Summary Background Human papillomavirus-related (HPV+) oropharyngeal cancer is a rapidly emerging disease with generally good prognosis. Many prognostic algorithms for oropharyngeal cancer ...incorporate HPV status as a stratification factor, rather than recognising the uniqueness of HPV+ disease. The International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) aimed to develop a TNM classification specific to HPV+ oropharyngeal cancer. Methods The ICON-S study included patients with non-metastatic oropharyngeal cancer from seven cancer centres located across Europe and North America; one centre comprised the training cohort and six formed the validation cohorts. We ascertained patients' HPV status with p16 staining or in-situ hybridisation. We compared overall survival at 5 years between training and validation cohorts according to 7th edition TNM classifications and HPV status. We used recursive partitioning analysis (RPA) and adjusted hazard ratio (AHR) modelling methods to derive new staging classifications for HPV+ oropharyngeal cancer. Recent hypotheses concerning the effect of lower neck lymph nodes and number of lymph nodes were also investigated in an exploratory training cohort to assess relevance within the ICON-S classification. Findings Of 1907 patients with HPV+ oropharyngeal cancer, 661 (35%) were recruited at the training centre and 1246 (65%) were enrolled at the validation centres. 5-year overall survival was similar for 7th edition TNM stage I, II, III, and IVA (respectively; 88% 95% CI 74–100; 82% 71–95; 84% 79–89; and 81% 79–83; global p=0·25) but was lower for stage IVB (60% 53–68; p<0·0001). 5-year overall survival did not differ among N0 (80% 95% CI 73–87), N1–N2a (87% 83–90), and N2b (83% 80–86) subsets, but was significantly lower for those with N3 disease (59% 51–69; p<0·0001). Stage classifications derived by RPA and AHR models were ranked according to survival performance, and AHR-New was ranked first, followed by AHR-Orig, RPA, and 7th edition TNM. AHR-New was selected as the proposed ICON-S stage classification. Because 5-year overall survival was similar for patients classed as T4a and T4b, T4 is no longer subdivided in the re-termed ICON-S T categories. Since 5-year overall survival was similar among N1, N2a, and N2b, we re-termed the 7th edition N categories as follows: ICON-S N0, no lymph nodes; ICON-S N1, ipsilateral lymph nodes; ICON-S N2, bilateral or contralateral lymph nodes; and ICON-S N3, lymph nodes larger than 6 cm. This resembles the N classification of nasopharyngeal carcinoma but without a lower neck lymph node variable. The proposed ICON-S classification is stage I (T1–T2N0–N1), stage II (T1–T2N2 or T3N0–N2), and stage III (T4 or N3). Metastatic disease (M1) is classified as ICON-S stage IV. In an exploratory training cohort (n=702), lower lymph node neck involvement had a significant effect on survival in ICON-S stage III but had no effect in ICON-S stage I and II and was not significant as an independent factor. Overall survival was similar for patients with fewer than five lymph nodes and those with five or more lymph nodes, within all ICON-S stages. Interpretation Our proposed ICON-S staging system for HPV+ oropharyngeal cancer is suitable for the 8th edition of the Union for International Cancer Control/American Joint Committee on Cancer TNM classification. Future work is needed to ascertain whether T and N categories should be further refined and whether non-anatomical factors might augment the full classification. Funding None.
Summary Background Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of growth-inhibitory activity in oestrogen ...receptor-positive breast cancer cells and synergy with anti-oestrogens. We aimed to assess the safety and efficacy of palbociclib in combination with letrozole as first-line treatment of patients with advanced, oestrogen receptor-positive, HER2-negative breast cancer. Methods In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen receptor-positive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate. Patients were enrolled in two separate cohorts that accrued sequentially: in cohort 1, patients were enrolled on the basis of their oestrogen receptor-positive and HER2-negative biomarker status alone, whereas in cohort 2 they were also required to have cancers with amplification of cyclin D1 ( CCND1 ), loss of p16 (INK4A or CDKN2A), or both. In both cohorts, patients were randomly assigned 1:1 via an interactive web-based randomisation system, stratified by disease site and disease-free interval, to receive continuous oral letrozole 2·5 mg daily or continuous oral letrozole 2·5 mg daily plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over 28-day cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis of cohorts 1 and 2 (instead of cohort 2 alone). The study is ongoing but closed to accrual; these are the results of the final analysis of progression-free survival. The study is registered with the ClinicalTrials.gov , number NCT00721409. Findings Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus letrozole and 81 to letrozole alone. At the time of the final analysis for progression-free survival (median follow-up 29·6 months 95% CI 27·9–36·0 for the palbociclib plus letrozole group and 27·9 months 25·5–31·1 for the letrozole group), 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival was 10·2 months (95% CI 5·7–12·6) for the letrozole group and 20·2 months (13·8–27·5) for the palbociclib plus letrozole group (HR 0·488, 95% CI 0·319–0·748; one-sided p=0·0004). In cohort 1 (n=66), median progression-free survival was 5·7 months (2·6–10·5) for the letrozole group and 26·1 months (11·2–not estimable) for the palbociclib plus letrozole group (HR 0·299, 0·156–0·572; one-sided p<0·0001); in cohort 2 (n=99), median progression-free survival was 11·1 months (7·1–16·4) for the letrozole group and 18·1 months (13·1–27·5) for the palbociclib plus letrozole group (HR 0·508, 0·303–0·853; one-sided p=0·0046). Grade 3–4 neutropenia was reported in 45 (54%) of 83 patients in the palbociclib plus letrozole group versus one (1%) of 77 patients in the letrozole group, leucopenia in 16 (19%) versus none, and fatigue in four (4%) versus one (1%). Serious adverse events that occurred in more than one patient in the palbociclib plus letrozole group were pulmonary embolism (three 4% patients), back pain (two 2%), and diarrhoea (two 2%). No cases of febrile neutropenia or neutropenia-related infections were reported during the study. 11 (13%) patients in the palbociclib plus letrozole group and two (2%) in the letrozole group discontinued the study because of adverse events. Interpretation The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is currently underway. Funding Pfizer.
Background Inability of topical medications to penetrate via nail plate brings a great challenge to clinicians in treating onychomycosis. Furthermore, oral medications are not appropriate for all ...patients because of drug interactions, adverse effects, and contraindications. Objective We sought to evaluate the clinical efficacy of fractional carbon-dioxide laser-assisted topical therapy for onychomycosis. Methods In total, 75 patients with 356 onychomycotic nails confirmed by mycologic examination were included in this study. All the affected nails received 3 sessions of laser therapy at 4-week intervals and once-daily application of terbinafine cream for 3 months. Results In all, 94.66% and 92% of the treated patients were potassium hydroxide and culture negative, respectively, after 3 months of treatment. However, only 84% and 80% were potassium hydroxide and culture negative, respectively, at 6 months of follow-up. Using Scoring Clinical Index for Onychomycosis electronic calculator, 73.33% of the patients scored higher than 6 and 26.66% of the patients scored 6 or less. Those who scored more than 6 were evaluated clinically and 98.18% of them showed response to treatment at 3 months and 78.18% of them at 6 months of follow-up. Limitation Lack of control group and short duration of follow-up are limitations. Conclusions Fractional carbon-dioxide laser therapy combined with topical antifungal was found to be effective in the treatment of onychomycosis. However, randomized clinical studies are needed before it can be widely used in clinics.
Abstract Rising heart rate (HR) and elevated blood pressure (BP) cause a higher frequency of cardiovascular events. Many patients cannot maintain target HR and BP by using pharmacological therapies. ...To evaluate the effectiveness of voluntary slow breathing exercises (VSBE) in reducing resting HR and BP, we searched Embase (1974 to April 2016), PubMed (1966 to April 2016), the Cochrane Central Register of Controlled Trials (Issue 4, April 2016) and PEDro ( www.pedro.org.au ) (1999 to April 2016) .The primary outcome was the mean change in resting HR. Secondary outcomes included changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) as well as compliance with the breathing training.Finally, we included 6 studies consisting of 269 subjects. Practice of the breathing exercises resulted in statistically significant HR reduction mean difference: -1.72 beats/min, 95% confidence interval (CI): -2.70 to -0.75. Reductions were seen in SBP (mean difference: -6.36 mmHg, 95% CI: -10.32 to -2.39) and DBP (mean difference: -5.63 mmHg, 95% CI: -7.40 to -3.86) compared to the controls. Trial durations ranged from 2 weeks to 6 months. In conclusion, the existing evidence from RCTs demonstrates that short-term VSBE can reduce resting HR, SBP, and DBP for patients with cardiovascular diseases.
Abstract Background Offering patients in oncology trials the opportunity to cross over to active treatment at disease progression is a common strategy to address ethical issues associated with ...placebo controls but may lead to statistical challenges in the analysis of overall survival and cost-effectiveness because crossover leads to information loss and dilution of comparative clinical efficacy. Objectives We provide an overview of how to address crossover, implications for risk-effect estimates of survival (hazard ratios) and cost-effectiveness, and how this influences decisions of reimbursement agencies. Two case studies using data from two phase III sunitinib oncology trials are used as illustration. Methods We reviewed the literature on statistical methods for adjusting for crossover and recent health technology assessment decisions in oncology. Results We show that for a trial with a high proportion of crossover from the control arm to the investigational arm, the choice of the statistical method greatly affects treatment-effect estimates and cost-effectiveness because the range of relative mortality risk for active treatment versus control is broad. With relatively frequent crossover, one should consider either the inverse probability of censoring weighting or the rank-preserving structural failure time model to minimize potential bias, with choice dependent on crossover characteristics, trial size, and available data. A large proportion of crossover favors the rank-preserving structural failure time model, while large sample size and abundant information about confounding factors favors the inverse probability of censoring weighting model. When crossover is very infrequent, methods yield similar results. Conclusions Failure to correct for crossover may lead to suboptimal decisions by pricing and reimbursement authorities, thereby limiting an effective drug’s potential.
No therapy has been shown to improve survival rate in heart failure with preserved ejection fraction (HFPEF). Recent observational studies of the association between statin use and the risk of ...mortality in HFPEF have shown mixed results. The goal of the present study was to systematically review all published observational studies evaluating the effect of statins on the risk of mortality in HFPEF. A literature search in the PubMed and EMBASE databases was undertaken through December of 2013. Combined relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random-effects model. Subgroup analyses, sensitivity analysis, and cumulative meta-analysis were also performed. A total of 11 eligible studies with 17,985 patients with HFPEF were included in the analysis. Statin use was associated with a 40% lower risk of mortality (RR 0.60, 95% CI 0.49 to 0.74, p <0.001). Stratification of studies by controlled or uncontrolled confounding factors affected the final estimate (confounder-controlled RR 0.63, 95% CI 0.51 to 0.77, p <0.001 and confounder-uncontrolled RR 0.49, 95% CI 0.24 to 1.01, p = 0.053). Furthermore, sensitivity analysis confirmed the stability of the results. Cumulative meta-analysis showed an obvious trend of reduction in mortality rates in statin users from 2005 to 2013. In conclusion, our meta-analysis supports the hypothesis that statin therapy may be associated with improved survival rates in patients with HFPEF. Nevertheless, randomized controlled trials are needed to confirm the efficacy of statins in HFPEF.
Summary Nasopharyngeal carcinoma (NPC) is a particularly common malignant disease in areas of south China and Southeast Asia. To characterize the gene expression profiling of NPC, we detected the ...gene expression profiles in 22 NPC and 10 nontumor nasopharyngeal epithelial tissues by complementary DNA microarray. We identified 503 genes that were significantly ( P < .001) differentially regulated between NPC and nontumor nasopharyngeal epithelial tissues. The differentially expressed genes are involved in many signaling pathways, such as the Wnt, transforming growth factor– β , and mitogen-activated protein kinase signaling pathways. The aberrant expression of the Wnt signaling pathway components, such as wingless-type MMTV integration site family, member 5A, Frizzled homolog 7, casein kinase II β , β -catenin, CREB-binding protein, and Dishevelled-associated activator of morphogenesis 2 was validated on the NPC tissue microarrays. The data suggest that the Wnt signaling pathway may be abnormally regulated in NPC, which provides insight into the molecular mechanisms of NPC.
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. The goal of the present study was to quantify the association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) ...and risk of AF incidence. MEDLINE and EMBASE were searched for studies that reported risk of AF associated with nonaspirin NSAID use. Combined relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random-effects model. Stratified meta-analyses were used to discern which patients were at the highest risk of AF due to NSAID use. Five studies were identified that met the inclusion criteria, 3 of which additionally reported specifically on the association between selective NSAIDs and risk of AF. Overall, NSAID use was associated with a 12% increased risk for AF incidence (RR 1.12, 95% CI 1.06 to 1.18). The association was found to be apparent among new users (RR 1.53, 95% CI 1.37 to 1.70). The increased risk of AF might be explained by the occurrence of chronic heart failure and kidney disease. In addition, use of selective NSAIDs was still related to an increased risk of AF (RR 1.24, 95% CI 1.18 to 1.30). Sensitivity analyses found results to be robust. In conclusion, use of nonaspirin NSAIDs was associated with an increased risk of incident AF. The association was found to be apparent for new users, with a 53% increase in risk. These findings suggest that AF needs to be added to the cardiovascular risks to be considered when prescribing NSAIDs.
Asthma is the most common chronic disease in children and a major public health problem in adults. A relation between asthma and toxocariasis has been hypothesized.
To evaluate the strength of ...association between asthma and Toxocara species seropositivity by conducting a systematic review and a meta-analysis of available data.
PubMed, EMBASE, Web of Science, and the reference lists of all relevant articles and books were screened until October 2013. Two authors independently assessed eligibility and study quality and extracted data. A common odds ratio was estimated using a random-effects meta-analysis model of aggregated published data.
Ten studies met the inclusion criteria, for a total of 1,530 participants (723 cases and 807 controls). This meta-analysis found a significantly higher prevalence of Toxocara canis infection in patients with asthma than in controls (odds ratio 3.36, 95% confidence interval 1.76-6.42, P < .001). Similar results were found when meta-analysis was restricted to the studies considering only children or adults.
The results support the existence of a positive association between asthma and Toxocara species seropositivity.
Purpose To assess the incidence, risk factors, treatment, and outcomes of life-threatening complications of multi-space infections (LCMIs) in the head and neck. Patients and Methods This was a ...retrospective cohort study that enrolled a sample of patients with multi-space infections who were referred from February 2006 through July 2014. The patients were classified into LCMI and non-LCMI groups. The primary predictor in this study was underlying systemic disease. The primary outcome variable was LCMI. Univariate analyses were used for data statistics. Results A total of 549 patients were included, and an LCMI was found in 66 patients (12.20%). Descending mediastinitis was the most frequent LCMI (n = 37; 56.06%), followed by airway obstruction (n = 27; 40.91%), pneumonia (n = 12; 18.18%), pericarditis (n = 6; 9.09%), intraorbital infection (n = 2; 3.03%), multiple organ failure (n = 2; 3.03%), intracranial infection (n = 2; 3.03%), and sudden cardiac death (n = 1; 1.52%). Twelve patients with LCMI died during treatment. Elderly patients with an underlying systemic disease more commonly developed an LCMI. Conclusions Multi-space infections in the head and neck can cause several life-threatening complications, and the morbidity of LCMI is considerable. Older age and underlying systemic disease can increase the risk of an LCMI.
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