Affect Treatment Effectiveness Research Articles

How unmeasured confounding in a competing risks setting can affect treatment effect estimates in observational studies

BackgroundAnalysis of competing risks is commonly achieved through a cause specific or a subdistribution framework using Cox or Fine & Gray models, respectively. The estimation of treatment effects in observational data is prone to unmeasured confounding which causes bias. There has been limited research into such biases in a competing risks framework.MethodsWe designed simulations to examine bias in the estimated treatment effect under Cox and Fine & Gray models with unmeasured confounding present. We varied the strength of the unmeasured confounding (i.e. the unmeasured variable’s effect on the probability of treatment and both outcome events) in different scenarios.ResultsIn both the Cox and Fine & Gray models, correlation between the unmeasured confounder and the probability of treatment created biases in the same direction (upward/downward) as the effect of the unmeasured confounder on the event-of-interest. The association between correlation and bias is reversed if the unmeasured confounder affects the competing event. These effects are reversed for the bias on the treatment effect of the competing event and are amplified when there are uneven treatment arms.ConclusionThe effect of unmeasured confounding on an event-of-interest or a competing event should not be overlooked in observational studies as strong correlations can lead to bias in treatment effect estimates and therefore cause inaccurate results to lead to false conclusions. This is true for cause specific perspective, but moreso for a subdistribution perspective. This can have ramifications if real-world treatment decisions rely on conclusions from these biased results. Graphical visualisation to aid in understanding the systems involved and potential confounders/events leading to sensitivity analyses that assumes unmeasured confounders exists should be performed to assess the robustness of results.

Patient related outcomes in cancer patients in Croatia.

TPS6650 Background: Accurate evaluation of symptom intensities is essential for optimal cancer care and improving the quality of life of patients. An inappropriate interpretation of symptoms may lead to treatment outcomes failure, overdose of medication, or may leave the patients undertreated. However, the perception of symptoms can vary between the treating physician and patient. Physicians appear to underestimate the patient symptoms. And this variation in the perception of side effects can lead to wrong assumptions and subsequent treatment changes, affecting treatment effectiveness and quality of life. There is growing interest to enhance symptom monitoring during routine cancer care using patient-reported outcomes, leaving open the question of whether the benefits of systems to reveal self-reports outweigh their added cost. There are several tools for assessment of symptoms in oncology. In cancer treatment clinical trials, the standard source of adverse symptom data is clinician reporting by use of items from PRO-CTCAE, developed by NCI. To address these questions, we conducted a single-center prospective trial to test whether systematic tablet computer-based collection of patient-reported symptoms during chemotherapy treatment, with automated alerts to clinicians for severe adverse events (grade 3-4) will change in questionnaire score at 6 months compared with baseline. Secondary endpoints will include difference in unscheduled clinic visits frequency, and survival. Methods: Patients initiating chemotherapy at General Hospital Pula Oncology Clinic for advanced or metastatic gastrointestinal, lung, breast, genitourinary, or gynecologic cancers will be enrolled in a nonblinded, prospective trial of self-reporting of symptoms, compare with usual care. Patients receiving chemotherapy and their clinicians will be independently asked on the same day to complete 10 symptoms (including fatigue, pain, nausea, vomiting, diarrhea, dysgeusia, appetite, sleep disturbance, fever and hair loss). Participants will remain on study until discontinuation of cancer treatment, withdrawal, or death. All participants will provide written informed consent and followed for up to 28 months or until death. To compare how patient’s vs clinician’s reports relate to clinical events, a time-dependent Cox regression model adjusted for covariates including cancer type, age, sex, and education level will be used to measure associations between reaching particular grade severity thresholds with the risk of death and unscheduled clinic visits. Clinical trial information: 2019-000855-15.

Impact of pre-enrolment medication use on clinical outcomes in SUMMIT.

In mortality trials including patients with COPD and heightened cardiovascular risk, patients' treatments before entering the trial may affect the effects of inhaled medications during the study http://ow.ly/WRRb30nwyIE

Factors Associated with the Effectiveness of Intravenous Administration of Chlorpromazine for Delirium in Patients with Terminal Cancer.

Delirium in patients with terminal cancer is irreversible and increases treatment resistance, which leads to a deterioration in quality of life. To investigate factors affecting the effectiveness and safety of intravenous chlorpromazine for irreversible delirium in patients with terminal cancer. Multiple regression analysis for factors affecting treatment effectiveness was carried out based on a retrospective comparison between responders and nonresponders to intravenous chlorpromazine. Ninety-seven patients with terminal cancer who were treated with intravenous chlorpromazine for irreversible delirium were included. The rate of patients with ≥50% improvement in mean Nursing Delirium Screening Scale score from pretreatment to day three of chlorpromazine treatment was 0.48 (95% confidence interval [CI]: 0.38-0.58). Factors affecting chlorpromazine treatment effectiveness were hyperactive delirium (odds ratio [OR]: 6.25, 95% CI: 1.14-34.5) and longer survival (OR: 1.096, 95% CI: 1.05-1.14). The mean chlorpromazine dose was low, at 17.9 mg/day. Adverse events were reported in 11 patients (11.3%) by day three of chlorpromazine treatment, and all were observed in patients who survived less than two weeks after chlorpromazine treatment. Patients who died, who had decreased blood pressure during chlorpromazine administration, and who showed acute akathisia all displayed shock index ≥1. Intravenous administration of low-dose chlorpromazine may be an effective and safe treatment option for delirium in patients with terminal cancer who have hyperactive delirium, longer predictive prognosis, and shock index <1.

Multilevel Analysis as a Tool to Analyze Research Questions in Rehabilitation Science

Studies in rehabilitation science often investigate data representing different hierarchical data levels. Hierarchical sample structures prevail if single cases (e. g. rehabilitation patients) are grouped or are members of grouped entities or clusters (e. g. teams, groups, institutions), respectively. Analyzing data of rehabilitation patients treated in different institutions it has to be regarded that belonging to a specific institution (level 2; cluster-level) may be associated with individuals' (level 1) characteristics systematically. If rehabilitation patients take part in different training groups, specific characteristics of the training groups (level 2) may affect treatment effects of individuals (level 1) significantly. Multilevel analysis or hierarchical linear models allow for simultaneously modelling such multilevel data structures in an integrative and comprehensive manner. In this article it will be shown which specific aspects concerning hierarchical sampling procedures, data organization, specification of research hypotheses, statistical data analysis as well as interpretation of study results have be regarded to model potential clustering effects appropriately.

Effects of Panax ginseng on Obesity in Animal Models: A Systematic Review and Meta-Analysis.

Objective To determine the antiobesity effects of Panax ginseng in animals. Methods We conducted a systematic search for all controlled trials (up to March 2017) that assessed the antiobesity effects of P. ginseng in animal obesity models in the PubMed, EMBASE, Cochrane library, Web of Science, and Scopus databases. The primary outcome was final body weight measured at the longest follow-up time after administration of the intervention. The secondary outcome was the lipid profile. We assessed methodological quality using the SYRCLE risk of bias tool, and RevMan 5.3 was used to perform a meta-analysis. Finally, a subgroup analysis of parameters including intervention duration, animal models, and type of ginseng was performed. Result We identified 16 studies that met the inclusion criteria. Data from the meta-analysis indicated that the intervention group had a significantly lower body weight than the control group (SMD: −1.50, 95% CI: −1.90 to −1.11, χ2: 78.14, P < 0.0001, I2 = 58%). Final body weight was lower in an animal obesity model induced by high-fat diet than in genetic models. Also the intervention group had a significantly higher serum HDL level and lower serum LDL, TG, and TC level than the control group. Conclusion Our meta-analysis indicated that oral administration of P. ginseng significantly inhibits weight gain and improves serum lipid profiles in animal obesity models. However, causes of obesity and type of ginseng may affect treatment effects.

Treatment of mild-to-moderate hypoglycemia in patients with type 1 diabetes treated with insulin pump therapy: are current recommendations effective?

Mild-to-moderate hypoglycemia (blood glucose<4.0mmol/L) is recommended to be treated with 15g of carbohydrates and to repeat the treatment if hypoglycemia persists after 15min. This recommendation was established before intensive insulin therapy and based on studies using insulin with different pharmacokinetic profiles from actual insulin analogs showing that 15g of glucose increases blood glucose by~1.5mmol/L in 15min. We aimed to explore the effect of current recommended treatment of mild-to-moderate hypoglycemia in type 1 diabetes (T1D) participants and factors associated with treatment effectiveness. This is a secondary analysis from three observational inpatient studies with a standardized and supervised treatment (16g carbohydrates) of hypoglycemia (<3.3mmol/L with symptoms or<3.0mmol/L without symptom) in participants (47 adults-10 adolescents) with T1D using continuous subcutaneous insulin infusion ("insulin pumps"; CSII)). Twenty-seven participants presented a total of 48 hypoglycemia episodes treated by a single intake of 16g of carbohydrates. Time required for normoglycemia recovery was 19.5±12.0min. The rise in plasma glucose following treatment was 0.85±0.66mmol/L in 15min. Eighteen episodes (38%) were resolved (>4.0mmol/L) 15-min post-treatment. Glycemia at the time of treatment (<3.2mmol/L; p<0.001) and a higher proportion of total daily insulin from basal doses (p=0.03) were associated with a slower post-treatment plasma glucose rise. These results raise the possibility that sixteen grams of carbohydrates could be insufficient to treat a large proportion of hypoglycemia episodes in T1D patients treated with CSII. Factors affecting treatment effectiveness need to be investigated.

Using Microwave Soil Heating to Inhibit Invasive Species Seed Germination

Successful invasive plant eradication is rare, because the methods used target the adult stage, not taking into account the development capacity of a large seedbank. Heating by microwave was considered, because it offers a means to quickly reach the temperature required for loss of seed viability and inhibition of germination. Previous results were not encouraging, because homogeneous and deep-wave penetration was not achieved, and the various parameters that can affect treatment effectiveness were incompletely addressed. This study aimed to determine, under experimental conditions, the best microwave treatment to inhibit invasive species seed germination in terms of power (2, 4, 6 kW) and duration (2, 4, 8 min) of treatments and depending on soil moisture (10%, 13%, 20%, 30%) and seed burial depth (2, 12 cm). Three invasive species were tested: Bohemian knotweed, giant goldenrod, and jimsonweed. The most effective treatments required relatively high power and duration (2kW8min, 4kW4min, 6kW2min, and 6kW4min; 4kW8min and 6kW8min were not tested for technical reasons), and their effectiveness diminished with increasing soil moisture with germination percentage between 0% and 2% for the lowest soil moisture, 0% and 56% for intermediate soil moisture, and 27% and 68% in control treatments. For the highest soil moisture, only 2kW8min and 4kW4min reduced germination percentage between 2% and 19%. Occasionally, germination of seeds located at the 12-cm depth was more strongly affected. Giant goldenrod seeds were the most sensitive, probably due to their small size. Results are promising and justify further experiments before developing a field microwave device to treat large volumes of soil infested by invasive seed efficiently and with reasonable energy requirements. Other types of soil, in terms of texture and organic matter content, should be tested in future experiments, because these factors influence soil water content and, consequently, microwave heating.

A Physiological Profile of Ovarian Cancer Survivors to Inform Tailored Exercise Interventions and the Development of Exercise Oncology Guidelines.

Physical activity has become increasingly important in supportive cancer care. However, physical activity and exercise guidelines for ovarian cancer survivors remain generic. The aim of this narrative review is to summarize existing data regarding the physiological characteristics (treatment-related adverse effects, concurrent comorbidities, body weight and composition, physical fitness and function, and physical activity behavior) of ovarian cancer survivors to further understanding of their cancer-specific physical activity and exercise needs. We also highlight gaps in the current knowledge base. We undertook a narrative review of current literature on the physiological status of ovarian cancer survivors. We defined physiological status as treatment-related adverse effects, concurrent comorbidities, body weight and composition, physical fitness and function, and physical activity behavior. In addition to disease- and treatment-related symptoms and adverse effects, the majority of ovarian cancer survivors have comorbidities, which may adversely affect treatment effectiveness and safety, as well as survival. Despite high overweight and obesity rates, a large percentage of women are malnourished at diagnosis, with potentially compromised muscle mass and muscle density. Low muscle density at diagnosis and loss of muscle mass during treatment may be associated with worse survival outcomes. A small number of studies have observed impaired physical function and cardiorespiratory fitness in ovarian cancer survivors. The majority of ovarian cancer survivors are insufficiently active or sedentary. Our review suggests that ovarian cancer survivors could benefit from physical activity and exercise oncology interventions aimed at addressing detrimental changes to physiological status due to disease and treatment. However, current knowledge gaps regarding the physiological characteristics of ovarian cancer survivors throughout the entire survivorship spectrum challenge the development of tailored exercise intervention studies and exercise oncology guidelines.

Abstract 1618: Immune-modulating effect of bevacizumab in EGFR mutated lung adenocarcinoma

Abstract Background: Host immunity affect treatment effect of lung cancer. Peripheral blood S100A9+ monocytic myeloid derived suppressor cells (MDSCs) is a predictive factor for treatment response of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) of lung adenocarcinoma patients. Bevacizumab have immune-modulating effect, including decreasing MDSCs, and improve treatment effect in combination with immunotherapy. However, the effect of immune modulation in combination of bevacizumab and EGFR-TKI in EGFR mutated lung adenocarcinoma patients is not clear. Methods: Stage IV lung adenocarcinoma harboring sensitive EGFR mutation patients receiving first line EGFR-TKI or combination EGFR-TKI and bevacizumab were enrolled. The peripheral blood mononuclear cell (PBMCs) were collected, and S100A9+ MDSCs percentage was calculated by flow cytometry from CD14+S100A9+ in PBMC. Clinical data was collected. Results: Eight patients receiving EGFR-TKI and bevacizumab, as combination group, and twenty patients received EGFR-TKI alone, as control group, were enrolled. PBMC S100A9+ MDSC decreased in combination group (decrease 39±18% from baseline), but not in control group. Combination group had longer progress free survival (PFS) comparing with control group. (Median PFS combination vs control group: 15.2 vs 9.9 months, Log Rank test, p=0.05) Increased of peripheral blood cytotoxic T cells also had trend in combination group but not in control group. Conclusion: Besides the anti-angiogenesis effect, bevacizumab had immune modulated effect, especially in decreasing circulating S100A9+ MDSC in EGFR mutated lung adenocarcinoma patients. This might partially explain the longer PFS in combination of EGFR-TKI of anti-angiogenesis agent treatment. Citation Format: Po-Hao Feng, Kang-Yun Lee. Immune-modulating effect of bevacizumab in EGFR mutated lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1618. doi:10.1158/1538-7445.AM2017-1618

ESTROGEN REGULATION OF MITOCHONDRIAL RESPIRATION IS CELL TYPE AND ER SUBTYPE SPECIFIC

Late onset AD has an approximately 20-year prodromal period, during which brain glucose hypometabolism can be detected in at risk groups and is predictive of disease progression. Loss of estrogen during the perimenopausal transition is associated with deficits in brain glucose metabolism and mitochondrial function, which may explain the two-fold greater lifetime risk of LOAD in females than males. In postmenopausal women, estrogen replacement therapy can improve brain glucose metabolism and recognition, and in ovariectomized rodents, estrogen treatment preserved mitochondrial respiration capacity, supporting the role of E2 as a master regulator of brain bioenergetics via mitochondrial function. However, the underlying mechanism is not fully elucidated. Interestingly, in neuronal cells, estrogen receptor beta (ERβ), but not estrogen receptor alpha (ERα), was demonstrated to co-localize with mitochondria, and has a functional role in ATP production, suggesting potential differential contributions of ERα and ERβ to regulation of mitochondrial bioenergetics. To identify cell type specific responses to estrogen treatment, we used rat embryonic primary neurons and astrocytes. To identify the contribution of ER subtypes, cells were treated with either ERα selective antagonist (MPP), or ERβ selective antagonist (PHTPP) prior to E2 treatment. Cellular respiratory capacity was determined by XF24 metabolic flux analyzer, and Oxygen consumption rate (OCR) was used as an indicator for mitochondrial oxidative phosphorylation. To determine whether ERs regulate mitochondrial respiration via regulation of transcription of mitochondrial genome, gene expression of the 13 mitochondrial protein encoding genes will be determined by real-time rtPCR. Ongoing analysis also explores how mitochondrial genetic variances affect treatment effect of selective estrogen modulators on perimenopausal symptoms. Estrogen increased both ATP production and maximum respiration in neurons, but only ATP production in astrocytes. ERα antagonist prevented E2 mediated enhancement of mitochondrial respiration in astrocytes but not neurons, whereas ERβ antagonist abolished E2 mediated enhancement of mitochondrial respiration in both cell types. E2 regulation of mitochondrial respiration is cell type and ER subtype specific, possibly through differential regulation of transcription of the mitochondrial genome. Acknowledgement: This work was supported by NIA R01 AG032236 to RDB; NIA P01AG026572 to RDB, Project 1 to RDB & EC.

Efficiency of biological therapies in patients with moderate to severe psoriasis: impact of a pharmacotherapeutic protocol

Background: It is not clear how to best use biologics in the treatment of psoriasis. Our objective was to assess use of a protocol for biological therapies (BT) in psoriasis. Methods: A consensus protocol was established that included the indications for BT and dose optimization. Patient's characteristics, effectiveness, and cost of BT were analyzed before and after the implementation with two cross-sectional studies to assess its impact. Results: About 106 were treated before the protocol and 118 patients were treated after. After implementing the protocol, the dose was reduced in 43.4% of the patients receiving adalimumab, in 37.5% for etanercept, in 28.6% for infliximab, and in 14.7% for ustekinumab. No statistically significant differences were found in PASI score after the implementation of the protocol, except for the percentage of patients that achieved PASI 75 with ustekinumab, which was slightly higher. The global yearly savings achieved with the protocol implementation were 115 969 €. Conclusions: The protocol helped to increase the efficiency of BT, with decreasing doses of BT without affecting treatment effectiveness.

A Cross-Sectional Investigation of Fatigue, Mucositis, Hand-Foot Syndrome and Dysgeusia in Advanced Renal Cell Carcinoma Treatment: Final Results From the FAMOUS Study

BackgroundThe management of symptoms associated with treatment of metastatic renal cell carcinoma (mRCC) is crucial to ensure treatment adherence and outcome. The perception of symptoms can vary between the treating physician and patient, leading to assumptions and subsequent changes in treatment, potentially affecting treatment effectiveness. The aim of the present cross-sectional study was to evaluate the perception of the common symptoms of fatigue, mucositis, hand-foot syndrome, and dysgeusia in patients with mRCC receiving systemic therapies in routine practice. Patients and MethodsGerman patients receiving first-line systemic treatment for mRCC and their physicians were independently queried about the incidence and severity of fatigue, mucositis, hand-foot syndrome, and dysgeusia. Patients also completed the Functional Assessment of Cancer Therapy–General questionnaire to assess their quality of life (QOL). The effect of the 4 symptoms on QOL was analyzed using linear regression modeling. ResultsA total of 63 matching questionnaires were completed by both physicians and patients with first-line treatment. The incidence and severity of symptoms differed between the patients and physicians. Patients rated the severity of symptoms significantly higher than did the physicians. A greater severity of symptoms correlated with a lower QOL. In multivariate regression analysis, fatigue adversely affected overall QOL. ConclusionPhysicians underestimated the severity of common symptoms in patients with mRCC. The incorporation of patient-reported outcome measures into routine practice might increase awareness of patients' overall QOL and thereby potentially improve treatment adherence. A thorough evaluation of fatigue, its potential underlying causes, and active measures to manage fatigue could potentially improve patients' QOL.

The influence of healthy belief education on the diabetes nephrosis patient diet treat-ment adherence and the quality of life

Objective Based on health belief model, investigating patients with diabetic nephropathy of dietary factors affecting treatment compliance and effectiveness. Methods 122 cases of diabetic nephropathy were randomly divided into the observation group of 62 patients and the control group of 60 patients. Patients in two groups during hospitalization underwent conventional treatment of diabetic nephropathy drugs and nursing services. Patients in the observation group on the basis of conventional treatment and nursing services while accepting health education, informed the patients the seriousness of the diabetic nephropathy, the importance of diet therapy, the necessity of diet therapy adherence and the difficulty in the course of treatment and so on. patients often were given all kinds of encouragement to establish the health belief model, were given health faith education extension services by family visit, telephone, Internet and other forms after discharge. Diet therapy compliance and the quality of life after eight month discharge were compared. Results Diet treatment adherence and quality of life score of the observation group were significantly higher than those of control group(P<0.01). Fasting glucose, 2- hour postprandial blood glucose, serum creatinine, blood urea nitrogen were lower than those of the control group(P<0.01).The life quality and diet treatment adherence was significantly positive correlation(r= 0.521, P<0.05). Conclusions Appropriate scientific health belief education could improve diabetic nephropathy patients'diets treatment adherence and improve their quality of life. Key words: Health belief model; Diabetic nephropathy; Diet therapy; Compliance

Cerebral Hemodynamic Responses to Acupuncture in Migraine Patients: A Systematic Review

We review the literature conjoining acupuncture, migraine, and cerebral hemodynamics. To do so, we searched PubMed in March 2013 for studies investigating cerebral hemodynamics with functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS), transcranial Doppler (TCD) ultrasound, and other tools in migraineurs, acupuncture recipients, and migraineurs receiving acupuncture. Our search identified 1321 distinct articles – acupuncture (n = 463), migraine (n = 866), and both (n = 8). Only three (n = 3) satisfied our inclusion criteria. Based on these three, we found the following: (1) Acupuncture may positively influence not just dynamic, but also static cerebral autoregulation during the interictal phase, depending on the intervals between sessions of acupuncture as dose units. (2) TCD can detect pretreatment differences between responders and non-responders to acupuncture, which may be predictive of clinical response. (3) “Point-through-point” needling (at angles connecting acupoints) may be clinically superior to standard acupuncture, thus needling angles may affect treatment effectiveness. None of the reviewed articles investigated patient responses during migraine attack. Although the 2009 Cochrane review affirmed acupuncture as effective prophylaxis for migraine, few studies investigated the cerebrovascular aspects – only analyzing arterial blood flow, but not microcirculation. Future research is warranted in monitoring brain tissue oxygenation to investigate acupuncture as both a preventive and abortive treatment for migraine, varying the type and dose interval and analyzing variations in clinical response.

Inconsistency in the items included in tools used in general health research and physical therapy to evaluate the methodological quality of randomized controlled trials: a descriptive analysis

BackgroundAssessing the risk of bias of randomized controlled trials (RCTs) is crucial to understand how biases affect treatment effect estimates. A number of tools have been developed to evaluate risk of bias of RCTs; however, it is unknown how these tools compare to each other in the items included. The main objective of this study was to describe which individual items are included in RCT quality tools used in general health and physical therapy (PT) research, and how these items compare to those of the Cochrane Risk of Bias (RoB) tool.MethodsWe used comprehensive literature searches and a systematic approach to identify tools that evaluated the methodological quality or risk of bias of RCTs in general health and PT research. We extracted individual items from all quality tools. We calculated the frequency of quality items used across tools and compared them to those in the RoB tool. Comparisons were made between general health and PT quality tools using Chi-squared tests.ResultsIn addition to the RoB tool, 26 quality tools were identified, with 19 being used in general health and seven in PT research. The total number of quality items included in general health research tools was 130, compared with 48 items across PT tools and seven items in the RoB tool. The most frequently included items in general health research tools (14/19, 74%) were inclusion and exclusion criteria, and appropriate statistical analysis. In contrast, the most frequent items included in PT tools (86%, 6/7) were: baseline comparability, blinding of investigator/assessor, and use of intention-to-treat analysis. Key items of the RoB tool (sequence generation and allocation concealment) were included in 71% (5/7) of PT tools, and 63% (12/19) and 37% (7/19) of general health research tools, respectively.ConclusionsThere is extensive item variation across tools that evaluate the risk of bias of RCTs in health research. Results call for an in-depth analysis of items that should be used to assess risk of bias of RCTs. Further empirical evidence on the use of individual items and the psychometric properties of risk of bias tools is needed.

Refinement of the Magnetic Resonance Diffusion-Perfusion Mismatch Concept for Thrombolytic Patient Selection

The DIAS-2 study was the only large, randomized, intravenous, thrombolytic trial that selected patients based on the presence of ischemic penumbra. However, DIAS-2 did not confirm the positive findings of the smaller DEDAS and DIAS trials, which also used penumbral selection. Therefore, a reevaluation of the penumbra selection strategy is warranted. In post hoc analyses we assessed the relationships of magnetic resonance imaging-measured lesion volumes with clinical measures in DIAS-2, and the relationships of the presence and size of the diffusion-perfusion mismatch with the clinical effect of desmoteplase in DIAS-2 and in pooled data from DIAS, DEDAS, and DIAS-2. In DIAS-2, lesion volumes correlated with National Institutes of Health Stroke Scale (NIHSS) at both baseline and final time points (P<0.0001), and lesion growth was inversely related to good clinical outcome (P=0.004). In the pooled analysis, desmoteplase was associated with 47% clinical response rate (n=143) vs 34% in placebo (n=73; P=0.08). For both the pooled sample and for DIAS-2, increasing the minimum baseline mismatch volume (MMV) for inclusion increased the desmoteplase effect size. The odds ratio for good clinical response between desmoteplase and placebo treatment was 2.83 (95% confidence interval, 1.16-6.94; P=0.023) for MMV >60 mL. Increasing the minimum NIHSS score for inclusion did not affect treatment effect size. Pooled across all desmoteplase trials, desmoteplase appears beneficial in patients with large MMV and ineffective in patients with small MMV. These results support a modified diffusion-perfusion mismatch hypothesis for patient selection in later time-window thrombolytic trials. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique Identifiers: NCT00638781, NCT00638248, NCT00111852.

Biologically implausible carotid intima–media thickness measurement values: effects on rate of change over time

Objective:Carotid intima–media thickness (CIMT) is a marker of atherosclerosis that is commonly used to assess the effect of therapeutic interventions. It is currently unclear to what extent biologically implausible values affect treatment effects. We evaluated the impact of biologically implausible CIMT values on the estimated rate of change in CIMT.Methods:Data were used from the METEOR (Measuring Effects on Intima–media Thickness: an Evaluation of Rosuvastatin) trial. METEOR was a randomized, placebo-controlled trial showing that rosuvastatin reduced the 2-year change in CIMT among low-risk individuals with subclinical atherosclerosis. In the main METEOR analysis, the data were analyzed without exclusion of biologically implausible data. In this post-hoc analysis, we constructed twelve definitions to define mildly or extremely biologically implausible values using distance from the interquartile range, median or mean. We evaluated the effect of removing implausible values on the estimated rate of change in CIMT.Results:The percentage of biologically implausible CIMT values ranged from 0.6% to 9.7%, depending on the definition used. Across all definitions, removal of biologically implausible CIMT values marginally reduced standard errors and did not change the primary outcome (i.e., a nonsignificant change in the rosuvastatin group, significant progression in the placebo group, and a statistically significant difference between treatment groups).Limitation:This study was focussed on the impact of implausible values in the analytical part of a CIMT study. Ultrasound images were not re-examined to determine whether an implausible measurement was due to measurement error or temporal morphological thickening,Conclusion:Removal of biologically implausible CIMT values marginally decreased the variability of the estimated rate of change in CIMT without having a large impact on the estimated rate of change.

Abstract 2600: Refinement of the MR Diffusion-perfusion Mismatch Concept for Thrombolytic Patient Selection: Insights from the Desmoteplase In Acute Stroke Trials

The DIAS-2 study was the only large, randomized intravenous thrombolytic trial that selected patients based on the presence of ischemic penumbra. However, DIAS-2 did not confirm the positive findings of the smaller DEDAS and DIAS trials, which also used penumbral selection. Therefore a reevaluation of the penumbra selection strategy is warranted. In post-hoc analyses we assessed the relationships of MRI-measured lesion volumes to clinical measures in DIAS-2, and the relationships of the presence and size of the diffusion-perfusion mismatch to the clinical effect of desmoteplase in DIAS-2 (MRI-selected patients) and in pooled data from MRI-selected 90- and 125-μg/kg dose groups in DIAS, DEDAS, and DIAS-2. In DIAS-2, lesion volumes correlated with NIHSS at both baseline and final time points (P&lt;0·0001), and lesion growth was inversely related to good clinical outcome (P=0.004). In the pooled analysis, treatment was associated with 47% clinical response rate in desmoteplase (n=143) versus 34% in placebo (n=73; P=0.08). For both the pooled sample and for DIAS-2, increasing the minimum baseline mismatch volume (MMV) for inclusion increased the desmoteplase effect size, preferentially decreasing the placebo-response rate. There was a trend of statistically significant differences in effect size in ≤60 mL versus &gt;60 mL baseline mismatch subgroups (P=0.083). The odds ratio for good clinical response between desmoteplase and placebo treatment was 2.83 (95% CI, 1.16-6.94, P=0.023) for a MMV &gt;60 mL. Increasing the minimum NIHSS for inclusion did not affect treatment effect size. Pooled across all desmoteplase trials, penumbral selection by MRI diffusion-perfusion mismatch favored desmoteplase clinical benefit, especially for larger MMV. Based on these results, a three-fold reduction in future trial sample size requirements would be achieved using a criterion of baseline MMV &gt;60 mL over any visible mismatch. These results support a modified diffusion-perfusion mismatch hypothesis for patient selection in later-time-window thrombolytic trials.

A snapshot of smokers after lung and colorectal cancer diagnosis

Continued smoking after a cancer diagnosis may adversely affect treatment effectiveness, subsequent cancer risk, and survival. The prevalence of continued smoking after cancer diagnosis is understudied. In the multi-regional Cancer Care Outcomes Research and Surveillance cohort (lung cancer [N = 2456], colorectal cancer [N = 3063]), the authors examined smoking rates at diagnosis and 5 months after diagnosis and also study factors associated with continued smoking. Overall, 90.2% of patients with lung cancer and 54.8% of patients with colorectal cancer reported ever smoking. At diagnosis, 38.7% of patients with lung cancer and 13.7% of patients with colorectal cancer were smoking; whereas, 5 months after diagnosis, 14.2% of patients with lung cancer and 9.0% of patients with colorectal cancer were smoking. Factors that were associated independently with continued smoking among patients with nonmetastatic lung cancer were coverage by Medicare, other public/unspecified insurance, not receiving chemotherapy, not undergoing surgery, prior cardiovascular disease, lower body mass index, lower emotional support, and higher daily ever-smoking rates (all P < .05). Factors that were associated independently with continued smoking among patients with nonmetastatic colorectal cancer were male sex, high school education, being uninsured, not undergoing surgery, and higher daily ever-smoking rates (all P < .05). After diagnosis, a substantial minority of patients with lung and colorectal cancers continued smoking. Patients with lung cancer had higher rates of smoking at diagnosis and after diagnosis; whereas patients with colorectal cancer were less likely to quit smoking after diagnosis. Factors that were associated with continued smoking differed between lung and colorectal cancer patients. Future smoking-cessation efforts should examine differences by cancer type, particularly when comparing cancers for which smoking is a well established risk factor versus cancers for which it is not.