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The Cochrane Database of Systematic... Nov 2018Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane Review.
OBJECTIVES
To determine whether the timing of dornase alfa inhalation (in relation to airway clearance techniques or morning versus evening inhalation) has an impact on objective and subjective measures of clinical efficacy in people with cystic fibrosis.
SEARCH METHODS
Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, Physiotherapy Evidence Database (PEDro), clinical trial registries and international cystic fibrosis conference proceedings.Date of the most recent search: 06 June 2018.
SELECTION CRITERIA
Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the trial with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation.
DATA COLLECTION AND ANALYSIS
Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed.
MAIN RESULTS
We identified 115 trial reports representing 55 trials, of which five trials (providing data on 122 participants) met our inclusion criteria. All five trials used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials (98 participants) compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change forced expiratory volume at one second (very-low quality evidence). Similarly, forced vital capacity (low-quality evidence) and quality of life (very-low quality evidence) were not significantly affected; forced expiratory flow at 25% was significantly worse with dornase alfa inhalation after airway clearance, mean difference -0.17 litres (95% confidence interval -0.28 to -0.05), based on the pooled data from two small trials in children (7 to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant.In one trial (25 participants), morning versus evening inhalation had no impact on lung function or symptoms (low-quality evidence).
AUTHORS' CONCLUSIONS
The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and trials with variable follow-up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alfa inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted.
Topics: Administration, Inhalation; Adolescent; Child; Combined Modality Therapy; Cystic Fibrosis; Deoxyribonuclease I; Drug Administration Schedule; Humans; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Respiratory Therapy; Time Factors; Young Adult
PubMed: 30480755
DOI: 10.1002/14651858.CD007923.pub5 -
The Cochrane Database of Systematic... Sep 2018Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline enhances mucociliary clearance and may lessen the destructive... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review.
OBJECTIVES
To investigate efficacy and tolerability of treatment with nebulised hypertonic saline on people with CF compared to placebo and or other treatments that enhance mucociliary clearance.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also searched ongoing trials databases.Date of most recent searches: 08 August 2018.
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity).
DATA COLLECTION AND ANALYSIS
Two authors independently reviewed all identified trials and data, and assessed trial quality. The quality of the evidence was assessed using GRADE.
MAIN RESULTS
A total of 17 trials (966 participants, aged 4 months to 63 years) were included; 19 trials were excluded, three trials are ongoing and 16 are awaiting classification. We judged 14 of the 17 included trials to have a high risk of bias due to participants ability to discern the taste of the solutions.Hypertonic saline 3% to 7% versus placeboAt four weeks, we found very low-quality evidence from three placebo-controlled trials (n = 225) that hypertonic saline (3% to 7%, 10 mL twice-daily) increased the mean change from baseline of the forced expiratory volume at one second (FEV) (% predicted) by 3.44% (95% confidence interval (CI) 0.67 to 6.21), but there was no difference between groups in lung clearance index in one small trial (n = 10). By 48 weeks the effect was slightly smaller in one trial (n = 134), 2.31% (95% CI -2.72 to 7.34) (low-quality evidence). No deaths occurred in the trials. Two trials reporting data on exacerbations were not combined as the age difference between the participants in the trials was too great. One trial (162 adults) found 0.5 fewer exacerbations requiring antibiotics per person in the hypertonic saline group; the second trial (243 children, average age of two years) found no difference between groups (low-quality evidence). There was insufficient evidence reported across the trials to determine the rate of different adverse events such as cough, chest tightness, tonsillitis and vomiting (very low-quality evidence). Four trials (n = 80) found very low-quality evidence that sputum clearance was better with hypertonic saline.A further trial was performed in adults with an acute exacerbation of lung disease (n = 132). The effects of hypertonic saline on short-term lung function, 5.10% higher (14.67% lower to 24.87% higher) and the time to the subsequent exacerbation post-discharge, hazard ratio 0.86 (95% CI 0.57 to 1.30) are uncertain (low-quality evidence). No deaths were reported. Cough and wheeze were reported but no serious adverse events (very low-quality evidence).Hypertonic saline versus mucus mobilising treatments Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two (61 participants) provided data for inclusion in the review. There was insufficient evidence from one three-week trial (14 participants) to determine the effects of hypertonic saline on FEV % predicted, mean difference (MD) 1.60% (95% CI -7.96 to 11.16) (very low-quality evidence). In the second trial, rhDNase led to a greater increase in FEV % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease, MD 8.00% (95% CI 2.00 to 14.00) (low-quality evidence). One cross-over trial (47 participants) reported 15 exacerbations during treatment with hypertonic saline and 18 exacerbations in the rhDNase group (low-quality evidence). Increased cough was reported in 13 participants using hypertonic saline and 17 on daily rhDNase in one cross-over trial of 47 people (low-quality evidence). There was insufficient evidence to assess rates of other adverse events reported. No deaths were reported.One trial (12 participants) compared hypertonic saline to amiloride and one (29 participants) to sodium-2-mercaptoethane sulphonate. Neither trial found a difference between treatments in any measures of sputum clearance; additionally the comparison of hypertonic saline and sodium-2-mercaptoethane sulphonate reported no differences in courses of antibiotics or adverse events (very low-quality evidence).One trial (12 participants) compared hypertonic saline to mannitol but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low-quality evidence).
AUTHORS' CONCLUSIONS
Regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (very low-quality evidence from three trials), but this was not sustained at 48 weeks (low-quality evidence from one trial). The review did show that nebulised hypertonic saline reduced the frequency of pulmonary exacerbations (although we found insufficient evidence for this outcome in children under six years of age) and may have a small effect on improvement in quality of life in adults.Evidence from one small cross-over trial in children indicates that rhDNase may lead to better lung function at three months; qualifying this we highlight that while the study did demonstrate that the improvement in FEV was greater with daily rHDNase, there were no differences seen in any of the secondary outcomes.Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the quality of the evidence ranged from very low to at best moderate, according to the GRADE criteria.
Topics: Administration, Inhalation; Controlled Clinical Trials as Topic; Cystic Fibrosis; Forced Expiratory Volume; Humans; Mucociliary Clearance; Nebulizers and Vaporizers; Randomized Controlled Trials as Topic; Saline Solution, Hypertonic
PubMed: 30260472
DOI: 10.1002/14651858.CD001506.pub4 -
The Cochrane Database of Systematic... Sep 2018Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in the lungs, promoting improved clearance of secretions. This is an update of a previously published review.
OBJECTIVES
To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other medications that improve airway clearance, and to identify any adverse events associated with its use.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences. Date of the most recent search of the Group's Cystic Fibrosis Register: 23 April 2018.Clinicaltrials.gov and the International Clinical Trials Registry Platform were also searched to identify unpublished or ongoing trials. Date of most recent search: 07 June 2018.
SELECTION CRITERIA
All randomised and quasi-randomised controlled trials comparing dornase alfa to placebo, standard therapy or other medications that improve airway clearance.
DATA COLLECTION AND ANALYSIS
Authors independently assessed trials against the inclusion criteria; two authors carried out analysis of methodological quality and data extraction. GRADE was used to assess the level of evidence.
MAIN RESULTS
The searches identified 69 trials, of which 19 (2565 participants) met our inclusion criteria. Fifteen trials compared dornase alfa to placebo or no dornase alfa (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa to hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years.Dornase alfa compared to placebo or no treatmentDornase alfa improved forced expiratory volume at one second at one month (four trials, 248 participants), three months (one trial, 320 participants; moderate-quality evidence), six months (one trial, 647 participants; high-quality evidence) and two years (one trial, 410 participants). Limited low-quality evidence showed no difference between groups for changes in quality of life. There was a decrease in pulmonary exacerbations with dornase alfa in trials of up to two years (moderate-quality evidence). One trial that examined the cost of care, including the cost of dornase alfa, found that the cost savings from dornase alfa offset 18% to 38% of the medication costs.Dornase alfa: daily versus alternate dayOne cross-over trial (43 children) found no differences between treatment regimens for lung function, quality of life or pulmonary exacerbations (low-quality evidence).Dornase alfa compared to other medications that improve airway clearanceResults for these comparisons were mixed. One trial (43 children) showed a greater improvement in forced expiratory volume at one second for dornase alfa compared to hypertonic saline (low-quality evidence), and one trial (23 participants) reported no difference in lung function between dornase alfa and mannitol or dornase alfa and dornase alfa plus mannitol (low-quality evidence). One trial (23 participants) found a difference in quality of life favouring dornase alfa when compared to dornase alfa plus mannitol (low-quality evidence); other comparisons found no difference in this outcome (low-quality evidence). No trials in any comparison reported any difference between groups in the number of pulmonary exacerbations (low-quality evidence).When all comparisons are assessed, dornase alfa did not cause significantly more adverse effects than other treatments, except voice alteration and rash.
AUTHORS' CONCLUSIONS
There is evidence to show that, compared with placebo, therapy with dornase alfa improves lung function in people with cystic fibrosis in trials lasting from one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to other hyperosmolar agents in improving lung function.
Topics: Adolescent; Child; Child, Preschool; Cystic Fibrosis; Deoxyribonuclease I; Expectorants; Forced Expiratory Volume; Humans; Infant; Mannitol; Randomized Controlled Trials as Topic; Recombinant Proteins; Saline Solution, Hypertonic; Vital Capacity
PubMed: 30187450
DOI: 10.1002/14651858.CD001127.pub4 -
The Cochrane Database of Systematic... Feb 2018Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action is unknown. The dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser. Phase III trials of inhaled dry powder mannitol for the treatment of cystic fibrosis have been completed and it is now available in Australia and some countries in Europe. This is an update of a previous review.
OBJECTIVES
To assess whether inhaled dry powder mannitol is well tolerated, whether it improves the quality of life and respiratory function in people with cystic fibrosis and which adverse events are associated with the treatment.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic databases, handsearching relevant journals and abstracts from conferences.Date of last search: 28 September 2017.
SELECTION CRITERIA
All randomised controlled studies comparing mannitol with placebo, active inhaled comparators (for example, hypertonic saline or dornase alfa) or with no treatment.
DATA COLLECTION AND ANALYSIS
Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias in included studies. The quality of the evidence was assessed using GRADE.
MAIN RESULTS
Six studies (reported in 50 publications) were included with a total of 784 participants.Duration of treatment in the included studies ranged from 12 days to six months, with open-label treatment for an additional six months in two of the studies. Five studies compared mannitol with control (a very low dose of mannitol or non-respirable mannitol) and the final study compared mannitol to dornase alfa alone and to mannitol plus dornase alfa. Two large studies had a similar parallel design and provided data for 600 participants, which could be pooled where data for a particular outcome and time point were available. The remaining studies had much smaller sample sizes (ranging from 22 to 95) and data could not be pooled due to differences in design, interventions and population.Pooled evidence from the two large parallel studies was judged to be of low to moderate quality and from the smaller studies was judged to be of low to very low quality. In all studies, there was an initial test to see if participants tolerated mannitol, with only those who could tolerate the drug being randomised; therefore, the study results are not applicable to the cystic fibrosis population as a whole.While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the drug's manufacturer and the author of one of the studies.Pooling the large parallel studies comparing mannitol to control, up to and including six months, lung function (forced expiratory volume at one second) measured in both mL and % predicted was significantly improved in the mannitol group compared to the control group (moderate-quality evidence). Beneficial results were observed in these studies in adults and in both concomitant dornase alfa users and non-users in these studies. In the smaller studies, statistically significant improvements in lung function were also observed in the mannitol groups compared to the non-respirable mannitol groups; however, we judged this evidence to be of low to very low quality.For the comparisons of mannitol and control, we found no consistent differences in health-related quality of life in any of the domains except for burden of treatment, which was less for mannitol up to four months in the two pooled studies of a similar design; this difference was not maintained at six months. It should be noted that the tool used to measure health-related quality of life was not designed to assess mucolytics and pooling of the age-appropriate tools (as done in some of the included studies) may not be valid so results were judged to be low to very low quality and should be interpreted with caution. Cough, haemoptysis, bronchospasm, pharyngolaryngeal pain and post-tussive vomiting were the most commonly reported side effects in both treatment groups. Where rates of adverse events could be compared, statistically no significant differences were found between mannitol and control groups; although some of these events may have clinical relevance for people with CF.For the comparisons of mannitol to dornase alfa alone and to mannitol plus dornase alfa, very low-quality evidence from a 12-week cross-over study of 28 participants showed no statistically significant differences in the recorded domains of health-related quality of life or measures of lung function. Cough was the most common side effect in the mannitol alone arm but there was no occurrence of cough in the dornase alfa alone arm and the most commonly reported reason of withdrawal from the mannitol plus dornase alfa arm was pulmonary exacerbations.In terms of secondary outcomes of the review (pulmonary exacerbations, hospitalisations, symptoms, sputum microbiology), evidence provided by the included studies was more limited. For all comparisons, no consistent statistically significant and clinically meaningful differences were observed between mannitol and control treatments (including dornase alfa).
AUTHORS' CONCLUSIONS
There is moderate-quality evidence to show that treatment with mannitol over a six-month period is associated with an improvement in some measures of lung function in people with cystic fibrosis compared to control. There is low to very low-quality evidence suggesting no difference in quality of life for participants taking mannitol compared to control. This review provides very low-quality evidence suggesting no difference in lung function or quality of life comparing mannitol to dornase alfa alone and to mannitol plus dornase alfa.The clinical implications from this review suggest that mannitol could be considered as a treatment in cystic fibrosis; but further research is required in order to establish who may benefit most and whether this benefit is sustained in the longer term. Furthermore, studies comparing its efficacy against other (established) mucolytic therapies need to be undertaken before it can be considered for mainstream practice.
Topics: Administration, Inhalation; Adult; Child; Cystic Fibrosis; Deoxyribonuclease I; Humans; Mannitol; Mucociliary Clearance; Powders; Randomized Controlled Trials as Topic; Recombinant Proteins; Respiratory Function Tests
PubMed: 29424930
DOI: 10.1002/14651858.CD008649.pub3 -
Scientific Reports Jan 2018Results on the relationships between vitamin D receptor (VDR) gene polymorphisms and postmenopausal osteoporosis (PMOP) susceptibility and bone mineral density (BMD) are... (Meta-Analysis)
Meta-Analysis Review
Results on the relationships between vitamin D receptor (VDR) gene polymorphisms and postmenopausal osteoporosis (PMOP) susceptibility and bone mineral density (BMD) are conflicting. The aim of the study is to identify more eligible studies that calculated pooled OR and WMD with 95% CI to assess their associations. Overall, there were significant correlations between VDR ApaI, VDR FokI and PMOP susceptibility. Subgroup analysis showed that VDR ApaI polymorphism significantly decreased the osteoporosis risk in Caucasian postmenopausal women. In Asian populations, VDR BsmI and VDR FokI were associated with an increased risk of PMOP. As to the associations between VDR polymorphisms and BMD, Caucasian PMOP women carrying the ApaI aa genotype were at risk of high BMD in femoral neck, and low femoral neck BMD was observed in Caucasian PMOP women with FokI Ff genotype. PMOP women with the Cdx2 GA genotype had a lower lumbar spine BMD in overall and Caucasian populations compared with PMOP women with GG genotype. Different VDR gene polymorphisms have different impacts on PMOP risk and BMD.
Topics: Asian People; Bone Density; Bone and Bones; Deoxyribonucleases, Type II Site-Specific; Female; Gene Expression; Genetic Predisposition to Disease; Humans; Middle Aged; Osteoporosis, Postmenopausal; Polymorphism, Restriction Fragment Length; Postmenopause; Receptors, Calcitriol; White People
PubMed: 29343720
DOI: 10.1038/s41598-017-18670-7 -
Tumour Biology : the Journal of the... Oct 2017The purpose of this systemic review and meta-analysis was to examine the relationship between VDR gene polymorphisms and breast cancer. Literature was searched through... (Meta-Analysis)
Meta-Analysis Review
The purpose of this systemic review and meta-analysis was to examine the relationship between VDR gene polymorphisms and breast cancer. Literature was searched through PubMed database, Google scholar, and the web of knowledge from December 2015 to January 2017 and consists of 34 studies (26,372 cases and 32,883 controls). All statistical measures were done using STATA version 11.2. The heterogeneity among studies was tested using I statistics. Mantel-Haenszel method and DerSimonian-Laird method were used to combine data from studies using both random-effect model and fixed-effect model, respectively. Potential publication bias was evaluated by Egger's test. Sensitivity analysis was also performed to evaluate the quality and consistency in results. The results of this meta-analysis revealed that VDR gene polymorphisms (Bsm1 bb vs BB; SOR = 1.18, 95% CI = 1.054-1.322, Apa1 aa vs AA; SOR = 1.18, 95% CI = 0.87-1.59, Poly (A) LL vs SS; SOR = 1.41, 95% CI = 1.06-1.88, Fok1 ff + Ff vs FF; SOR = 1.25, 95% CI = 0.896-1.759, Apa1 aa+Aa vs AA; SOR = 1.13, 95% CI = 0.95-1.35, Poly (A) LL + LS vs SS; SOR = 1.19, 95% CI = 1.00-1.43, Poly (A) L vs S; SOR = 1.18, 95% CI = 1.03-1.35) are associated with the breast cancer. Cdx2, Bgl1, and Taq1 do not show association with breast cancer. Thus, the finding of this meta-analysis concluded that VDR Bsm1, Apa1, Fok1, and Poly (A) gene polymorphisms may be susceptible for breast cancer development.
Topics: Breast Neoplasms; DNA Restriction Enzymes; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Polymorphism, Genetic; Receptors, Calcitriol
PubMed: 29072133
DOI: 10.1177/1010428317731280 -
Respirology (Carlton, Vic.) Aug 2017Inhaled mucoactive agents are used in respiratory disease to improve mucus properties and enhance secretion clearance. The effect of mannitol, recombinant human... (Meta-Analysis)
Meta-Analysis Review
Inhaled mucoactive agents are used in respiratory disease to improve mucus properties and enhance secretion clearance. The effect of mannitol, recombinant human deoxyribonuclease/dornase alfa (rhDNase) and hypertonic saline (HS) or normal saline (NS) are not well described in chronic lung conditions other than cystic fibrosis (CF). The aim of this review was to determine the benefit and safety of inhaled mucoactive agents outside of CF. We searched Medline, Embase, CINAHL and CENTRAL for randomized controlled trials investigating the effects of mucoactive agents on lung function, adverse events (AEs), health-related quality of life (HRQOL), hospitalization, length of stay, exacerbations, sputum clearance and inflammation. There were detrimental effects of rhDNase in bronchiectasis, with average declines of 1.9-4.3% in forced expiratory volume in 1 s (FEV ) and 3.7-5.4% in forced vital capacity (FVC) (n = 410, two studies), and increased exacerbation risk (relative risk = 1.35, 95% CI = 1.01-1.79 n = 349, one study). Some participants exhibited a reduction in FEV (≥10-15%) with mucoactive agents on screening (mannitol = 158 of 1051 participants, rhDNase = 2 of 30, HS = 3 of 80). Most AEs were mild and transient, including bronchospasm, cough and breathlessness. NS eased symptomatic burden in COPD, while NS and HS improved spirometry, HRQOL and sputum burden in non-CF bronchiectasis. Mannitol improved mucociliary clearance in asthma and bronchiectasis, while the effects of N-acetylcysteine were unclear. In chronic lung diseases outside CF, there are small benefits of mannitol, NS and HS. Adverse effects of rhDNase suggest this should not be administered in non-CF bronchiectasis.
Topics: Acetylcysteine; Administration, Inhalation; Bronchiectasis; Chronic Disease; Deoxyribonuclease I; Expectorants; Forced Expiratory Volume; Humans; Lung Diseases; Mannitol; Mesna; Mucociliary Clearance; Quality of Life; Recombinant Proteins; Saline Solution, Hypertonic; Symptom Flare Up; Vital Capacity
PubMed: 28397992
DOI: 10.1111/resp.13047 -
Gastroenterology Jan 2017High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1,... (Review)
Review
High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene. We found sufficient evidence for NTHL1 to be considered a CRC predisposition gene-members of 3 unrelated Dutch families were homozygous for inactivating p.Gln90Ter mutations; a Canadian woman with polyposis, CRC, and multiple tumors was reported to be heterozygous for the inactivating NTHL1 p.Gln90Ter/c.709+1G>A mutations; and a man with polyposis was reported to carry p.Gln90Ter/p.Gln287Ter; whereas no inactivating homozygous or compound heterozygous mutations were detected in controls. Variants that disrupted RPS20 were detected in a Finnish family with early-onset CRC (p.Val50SerfsTer23), a 39-year old individual with metachronous CRC (p.Leu61GlufsTer11 mutation), and a 41-year-old individual with CRC (missense p.Val54Leu), but not in controls. We therefore found published evidence to support the association between variants in NTHL1 and RPS20 with CRC, but not of other recently reported CRC susceptibility variants. We urge the research community to adopt rigorous statistical and biological approaches coupled with independent replication before making claims of pathogenicity.
Topics: Adenomatous Polyposis Coli; Colorectal Neoplasms; Deoxyribonuclease (Pyrimidine Dimer); Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Ribosomal Proteins
PubMed: 27713038
DOI: 10.1053/j.gastro.2016.09.041 -
The Cochrane Database of Systematic... Jul 2016Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane review.
OBJECTIVES
To determine the effect of timing of dornase alfa inhalation on measures of clinical efficacy in people with cystic fibrosis (in relation to airway clearance techniques or time of day).
SEARCH METHODS
Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, Physiotherapy Evidence Database (PEDro), and international cystic fibrosis conference proceedings.Date of the most recent search: 25 April 2016.
SELECTION CRITERIA
Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the study with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation.
DATA COLLECTION AND ANALYSIS
Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed.
MAIN RESULTS
We identified 115 trial reports representing 55 studies, of which five studies (providing data on 122 participants) met our inclusion criteria. All five studies used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change forced expiratory volume at one second. Similarly, forced vital capacity and quality of life were not significantly affected; forced expiratory flow at 25% was significantly worse with dornase alfa inhalation after airway clearance, mean difference -0.17 litres (95% confidence interval -0.28 to -0.05), based on the pooled data from two small studies in children (seven to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant.In one trial, morning versus evening inhalation had no impact on lung function or symptoms.
AUTHORS' CONCLUSIONS
The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and studies with variable follow up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alpha inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted.
Topics: Administration, Inhalation; Adolescent; Child; Combined Modality Therapy; Cystic Fibrosis; Deoxyribonuclease I; Drug Administration Schedule; Humans; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Respiratory Therapy; Time Factors; Young Adult
PubMed: 27457496
DOI: 10.1002/14651858.CD007923.pub4 -
Scientific Reports Jul 2016An increasing number of studies have highlighted the potential link between EXO1 polymorphisms and cancer risk, although no consensus has yet been obtained. Thus, we... (Meta-Analysis)
Meta-Analysis
An increasing number of studies have highlighted the potential link between EXO1 polymorphisms and cancer risk, although no consensus has yet been obtained. Thus, we aimed to obtain a thorough and current assessment of EXO1 polymorphisms and cancer susceptibility by performing a meta-analysis. A comprehensive literature retrieval was performed on PubMed, EMbase, Web of Science and Wanfang databases. The odds ratio (OR) and 95% confidence interval (CI) were applied to assess the results. Finally, 39 case-control studies of the nine EXO1 polymorphisms that involved 21,651 cases and 21,348 controls met our inclusion criteria. The pooled analysis indicated that the rs1047840 polymorphism conferred a significantly increased susceptibility to cancer in an allelic model. Similarly, the rs3754093, rs1776177, rs9350, rs10802996, rs1635498, rs1776148 and rs851797 polymorphisms were also associated with an increased susceptibility to cancer in an allelic model, respectively, while no significant association was identified for rs1635517 polymorphism. For the rs1047840 polymorphism, in an ethnicity subgroup analysis, a significantly increased susceptibility to cancer for Asians was identified in all the genetic models, and for Caucasians in an allelic model. Our findings provide the evidence that the rs1047840, rs9350, rs10802996, rs1635498, rs1776148, rs1776177, rs3754093 and rs851797 polymorphisms may act as risk factors for cancer.
Topics: Case-Control Studies; DNA Repair Enzymes; Ethnicity; Exodeoxyribonucleases; Genetic Predisposition to Disease; Humans; Neoplasms; Polymorphism, Single Nucleotide
PubMed: 27387683
DOI: 10.1038/srep29270