Disease-specific Endpoints Research Articles

Current Treatments for Generalized Pustular Psoriasis: A Narrative Summary of a Systematic Literature Search.

Generalized pustular psoriasis (GPP) is a rare, chronic and potentially life-threatening autoinflammatory skin disease characterized by widespread eruption of sterile pustules, with or without systemic inflammation. GPP can significantly reduce patients' quality of life (QoL). Several therapeutic approaches have been described in the literature, but there is no consensus on optimal treatment. In this review, we summarize published literature on efficacy, safety and QoL outcomes associated with current treatment of GPP with both approved and non-approved products. Embase and MEDLINE databases were searched (1980-September 2023). A search protocol was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered on the PROSPERO database (CRD42021215437). Details on publication, population, intervention, efficacy, safety and QoL were captured and checked by independent reviewers. In total, 118 publications were included, with only 19% of publications reporting on the results of clinical trials. Treatment modalities reported for GPP included non-biologic systemic therapies such as retinoids, cyclosporine and methotrexate, topical agents, biologics and small molecules, among others. Results were highly heterogeneous and methodological quality was very low, with only the interleukin-36R inhibitor spesolimab reporting results from placebo-controlled randomized trials; based on this, spesolimab is now approved for GPP treatment in regions including the USA, Japan, China, the EU and several other countries. Some other biologics are approved exclusively in Japan and Taiwan for the treatment of GPP based on open-label studies with small patient numbers in lieu of double-blind studies. Non-standardization of clinical outcomes across studies remains a major hurdle in reaching a consensus on optimal treatment. However, recently trials have been conducted using well-defined, disease-specific endpoints to evaluate GPP-targeted treatments, which will hopefully advance patient care. In conclusion, this review highlights the need for prospective randomized studies with GPP-specific endpoints to determine the optimal treatment strategy.

The landscape of real-world evidence of rituximab utilization and clinical outcomes in patients with cancer, rheumatoid arthritis, and multiple sclerosis: A scoping review.

Rituximab (RTX) is an anti-CD20 monoclonal antibody that is used to treat various conditions in cancer, rheumatoid arthritis (RA), and multiple sclerosis (MS). Although RTX has been used in the United States for almost 3 decades, questions remain regarding its real-world utilization and effectiveness. To describe the state of observational research and real-world evidence evaluating RTX in oncology, RA, and off-label use in MS. A broad search was conducted in MEDLINE, Embase, and CINAHL covering the period of January 2010 to June 2022. Two reviewers independently screened all identified records for each disease category (cancer, RA, MS) beginning with title review, followed by abstract, and full-text review to identify relevant publications to include in the final analysis. Data were extracted and summarized for each disease based on overall trends, similarities, and differences across included studies and stratified by disease state. A total of 260 studies met eligibility criteria, with 79 studies for the RA cohort, 144 for cancer, and 37 for MS. Across all disease cohorts, most studies (n = 189; 72.7%) were retrospective. 171 (65.8%) studies used hospital or electronic health record data as their data source and 65 (23.2%) used registry databases. Most studies (n = 153; 58.8%) assessed the effectiveness of RTX measured by disease-specific endpoints, followed by safety (n = 60; 23.1%), treatment patterns (n = 32; 12.3%), and descriptive analyses assessing treatment adherence and economic burden of disease (n = 16; 6.2%). Although safety was not the primary outcome for most studies, the majority of studies across all disease states still reported some form of safety measure. Conclusive statements on RTX's benefit varied across disease states, with MS having the most (n = 30; 81.1%) studies suggesting the drug's positive benefit. There were limited studies assessing RTX use, associated economic burden, and biosimilar switching. The findings underscore the need for health care providers to better understand the treatment landscape and utilization of RTX, particularly in terms of patient selection, timing of initiation, and long-term outcomes. Real-world evidence can help support health care decisions and treatment using rituximab.

Dose selection for biological enzyme replacement therapy indicated for inborn errors of metabolism.

This paper summarizes key features of the dose-finding strategies used in the development of 11 approved new molecular entities that are first-in-class enzyme replacement therapy (ERT), with a goal to gain insight into the dose exploration approaches to inform efficient dose-finding in future development of biological products for Inborn Errors of Metabolism (IEM). Dose exploration should preferably begin in invitro studies, followed by testing multiple doses in an appropriate animal disease model, when available, which can provide important information for dose assessment in humans. Performing adequate dose-finding in early phase clinical studies in a well-defined study population, including pediatric subjects, is generally critical to inform dose selection for pivotal trials; alternatively, additional dose exploration can be incorporated as part of a pivotal trial. Two important considerations for successful dose selection include (1) identifying appropriate disease-specific endpoints, including pharmacodynamic (PD) end points and intermediate clinical end points or clinical end points, and (2) designing a study with adequate treatment durations for evaluating these end points. Appropriately selected PD biomarkers is useful for dose selection, and early development of these biomarkers can facilitate the overall clinical development program. Optimization of ERT doses, as well as evaluations of patient intrinsic factors and/or immune tolerance strategies may be necessary to overcome antibody responses or increase efficacy in IEM.

Real-world effectiveness of golimumab in the treatment of patients with active rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis who failed initial TNF-α inhibitor therapy: a pooled analysis of European prospective observational studie.

Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) patients often experience secondary non-response to a first-line tumour necrosis factor alpha inhibitor (TNFαi). This pooled analysis of six observational studies in Europe (GO-BEYOND program) provides an estimate of second-line golimumab (GLM) effectiveness for these rheumatic diseases. The GO-BEYOND studies included common disease-specific endpoints allowing for a pooled analysis. Patients had discontinued one prior TNFαi (due to loss of efficacy, tolerability, or inconvenience) and were followed for 12 months after GLM initiation. Primary endpoints included the proportion of patients achieving low disease activity (LDA, DAS28-CRP<3.2) in RA, minimal disease activity (MDA, fulfilment of 5 of 7 outcome measures) in PsA, or low disease activity (ASDAS<2.1) in axSpA at 6 months. Disease activity at 3 and 12 months and quality of life (QoL; EQ-5D-3L) were also assessed. Adverse events were monitored. Protocol-specified analyses were based on observed data. In 712 patients, (n=325, RA; 186, PsA; 201, axSpA), mean age was 54 years, 64% were female, and median disease duration was 5 years. Primary endpoints were achieved in 58.3% (RA), 45.5% (PsA), and 45.4% (axSpA) of patients; disease activity improvements were observed at 3 and 12 months and EQ-5D-3L results showed improved QoL over time. The treatment persistence rate at 12 months was 67.8% of patients. No new safety signals were observed. This pooled analysis of the GO-BEYOND studies showed that treatment with GLM was effective and represented a valid second-line option for RA, PsA, and axSpA patients.

Burden of disease due to PM2.5 and NO2 emissions from coal-fired power plants in Germany

Background Coal combustion emits pollutants that affect human health. We aimed to quantify the environmental burden of disease (EBD) due to PM2.5 and NO2 emissions from coal-fired power-plants (CFPPs) in Germany. Methods Emissions from CFPPs and other sources were extracted from official German and European inventories. The contribution of CFPPs to AP in Germany was calculated with the chemical transport model REM-CALGRID on a grid of 2x2 km2 for 2015. Mean annual PM2.5 and NO2 exposure was assessed by intersecting the contribution of CFPPs to AP with the population distribution in Germany for 2015. Age- and sex-stratified mortality data and life-expectancy were extracted from the Federal Health Monitoring. The attributable EBD, expressed as Years of Life Lost (YLL), was calculated based on relative risk estimates for natural cause mortality from single- and multi-pollutant models for PM2.5 and NO2 from the ELAPSE (Effects of Low-Level Air Pollution: A Study in Europe) study. For disease-specific endpoints, we calculated YLL using relative risk estimates for PM2.5 from the Global Burden of Disease 2019 study and for NO2 from the ELAPSE study. Results The mean (min; max) calculated contributions of CFPPs to ambient PM2.5 and NO2 concentrations in Germany in 2015 were 0.25 µg/m3 (0.05 µg/m3; 3.11 µg/m3) and 0.48 µg/m3 (0.03 µg/m3; 14.95 µg/m3), respectively. The combined attributable EBD for natural cause mortality was 71,912 YLL (95% CI 52,818; 91,510). The sum of YLL for disease specific endpoints was 12,483 YLL for PM2.5 (coronary heart disease 49.7% of YLL, lung cancer 29.5%, COPD 8.9%, stroke 8.6% and diabetes mellitus type 2 3.3%) and 18,380 YLL for NO2 (cardiovascular mortality 96.8%, COPD mortality 3.2%). Conclusion In 2015, disease burden due to PM2.5 and NO2 emissions from CFPPs in Germany was substantial and dominated by coronary heart disease and cardiovascular mortality. Keywords Coal-fired power-plants; health

Comparing Local and Systemic Control between Partial- and Whole-Breast Radiotherapy in Low-Risk Breast Cancer-A Meta-Analysis of Randomized Trials.

Simple SummaryThis meta-analysis compares the treatment results of partial-breast radiotherapy to those of whole-breast radiotherapy after breast conserving surgery in early-stage breast cancer. The results show that the tumor is slightly more likely to recur in the operated breast after partial radiotherapy compared to radiation therapy to the whole breast. These additional recurrences are located away from the original tumor bed. The technique by which partial-breast radiotherapy is applied also appears to affect the likeliness of tumor regrowth. Intraoperative radiation, given during the removal of the tumor, might lead to more relapses compared to other techniques. Partial-breast treatment also led to more lymph node recurrences in a very small number of patients. However, rates of distant relapses were not increased. We were unable to identify a specific subgroup that was most suitable for partial-breast irradiation. The differences between treatment of partial- and whole-breast radiotherapy are small when the patient groups and the radiation technique are appropriately selected.Purpose/Objective: The standard treatment for localized low-risk breast cancer is breast-conserving surgery, followed by adjuvant radiotherapy and appropriate systemic therapy. As the majority of local recurrences occur at the site of the primary tumor, numerous trials have investigated partial-breast irradiation (PBI) instead of whole-breast treatment (WBI) using a multitude of irradiation techniques and fractionation regimens. This meta-analysis addresses the impact on disease-specific endpoints, such as local and regional control, as well as disease-free survival of PBI compared to that of WBI in published randomized trials. Material and Methods: We conducted a systematic literature review and searched for randomized trials comparing WBI and PBI in early-stage breast cancer with publication dates after 2009. The meta-analysis was based on the published event rates and the effect sizes for available oncological endpoints of at least two trials reporting on them. We evaluated in-breast tumor recurrences (IBTR), local recurrences at the primary site and elsewhere in the ipsilateral breast, regional recurrences (RR), distant metastasis-free interval (DMFI), disease-free survival (DFS), contralateral breast cancer (CBC), and second primary cancer (SPC). Furthermore, we aimed to assess the impact of different PBI techniques and subgroups on IBTR. We performed all statistical analyses using the inverse variance heterogeneity model to pool effect sizes. Results: For the intended meta-analysis, we identified 13 trials (overall 15,561 patients) randomizing between PBI and WBI. IBTR was significantly higher after PBI (OR = 1.66; CI-95%: 1.07–2.58; p = 0.024) with an absolute difference of 1.35%. We detected significant heterogeneity in the analysis of the PBI technique with intraoperative radiotherapy resulting in higher local relapse rates (OR = 3.67; CI-95%: 2.28–5.90; p < 0.001). Other PBI techniques did not show differences to WBI in IBTR. Both strategies were equally effective at the primary tumor site, but PBI resulted in statistically more IBTRs elsewhere in the ipsilateral breast. IBTRs after WBI were more likely to be located at the primary tumor bed, whereas they appeared equally distributed within the breast after PBI. RR was also more frequent after PBI (OR = 1.75; CI-95%: 1.07–2.88; p < 0.001), yet we did not detect any differences in DMFI (OR = 1.08; CI-95%: 0.89–1.30; p = 0.475). DFS was significantly longer in patients treated with WBI (OR = 1.14; CI-95%: 1.02–1.27; p = 0.003). CBC and SPC were not different in the test groups (OR = 0.81; CI-95%: 0.65–1.01; p = 0.067 and OR = 1.09; CI-95%: 0.85–1.40; p = 0.481, respectively). Conclusion: Limiting the target volume to partial-breast radiotherapy appears to be appropriate when selecting patients with a low risk for local and regional recurrences and using a suitable technique.

OP0228 EFFICACY AND SAFETY OF IXEKIZUMAB VERSUS ADALIMUMAB (SPIRIT-H2H) WITH AND WITHOUT CONCOMITANT CONVENTIONAL SYNTHETIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARD) IN BIOLOGIC DMARD-NAÏVE PATIENTS WITH PSORIATIC ARTHRITIS: 52-WEEK RESULTS

Background:Ixekizumab (IXE), a high-affinity monoclonal antibody selectively targeting IL-17A, was superior to adalimumab (ADA) at Week (Wk) 24 for simultaneous achievement of ACR50 and 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI 100) (primary endpoint) in patients (pts) with active PsA from SPIRIT-H2H1. SPIRIT-H2H had two major secondary endpoints and achieved both: noninferiority of IXE to ADA for ACR50 at Wk 24, and superiority of IXE to ADA for PASI 100 at Wk 24.Objectives:To determine how concomitant conventional synthetic DMARD (csDMARD) use affects safety and efficacy of IXE and ADA in prespecified subgroups defined by biologic monotherapy, concomitant MTX use, and concomitant csDMARD use through Wk 52 in SPIRIT-H2H.Methods:SPIRIT-H2H (NCT03151551) was a 52-week, multicentre, randomised, open-label, assessor-blinded, parallel-group study evaluating the efficacy and safety of IXE versus ADA in adults with PsA and naïve to biologic DMARDs. Patients were required to have active PsA fulfilling Classification for Psoriatic Arthritis (CASPAR) criteria and ≥3/68 tender and ≥3/66 swollen joints, ≥3% plaque psoriasis BSA involvement, no prior treatment with bDMARDs, and with prior inadequate response to ≥1 csDMARD (but not necessarily current treatment with csDMARDs). Randomization (1:1) was stratified by concomitant use of csDMARD and the presence/absence of moderate to severe PsO (baseline: BSA≥10% + PASI≥12, + static Physician’s Global Assessment≥3). Patients (N=566) received IXE/ADA through 52 wks according to the labelled dose dependent on presence/absence of moderate-to-severe PsO. In this prespecified subgroup analysis by presence or absence of csDMARDs, efficacy outcomes through wk 52 were compared between IXE and ADA using logistic regression models and Fisher’s exact tests. Missing data were imputed using non-responder imputation.Results:At baseline, 167 of 283 IXE-treated patients and 169 of 283 ADA-treated patients had concomitant MTX use. Of these, 9.0% (15/167) and 7.1% (12/169) treated with IXE and ADA, respectively, were taking an additional csDMARD (sulfasalazine, cyclosporine, or leflunomide). A significantly greater proportion of patients on IXE versus ADA achieved the primary endpoint or PASI 100 when used as monotherapy or in combination with csDMARD (Figure 1A and 1C). At Wk 52, the proportion of patients achieving ACR50 was not statistically different between IXE and ADA, regardless of monotherapy or concomitant csDMARD use (Figure 1B). A significantly higher proportion of patients achieved MDA on IXE compared to ADA in the monotherapy subgroup (49% vs 33%), while the response rates were similar in both combination subgroups (Figure 1D). These data support consistent ACR50, PASI 100, and MDA response for IXE across all three subgroups. Frequencies of adverse events were similar across the three subgroups for IXE and ADA (Figure 2).Conclusion:As with prior studies,2,3consistent efficacy across multiple PsA disease-specific endpoints was observed with IXE in SPIRIT-H2H, regardless of whether IXE was taken as monotherapy or in combination with MTX or another csDMARD. No unexpected safety signals were found for either agent.

Using the multidimensional prognostic index for treatment decisions and monitoring in frail older patients

The routine applicability of clinical guidelines and disease-specific end-points in frail older patients is problematic because of the exclusion of this group from clinical trials, their limited life expectancy, the co-existence of multiple disease states and poor functional status, and the presence of complex drug-drug and drug-disease interactions. In this context, the use of patient-centred end-points that include measures of quality of life might be particularly useful for designing tailored treatment strategies, monitor progress and, ultimately, improve outcomes. The multidimensional prognostic index, an objective, quantifiable, and validated scoring system based on core domains of the comprehensive geriatric assessment, might represent an important tool for the development of clinical guidelines that take into account measures of frailty and patientcentred end-points. However, research is warranted to investigate whether this approach leads to more effective and safe management strategies in old age.

A randomised controlled trial on the effect of inhaled hypertonic saline on quality of life in primary ciliary dyskinesia.

Hypertonic saline inhalation lowers airway mucous viscosity. Increased cough transportability may improve quality of life (QoL) in primary ciliary dyskinesia (PCD).In this randomised controlled trial (RCT), PCD patients received twice-daily inhalations of hypertonic (7%) saline or isotonic (0.9%) saline for 12 weeks, with 4 weeks washout during crossover. Primary outcome was change in QoL measured by the St George's Respiratory Questionnaire (SGRQ) total score. Secondary outcomes were SGRQ subscores, Quality of Life Questionnaire-Bronchiectasis (QoL-B) scores, lower respiratory tract infection symptoms, exacerbations, spirometry, systemic and sputum inflammatory markers, adherence, and adverse events.There was no significant change in median (interquartile range) SGRQ total score between hypertonic saline (-2.6 (-9.0-1.5)) and isotonic saline (-0.3 (-8.1-6.1)) in 22 patients (age range 22-73 years) (p=0.38). QoL-B Health Perception scale improved with hypertonic saline (p=0.03). Adverse events occurred more frequently with hypertonic saline, but were mild.12 weeks of inhaled hypertonic saline did not improve SGRQ total score in adult PCD patients in this RCT, but the sample size was small. On the secondary and more disease-specific end-point of the QoL-B, a significant improvement was observed in the Health Perception scale. This study found little evidence to support the hypothesis that hypertonic saline improves QoL in PCD patients. Weadvise the use of disease-specific outcome measures in future trials.

An analysis of the association between prostate cancer risk loci, PSA levels, disease aggressiveness and disease-specific mortality.

Background:Genome-wide association studies have identified multiple single-nucleotide polymorphsims (SNPs) associated with prostate cancer (PCa). Although these SNPs have been clearly associated with disease risk, their relationship with clinical outcomes is less clear. Our aim was to assess the frequency of known PCa susceptibility alleles within a single institution ascertainment and to correlate risk alleles with disease-specific outcomes.Methods:We genotyped 1354 individuals treated for localised PCa between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to phenotypic data. We investigated associations between 61 SNPs and disease-specific end points using multivariable analysis and also determined if SNPs were associated with PSA at diagnosis.Results:Seven SNPs showed associations on multivariable analysis (P<0.05), rs13385191 with both biochemical recurrence (BR) and castrate metastasis (CM), rs339331 (BR), rs1894292, rs17178655 and rs11067228 (CM), and rs11902236 and rs4857841 PCa-specific mortality. After applying a Bonferroni correction for number of SNPs (P<0.0008), the only persistent significant association was between rs17632542 (KLK3) and PSA levels at diagnosis (P=1.4 × 10−5).Conclusions:We confirmed that rs17632542 in KLK3 is associated with PSA at diagnosis. No significant association was seen between loci and disease-specific end points when accounting for multiple testing. This provides further evidence that known PCa risk SNPs do not predict likelihood of disease progression.

Developments and controversies in the management of noninvasive bladder cancer

To summarize recent developments and controversies in the diagnosis and management of nonmuscle invasive bladder cancer (NMIBC). The majority of incident bladder cancer diagnoses are noninvasive. The mainstay of diagnosis remains cystoscopy and transurethral resection, with enhanced optical techniques potentially improving detection of nascent disease. Intravesical chemotherapeutic and immunotherapeutic agents reduce the likelihood of recurrence and progression, with novel agents showing promise. The identification of variant histology with aggressive phenotypes permits identification of patients unlikely to respond to intravesical agents, in whom early cystectomy is advocated. Risk stratification of patients with NMIBC continues to improve and should be used to inform surveillance and treatment paradigms. Tobacco cessation may improve disease-specific endpoints and overall mortality. NMIBC encompasses a variety of tumors with heterogeneous natural histories, making clinical management challenging. Improved detection with novel technologies and optimization of existing treatment modalities hold promise of improving oncologic outcomes in the future.

Effect of treatment gaps in elderly patients with dementia treated with cholinesterase inhibitors

Pariente et al.1 concluded that “Treatment gaps do not compromise the outcome of patients treated with cholinesterase inhibitors in a real-life setting.” However, their conclusion is based on the effect of treatment gaps on risk of institutionalization and death, rather than on disease-specific endpoints. It has been shown that the beneficial effect of cholinesterase inhibitors on cognition, an important disease-specific endpoint, disappears within 3 weeks of discontinuation.2,3 In addition, as mentioned by Pariente et al., treatment gaps are likely to occur in patients in whom reinitiation of treatment is worthwhile. From this, we infer that selection may have played a role, consequently limiting the generalizability of the study to a real-life setting.4 This study is welcome because the authors address an important issue. However, because of these caveats, clinicians should not discontinue treatment too readily, as discontinuation of treatment does affect cognition, thereby compromising the outcome of patients.

Psychiatric co‐morbidity is associated with increased risk of surgery in Crohn's disease

Psychiatric co-morbidity, in particular major depression and anxiety, is common in patients with Crohn's disease (CD) and ulcerative colitis (UC). Prior studies examining this may be confounded by the co-existence of functional bowel symptoms. Limited data exist examining an association between depression or anxiety and disease-specific endpoints such as bowel surgery. To examine the frequency of depression and anxiety (prior to surgery or hospitalisation) in a large multi-institution electronic medical record (EMR)-based cohort of CD and UC patients; to define the independent effect of psychiatric co-morbidity on risk of subsequent surgery or hospitalisation in CD and UC, and to identify the effects of depression and anxiety on healthcare utilisation in our cohort. Using a multi-institution cohort of patients with CD and UC, we identified those who also had co-existing psychiatric co-morbidity (major depressive disorder or generalised anxiety). After excluding those diagnosed with such co-morbidity for the first time following surgery, we used multivariate logistic regression to examine the independent effect of psychiatric co-morbidity on IBD-related surgery and hospitalisation. To account for confounding by disease severity, we adjusted for a propensity score estimating likelihood of psychiatric co-morbidity influenced by severity of disease in our models. A total of 5405 CD and 5429 UC patients were included in this study; one-fifth had either major depressive disorder or generalised anxiety. In multivariate analysis, adjusting for potential confounders and the propensity score, presence of mood or anxiety co-morbidity was associated with a 28% increase in risk of surgery in CD (OR: 1.28, 95% CI: 1.03-1.57), but not UC (OR: 1.01, 95% CI: 0.80-1.28). Psychiatric co-morbidity was associated with increased healthcare utilisation. Depressive disorder or generalised anxiety is associated with a modestly increased risk of surgery in patients with Crohn's disease. Interventions addressing this may improve patient outcomes.

Longitudinal changes of outcome measures in spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy is an adult-onset, hereditary motor neuron disease caused by the expansion of a trinucleotide CAG repeat within the gene encoding the androgen receptor. To date, several agents have been shown to prevent or slow disease progression in animal models of this disease. For the translational research of these agents, it is necessary to perform the detailed analysis of natural history with quantitative outcome measures and to establish sensitive and validated disease-specific endpoints in the clinical trials. To this end, we performed a prospective observation of disease progression over 3 years in 34 genetically confirmed Japanese patients with spinal and bulbar muscular atrophy by using quantitative outcome measures, including functional and blood parameters. The baseline evaluation revealed that CAG repeat length in the androgen receptor gene correlated not only with the age of onset but also with the timing of substantial changes in activity of daily living. Multiple regression analyses indicated that the serum level of creatinine is the most useful blood parameter that reflects the severity of motor dysfunction in spinal and bulbar muscular atrophy. In 3-year prospective analyses, a slow but steady progression was affirmed in most of the outcome measures we examined. In the analyses using random coefficient models that summarize the individual data into a representative line, disease progression was not affected by CAG repeat length or onset age. These models showed large interindividual variation, which was also independent of the differences of CAG repeat size. Analyses using these models also demonstrated that the subtle neurological deficits at an early or preclinical stage were more likely to be detected by objective motor functional tests such as the 6-min walk test and grip power or serum creatinine levels than by functional rating scales, such as the revised amyotrophic lateral sclerosis functional rating scale or modified Norris scale. Categorization of the clinical phenotypes using factor analysis showed that upper limb function is closely related to bulbar function, but not to lower limb function at baseline, whereas the site of onset had no substantial effects on disease progression. These results suggest that patients with spinal and bulbar muscular atrophy show a slow but steady progression of motor dysfunction over time that is independent of CAG repeat length or clinical phenotype, and that objective outcome measures may be used to evaluate disease severity at an early stage of this disease.

VITAMIN D Insufficiency Affects Time to FIRST TREATMENT (TFT) In EARLY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Abstract 4601Recent data suggest that vitamin D insufficiency is related to inferior prognosis in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We evaluated whether 25(OH)D serum levels affect time to first treatment (TFT), a disease-specific end point, in 130 previously untreated CLL patients with early disease (i.e., Binet stage A). Measurement of 25(OH)D was conducted by means of a direct, competitive chemiluminescence immunoassay using the DiaSorin LIAISON 25(OH)D TOTAL assay (DiaSorin, Inc., Stillwater, Minnesota). Levels of 25(OH)D did not reflect Rai substages (P=0.27), Beta2-microglobulin (P=0.52), absolute lymphocyte count (P=0.21), FISH chromosome abnormalities (P=0.11), mutational status of IgVH (P=0.43), ZAP-70- (P=0.53) or CD38-expression (P=0.82).Overall, 42 patients (31.8%) had severe vitamin D insufficiency (< 10 ng/mL), 66 (50%) had mild to moderate insufficiency (10–24 ng/mL), and 24 (18.1%) had 25(OH)D levels within the optimal range(25–80 ng/mL), with no relationship between the month of sample collection and 25(OH)D level (P=0.188). A patient stratification according to these 3 groups led to significant difference in terms of TFT, with vitamin D insufficient patients having the shortest TFT (P=0.02). With respect to continuous 25(OH)D levels and clinical outcome, TFT was shorter as 25(OH)D decreased until a value of 13.5 ng/mL at which point the association of 25(OH)D and TFT remained constant. As a matter of fact, the 25(OH)D value of 13.5 ng/mL identified two patients subsets with different TFT risk (HR=1.91; 95%CI=1.06–3.44;P=0.03). In multivariate analysis the variable entering the model at a significant level were mutational status of IgVH (P<0.0001), serum thymidine kinase ((P=0.02) and absolute lymphocyte count (P=0.03). Thus confirming the Mayo clinic experience, our data provide further evidence that 25(OH)D levels may be an important host factor influencing TFT of Binet stage A patients. Since the effect of 25(OH)D insufficiency may be may be relevant in this subset of patients who are generally observed for years before starting therapy future trials should address the role of vitamin D therapy in delaying disease-progression. Disclosures:No relevant conflicts of interest to declare.

Vitamin D insufficiency predicts time to first treatment (TFT) in early chronic lymphocytic leukemia (CLL)

Although vitamin D insufficiency is related to inferior prognosis in some cancers, limited data exist in hematologic malignancies. We evaluated the relationship between 25(OH)D serum levels and time to first treatment (TFT), a disease-specific end point, in 130 previously untreated Binet stage A chronic lymphocytic leukemia (CLL) patients. Measurement of 25(OH)D was performed by means of a direct, competitive chemiluminescence immunoassay using the DiaSorin LIAISON 25(OH)D TOTAL assay (DiaSorin, Inc., Stillwater, Minnesota). Overall, 41 patients (31.5%) had severe vitamin D insufficiency (<10ng/mL), 66 (50.7%) had mild to moderate insufficiency (10–24ng/mL), and 23 (17.6%) had 25(OH)D levels within the optimal range (25–80ng/mL), with no relationship with between the season of sample collection and 25(OH)D level (P=0.188). A patient stratification according to these 3 groups led to significant difference in terms of TFT, with vitamin D insufficient patients having the shortest TFT (P=0.02). With respect to continuous 25(OH)D levels and clinical outcome, TFT was shorter as 25(OH)D decreased until a value of 13.5ng/mL at which point the association of 25(OH)D and TFT remained constant. As a matter of fact, the 25(OH)D value of 13.5ng/mL identified two patients subsets with different TFT risk (HR=1.91; 95% CI=1.06–3.44; P=0.03). In multivariate analysis the variable entering the model at a significant level were mutational status of IgVH (P<0.0001), serum thymidine kinase (P=0.02) and absolute lymphocyte count (P=0.03). Thus confirming the Mayo clinic experience, our data provide further evidence that 25(OH)D levels may be an important host factor influencing TFT of Binet stage A patients. Whether normalizing vitamin D levels may delay disease-progression of patients with early disease will require testing in future trials.

The Factors Affecting Treatment Outcomes of a Single Institution's Experience with Locally Advanced NSCLC Treated with PET guided IMRT

Our goal is to assess the patterns of failure and toxicity for a cohort of IIIA or IIIB non small cell lung cancer patients who were treated at a single institution using PET guided IMRT. We identified 49 consecutive patients who underwent pre treatment PET scans and were treated with IMRT without elective nodal irradiation from January 2006 to January 2010. A median dose of 66 Gy (59.4 - 72) with 95% PTV volume receiving at least 95% of the prescription dose; 39 patients (80%) underwent concurrent chemotherapy. 43 patients (87%) underwent a 4DCT; of these, 9 (18%) were treated with Respiratory Gating (RG) (Varian RPM™). All treatment plans were generated using Varian Eclipse ™ with lung inhomogeneity correction. The study endpoints were local control (LC), distant metastasis (DM), overall survival (OS) and late grade ≥3 radiation pneumonitis. All local failures were assessed with co-registration of follow up CT and planning CT. Disease or treatment covariates include: PTV size, histology, T, N, KPS, RG, total dose, concurrent chemotherapy and smoking pack years. Data was analyzed using the Cox proportional hazards model, Kaplan Meier curve, Fisher exact test and Wilson rank test for comparison of RG versus non RG. The median follow up time was 636 days (280 to 1779 days) with LC of 57%, DM of 55% and OS of 55%. Of the 21 local failures: 19 (90%) occurred within the 95% isodose curve and 2 (10%) failures occurred adjacent to the 95% isodose curve. Grade 3 pneumonitis occurred in 2 patients (4%). In Cox regression analyses, at 2 years, PTV size, histology, T, N, KPS, total dose, concurrent chemotherapy and smoking history were not associated with the disease specific endpoints. For the 9 patients treated with RG, LC was 27% vs. 63% for non RG (HR 3.05 (1.21 - 7.69) p = 0.013), DM rate was 79% vs. 51% (HR 3.36 (1.36 - 8.33) p = 0.006) and OS was 43% vs. 52% (HR 1.92 (0.19 - 1.44) p = 0.52) The RG group had a higher nodal stage (p = 0.047) and a larger PTV volume (p = 0.021), but on multivariate analysis controlling for nodal stage and PTV volume, RG still predicted for worse LC (p = 0.042). PET guided IMRT for this locally advanced NSCLC cohort had low grade 3 toxicity and good LC; a high DM rate was seen which is consistent with the nature of the disease. On multivariate analysis, the only co-variate to register significance was RG, which was associated with decreased LC and increased DM. While an underlying selection bias cannot be excluded, this study raises caution with the use of RG in IMRT. Studies with improved techniques for respiratory control and fiducial placement will be forthcoming.

Competing risks and the clinical community: irrelevance or ignorance?

Life expectancy has dramatically increased in industrialized nations over the last 200 hundred years. The aging of populations carries over to clinical research and leads to an increasing representation of elderly and multimorbid individuals in study populations. Clinical research in these populations is complicated by the fact that individuals are likely to experience several potential disease endpoints that prevent some disease-specific endpoint of interest from occurrence. Large developments in competing risks methodology have been achieved over the last decades, but we assume that recognition of competing risks in the clinical community is still marginal. It is the aim of this article to address translational aspects of competing risks to the clinical community. We describe clinical populations where competing risks issues may arise. We then discuss the importance of agreement between the competing risks methodology and the study aim, in particular the distinction between etiologic and prognostic research questions. In a review of 50 clinical studies performed in individuals susceptible to competing risks published in high-impact clinical journals, we found competing risks issues in 70% of all articles. Better recognition of issues related to competing risks and of statistical methods that deal with competing risks in accordance with the aim of the study is needed. Copyright © 2011 John Wiley & Sons, Ltd.

The value of cardiovascular hospitalization as an endpoint for clinical atrial fibrillation research

This editorial refers to ‘Cardiovascular hospitalization as a surrogate endpoint for mortality in studies of atrial fibrillation: report from the Stockholm Cohort Study of Atrial Fibrillation’ by L. Friberg and M. Rosenqvist, on page 626. Cardiovascular (CV) hospitalization has been used as a primary endpoint in clinical studies on atrial fibrillation (AF), but its value remains controversial. Cardiovascular hospitalization is associated with a decreased quality of life, 1 increased costs of care, 2 and increased risk of mortality. 3,4 However, it is also composed of a multiplicity of different clinical conditions ranging from heart failure to angina, and rates may vary among geographical regions and clinical settings. The operational definition and value of CV hospitalization as an endpoint should be well understood to draw valid conclusions in AF research. Mortality is a relevant outcome to assess the effect of therapies in AF patients. However, because death rates are low and existing therapies are effective, mortality trials are challenging to conduct. From the feasibility and cost perspective it is useful to employ surrogate and combined endpoints, but these should be well understood and validated. 5,6 Cardiovascular hospitalization is a potentially useful outcome of clinical importance. The Atrial Fibrillation Follow up Investigation of Rhythm Management (AFFIRM) investigators have shown that CV hospitalization could be a valid outcome in AF trials since it occurs prior to and more often than the true endpoint (mortality), can be objectively measured, and accurately predicted mortality independent of the application of rate or rhythm control. 3 The first time CV hospitalization or death was used as a primary outcome in a major AF trial was in the ATHENA (A placebo controlled, double blind Trial to assess the efficacy of dronedarone for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation and flutter) study, which was also the first study to demonstrate a reduction in important clinical CV outcomes with an antiarrhythmic drug (dronedarone). 7 With the Stockholm Cohort Study of Atrial Fibrillation (SCAF) analysis, Friberg and Rosenqvist 4 demonstrate an association between CV hospitalization and all-cause mortality among 2912 AF patients during a 6.5-year follow-up using a prospective observational cohort with detailed patient information. The SCAF analysis confirms the original findings of the AFFIRM analysis regarding the significant association of CV hospitalization with mortality. The strength of the association did not differ greatly from that in AFFIRM, although it depends on which SCAF analysis you look at. The AFFIRM reported a hazard ratio of 2.15 in the rhythm control group and 1.71 in the rate control group. 3 The SCAF hazard ratio for mortality during the first 3 months following hospitalization was 1.69, but decreased to 1.43 when taking into account deaths during 1 year and even to 1.35 when using a propensity score to correct for unmeasured differences between groups and improve comparability in this observational study. When adding medication use to the model of the final 2.5 years of the follow-up, the hazard ratios for mortality during 3 and 12 months were 2.08 and 1.63 respectively, which compared favourably with those observed in AFFIRM. All analyses of the SCAF verified the significance of the association of CV hospitalization and mortality, but also indicated the importance of the nature of the analysis to assess the strength of the association. Using hospitalization as an endpoint is not a new concept since hospitalization for heart failure has been widely used in heart failure research. Although any CV hospitalization is less of a disease-specific endpoint in AF research, its use as a mortality substitute seems justified considering that a two-fold increased risk for mortality associated with AF mainly relates to the presence of concomitant CV disease and risk factors. 8 The exact definition of CV hospitalization therefore needs some thought. The SCAF analysis showed that hospitalization primarily for AF was associated with lower mortality than hospitalization for other CV diagnoses. Considering that AF hospitalization was the main driver for CV hospitalization, with 44% of all hospitalizations, a treatment specifically targeting AF might lower the overall CV hospitalization rate without significantly affecting mortality. In the ATHENA study

S98 Ventilatory efficiency in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: physiological differences and implications for disease-specific end-points

<i>Objectives and setting</i>—Injuries from in-line skating have risen sharply in many cities around the world. To understand risk taking behavior and safety practices associated with urban in-line skating, 2210 outdoor skaters were observed in Boston, Massachusetts. <i>Methods</i>—Estimated age, gender, use of helmets, wrist guards, elbow and kneepads were recorded. Skaters were coded as beginner, average, or advanced, and skating locations were classified as street, sidewalk, or bicycle path. <i>Results</i>—About 60% of skaters wore wrist guards, but only 5.7% wore helmets. Males wore less protective equipment than females, and were more likely to skate on streets. Beginners and advanced skaters wore more protective gear than average skaters. Surprisingly, street skaters wore less protective gear than skaters on sidewalks or paths. <i>Conclusions</i>—Renewed focus on the importance of wearing helmets is needed. Given the higher injury risks for males, clinicians and public health experts need to target male skaters in prevention efforts. In addition, average and advanced skaters need to be convinced that even though they have improved, it is still important to wear protective gear.