Adherence to CPAP Treatment and the Risk of Recurrent Cardiovascular Events: A Meta-Analysis.

Importance: The effect of continuous positive airway pressure (CPAP) on secondary cardiovascular disease prevention is highly debated. Objective: To assess the effect of CPAP treatment for obstructive sleep apnea (OSA) on the risk of adverse cardiovascular events in randomized clinical trials. Data Sources: PubMed (MEDLINE), EMBASE, Current Controlled Trials: metaRegister of Controlled Trials, ISRCTN Registry, European Union clinical trials database, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov databases were systematically searched through June 22, 2023. Study Selection: For qualitative and individual participant data (IPD) meta-analysis, randomized clinical trials addressing the therapeutic effect of CPAP on cardiovascular outcomes and mortality in adults with cardiovascular disease and OSA were included. Data Extraction and Synthesis: Two reviewers independently screened records, evaluated potentially eligible primary studies in full text, extracted data, and cross-checked errors. IPD were requested from authors of the selected studies (SAVE [NCT00738179], ISAACC [NCT01335087], and RICCADSA [NCT00519597]). Main Outcomes and Measures: One-stage and 2-stage IPD meta-analyses were completed to estimate the effect of CPAP treatment on risk of recurrent major adverse cardiac and cerebrovascular events (MACCEs) using mixed-effect Cox regression models. Additionally, an on-treatment analysis with marginal structural Cox models using inverse probability of treatment weighting was fitted to assess the effect of good adherence to CPAP (≥4 hours per day). Results: A total of 4186 individual participants were evaluated (82.1% men; mean [SD] body mass index, 28.9 [4.5]; mean [SD] age, 61.2 [8.7] years; mean [SD] apnea-hypopnea index, 31.2 [17] events per hour; 71% with hypertension; 50.1% receiving CPAP [mean {SD} adherence, 3.1 {2.4} hours per day]; 49.9% not receiving CPAP [usual care], mean [SD] follow-up, 3.25 [1.8] years). The main outcome was defined as the first MACCE, which was similar for the CPAP and no CPAP groups (hazard ratio, 1.01 [95% CI, 0.87-1.17]). However, an on-treatment analysis by marginal structural model revealed a reduced risk of MACCEs associated with good adherence to CPAP (hazard ratio, 0.69 [95% CI, 0.52-0.92]). Conclusions and Relevance: Adherence to CPAP was associated with a reduced MACCE recurrence risk, suggesting that treatment adherence is a key factor in secondary cardiovascular prevention in patients with OSA.

De-escalated neoadjuvant pertuzumab plus trastuzumab therapy with or without weekly paclitaxel in HER2-positive, hormone receptor-negative, early breast cancer (WSG-ADAPT-HER2+/HR-): survival outcomes from a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: Several de-escalation neoadjuvant strategies have been investigated to reduce the use of chemotherapy in HER2-positive early breast cancer using pathological complete response as a surrogate endpoint; there are few survival data from these trials. Here, we report 5-year survival data in the WSG-ADAPT-HER2+/HR- trial and address the effect of pathological complete response, early therapy response, and molecular subtype. METHODS: WSG-ASAPT-HER2+/HR-, a part of the ADAPT umbrella trial performed in patients with different subtypes of early breast cancer, was an investigator-initiated, multicentre, open-label, randomised, phase 2 trial done at 40 Breast Cancer Centres in Germany. Eligible patients were aged 18 years or older with histologically confirmed, unilateral, primary invasive, non-inflammatory early breast cancer, hormone receptor-negative and HER2-positive status, and an Eastern Cooperative Oncology Group performance status of 0 or 1 or a Karnofsky performance status of at least 80%. Patients were randomly assigned (5:2, block size 21, stratified by centre and clinical nodal status) to 12 weeks of either trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks) plus pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) or trastuzumab plus pertuzumab plus paclitaxel (80 mg/m2 weekly); all drugs were administered intravenously. The primary objective of the trial was to compare the number of patients with a pathological complete response at surgery (ie, no invasive tumour cells in breast and lymph nodes [ypT0/is ypN0], the primary endpoint) in early responders (ie, low cellularity or Ki67 decrease ≥30% after 3 weeks) in the trastuzumab plus pertuzumab group versus all patients (irrespective of an early response) in the trastuzumab plus pertuzumab plus paclitaxel group. Non-inferiority was defined as a pathological complete response no worse than 23% lower in the early-responder proportion of patients in the trastuzumab plus pertuzumab group than in the entire trastuzumab plus pertuzumab plus paclitaxel group. The primary endpoint has been reported previously. Additionally, the primary objective of the ADAPT umbrella trial was the evaluation of the effect of pathological complete response on invasive disease-free survival. At investigator's discretion, further chemotherapy could be omitted in patients with a pathological complete response. Secondary survival endpoints were 5-year invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. The effect of pathological complete response on survival was estimated by Cox regression analysis. All analyses are reported in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01817452, and is closed to recruitment. FINDINGS: Between March 3, 2014, and Oct 6, 2015, 134 patients were recruited and randomly assigned to treatment, 92 to trastuzumab plus pertuzumab and 42 to trastuzumab plus pertuzumab plus paclitaxel. Median follow-up in survivors was 59·9 months (IQR 53·4-61·4). There were no significant differences between the treatment groups in invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. In the trastuzumab plus pertuzumab plus paclitaxel group and in the trastuzumab plus pertuzumab group, the proportions of patients achieving 5-year survival respectively were 98% (95% CI 84-100) and 87% (78-93) for invasive disease-free survival (hazard ratio [HR] 0·32, 95% CI 0·07-1·49; p=0·15); 98% (95% CI 84-100) and 89% (79-94) for relapse-free survival (HR 0·41, 95% CI 0·09-1·91; p=0·25); 100% (95% CI not estimable) and 95% (88-98) for locoregional relapse-free survival (HR 0·41, 95% CI 0·05-3·75; p=0·43); 98% (95% CI 84-100) and 92% (83-96) for distant disease-free survival (HR 0·35, 95% CI 0·04-3·12; p=0·36), and 98% (95% CI 84-100) and 94% (86-97) for overall survival (HR 0·41, 95% CI 0·05-3·63; p=0·43). Pathological complete response was associated with improved invasive disease-free survival (HR 0·14, 95% CI 0·03-0·64; p=0·011). Two invasive disease-free survival events occurred after a pathological complete response (one in each treatment group). INTERPRETATION: The WSG-ADAPT-HER2+/HR- trial showed good survival rates in patients with a pathological complete response after de-escalated 12-week trastuzumab plus pertuzumab with or without weekly paclitaxel. Omission of further chemotherapy did not affect invasive disease-free survival in patients with a pathological complete response. 12 weeks of weekly paclitaxel plus dual HER2 blockade could be an efficacious de-escalated neoadjuvant regimen in patients with hormone receptor-negative, HER2-positive early breast cancer with high pathological complete response rates and good 5-year outcomes. Further trials of this approach are ongoing. FUNDING: Roche, Bayer. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Adjuvant radiotherapy and local recurrence in vulvar cancer - a subset analysis of the AGO-CaRE-1 study.

BACKGROUND: The impact of adjuvant radiotherapy (RT) to the vulva with regard to prognosis and local recurrence in patients with vulvar squamous cell cancer (VSCC) is poorly described. PATIENTS AND METHODS: In the AGO-CaRE-1 study 1618 patients with primary VSCC FIGO stage ≥ IB, treated between 1998-2008, were documented. In this retrospective subanalysis, 360 patients were included based on the following criteria: nodal involvement (pN+), known RT treatment and known radiation fields. RESULTS: The majority had pT1b/pT2 tumors (n=299; 83.1%). In 76.7%, R0 resection was achieved. 57/360 (15.8%) N+ patients were treated with adjuvant RT to the groins/pelvis and 146/360 (40.5%) received adjuvant RT to the vulva and groins/pelvis. 157/360 (43.6%) patients did not receive any adjuvant RT. HPV status was available in 162/360 patients (45.0%), 75/162 tumors were HPV+(46.3%), 87/162 (53.7%) HPV-. During a median follow-up of 17.2 months, recurrence at the vulva only occurred in 25.5% of patients without adjuvant RT, in 22.8% of patients with adjuvant RT to groins/pelvis and in 15.8% of patients with adjuvant RT to the vulva and groins/pelvis respectively. The risk reducing effect of local RT was independent of the resection margin status. 50% disease free survival time (50% DFST) indicated a stronger impact of adjuvant RT to the vulva in HPV+ compared to HPV- patients (50% DFST 20.7 months vs. 17.8 months). CONCLUSION: Adjuvant RT to the vulva was associated with a lower risk for local recurrence in N+ VSCC independent of the resection margin status. This observation was more pronounced in patients with HPV+ tumors in comparison to HPV- tumors.

Magnetic resonance imaging and ultrasound for prediction of residual tumor size in early breast cancer within the ADAPT subtrials.

BACKGROUND: Prediction of histological tumor size by post-neoadjuvant therapy (NAT) ultrasound and magnetic resonance imaging (MRI) was evaluated in different breast cancer subtypes. METHODS: Imaging was performed after 12-week NAT in patients enrolled into three neoadjuvant WSG ADAPT subtrials. Imaging performance was analyzed for prediction of residual tumor measuring ≤10 mm and summarized using positive (PPV) and negative (NPV) predictive values. RESULTS: A total of 248 and 588 patients had MRI and ultrasound, respectively. Tumor size was over- or underestimated by < 10 mm in 4.4% and 21.8% of patients by MRI and in 10.2% and 15.8% by ultrasound. Overall, NPV (proportion of correctly predicted tumor size ≤10 mm) of MRI and ultrasound was 0.92 and 0.83; PPV (correctly predicted tumor size > 10 mm) was 0.52 and 0.61. MRI demonstrated a higher NPV and lower PPV than ultrasound in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive and in HR-/HER2+ tumors. Both methods had a comparable NPV and PPV in HR-/HER2- tumors. CONCLUSIONS: In HR+/HER2+ and HR-/HER2+ breast cancer, MRI is less likely than ultrasound to underestimate while ultrasound is associated with a lower risk to overestimate tumor size. These findings may help to select the most optimal imaging approach for planning surgery after NAT. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01815242 (registered on March 21, 2013), NCT01817452 (registered on March 25, 2013), and NCT01779206 (registered on January 30, 2013).

Role of Pelvic Lymph Node Resection in Vulvar Squamous Cell Cancer: A Subset Analysis of the AGO-CaRE-1 Study.

BACKGROUND: As the population at risk for pelvic nodal involvement remains poorly described, the role of pelvic lymphadenectomy (LAE) in vulvar squamous cell cancer (VSCC) has been a matter of discussion for decades. METHODS: In the AGO-CaRE-1 study, 1618 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB or higher primary VSCC treated at 29 centers in Germany between 1998 and 2008 were documented. In this analysis, only patients with pelvic LAE (n = 70) were analyzed with regard to prognosis and correlation between inguinal and pelvic lymph node involvement. RESULTS: The majority of patients had T1b/T2 tumors (n = 47; 67.1%), with a median diameter of 40 mm (2-240 mm); 54/70 patients (77.1%) who received pelvic LAE had positive groin nodes. For 42 of these 54 patients, the number of affected groin nodes had been documented as a median of 3; 14/42 (33.3%) of these patients had histologically confirmed pelvic nodal metastases (median number of affected pelvic nodes 3 [1-12]). In these 14 patients, the median number of affected groin nodes was 7 (1-30), with a groin metastases median maximum diameter of 42.5 mm (12-50). Receiver operating characteristic analysis showed an area under the curve of 0.85, with 83.3% sensitivity and 92.6% specificity for the prediction of pelvic involvement in cases of six or more positive groin nodes. No cases of pelvic nodal involvement without groin metastases were observed. Prognosis in cases of pelvic metastasis was poor, with a median progression-free survival of only 12.5 months. CONCLUSION: For the majority of node-positive patients with VSCC, pelvic nodal staging appears unnecessary since a relevant risk for pelvic nodal involvement only seems to be present in highly node-positive disease.

Age, treatment and prognosis of patients with squamous cell vulvar cancer (VSCC) - analysis of the AGO-CaRE-1 study.

BACKGROUND: Despite an increasing incidence with simultaneous decreasing age of onset, vulvar squamous cell carcinoma (VSCC) is still a disease that mainly effects the elderly population. Data on the association of age with prognosis and treatment patterns in VSCC are sparse. METHODS: This is an analysis of the AGO-CaRE-1 cohort. Patients with VSCC (FIGO stage ≥1B), treated at 29 cancer centers in Germany from 1998 to 2008, were included in a centralized database (n = 1618). In this subgroup analysis patients were analyzed according to age [<50 yrs. (n = 220), 50-69 yrs. (n = 506), ≥70 yrs. (n = 521)] with regard to treatment patterns and prognosis. Only patients with documented age, surgical groin staging and known nodal status were included (n = 1247). Median follow-up was 27.5 months. RESULTS: At first diagnosis, women ≥70 yrs. presented with more advanced tumor stages (<0.001), larger tumor diameter (<0.001), poorer ECOG status (<0.001), more frequent HPV negative tumors (p = 0.03) as well as a higher rate of nodal involvement (<0.001). Disease recurrence occurred significantly more often in elderly patients (p = 0.001) and age as well as ECOG status, microscopic residual resection, tumor stage, grading, and (chemo)radiation were independent prognostic factors for death or recurrence in multivariate analysis. 2-year disease-free survival rates were 59.3% (≥70 yrs), 65.8% (50-69 yrs) and 81.1% (<50 yrs), respectively (p < 0.001). CONCLUSIONS: Older women with VSCC present with advanced tumor stages at first diagnosis and have an increased risk of recurrence as well as a decreased 2-year DFS in comparison to younger patients. Potential reasons could be self-awareness and/or more aggressive tumor biology due to HPV independent disease.

p53 and p16 expression profiles in vulvar cancer: a translational analysis by the Arbeitsgemeinschaft Gynäkologische Onkologie Chemo and Radiotherapy in Epithelial Vulvar Cancer study group.

BACKGROUND: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma-a human papillomavirus-dependent pathway characterized by p16 overexpression and a human papillomavirus-independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed. OBJECTIVE: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance. STUDY DESIGN: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction. RESULTS: p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53- (n=132), and p16-/p53- (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53- tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16-/p53- tumors; P<.0001) and showed lower rates of lymph-node involvement (28.0% vs 42.3% for p53+, respectively, 30.2% for p16-/p53- tumors; P=.050). Notably, 2-year-disease-free and overall survival rates were significantly different among the groups: disease-free survival, 47.1% (p53+), 60.2% (p16-/p53-), and 63.9% (p16+/p53-) (P<.001); overall survival, 70.4% (p53+), 75.4% (p16-/p53-), and 82.5% (p16+/p53-) (P=.002). In multivariate analysis, the p16+/p53- phenotype showed a consistently improved prognosis compared with the other groups (hazard ratio, 0.66; 95% confidence interval, 0.44-0.99; P=.042). CONCLUSION: p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.

Vascular aging in long-term survivors of testicular cancer more than 20 years after treatment with cisplatin-based chemotherapy.

BACKGROUND: Late effects of cisplatin-based chemotherapy in testicular cancer survivors (TCS) include cardiovascular morbidity, but little data is available beyond 20 years. The objective was to assess vascular damage in very long-term TCS. METHODS: TCS (treated with chemotherapy or orchiectomy only) and age-matched healthy controls were invited. Study assessment included vascular stiffness with ultrasound measurement of carotid-femoral pulse wave velocity (cf-PWV). RESULTS: We included 127 TCS consisting of a chemotherapy group (70 patients) and an orchiectomy group (57 patients) along with 70 controls. Median follow-up was 28 years (range: 20-42). The cf-PWV (m/s) was higher in TCS than in controls (geometrical mean 8.05 (SD 1.23) vs. 7.60 (SD 1.21), p = 0.04). The cf-PWV was higher in the chemotherapy group than in the orchiectomy group (geometrical mean 8.39 (SD 1.22) vs. 7.61 (SD 1.21), p < 0.01). In the chemotherapy group cf-PWV increased more rapidly as a function of age compared to controls (regression coefficient b 7.59 × 10-3 vs. 4.04 × 10-3; p = 0.03). CONCLUSION: Very long-term TCS treated with cisplatin-based chemotherapy show increased vascular damage compatible with "accelerated vascular aging" and continue to be at risk for cardiovascular morbidity, thus supporting the need for intensive cardiovascular risk management. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is NCT02572934.

Evaluation of soluble carbonic anhydrase IX as predictive marker for efficacy of bevacizumab: A biomarker analysis from the geparquinto phase III neoadjuvant breast cancer trial.

We analyzed the predictive potential of pretreatment soluble carbonic anhydrase IX levels (sCAIX) for the efficacy of bevacizumab in the phase III neoadjuvant GeparQuinto trial. sCAIX was determined by enzyme-linked immunosorbent assay (ELISA). Correlations between sCAIX and pathological complete response (pCR), disease-free and overall survival (DFS, OS) were assessed with logistic and Cox proportional hazard regression models using bootstrapping for robust estimates and internal validation. 1,160 HER2-negative patient sera were analyzed, of whom 577 received bevacizumab. Patients with low pretreatment sCAIX had decreased pCR rates (12.1 vs. 20.1%, p = 0.012) and poorer DFS (adjusted 5-year DFS 71.4 vs. 80.5 months, p = 0.010) compared to patients with high sCAIX when treated with neoadjuvant chemotherapy (NCT). For patients with low sCAIX, pCR rates significantly improved upon addition of bevacizumab to NCT (12.1 vs. 20.4%; p = 0.017), which was not the case in patients with high sCAIX (20.1% for NCT vs. 17.0% for NCT-B, p = 0.913). When analyzing DFS we found that bevacizumab improved 5-year DFS for patients with low sCAIX numerically but not significantly (71.4 vs. 78.5 months; log rank 0.234). In contrast, addition of bevacizumab worsened 5-year DFS for patients with high sCAIX (81 vs. 73.6 months, log-rank 0.025). By assessing sCAIX levels we identified a patient cohort in breast cancer that is potentially undertreated with NCT alone. Bevacizumab improved pCR rates in this group, suggesting sCAIX is a predictive biomarker for bevacizumab with regards to treatment response. Our data also show that bevacizumab is not beneficial in patients with high sCAIX.

Predicting the course of disease in recurrent vulvar cancer - A subset analysis of the AGO-CaRE-1 study.

OBJECTIVE: In vulvar cancer (VSCC), the course of disease with regard to localization of recurrence and relation of different recurrence sites is poorly described. METHODS: The AGO CaRE-1 study is a retrospective survey of treatment patterns and prognostic factors in vulvar cancer. Patients (pts) with primary VSCC, FIGO stage ≥1B treated in Germany from 1998 to 2008 were included in a centralized database (n = 1618). In the current subgroup analysis, different sites of primary recurrence and their impact on disease course and survival were analyzed using multistate and competing risks methods. RESULTS: 1249 pts with surgical groin staging and known lymph-node status (35.8% N+) were included in the analysis. 360 pts (28.8%) developed disease recurrence; thereof 193 (53.6%) at the vulva only, with a cumulative incidence of 12.6% after 2 years. Generally, prognosis after disease depended on recurrence site: Hazard ratios (HRs) (95% confidence interval) to die for pts with compared to without recurrence at the same time: vulvar only: 5.9 (4.3-8.2); groins only: 6.0 (3.0-10.2); vulvar and groins: 14.1 (7.6-26.4); pelvic/distant: 21.2 (15.3-29.4). Fifty-eight (30.1%) pts with local recurrence developed second recurrence. 2-year mortality after any recurrence was 56.3%. After vulvar recurrence pts had a 2-year and 5-year overall survival rate of 82.2% and 66.9%. CONCLUSIONS: Prognosis after recurrence is highly depending on recurrence site. Pts with isolated vulvar recurrence have an impaired prognosis as many affected pts develop second recurrences.

Influence of oral vitamin and mineral supplementation on male infertility: a meta-analysis and systematic review.

This meta-analysis and systematic review investigated evidence of the effect of oral micronutrient supplementation on male fertility. Following searches of PubMed, Ovid/Ovid Medline(r) and Embase, 18 randomized, double-blind, placebo-controlled trials were included in the meta-analysis (seven studies) and/or the systematic review (12 studies). The meta-analysis showed significant improvement in semen parameters for selenium (200µg/day and 100µg/day) (standard mean difference [SMD] 0.64 for oligozoospermia, 1.39 for asthenozoospermia), L-carnitine (2 g/day) and acetyl-L-carnitine (LAC; 1 g/day) combined (SMD 0.57 for asthenozoospermia), and co-enzyme Q10 (200 and 300 mg/day) (SMD 0.95 for oligozoospermia, 1.48 for asthenozoospermia, 0.63 for teratozoospermia). The systematic review identified promising data for supplementation with 66 mg/day zinc combined with folic acid (5 mg/day), and the polyunsaturated fatty acids eicosapentaenoic acid (EPA; 1.12 g/day) and docosahexaenoic acid (DHA; 0.72 g/day). Pregnancy rate was evaluated in a limited number of trials (four in the meta-analysis, three in the systematic review). This analysis suggests supplementation with selenium (alone or combined with N-acetylcysteine), co-enzyme Q10 and the combinations L-carnitine + acetyl-L-carnitine, folic acid + zinc and EPA + DHA is beneficial in the treatment of male infertility. Because of the small number of available studies and low number of participants, further well-designed clinical studies are needed to obtain a better overview of efficient methods of treating male infertility.

Analysis of cause of death: Competing risks or progressive illness-death model?

The analysis of cause of death is increasingly becoming a topic in oncology. It is usually distinguished between disease-related and disease-unrelated death. A frequently used approach is to define death as disease-related when a progression to advanced phases has occurred before, otherwise as disease-unrelated. The data are often analyzed as competing risks, while a progressive illness-death model might in fact describe the situation more precisely. In this study, we investigated under which circumstances this misspecification leads to biased estimations of the state occupation probabilities. We simulated data according to the progressive illness-death model in various settings, analyzed them with a competing risks model and with a progressive illness-death model and compared them to the true state occupation probabilities. Censoring was either added independently of the status or based on the patients' status. The simulations showed that the censoring mechanism was decisive for the bias while neither the progression hazard nor the Markov property was important. Further, we found a slightly increased standard deviation for the competing risk estimator when censoring was independent of the patients' status. For illustration, both methods were applied to two practical examples of chronic myeloid leukemia (CML): one randomized controlled trial and one registry data set. While in the first case both estimators yielded almost identical results, in the latter case, visible differences were found between both methods.

Course and predictors of supportive care needs among Mexican breast cancer patients: A longitudinal study.

OBJECTIVE: This study examined the course and predictors of supportive care needs among Mexican breast cancer patients for different cancer treatment trajectories. METHODS: Data from 172 (66.4% response rate) patients were considered in this observational longitudinal study. Participants were measured after diagnosis, neoadjuvant treatment, surgery, adjuvant treatment, and the first post-treatment follow-up visit. Psychological, Health System and Information, Physical and Daily Living, Patient Care and Support, Sexual, and Additional care needs were measured with the Supportive Care Needs Survey (SCNS-SF34). Linear mixed models with maximum-likelihood estimation were computed. RESULTS: The course of supportive care needs was similar across the different cancer treatment trajectories. Supportive care needs declined significantly from diagnosis to the first post-treatment follow-up visit. Health System and Information care needs were the highest needs over time. Depressive symptoms and time since diagnosis were the most consistent predictors of changes in course of supportive care needs of these patients. CONCLUSIONS: Health system and information care needs of Mexican breast cancer patients need to be addressed with priority because these needs are the least met. Furthermore, patients with high depressive symptoms at the start of the disease trajectory have greater needs for supportive care throughout the disease trajectory.

A weighted combined effect measure for the analysis of a composite time-to-first-event endpoint with components of different clinical relevance.

Composite endpoints combine several events within a single variable, which increases the number of expected events and is thereby meant to increase the power. However, the interpretation of results can be difficult as the observed effect for the composite does not necessarily reflect the effects for the components, which may be of different magnitude or even point in adverse directions. Moreover, in clinical applications, the event types are often of different clinical relevance, which also complicates the interpretation of the composite effect. The common effect measure for composite endpoints is the all-cause hazard ratio, which gives equal weight to all events irrespective of their type and clinical relevance. Thereby, the all-cause hazard within each group is given by the sum of the cause-specific hazards corresponding to the individual components. A natural extension of the standard all-cause hazard ratio can be defined by a "weighted all-cause hazard ratio" where the individual hazards for each component are multiplied with predefined relevance weighting factors. For the special case of equal weights across the components, the weighted all-cause hazard ratio then corresponds to the standard all-cause hazard ratio. To identify the cause-specific hazard of the individual components, any parametric survival model might be applied. The new weighted effect measure can be tested for deviations from the null hypothesis by means of a permutation test. In this work, we systematically compare the new weighted approach to the standard all-cause hazard ratio by theoretical considerations, Monte-Carlo simulations, and by means of a real clinical trial example.

Epidemiology of injuries in outdoor and indoor hockey players over one season: a prospective cohort study.

OBJECTIVES: To determine the incidence and characteristics of hockey ('field hockey') injuries over the course of one outdoor and indoor season. Comparisons of female versus male players, outdoor versus indoor season and match versus practice were performed. METHODS: Female and male teams of the first, second, third, regional and youth divisions were recruited among a local hockey association in Northern Germany, and followed over an indoor and an outdoor season. Exposure times and location, type, severity and cause of injuries during practice and matches were documented by the coaches or medical staff and collected weekly. Prevalence and incidence rates were calculated. RESULTS: Of the 232 players (mean±SD age 20.7±4.7 years, 68.1% male, 31.9% first division), 84 players (36.2%) suffered 108 new injuries during the season. The overall incidence rate was 3.7 injuries per 1000 player hours (95% CI 3.0 to 4.4). The injury incidence was lower in practice (2.7 per 1000 player practice hours, 95% CI 2.0 to 3.3) than in matches (9.7 per 1000 player match hours, 95% CI 6.8 to 12.7), and was similar for female and male players as well as during the outdoor and the indoor season. Most injuries affected the lower limb (thigh, knee and ankle) and occurred without contact (58.3%). Severe injuries (n=34; 31.5%) were predominantly located at the knee and hand/finger. CONCLUSION: Hockey players have a high prevalence and incidence of injuries, especially at the lower limb.

[The behavioral and psychological symptoms of dementia in down syndrome (BPSD-DS) scale: comprehensive assessment of psychopathology in down syndrome]. / De BPSD-DS evaluatieschaal voor dementiegerelateerde gedragsveranderingen bij mensen met downsyndroom.

Behavioral and psychological symptoms of dementia (BPSD) have not been comprehensively studied in people with Down syndrome, despite their high risk on dementia. A novel evaluation scale was developed to identify the nature, frequency and severity of behavioral changes (83 behavioral items in 12 clinically defined sections). Central aim was to identify items that change in relation to the dementia status. Structured interviews were conducted with informants of people with Down syndrome without dementia (DS, N = 149), with questionable dementia (DS + TD, N = 65) and with diagnosed dementia (DS + AD, N = 67). Group comparisons showed a pronounced increase in frequency and severity of items about anxiety, sleep disturbances, agitation & stereotypical behavior, aggression, apathy, depressive symptoms, and, eating/drinking behavior. The proportion of individuals presenting an increase was highest in the DS + AD group and lowest in the DS group. Interestingly, among DS + TD individuals, a substantial proportion already presented increased anxiety, sleep disturbances, apathy and depressive symptoms, suggesting that these changes may be early alarm signals of dementia. The scale may contribute to a better understanding of the changes, adapting daily care/support, and providing suitable therapies to people with Down syndrome. The scale needs to be optimized based on the results and experiences. The applicability, reliability and validity require further study.

Acute versus Chronic Myocardial Infarction: Diagnostic Accuracy of Quantitative Native T1 and T2 Mapping versus Assessment of Edema on Standard T2-weighted Cardiovascular MR Images for Differentiation.

Purpose To analyze the diagnostic accuracy of native T1 and T2 mapping compared with visual and quantitative assessment of edema on T2-weighted cardiac magnetic resonance (MR) images to differentiate between acute and chronic myocardial infarction. Materials and Methods This study had institutional ethics committee approval. Written informed consent was obtained from 67 consecutive patients (57 years ± 12; 78% men) with a first acute myocardial infarction, who were prospectively enrolled between April 2011 and June 2015. Four serial 1.5-T MR imaging examinations were performed at 8 days ± 5, 7 weeks ± 2, 3 months ± 0.5, and 6 months ± 1.4 after infarction and included T2-weighted, native T1/T2 mapping, and late gadolinium enhancement MR imaging. Complete follow-up data were obtained in 42 patients. Regional native T1/T2 relaxation time, T2-weighted ratio, and extracellular volume were serially measured in infarcted and remote myocardium. Receiver operating characteristic (ROC) analysis was used to determine the diagnostic accuracy of the MR imaging parameters for discriminating between acute and chronic myocardial infarction. Results Native T1 of infarcted myocardium decreased from 1286 msec ± 99 at baseline to 1077 msec ± 50 at 6 months (P < .0001), whereas T2 decreased from 84 msec ± 10 to 58 msec ± 4 (P < .0001). The T2-weighted ratio decreased from 4.1 ± 1.0 to 2.4 ± 0.6 (P < .0001). Of all the MR imaging parameters obtained, native T1 and T2 yielded the best areas under the ROC curve (AUCs) of 0.975 and 0.979, respectively, for differentiating between acute and chronic myocardial infarction. Visual analysis of the presence of edema at standard T2-weighted cardiac MR imaging resulted in an inferior AUC of 0.863 (P < .01). Conclusion Native T1 and T2 of infarcted myocardium are excellent discriminators between acute and chronic myocardial infarction and are superior to all other MR imaging parameters. Online supplemental material is available for this article.

Outcomes in coronary artery disease patients with sleepy obstructive sleep apnoea on CPAP.

Coronary artery disease (CAD) patients with obstructive sleep apnoea (OSA) have increased risk for major adverse cardiovascular and cerebrovascular events (MACCEs) compared with CAD patients without OSA. We aimed to address if the risk is similar in both groups when OSA patients are treated.This study was a parallel observational arm of the RICCADSA randomised controlled trial, conducted in Sweden between 2005 and 2013. Patients with revascularised CAD and OSA (apnoea-hypopnoea index (AHI) ≥15 events·h-1) with daytime sleepiness (Epworth Sleepiness Scale score ≥10) were offered continuous positive airway pressure (CPAP) (n=155); CAD patients with no OSA (AHI <5 events·h-1) acted as controls (n=112), as a randomisation of sleepy OSA patients to no treatment would not be ethically feasible. The primary end-point was the first event of MACCEs. Median follow-up was 57 months.The incidence of MACCEs was 23.2% in OSA patients versus 16.1% in those with no OSA (adjusted hazard ratio 0.96, 95% CI 0.40-2.31; p=0.923). Age and previous revascularisation were associated with increased risk for MACCEs, whereas coronary artery bypass grafting at baseline was associated with reduced risk.We conclude that the risk for MACCEs was not increased in CAD patients with sleepy OSA on CPAP compared with patients without OSA.

Adaptive servo ventilation for central sleep apnoea in heart failure: SERVE-HF on-treatment analysis.

This on-treatment analysis was conducted to facilitate understanding of mechanisms underlying the increased risk of all-cause and cardiovascular mortality in heart failure patients with reduced ejection fraction and predominant central sleep apnoea randomised to adaptive servo ventilation versus the control group in the SERVE-HF trial.Time-dependent on-treatment analyses were conducted (unadjusted and adjusted for predictive covariates). A comprehensive, time-dependent model was developed to correct for asymmetric selection effects (to minimise bias).The comprehensive model showed increased cardiovascular death hazard ratios during adaptive servo ventilation usage periods, slightly lower than those in the SERVE-HF intention-to-treat analysis. Self-selection bias was evident. Patients randomised to adaptive servo ventilation who crossed over to the control group were at higher risk of cardiovascular death than controls, while control patients with crossover to adaptive servo ventilation showed a trend towards lower risk of cardiovascular death than patients randomised to adaptive servo ventilation. Cardiovascular risk did not increase as nightly adaptive servo ventilation usage increased.On-treatment analysis showed similar results to the SERVE-HF intention-to-treat analysis, with an increased risk of cardiovascular death in heart failure with reduced ejection fraction patients with predominant central sleep apnoea treated with adaptive servo ventilation. Bias is inevitable and needs to be taken into account in any kind of on-treatment analysis in positive airway pressure studies.

Effect of Positive Airway Pressure on Cardiovascular Outcomes in Coronary Artery Disease Patients with Nonsleepy Obstructive Sleep Apnea. The RICCADSA Randomized Controlled Trial.

RATIONALE: Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), many of whom do not report daytime sleepiness. First-line treatment for symptomatic OSA is continuous positive airway pressure (CPAP), but its value in patients without daytime sleepiness is uncertain. OBJECTIVES: To determine the effects of CPAP on long-term adverse cardiovascular outcome risk in patients with CAD with nonsleepy OSA. METHODS: This single-center, prospective, randomized, controlled, open-label, blinded evaluation trial was conducted between December 2005 and November 2010. Consecutive patients with newly revascularized CAD and OSA (apnea-hypopnea index ≥15/h) without daytime sleepiness (Epworth Sleepiness Scale score <10) were randomized to auto-titrating CPAP (n = 122) or no positive airway pressure (n = 122). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Median follow-up was 57 months. The incidence of the primary endpoint did not differ significantly in patients who did versus did not receive CPAP (18.1% vs. 22.1%; hazard ratio, 0.80; 95% confidence interval, 0.46-1.41; P = 0.449). Adjusted on-treatment analysis showed a significant cardiovascular risk reduction in those who used CPAP for ≥4 versus <4 hours per night or did not receive treatment (hazard ratio, 0.29; 95% confidence interval, 0.10-0.86; P = 0.026). CONCLUSIONS: Routine prescription of CPAP to patients with CAD with nonsleepy OSA did not significantly reduce long-term adverse cardiovascular outcomes in the intention-to-treat population. There was a significant reduction after adjustment for baseline comorbidities and compliance with the treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 00519597).