Cancer survival in kidney transplant recipients in Ireland.

BACKGROUND: Transplantation is a well-known risk factor for malignancy. However, outcomes of cancer in transplant recipients compared with non-transplant recipients are less well studied. We aim to study the survival in kidney transplant recipients who develop cancer and compare this with cancer outcomes in the general population. METHODS: We linked data from the National Cancer Registry Ireland with the National Kidney Transplant Database. The period of observation was from 1 January 1994 until 31 December 2014. Transplant recipients were considered at risk from the time of diagnosing cancer. We administratively censored data at 10 years post-cancer diagnosis. Survival was compared with all patients in the general population that had a recorded diagnosis of cancer. RESULTS: There were 907 renal transplant recipients and 426679 individuals in the general population diagnosed with cancer between 1 January 1994 and 31 December 2014. In those with non-melanoma skin cancer, the hazard ratio (HR) for 10-year, all-cause mortality [HR = 3.06, 95% confidence interval (CI) 2.66-3.52] and cancer-specific mortality (HR = 3.91, 95% CI 2.57-5.96) was significantly higher among transplant recipients than the general population. Patients who developed non-Hodgkin lymphoma (HR = 2.89, 95% CI 1.96-4.25) and prostate cancer (HR = 4.32, 95% CI 2.39-7.82) had increased all-cause but not cancer-specific mortality. Colorectal, lung, breast and renal cell cancer did not show an increased risk of death in transplant recipients. CONCLUSION: Cancer-attributable mortality is higher in kidney transplant recipients with non-melanoma skin cancer compared with non-transplant patients. The American Joint Committee on Cancer staging should reflect the increased hazard of death in these immunosuppressed patients.

The impact of switching to mTOR inhibitor-based immunosuppression on long-term non-melanoma skin cancer incidence and renal function in kidney and liver transplant recipients.

Background: Solid organ transplantation is associated with increased risk of non-melanoma skin cancer. Studies with short follow up times have suggested a reduced occurrence of these cancers in recipients treated with mammalian target of rapamycin inhibitors as maintenance immunosuppression. We aimed to describe the occurrence of skin cancers in renal and liver transplant recipients switched from calcineurin inhibitor to sirolimus-based regimes.Methods: We performed a retrospective study of sirolimus conversion within the Irish national kidney and liver transplant programs. These data were linked with the National Cancer Registry Ireland to determine the incidence of NMSC among these recipients. The incidence rate ratio (IRR) for post versus pre-conversion NMSC rates are referred in this study as an effect size with [95% confidence interval].Results: Of 4,536 kidney transplants and 574 liver transplants functioning on the 1 January 1994 or transplanted between 1 January 1994 and 01 January 1994 and 01 January 2015, 85 kidney and 88 liver transplant recipients were transitioned to sirolimus-based immunosuppression. In renal transplants, the rate of NMSC was 131 per 1000 patient years pre-switch to sirolimus, and 68 per 1000 patient years post switch, with adjusted effect size of 0.48 [0.31 - 0.74] (p = .001) following the switch. For liver transplant recipients, the rate of NMSC was 64 per 1,000 patient years pre-switch and 30 per 1,000 patient years post switch, with an adjusted effect size of 0.49 [0.22 - 1.09] (p .081). Kidney transplant recipients were followed up for a median 3.4 years. Liver transplants were followed for a median 6.6 years.Conclusions: In this study, the conversion of maintenance immunosuppression from calcineurin inhibitors to mTOR inhibitors for clinical indications did appear to reduce the incidence of NMSC in kidney and liver transplant recipients.

Post-transplant malignancy in solid organ transplant recipients in Ireland, The Irish Transplant Cancer Group.

OBJECTIVE: Solid organ transplant recipients are at increased risk of cancer compared to the general population. To date, this risk in Ireland has not been investigated. We conducted a national registry study of cancer incidence following solid organ transplantation. METHODS: National centers for solid organ transplantation supplied their respective registry databases to cross-reference with episodes of malignancy from the National Cancer Registry Ireland (NCRI) between 1994 and 2014. Standardized incidence of cancer post-transplant was compared to the general population by means of standardized incidence ratios (SIRs), and between solid organ transplant types by incidence rate ratios. RESULTS: A total of 3346 solid organ transplant recipients were included in this study. Kidney transplant recipients constituted the majority of participants (71.2%), followed by liver (16.8%), heart (6.4%), and lung (5.6%) transplants. The most common cancers within the composite of all transplant recipients included the following (SIR [95% CI]): squamous and basal cell carcinoma (20.05 [17.97, 22.31] and 7.16 [6.43, 7.96], respectively), non-Hodgkin lymphoma (6.23 [4.26, 8.59]), and renal cell carcinoma (3.36 [1.96, 5.38]). CONCLUSIONS: This study reports the incidence of cancer following solid organ transplantation in Ireland. These results have significant national policy implications for surveillance, and early diagnosis in this patient group.

Relief of Neuropathic Pain Through Epidermal Growth Factor Receptor Inhibition: A Randomized Proof-of-Concept Trial.

OBJECTIVE: Case reports and a case series have described relief of neuropathic pain (NP) after treatment with epidermal growth factor receptor inhibitors (EGFR-Is). These observations are supported by preclinical findings. The aim of this trial was to explore a potential clinical signal supporting the therapeutic efficacy of EGFR-Is in NP. METHODS: In a proof-of-concept trial using a randomized, double-blind, placebo-controlled design, 14 patients with severe, chronic, therapy-resistant NP due to compressed peripheral nerves or complex regional pain syndrome were randomized to receive a single infusion of the EGFR-I cetuximab and placebo in crossover design, followed by a single open-label cetuximab infusion. RESULTS: The mean reduction in daily average pain scores three to seven days after single-blinded cetuximab infusion was 1.73 points (90% confidence interval [CI] = 0.80 to 2.66), conferring a 1.22-point greater reduction than placebo (90% CI = -0.10 to 2.54). Exploratory analyses suggested that pain reduction might be greater in the 14 days after treatment with blinded cetuximab than after placebo. The proportion of patients who reported ≥50% reduction in average pain three to seven days after cetuximab was 36% (14% after placebo), and comparison of overall pain reduction suggests a trend in favor of cetuximab. Skin rash (grade 1-2) was the most frequent side effect (12/14, 86%). CONCLUSIONS: This small proof-of-concept evaluation of an EGFR-I against NP did not provide statistical evidence of efficacy. However, substantial reductions in pain were reported, and confidence intervals do not rule out a clinically meaningful treatment effect. Evaluation of EGFR-I against NP therefore warrants further investigation.

Antiviral treatment for Bell's palsy (idiopathic facial paralysis).

BACKGROUND: Corticosteroids are widely used in the treatment of idiopathic facial paralysis (Bell's palsy), but the effectiveness of additional treatment with an antiviral agent is uncertain. This review was first published in 2001 and most recently updated in 2015. Since a significant benefit of corticosteroids for the early management of Bell's palsy has been demonstrated, the main focus of this update, as in the previous version, was to determine the effect of adding antivirals to corticosteroid treatment. We undertook this update to integrate additional evidence and to better assess the robustness of findings, taking risk of bias fully into account. OBJECTIVES: To assess the effects of antiviral treatments alone or in combination with any other therapy for Bell's palsy. SEARCH METHODS: We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS in July 2019. We reviewed the bibliographies of the identified trials and contacted trial authors to identify additional published or unpublished data. We searched clinical trials registries for ongoing studies. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) or quasi-RCTs of antivirals with and without corticosteroids versus control therapies for the treatment of Bell's palsy. We excluded trials that followed-up participants for less than three months. DATA COLLECTION AND ANALYSIS: We independently assessed trials for relevance, eligibility, and risk of bias, using standard Cochrane procedures. We performed sensitivity analyses excluding trials at high or unclear risk of bias in at least five domains, and reported these data as the primary analyses. MAIN RESULTS: Fourteen trials, including 2488 participants, met the inclusion criteria. Most were small, and most were at high or unclear risk of bias in multiple domains. We included four new studies at this update.Incomplete recoveryA combination of antivirals and corticosteroids may have little or no effect on rates of incomplete recovery in people with Bell's palsy compared to corticosteroids alone (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.38 to 1.74; 3 trials, N = 766; random-effects; low-certainty evidence). We excluded 10 trials that were at high or unclear risk of bias in several domains from this analysis and limited all analyses to studies at lower risk of bias. Recovery rates were better in participants receiving corticosteroids alone than antivirals alone (RR 2.69, 95% CI 0.73 to 10.01; 2 trials, N = 667; random-effects), but the result was imprecise and allowed for the possibility of no effect. The rate of incomplete recovery was lower with antivirals plus corticosteroids than with placebo or no treatment (RR 0.56, 95% CI 0.42 to 0.76; 2 trials, N = 658; random-effects). Antivirals alone had no clear effect on incomplete recovery rates compared with placebo, but the result was imprecise (RR 1.10, 95% CI 0.87 to 1.40; 2 trials, N = 658; fixed-effect). For people with severe Bell's palsy (House-Brackmann score of 5 and 6, or equivalent on other scales), we found that the combination of antivirals and corticosteroids had no clear effect on incomplete recovery at month six compared to corticosteroids alone, although the result was again imprecise (RR 0.82, 95% CI 0.57 to 1.17; 2 trials, N = 98; random-effects).Motor synkinesis or crocodile tearsAntivirals plus corticosteroids reduced the proportion of participants who experienced these long-term sequelae from Bell's palsy compared to placebo plus corticosteroids (RR 0.56, 95% CI 0.36 to 0.87; 2 trials, N = 469; fixed-effect; moderate-certainty evidence). Antivirals plus corticosteroids reduced long-term sequelae compared to placebo but there was no clear difference in this outcome with antivirals alone compared to placebo.Adverse events Adverse event data were available in four studies providing data on 1592 participants. None of the four comparisons showed clear differences in adverse events between treatment and comparison arms (very low-certainty evidence); for the comparison of antivirals plus corticosteroids and corticosteroids alone in studies at lower risk of bias, the RR was 1.17 (95% CI 0.81 to 1.69; 2 trials, N = 656; fixed-effect; very low-certainty evidence). AUTHORS' CONCLUSIONS: The combination of antivirals and corticosteroids may have little or no effect on rates of incomplete recovery in comparison to corticosteroids alone in Bell's palsy of various degrees of severity, or in people with severe Bell's palsy, but the results were very imprecise. Corticosteroids alone were probably more effective than antivirals alone and antivirals plus corticosteroids were more effective than placebo or no treatment. There was no clear benefit from antivirals alone over placebo.The combination of antivirals and corticosteroids probably reduced the late sequelae of Bell's palsy compared with corticosteroids alone. Studies also showed fewer episodes of long-term sequelae in corticosteroid-treated participants than antiviral-treated participants.We found no clear difference in adverse events from the use of antivirals compared with either placebo or corticosteroids, but the evidence is too uncertain for us to draw conclusions.An adequately powered RCT in people with Bell's palsy that compares different antiviral agents may be indicated.

Corticosteroids for Bell's palsy (idiopathic facial paralysis).

BACKGROUND: Inflammation and oedema of the facial nerve are implicated in causing Bell's palsy. Corticosteroids have a potent anti-inflammatory action that should minimise nerve damage. This is an update of a review first published in 2002 and last updated in 2010. OBJECTIVES: To determine the effectiveness and safety of corticosteroid therapy in people with Bell's palsy. SEARCH METHODS: On 4 March 2016, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS. We reviewed the bibliographies of the randomised trials and contacted known experts in the field to identify additional published or unpublished trials. We also searched clinical trials registries for ongoing trials. SELECTION CRITERIA: Randomised trials and quasi-randomised trials comparing different routes of administration and dosage schemes of corticosteroid or adrenocorticotrophic hormone therapy versus a control group receiving no therapy considered effective for this condition, unless the same therapy was given in a similar way to the experimental group. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. The main outcome of interest was incomplete recovery of facial motor function (i.e. residual facial weakness). Secondary outcomes were cosmetically disabling persistent sequelae, development of motor synkinesis or autonomic dysfunction (i.e. hemifacial spasm, crocodile tears) and adverse effects of corticosteroid therapy manifested during follow-up. MAIN RESULTS: We identified seven trials, with 895 evaluable participants for this review. All provided data suitable for the primary outcome meta-analysis. One of the trials was new since the last version of this Cochrane systematic review. Risk of bias in the older, smaller studies included some unclear- or high-risk assessments, whereas we deemed the larger studies at low risk of bias. Overall, 79/452 (17%) participants allocated to corticosteroids had incomplete recovery of facial motor function six months or more after randomisation; significantly fewer than the 125/447 (28%) in the control group (risk ratio (RR) 0.63, 95% confidence interval (CI) 0.50 to 0.80, seven trials, n = 895). The number of people who need to be treated with corticosteroids to avoid one incomplete recovery was 10 (95% CI 6 to 20). The reduction in the proportion of participants with cosmetically disabling sequelae six months after randomisation was very similar in the corticosteroid and placebo groups (RR 0.96, 95% CI 0.40 to 2.29, two trials, n = 75, low-quality evidence). However, there was a significant reduction in motor synkinesis during follow-up in participants receiving corticosteroids (RR 0.64, 95% CI 0.45 to 0.91, three trials, n = 485, moderate-quality evidence). Three studies explicitly recorded the absence of adverse effects attributable to corticosteroids. One trial reported that three participants receiving prednisolone had temporary sleep disturbances and two trials gave a detailed account of adverse effects occurring in 93 participants, all non-serious; the combined analysis of data from these three trials found no significant difference in adverse effect rates between people receiving corticosteroids and people receiving placebo (RR 1.04, 95% CI 0.71 to 1.51, n = 715). AUTHORS' CONCLUSIONS: The available moderate- to high-quality evidence from randomised controlled trials showed significant benefit from treating Bell's palsy with corticosteroids.

Antiviral Agents Added to Corticosteroids for Early Treatment of Adults With Acute Idiopathic Facial Nerve Paralysis (Bell Palsy).

CLINICAL QUESTION: Compared with oral corticosteroids alone, are oral antiviral drugs associated with improved outcomes when combined with oral corticosteroids in patients presenting within 72 hours of the onset of Bell palsy? BOTTOM LINE: Compared with oral corticosteroids alone, the addition of acyclovir, valacyclovir, or famcyclovir to oral corticosteroids for treatment of Bell palsy was associated with a higher proportion of people who recovered at 3- to 12-month follow-up. The quality of evidence is limited by heterogeneity, imprecision of the result estimates, and risk of bias.

WITHDRAWN. Antiviral treatment for Bell's palsy (idiopathic facial paralysis).

BACKGROUND: Corticosteroids are widely used in the treatment of idiopathic facial paralysis (Bell's palsy), but the effectiveness of additional treatment with an antiviral agent is uncertain. Significant morbidity can be associated with severe cases of Bell's palsy. OBJECTIVES: To assess the effects of antiviral treatments alone or in combination with any other therapy for Bell's palsy. SEARCH METHODS: On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, DARE, NHS EED, and HTA. We also reviewed the bibliographies of the identified trials and contacted trial authors and known experts in the field and relevant drug companies to identify additional published or unpublished data. We searched clinical trials registries for ongoing studies. SELECTION CRITERIA: We considered randomised controlled trials or quasi-randomised controlled trials of antivirals with and without corticosteroids versus control therapies for the treatment of Bell's palsy. We excluded trials that had a high risk of bias in several domains. DATA COLLECTION AND ANALYSIS: Pairs of authors independently assessed trials for relevance, eligibility, and risk of bias, using standard Cochrane procedures. MAIN RESULTS: Eleven trials, including 2883 participants, met the inclusion criteria and are included in the final analysis. We added four studies to the previous review for this update. Some of the trials were small, and a number were at high or unclear risk of bias. Other trials did not meet current best standards in allocation concealment and blinding. Incomplete recoveryWe found no significant benefit from adding antivirals to corticosteroids in comparison with corticosteroids alone for people with Bell's palsy (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.47 to 1.02, n = 1715). For people with severe Bell's palsy (House-Brackmann scores of 5 and 6 or the equivalent in other scales), we found a reduction in the rate of incomplete recovery at month six when antivirals plus corticosteroids were used (RR 0.64, 95% CI 0.41 to 0.99, n = 478). The outcome for the participants receiving corticosteroids alone was significantly better than for those receiving antivirals alone (RR 2.09, 95% CI 1.36 to 3.20, n = 1169). The treatment effect of placebo was significantly lower than that of antivirals plus corticosteroids (RR 0.56, 95% CI 0.41 to 0.76, n = 658). Antivirals alone had a non-significant detrimental effect on the outcome compared with placebo (RR 1.10, 95% CI 0.87 to 1.40, n = 658). Motor synkinesis or crocodile tearsIn three trials comparing antivirals and corticosteroids with corticosteroids and placebo that assessed this outcome, we found a significant difference in long-term sequelae in favour or antivirals plus corticosteroids (RR 0.73, 95% CI 0.54 to 0.99, n = 869). Three trials comparing antivirals alone with corticosteroids alone investigating this outcome showed fewer sequelae with corticosteroids (RR 1.44, 95% CI 1.11 to 1.85, n = 873). We found no data on long-term sequelae for other comparisons. Adverse events Adverse event data were available in three studies giving comparison data on 1528 participants. None of the four comparisons (antivirals plus corticosteroids versus corticosteroids plus placebo or no treatment; antivirals versus corticosteroids; antivirals plus corticosteroids versus placebo; antivirals versus placebo) showed significant differences in adverse events between treatment and control arms. We could find no correlation with specific treatment within these results. AUTHORS' CONCLUSIONS: Moderate-quality evidence from randomised controlled trials showed no additional benefit from the combination of antivirals with corticosteroids compared to corticosteroids alone or with placebo, and no benefit from antivirals alone compared to placebo, for the treatment of Bell's palsy. Moderate-quality evidence showed a small but just significant benefit of combination therapy compared with corticosteroids alone in severe Bell's palsy. We found no significant increase in adverse events from the use of antivirals compared with either placebo or corticosteroids.

Antiviral treatment for Bell's palsy (idiopathic facial paralysis).

BACKGROUND: Corticosteroids are widely used in the treatment of idiopathic facial paralysis (Bell's palsy), but the effectiveness of additional treatment with an antiviral agent is uncertain. Significant morbidity can be associated with severe cases of Bell's palsy. This review was first published in 2001 and revised several times, most recently in 2009. This version replaces an update of the review in Issue 7 of the Cochrane Library subsequently withdrawn because of an ongoing investigation into the reliability of data from an included study. OBJECTIVES: To assess the effects of antiviral treatments alone or in combination with any other therapy for Bell's palsy. SEARCH METHODS: On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, DARE, NHS EED, and HTA. We also reviewed the bibliographies of the identified trials and contacted trial authors and known experts in the field and relevant drug companies to identify additional published or unpublished data. We searched clinical trials registries for ongoing studies. SELECTION CRITERIA: We considered randomised controlled trials or quasi-randomised controlled trials of antivirals with and without corticosteroids versus control therapies for the treatment of Bell's palsy. We excluded trials that had a high risk of bias in several domains. DATA COLLECTION AND ANALYSIS: Pairs of authors independently assessed trials for relevance, eligibility, and risk of bias, using standard Cochrane procedures. MAIN RESULTS: Ten trials, including 2280 participants, met the inclusion criteria and are included in the final analysis. Some of the trials were small, and a number were at high or unclear risk of bias. Other trials did not meet current best standards in allocation concealment and blinding. Incomplete recoveryWe found a significant benefit from adding antivirals to corticosteroids in comparison with corticosteroids alone for people with Bell's palsy (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.39 to 0.97, n = 1315). For people with severe Bell's palsy (House-Brackmann scores of 5 and 6 or the equivalent in other scales), we found a reduction in the rate of incomplete recovery at month six when antivirals plus corticosteroids were used, compared to corticosteroids alone (RR 0.64, 95% CI 0.41 to 0.99, n = 478). The outcome for the participants receiving corticosteroids alone was significantly better than for those receiving antivirals alone (RR 2.82, 95% CI 1.09 to 7.32, n = 768). The treatment effect of placebo was significantly lower than that of antivirals plus corticosteroids (RR 0.56, 95% CI 0.41 to 0.76, n = 658). Antivirals alone produced no benefit compared with placebo (RR 1.10, 95% CI 0.87 to 1.40, n = 658). Motor synkinesis or crocodile tearsIn two trials comparing antivirals and corticosteroids with corticosteroids and placebo that assessed this outcome, we found a significant difference in long-term sequelae in favour of antivirals plus corticosteroids (RR 0.56, 95% CI 0.36 to 0.87, n = 469). Two trials comparing antivirals alone with corticosteroids alone investigating this outcome showed fewer sequelae with corticosteroids (RR 1.52, 95% CI 1.08 to 2.12, n = 472). We found no data on long-term sequelae for other comparisons. Adverse events Adverse event data were available in three studies giving comparison data on 1528 participants. None of the four comparisons (antivirals plus corticosteroids versus corticosteroids plus placebo or no treatment; antivirals versus corticosteroids; antivirals plus corticosteroids versus placebo; antivirals versus placebo) showed significant differences in adverse events between treatment and control arms. We could find no correlation with specific treatment within these results. AUTHORS' CONCLUSIONS: Low-quality evidence from randomised controlled trials showed a benefit from the combination of antivirals with corticosteroids compared to corticosteroids alone for the treatment of Bell's palsy of various degrees of severity. Low-quality evidence showed a benefit of combination therapy compared with corticosteroids alone in severe Bell's palsy. Corticosteroids alone were more effective than antivirals alone and antivirals plus corticosteroids were more effective than placebo or no treatment. There was no benefit from antivirals alone over placebo.Moderate-quality evidence indicated that the combination of antivirals and corticosteroids reduced sequelae of Bell's palsy compared with corticosteroids alone.We found no significant increase in adverse events from the use of antivirals compared with either placebo or corticosteroids, based on low-quality evidence.

Antiviral treatment for Bell's palsy (idiopathic facial paralysis).

BACKGROUND: Corticosteroids are widely used in the treatment of idiopathic facial paralysis (Bell's palsy), but the effectiveness of additional treatment with an antiviral agent is uncertain. Significant morbidity can be associated with severe cases of Bell's palsy. OBJECTIVES: To assess the effects of antiviral treatments alone or in combination with any other therapy for Bell's palsy. SEARCH METHODS: On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, DARE, NHS EED, and HTA. We also reviewed the bibliographies of the identified trials and contacted trial authors and known experts in the field and relevant drug companies to identify additional published or unpublished data. We searched clinical trials registries for ongoing studies. SELECTION CRITERIA: We considered randomised controlled trials or quasi-randomised controlled trials of antivirals with and without corticosteroids versus control therapies for the treatment of Bell's palsy. We excluded trials that had a high risk of bias in several domains. DATA COLLECTION AND ANALYSIS: Pairs of authors independently assessed trials for relevance, eligibility, and risk of bias, using standard Cochrane procedures. MAIN RESULTS: Eleven trials, including 2883 participants, met the inclusion criteria and are included in the final analysis. We added four studies to the previous review for this update. Some of the trials were small, and a number were at high or unclear risk of bias. Other trials did not meet current best standards in allocation concealment and blinding. Incomplete recoveryWe found no significant benefit from adding antivirals to corticosteroids in comparison with corticosteroids alone for people with Bell's palsy (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.47 to 1.02, n = 1715). For people with severe Bell's palsy (House-Brackmann scores of 5 and 6 or the equivalent in other scales), we found a reduction in the rate of incomplete recovery at month six when antivirals plus corticosteroids were used (RR 0.64, 95% CI 0.41 to 0.99, n = 478). The outcome for the participants receiving corticosteroids alone was significantly better than for those receiving antivirals alone (RR 2.09, 95% CI 1.36 to 3.20, n = 1169). The treatment effect of placebo was significantly lower than that of antivirals plus corticosteroids (RR 0.56, 95% CI 0.41 to 0.76, n = 658). Antivirals alone had a non-significant detrimental effect on the outcome compared with placebo (RR 1.10, 95% CI 0.87 to 1.40, n = 658). Motor synkinesis or crocodile tearsIn three trials comparing antivirals and corticosteroids with corticosteroids and placebo that assessed this outcome, we found a significant difference in long-term sequelae in favour of antivirals plus corticosteroids (RR 0.73, 95% CI 0.54 to 0.99, n = 869). Three trials comparing antivirals alone with corticosteroids alone investigating this outcome showed fewer sequelae with corticosteroids (RR 1.44, 95% CI 1.11 to 1.85, n = 873). We found no data on long-term sequelae for other comparisons. Adverse events Adverse event data were available in three studies giving comparison data on 1528 participants. None of the four comparisons (antivirals plus corticosteroids versus corticosteroids plus placebo or no treatment; antivirals versus corticosteroids; antivirals plus corticosteroids versus placebo; antivirals versus placebo) showed significant differences in adverse events between treatment and control arms. We could find no correlation with specific treatment within these results. AUTHORS' CONCLUSIONS: Moderate-quality evidence from randomised controlled trials showed no additional benefit from the combination of antivirals with corticosteroids compared to corticosteroids alone for the treatment of Bell's palsy of various degrees of severity. Moderate-quality evidence showed a small but just significant benefit of combination therapy compared with corticosteroids alone in severe Bell's palsy. Corticosteroids alone were more effective than antivirals alone and antivirals plus corticosteroids were more effective than placebo or no treatment. There was no benefit from antivirals alone over placebo.Moderate-quality evidence indicated that the combination of antivirals and corticosteroids reduced sequelae of Bell's palsy compared with corticosteroids alone.We found no significant increase in adverse events from the use of antivirals compared with either placebo or corticosteroids, based on moderate-quality evidence.

Study protocol for BeWEL: the impact of a BodyWEight and physicaL activity intervention on adults at risk of developing colorectal adenomas.

BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second highest cause of cancer death in the UK. Most cases occur in people over 50 years and CRC often co-exists with other lifestyle related disorders including obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). These diseases share risk factors related to the metabolic syndrome including large body size, abnormal lipids and markers of insulin resistance indicating common aetiological pathways. METHODS/DESIGN: This 3 year study will be a two-arm, multicentre, randomised controlled trial comparing the BeWEL lifestyle (diet, physical activity and behaviour change) programme against usual care. The pre-trial development will take 6 months and participants will be recruited over a 12 month period and undertake the intervention and follow up for 12 months (total 24 months recruitment and intervention implementation) with a further 6 months for data collection, analysis and interpretation.Four hundred and fifty two participants who have had a colorectal adenoma detected and removed (through the national colorectal screening programme) will provide 80% power to detect a weight loss of 7% over 12 months.Primary outcomes are changes in body weight and waist circumference. Secondary outcomes will include cardiovascular risk factors, psycho-social measures and intervention costs. DISCUSSION: The results from this study will enhance the evidence base for lifestyle change in patients at higher risk of chronic disease including obesity related cancers.International Standard Randomised Controlled Trials No: ISRCTN53033856.

Early treatment with prednisolone or acyclovir in Bell's palsy.

BACKGROUND: Corticosteroids and antiviral agents are widely used to treat the early stages of idiopathic facial paralysis (i.e., Bell's palsy), but their effectiveness is uncertain. METHODS: We conducted a double-blind, placebo-controlled, randomized, factorial trial involving patients with Bell's palsy who were recruited within 72 hours after the onset of symptoms. Patients were randomly assigned to receive 10 days of treatment with prednisolone, acyclovir, both agents, or placebo. The primary outcome was recovery of facial function, as rated on the House-Brackmann scale. Secondary outcomes included quality of life, appearance, and pain. RESULTS: Final outcomes were assessed for 496 of 551 patients who underwent randomization. At 3 months, the proportions of patients who had recovered facial function were 83.0% in the prednisolone group as compared with 63.6% among patients who did not receive prednisolone (P<0.001) and 71.2% in the acyclovir group as compared with 75.7% among patients who did not receive acyclovir (adjusted P=0.50). After 9 months, these proportions were 94.4% for prednisolone and 81.6% for no prednisolone (P<0.001) and 85.4% for acyclovir and 90.8% for no acyclovir (adjusted P=0.10). For patients treated with both drugs, the proportions were 79.7% at 3 months (P<0.001) and 92.7% at 9 months (P<0.001). There were no clinically significant differences between the treatment groups in secondary outcomes. There were no serious adverse events in any group. CONCLUSIONS: In patients with Bell's palsy, early treatment with prednisolone significantly improves the chances of complete recovery at 3 and 9 months. There is no evidence of a benefit of acyclovir given alone or an additional benefit of acyclovir in combination with prednisolone. (Current Controlled Trials number, ISRCTN71548196 [controlled-trials.com].).

Corticosteroids for Bell's palsy (idiopathic facial paralysis).

BACKGROUND: Inflammation and oedema of the facial nerve are implicated in causing Bell's palsy. Corticosteroids have a potent anti-inflammatory action which should minimise nerve damage. OBJECTIVES: The objective of this review was to assess the effect of corticosteroid therapy in Bell's palsy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register (9 December 2008) for randomised trials, as well as MEDLINE (January 1966 to December 2008), EMBASE (January 1980 to December 2008) and LILACS (9 December 2008). We contacted known experts in the field to identify additional published or unpublished trials. SELECTION CRITERIA: Randomised trials comparing different routes of administration and dosage schemes of corticosteroid or adrenocorticotrophic hormone therapy versus a control group where no therapy considered effective for this condition was administered, unless it was also given in a similar way to the experimental group. DATA COLLECTION AND ANALYSIS: Two authors independently assessed eligibility, trial quality, and extracted the data. MAIN RESULTS: Eight trials with a total of 1569 participants were included. Allocation concealment was appropriate in six trials, and the data reported allowed an intention-to-treat analysis in four, while unpublished data from the fifth and sixth trials were provided by the authors. The data included in the main outcome of this meta-analysis were collected from seven trials with a total of 1507 participants. Overall 175/754 (23%) of the participants allocated to corticosteroids had incomplete recovery of facial motor function six months or more after randomisation, significantly less than 245/753 (33%) in the control group (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.61 to 0.83). There was, also, a significant reduction in motor synkinesis during follow-up in those receiving corticosteroids (RR 0.6, 95% CI 0.44 to 0.81). The reduction in the proportion of patients with cosmetically disabling sequelae six months after randomisation, however, was not significant (RR 0.97, 95% CI 0.44 to 2.15). The trial not included in the primary outcome of this meta-analysis showed a non-significant difference in outcomes between the arms. AUTHORS' CONCLUSIONS: The available evidence from randomised controlled trials shows significant benefit from treating Bell's palsy with corticosteroids.

Lucitanib for the Treatment of HR+/HER2- Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study.

PURPOSE: The FGFR1 gene is amplified in 14% of patients with HR + /HER2 - breast cancer. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3, and PDGFRα/ß, were assessed. PATIENTS AND METHODS: Patients with HR + /HER2 - metastatic breast cancer (MBC) received oral lucitanib in three centrally confirmed cohorts: (i) FGFR1 amplified, (ii) FGFR1 nonamplified, 11q13 amplified, and (iii) FGFR1 and 11q13 nonamplified. Key inclusion criteria included Eastern Cooperative Oncology Group Performance Status ≤2, ≥1 line of anticancer therapy, but ≤2 lines of chemotherapy. Primary endpoint was overall response rates (ORR) by RECIST1.1. Simon's two-stage design was used: If ≥2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort. FGFR1 copy-number variation (CNV) was determined by FISH and droplet digital PCR, whereas FGFR1 expression was determined by IHC. RESULTS: Seventy-six patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The prespecified primary endpoint was met in cohort 1 with ORR of 19% [95% confidence interval (CI), 9%-35%], but not in cohorts 2 and 3 with ORR of 0% (95% CI, 0%-18%) and 15% (95% CI, 6%-34%), respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%), and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high FGFR1 amplification (≥4 CNV) than those without high amplification (22% vs. 9%). ORR in patients with FGFR1-high tumors (IHC, H-score ≥50) was 25% versus 8% in FGFR1-low cancers. CONCLUSIONS: Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR + /HER2 - MBC. Although based on small sample sizes, exploratory biomarker analyses suggested that patients with high FGFR1 amplification or expression might derive greater benefit.

Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women.

OBJECTIVES: To compare the effectiveness of cranberry extract with low-dose trimethoprim in the prevention of recurrent urinary tract infections (UTIs) in older women. PATIENTS AND METHODS: One hundred and thirty-seven women with two or more antibiotic-treated UTIs in the previous 12 months were randomized to receive either 500 mg of cranberry extract or 100 mg of trimethoprim for 6 months. RESULTS: Thirty-nine of 137 participants (28%) had an antibiotic-treated UTI (25 in the cranberry group and 14 in the trimethoprim group); difference in proportions relative risk 1.616 (95% CI: 0.93, 2.79) P = 0.084. The time to first recurrence of UTI was not significantly different between the groups (P = 0.100). The median time to recurrence of UTI was 84.5 days for the cranberry group and 91 days for the trimethoprim group (U = 166, P = 0.479). There were 17/137 (12%) withdrawals from the study, 6/69 (9%) from the cranberry group and 11/68 (16%) from the trimethoprim group (P = 0.205), with a relative risk of withdrawal from the cranberry group of 0.54 (95% CI: 0.19, 1.37). CONCLUSIONS: Trimethoprim had a very limited advantage over cranberry extract in the prevention of recurrent UTIs in older women and had more adverse effects. Our findings will allow older women with recurrent UTIs to weigh up with their clinicians the inherent attractions of a cheap, natural product like cranberry extract whose use does not carry the risk of antimicrobial resistance or super-infection with Clostridium difficile or fungi.

Antiviral treatment for Bell's palsy (idiopathic facial paralysis).

BACKGROUND: Antiviral agents against herpes simplex virus are widely used in the treatment of idiopathic facial paralysis (Bell's palsy), but their effectiveness is uncertain. Significant morbidity can be associated with severe cases. OBJECTIVES: This review addresses the effect of antiviral therapy on Bell's palsy. SEARCH STRATEGY: We updated the search of the Cochrane Neuromuscular Disease Group Trials Register (December 2008), MEDLINE (from January 1966 to December 8 2008), EMBASE (from January 1980 to December 8 2008) and LILACS (from January 1982 to December 2008). SELECTION CRITERIA: Randomized trials of antivirals with and without corticosteroids versus control therapies for the treatment of Bell's palsy. DATA COLLECTION AND ANALYSIS: Twenty-three papers were selected for consideration. MAIN RESULTS: Seven trials including 1987 participants met the inclusion criteria, adding five studies to the two in the previous review.Incomplete recovery at one year. There was no significant benefit in the rate of incomplete recovery from antivirals compared with placebo (n = 1886, RR 0.88, 95% CI 0.65 to 1.18). In meta-analyses with some unexplained heterogeneity, the outcome with antivirals was significantly worse than with corticosteroids (n = 768, RR 2.82, 95% CI 1.09 to 7.32) and the outcome with antivirals plus corticosteroids was significantly better than with placebo (n = 658, RR 0.56, 95% CI 0.41 to 0.76).Motor synkinesis or crocodile tears at one year. In single trials, there was no significant difference in long term sequelae comparing antivirals and corticosteroids with corticosteroids alone (n = 99, RR 0.39, 95% CI 0.14 to 1.07) or antivirals with corticosteroids (n = 101, RR 1.03, 95% CI 0.51 to 2.07).Adverse events.There was no significant difference in rates of adverse events between antivirals and placebo (n = 1544, RR 1.06, 95% CI 0.81 to 1.38), between antivirals and corticosteroids (n = 667, RR 0.96, 95% CI 0.65 to 1.41) or between the antiviral-corticosteroid combination and placebo (n = 658, RR 1.15, 95% CI 0.79 to 1.66). AUTHORS' CONCLUSIONS: High quality evidence showed no significant benefit from anti-herpes simplex antivirals compared with placebo in producing complete recovery from Bell's palsy. Moderate quality evidence showed that antivirals were significantly less likely than corticosteroids to produce complete recovery.

Variation in Nonmelanoma Skin Cancer Incidence by Treatment Modality Among Patients Receiving Multiple Kidney Transplants.

IMPORTANCE: Existing data suggest that nonmelanoma skin cancer (NMSC) is more common in renal transplant recipients than in maintenance dialysis patients. However, whether the risk of NMSC varies as the treatment modality for end-stage kidney disease (ESKD) changes between dialysis and transplantation is not well described. OBJECTIVE: To determine whether the incidence of NMSC is attenuated during periods of graft loss with a return to dialysis in those who receive multiple kidney transplants. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of data from recipients of kidney transplants from the Irish National Kidney Transplant Service database, linked with the Irish Cancer Registry, from 1994 to 2014. All analysis took place between January 10, 2018 and March 31, 2018. Standardized incidence ratios (SIRs) were calculated for NMSC incidence in comparison with the general population using Irish census data as the denominator. Incidence of NMSC was calculated with modality of treatment for ESKD varying over time; incidence rates and rate ratios associated with dialysis intervals were calculated using Poisson regression; and disease was defined according to International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes for cancer diagnosis. EXPOSURES: Kidney transplantation. MAIN OUTCOMES AND MEASURES: Incidence rates per 1000 patient-years and incident rate ratios of NMSC after kidney transplant. RESULTS: Data from the records of 3821 deceased or living donor kidney transplant recipients were assessed; 2399 (62.8%) male and 1422 (37.2%) female recipients; mean (SD) age at time of first data recorded, 41.9 (16.0) years. A total of 3433 recipients were included who had a functioning transplant on January 1, 1994, or received a transplant after that date up to December 31, 2014: 3215 received 1 transplant, 522 a second kidney transplant, and 84 had 3 or more kidney transplants. Periods of treatment with a functioning transplant were associated with a higher incidence of NMSC diagnosis than periods of graft failure: adjusted incidence rate ratio (aIRR), 2.19 (95% CI, 1.56-3.07), P < .001. The aIRRs of NMSC fell from 41.7 (95% CI, 39.38-44.15) per 1000 patient-years in the first transplant to 19.29 (95% CI, 13.41-27.76) in the dialysis period following the first allograft failure. Incidence similarly rose and fell following each subsequent consecutive transplant. CONCLUSIONS AND RELEVANCE: In recipients of multiple kidney transplants, while the incidence of NMSC fell during periods defined by transplant failure, there was residual elevated risk. While ascertainment bias may have contributed to the observed trends, the stagnant incidence of invasive cancer overall highlights the need for continued cancer surveillance during graft failure.

Recruitment and retention in a multicentre randomised controlled trial in Bell's palsy: a case study.

BACKGROUND: It is notoriously difficult to recruit patients to randomised controlled trials in primary care. This is particularly true when the disease process under investigation occurs relatively infrequently and must be investigated during a brief time window. Bell's palsy, an acute unilateral paralysis of the facial nerve is just such a relatively rare condition. In this case study we describe the organisational issues presented in setting up a large randomised controlled trial of the management of Bell's palsy across primary and secondary care in Scotland and how we managed to successfully recruit and retain patients presenting in the community. METHODS: Where possible we used existing evidence on recruitment strategies to maximise recruitment and retention. We consider that the key issues in the success of this study were; the fact that the research was seen as clinically important by the clinicians who had initial responsibility for recruitment; employing an experienced trial co-ordinator and dedicated researchers willing to recruit participants seven days per week and to visit them at home at a time convenient to them, hence reducing missed patients and ensuring they were retained in the study; national visibility and repeated publicity at a local level delivered by locally based principal investigators well known to their primary care community; encouraging recruitment by payment to practices and reducing the workload of the referring doctors by providing immediate access to specialist care; good collaboration between primary and secondary care and basing local investigators in the otolarnygology trial centres RESULTS: Although the recruitment rate did not meet our initial expectations, enhanced retention meant that we exceeded our planned target of recruiting 550 patients within the planned time-scale. CONCLUSION: While difficult, recruitment to and retention within multi-centre trials from primary care can be successfully achieved through the application of the best available evidence, establishing good relationships with practices, minimising the workload of those involved in recruitment and offering enhanced care to all participants. Primary care trialists should describe their experiences of the methods used to persuade patients to participate in their trials when publishing their results.