterial acquisition in advanced NSCLC from a pilot project. METHODS: Main objective was the longitudinal collection of high-quality, cryoconserved biopsies in addition to formalin-fixed paraffin-embedded (FFPE) biopsies required for routine diagnostics, along with blood samples and detailed clinical annotation using standardized questionnaires. RESULTS: Over five years, 205 patients were enrolled for the project, yielding 387 cryoconserved biopsies and 1,098 serum, plasma and buffy-coat samples. The feasibility of obtaining the cryoconserved biopsies in addition to the FFPE biopsies was 89% for newly diagnosed cases, but dropped down to 56% and 47% at first and second disease progression, respectively. While forceps biopsy was the preferred procedure for tissue acquisition, the highest tissue amounts were received using the cryobiopsy method. Biopsies had a median tumor cellularity of 34% and yielded in median 13.6 µg DNA and 12 µg RNA (median RIN =8). During the five-year project, a maximum of 38 follow-up blood samples per patient were assembled in up to four therapy lines. CONCLUSIONS: Despite the poor condition and limited prognosis of most NSCLC patients, this serial biomaterial acquisition including routine collection of cryoconserved biopsies is feasible to support individualized management. The standardized collection of high-quality material has enabled and enriched several translational research studies that can advance therapeutic options.

Impact of pantoprazole on absorption and disposition of hydroxychloroquine, a drug used in Corona Virus Disease-19 (Covid-19): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Primary objective: Evaluation of the effect of the proton pump inhibitor (PPI) pantoprazole on the absorption of hydroxychloroquine (HCQ). Secondary objectives: • Evaluation of the relationship between HCQ concentrations in whole blood, plasma and intracellular concentrations in target cells - peripheral blood mononuclear cells (PBMCs). • Evaluation of HCQ as a potential perpetrator in drug-drug interactions at the level of cytochrome P450 (CYP) 3A4 and CYP2D6 (major drug metabolizing enzymes). TRIAL DESIGN: Single centre, open-label, parallel group, two-arm, phase I drug-drug interaction trial. PARTICIPANTS: Healthy volunteers (18-60 years old) are treated in the Clinical Pharmacological Trial Center of Heidelberg University Hospital, Germany. INTERVENTION AND COMPARATOR: • Participants are randomized in a group to either receive a nine-day course of pantoprazole, or to a control group without pantoprazole. All participants receive a single dose of HCQ 400 mg. • Additionally, CYP3A4 and CYP2D6 phenotyping with microdosed probe drugs is performed using midazolam and yohimbine as enzyme activity markers, respectively. MAIN OUTCOMES: Primary endpoint: Area under the curve (AUC)0-72 h and maximum concentration (Cmax) of a single oral dose of 400 mg HCQ with and without pantoprazole (changes in these two values describe relevant aspects of exposure to HCQ with and without administration of pantoprazole). Secondary endpoints: • AUC2-4 h, AUC0-6 h and Cmax of midazolam and yohimbine. • Correlation of HCQ concentrations in whole blood with concentrations in plasma and peripheral blood mononuclear cells (PBMC). RANDOMISATION: Participants are assigned to treatment groups by using a randomisation list (1:1, block size = 4) and consecutive enrolment. BLINDING (MASKING): The trial is an open-label trial, participants and investigators are not blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total number of 24 participants (12 per group) are planned to be randomised. TRIAL STATUS: Protocol version 2.1 dated 24/04/2020, first patient first visit. April 30th, 2020, recruitment ongoing, anticipated end of study June 30th, 2020. TRIAL REGISTRATION: EudraCT Number: 2020-001470-30 , registered on 31 March 2020 German Clinical trials register number / International Clinical Trials Registry Platform: DRKS00021573, registered on 27 April 2020 FULL PROTOCOL: The full trial protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full trial protocol. The trial protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Exercise behavior and physical fitness in patients with advanced lung cancer.

PURPOSE: The aim of this work was to evaluate exercise behavior and physical fitness of advanced lung cancer patients shortly after primary diagnosis. METHODS: Between November 2013 and December 2016, advanced lung cancer patients (n = 227, mean age 62.2 years) were enrolled shortly after diagnosis and 211 patients were tested for endurance capacity (six-minute walk test) and strength performance (maximum voluntary isometric contraction of upper and lower extremities). Current and previous exercise and walking behavior were assessed using a self-reported questionnaire regarding type, frequency, intensity, and duration. Paired Student's t tests were used to compare physical fitness to reference data. The relation of potential determinants with physical fitness was assessed using linear regression analysis. RESULTS: Exercise behavior was superior in the year before diagnosis compared to the time of study enrollment. Patients reduced frequency, intensity, and duration of sports/exercise after their lung cancer diagnosis. We observed significantly lower endurance capacity (p < .01) and strength performance in lower extremities (p < .01) in male and female patients compared to age and sex-matched reference data. We found significant correlations of previous exercise and walking behavior with physical fitness shortly after diagnosis in patients with advanced lung cancer. CONCLUSION: Patients with advanced lung cancer showed impaired physical fitness regarding endurance and strength capacity. The strong decline in participation of sports/exercise shortly after diagnosis supports early implementation of physical exercise during anti-cancer treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02055508.

Prognosis and longitudinal changes of physical activity in idiopathic pulmonary fibrosis.

BACKGROUND: Physical activity (PA) is associated with disease severity in idiopathic pulmonary fibrosis (IPF), but longitudinal studies evaluating its prognostic value and changes over time are lacking. METHODS: We measured PA (steps per day, SPD) in a cohort of 46 IPF-patients (mean age, 67 years; mean FVC, 76.1%pred.) by accelerometry at baseline, recorded survival status during 3 years follow-up and repeated measurements in survivors. We compared the prognostic value of PA to established mortality predictors including lung function (FVC, DLCO) and 6-min walking-distance (6MWD). RESULTS: During follow-up (median 34 months) 20 patients (43%) died. SPD and FVC best identified non-survivors (AUROC-curve 0.79, p < 0.01). After adjustment for confounders (sex, age, therapy), a standardized increase (i.e. one SD) in SPD, FVC%pred. or DLCO%pred. was associated with a more than halved risk of death (HR < 0.50; p < 0.01). Compared to baseline, SPD, FVC, and 6MWD annually declined in survivors by 973 SPD, 130 ml and 9 m, resulting in relative declines of 48.3% (p < 0.001), 13.3% (p < 0.001) and 7.8% (p = 0.055), respectively. CONCLUSION: While PA predicts mortality of IPF patients similar to established functional measures, longitudinal decline of PA seems to be disproportionally large. Our data suggest that the clinical impact of disease progression could be underestimated by established functional measures.

What patients with pulmonary fibrosis and their partners think: a live, educative survey in the Netherlands and Germany.

Pulmonary fibrosis greatly impacts patients and their partners. Unmet needs of patients are increasingly acknowledged; the needs of partners often remain unnoticed. Little is known about the best way to educate patients and partners. We investigated pulmonary fibrosis patients' and partners' perspectives and preferences in care, and the differences in these between the Netherlands and Germany. Additionally, we evaluated whether interactive interviewing could be a novel education method in this population. Patients and partners were interviewed during pulmonary fibrosis patient information meetings. In the Netherlands, voting boxes were used and results were projected directly. In Germany, questionnaires were used. In the Netherlands, 278 patients and partners participated; in Germany, 51. Many participants experienced anxiety. Almost all experienced misunderstanding, because people do not know what pulmonary fibrosis is. All expressed a need for information, psychological support and care for partners. Use of the interactive voting system was found to be pleasant (70%) and informative (94%). This study improves the knowledge of care needs of patients with pulmonary fibrosis and their partners. There were no major differences between the Netherlands and Germany. Interactive interviewing could be an attractive method to acquire insights into the needs and preferences of patients and partners, while providing them with information at the same time.

Prognostic Impact of CT-Quantified Muscle and Fat Distribution before and after First-Line-Chemotherapy in Lung Cancer Patients.

INTRODUCTION: Cachexia and sarcopenia are associated with poor outcome and increased chemotherapy-induced toxicity in lung cancer patients. However, the complex interplay of obesity, sarcopenia and cachexia, and its impact on survival in the context of first-line-chemotherapy is not yet understood. METHODS: In 200 consecutively recruited lung cancer patients (70 female, mean age 62y; mean BMI 25 kg/m2; median follow-up 15.97 months) with routine staging-CT before and after chemotherapy (CTX, mean interval: 4.3 months), densitometric quantification of total (TFA), visceral (VFA), and subcutaneous-fat-area (SFA), inter-muscular-fat-area (IMFA), muscle-density (MD), muscle-area (MA) and skeletal-muscle-index (SMI) was performed retrospectively to evaluate changes under chemotherapy and the impact on survival. RESULTS: We observed increases in TFA, VFA, SFA, VFA/SFA, and IMFA (p<0.05-0.001), while there were decreases in MA, MD and BMI (p<0.05-0.001) after chemotherapy. High pre-therapeutic VFA/SFA was a predictive factor for poor survival (HR = 1.272; p = 0.008), high pre-therapeutic MD for improved survival (HR = 0.93; p<0.05). Decrease in BMI (HR = 1.303; p<0.001), weight (HR = 1.067; p<0.001) and SMI (HR = 1.063; p<0.001) after chemotherapy were associated with poor survival. Patients with ≥4 CTX-cycles showed increased survival (17.6 vs. 9.1months), less muscle depletion (SMIdifference: p<0.05) and no BMI loss (BMIdifference: p<0.001). CONCLUSIONS: After chemotherapy, patients exhibited sarcopenia with decreased muscle and increased adipose tissue compartments, which was not adequately mirrored by BMI and weight loss but by imaging. Particularly sarcopenic patients received less CTX-cycles and had poorer survival. As loss of BMI, weight and muscle were associated with poor survival, early detection (via imaging) and prevention (via physical exercise and nutrition) of sarcopenia may potentially improve outcome and reduce chemotherapy-induced toxicity.

POSITIVE study: physical exercise program in non-operable lung cancer patients undergoing palliative treatment.

BACKGROUND: Patients with advanced stage non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) often experience multidimensional impairments, affecting quality of life during their course of disease. In lung cancer patients with operable disease, several studies have shown that exercise has a positive impact on quality of life and physical functioning. There is limited evidence regarding efficacy for advanced lung cancer patients undergoing palliative treatment. Therefore, the POSITIVE study aims to evaluate the benefit of a 24-week exercise intervention during palliative treatment in a randomized controlled setting. METHODS/DESIGN: The POSITIVE study is a randomized, controlled trial investigating the effects of a 24-week exercise intervention during palliative treatment on quality of life, physical performance and immune function in advanced, non-operable lung cancer patients. 250 patients will be recruited in the Clinic for Thoracic Diseases in Heidelberg, enrolment begun in November 2013. Main inclusion criterion is histologically confirmed NSCLC (stage IIIa, IIIb, IV) or SCLC (Limited Disease-SCLC, Extensive Disease-SCLC) not amenable to surgery. Patients are randomized into two groups. Both groups receive weekly care management phone calls (CMPCs) with the goal to assess symptoms and side effects. Additionally, one group receives a combined resistance and endurance training (3x/week). Primary endpoints are quality of life assessed by the Functional Assessment of Cancer Therapy for patients with lung cancer (FACT-L, subcategory Physical Well-Being) and General Fatigue measured by the Multidimensional Fatigue Inventory (MFI-20). Secondary endpoints are physical performance (maximal voluntary isometric contraction, 6-min walk distance), psychosocial (depression and anxiety) and immunological parameters and overall survival. DISCUSSION: The aim of the POSITIVE trial is the evaluation of effects of a 24-week structured and guided exercise intervention during palliative treatment stages. Analysis of various outcomes (such as quality of life, physical performance, self-efficacy, psychosocial and immunological parameters) will contribute to a better understanding of the potential of exercise in advanced lung cancer patients. In contrast to other studies with advanced oncological patients the POSITIVE trial provides weekly phone calls to support patients both in the intervention and control group and to segregate the impact of physical activity on quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT02055508 (Date: December 12, 2013).

Clinical Correlates of Reduced Physical Activity in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Little is known about the consequences of idiopathic pulmonary fibrosis (IPF) for physical activity (PA). OBJECTIVES: We aimed to investigate levels of PA in IPF and to study associations of PA with lung function, exercise capacity, symptoms, and quality of life. METHODS: In stable patients with IPF we measured PA (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) by accelerometry (SenseWear Armband) for 1 week. We also assessed lung function (forced vital capacity, FVC; diffusing capacity for carbon monoxide, DLCO); exercise capacity (6-minute walking distance, 6MWD); dyspnea (modified Medical Research Council, mMRC); fatigue (Multidimensional Fatigue Inventory, MFI-20), and generic (12-Item Short Form Survey, SF-12) and health-related quality of life (St. George's Respiratory Questionnaire) as further clinical variables. RESULTS: We investigated 48 patients with IPF in two centers (mean age, 67 years; 75% male; 23% on long-term oxygen therapy; mean FVC 75%pred.; mean DLCO 43%pred.; mean 6MWD 355 ± 140 m; mean SPD 5,017 ± 3,360). On a bivariate level, all clinical variables were significantly associated with SPD (p < 0.05). The associations of mMRC, MFI-20, SF-12 (physical health), and 6MWD with SPD were independent of impaired lung function (p < 0.05). At multivariate analyses, either 6MWD (total explained variance of the model, total R2: 42%) or MFI-20 (total R2: 39%) were the strongest independent predictors of SPD. CONCLUSION: Fatigue and exercise capacity are strong and independent predictors of PA in patients with IPF, which suggests that both measures should be assessed when the consequences of IPF for PA in daily life are studied.

Physical performance and psychosocial status in lung cancer patients: results from a pilot study.

BACKGROUND: The aim of this study was to assess the physical performance and psychosocial status of lung cancer patients. PATIENTS AND METHODS: Patients with predominantly advanced-stage non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) were recruited. Muscle strength was assessed via hand-held dynamometry (HHD) and endurance capacity via the 6-minute walk test (6MWT), and results were compared to healthy reference values. Psychosocial status, lung cancer-specific symptoms, and quality of life (QoL) outcomes were evaluated. RESULTS: 39 patients (NSCLC n = 22, SCLC n = 17) with predominantly advanced-stage disease and a median age of 62 years (range 44-83 years) were enrolled. Compared to a healthy reference population, mean muscle strength values of upper (elbow flexion -28.2% (±17.5), elbow extension -12.4% (±11.1)) and lower (knee extension -47.6% (±19.3), hip abduction -44.9% (±14.9), hip flexion -13% (±24.2)) extremities, and 6MWT were lower (male/female: 434/411 m vs. 597/514 m). Lung cancer-specific symptoms and QoL were comparable to published data. CONCLUSION: Our results indicate that lung cancer patients experience muscular weakness, lower endurance performance, and decreased QoL compared to a healthy reference population. The feasibility and benefit of a structured exercise intervention in this specific population need to be evaluated, in particular its effect on psychosocial well-being.

Exercise in patients with non-small cell lung cancer.

PURPOSE: This study aimed to evaluate the safety, feasibility, and effects of an 8-wk combined resistance and endurance exercise program in patients with advanced non-small cell lung cancer (NSCLC) during in- and outpatient care. METHODS: In this intervention study, 40 patients with predominantly advanced NSCLC receiving simultaneous or sequential radiochemotherapy or chemotherapy alone were enrolled. For a period of 8 wk, patients were instructed to exercise at least five times per week during the inpatient setting and at least three times per week in the outpatient setting. Physical performance status (endurance capacity: 6-min walk test; strength capacity: handheld dynamometry), quality-of-life (Functional Assessment of Cancer Therapy-Lung), fatigue (Multidimensional Fatigue Inventory), and depression (Patient Health Questionnaire) were assessed at baseline (T0), after the exercise intervention (T1), and at a follow-up time point 8 wk later (T2). The primary end point was adequate adherence (feasibility) defined as completing at least two training sessions per week during a minimum of 6 wk. RESULTS: Of 40 patients, 31 (77.5%) completed the postexercise assessment (T1) and 22 (55%) completed follow-up (T2). The stages were IIA (5%), IIIA (8%), IIIB (20%), and IV (67%), and the median age was 63 yr (range = 22-75 yr). Overall, adherence was 82% for those patients who completed T1, and 55% of the 40 participating patients fulfilled the adequate adherence criterion. Those who completed the intervention showed a significant improvement in the 6-min walk distance and in knee, elbow, and hip muscle strength after the intervention (T1). Quality of life, fatigue, and depression scores remained stable or declined slightly. Significant improvements in knee-muscle strength were also observed at T2. CONCLUSIONS: Exercise training is feasible in advanced and metastatic NSCLC patients during anticancer treatment. In this pilot study, endurance and strength capacity improved over time, indicating the rehabilitative importance of the applied intervention. To investigate the potential impact of exercise training in this patient group, a larger randomized trial is warranted.

Impact of genetic polymorphisms on adenoma recurrence and toxicity in a COX2 inhibitor (celecoxib) trial: results from a pilot study.

OBJECTIVE: Chemoprevention trials have shown that celecoxib reduces adenoma recurrence but can cause cardiovascular toxicity. In this pilot study, we evaluated associations between genetic variation in several candidate pathways (e.g. prostaglandin synthesis) and adenoma recurrence and cardiovascular and gastrointestinal toxicities. METHODS: Genotyping analysis was carried out on 117 Israeli colorectal adenoma patients who participated in the Prevention of Colorectal Sporadic Adenomatous Polyps trial. Reassessment followed after 3 years on celecoxib and after 2 years from termination of treatment with celecoxib. Efficacy (absence of colorectal adenomas) was measured by colonoscopy at years 1, 3, and 5. Toxicities were assessed by investigators during celecoxib treatment and by self-report post-treatment. A linkage disequilibrium-based selection algorithm (r2≥0.90, MAF≥4%) identified 255 tagSNPs in 25 analyzed candidate genes. Genotyping was performed by using Illumina GoldenGate technology. RESULTS: Multiple genetic variants were associated with adenoma recurrence and toxicity. Genetic variability in COX1, COX2, and ALOX12/15 genes played a role in adenoma recurrence, particularly among patients on placebo. More gene variants (especially variants in PGES, CRP, SRC, and GPX3) were associated with increased risk for cardiovascular toxicity and symptoms, compared with gastrointestinal toxicity and symptoms. The increased risk for cardiovascular toxicity/symptoms associated with the SRC gene variants (rs6017996, rs6018256, rs6018257) ranged from 6.61 (95% confidence interval 1.66-26.36, P<0.01) to 10.71 (95% confidence interval 1.96-58.60, P<0.01). CONCLUSION: Genetic polymorphisms in multiple inflammation-related genes appear to interact with celecoxib on adenoma recurrence and its attendant toxicity, particularly cardiovascular toxicity/symptoms. Larger studies validating these pharmacogenetic relationships are needed.

Topotecan/cisplatin compared with cisplatin/etoposide as first-line treatment for patients with extensive disease small-cell lung cancer: final results of a randomized phase III trial.

INTRODUCTION: This phase III study compared efficacy and safety of topotecan-cisplatin (TP) versus topotecan-etoposide (TE) versus cisplatin-etoposide (PE) in chemo-naïve extensive disease small-cell lung cancer patients. METHODS: Seven hundred and ninety-five previously untreated patients were randomly assigned to TP (topotecan 1mg/m IV, d1-5; cisplatin 75 mg/m IV, d5; n = 358), PE (cisplatin 75 mg/m IV, d1; etoposide 100 mg/m IV, d1-3; n = 345) or TE (topotecan 1mg/m IV, d1-5; etoposide 80 mg/m IV, d3-5; n = 92). Primary endpoint was superiority of TP compared with PE, with the possibility to switch to a noninferiority test. RESULTS: The TE arm was closed after recommendations by the Independent Data Safety Monitoring Board. Median survival was similar and met the predefined endpoint of noninferiority of TP to PE (44.9 versus 40.9 weeks; p = 0.40). One-year survival rate showed 39.7% for TP versus 36.1% for PE (p = 0.29). Median time to progression was significantly longer with TP (27.4 versus 24.3 weeks, p = 0.01). Overall response rates were significantly higher for TP (55.5% versus 45.5%, p = 0.01).Hematologic toxicity was slightly higher for TP regarding G 3/4 neutropenia (35.7/35.8%), G 3/4 thrombocytopenia (18.7/4.8%), G 3/4 anemia (11.6/6.7%), febrile neutropenia (2.0/2.7%), sepsis (1.7/1.2%), and toxicity-related deaths (5.2/2.7%). CONCLUSION: TP is noninferior to PE in overall survival and superior in time to progression and overall response rates. Because of slightly worse toxicity profile TP is not a first-line standard treatment for patients with extensive disease small-cell lung cancer.

Advances in ITP--therapy and quality of life--a patient survey.

BACKGROUND: Current guidelines recommend glucocorticoids and splenectomy as standard 1(st) and 2(nd) line treatments for chronic immune thrombocytopenia (ITP). We sought to find out how German ITP-patients are treated with respect to these guidelines. METHODS: Members of a patient support association ≥18 years with a self-reported history of chronic ITP>12 months were surveyed with a web-based questionnaire. RESULTS: 122 questionnaires were evaluated. 70% of patients had chronic ITP for more than 5 years and 20% an average platelet count of ≤30·10(9)/L. 41% of the patients reported haematomas or petechiae more than once or twice and up to 12 times or more per year and 17% oropharyngeal and nasal bleeds. 11% had been admitted to hospital during the last 12 months. 88% had received or currently receive glucocorticoids, 27% were splenectomised. IVIG had been given to 55%, rituximab to 22%, anti-D to 12%, ciclosporin to 7%, while complementary and alternative medical treatments had been used by 36%. 50 women responded to questions concerning pregnancy. 14 (28%) had been advised not to become pregnant. 23 reported pregnancies and 10 (44%) required treatment for their ITP during pregnancy. CONCLUSION: Glucocorticoids are the most common therapy for chronic ITP but complementary and alternative treatments already come second and less than ⅓ of patients are splenectomised. This and the frequent use of complementary medicines suggests patients' dissatisfaction with conventional approaches. Many patients receive off-label therapies. There is a major need for adequate counselling and care for pregnant ITP-patients.