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Response Assessment (response + assessment)
Selected AbstractsIntravesical alkalinized lidocaine (PSD597) offers sustained relief from symptoms of interstitial cystitis and painful bladder syndromeBJU INTERNATIONAL, Issue 7 2009J. Curtis Nickel OBJECTIVE To assess the immediate and sustained relief of the symptoms of interstitial cystitis/painful bladder syndrome (IC/PBlS) after a consecutive 5-day course of treatment with intravesical alkalinized lidocaine (PSD597), and to characterize the pharmacokinetics of single and multiple doses of intravesical PSD597 in a subgroup of patients. PATIENTS AND METHODS In all, 102 adult patients (99 women) with a clinical diagnosis of IC/PBlS were randomized from 19 centres in the USA and Canada to receive a daily intravesical instillation of PSD597 (200 mg lidocaine, alkalinized with a sequential instillation of 8.4% sodium bicarbonate solution, to a final volume of 10 mL) or placebo (double-blind), for 5 consecutive days. Patients were followed at intervals up to 29 days after the first instillation. Efficacy was assessed by changes in the Global Response Assessment (GRA), Likert scales for bladder pain, urgency and frequency, and validated O'Leary-Sant IC symptom and problem indices. RESULTS Significantly more patients treated with PSD597 rated their overall bladder symptoms as moderately or markedly improved on the GRA scale 3 days after completing the 5-day course of treatment (30% and 9.6%, respectively, for patients treated with PSD597 and placebo; P = 0.012). The treatment effects were also maintained beyond the end of treatment and are further supported by the secondary endpoints, including symptom and problem indices. The peak serum lidocaine concentration during the study was <2 µg/mL, and well below the toxic level (>5 µg/mL). CONCLUSION This preliminary study showed that PSD597 was effective for providing sustained amelioration of symptoms of IC/PBlS beyond the acute treatment phase. The drug was safe, well tolerated and devoid of the systemic side-effects often experienced with oral drug administration. Long-term studies are needed to determine the optimum regimen to maintain this favourable treatment effect. [source] A real-life multicentre clinical practice study to evaluate the efficacy and safety of intravesical chondroitin sulphate for the treatment of interstitial cystitisBJU INTERNATIONAL, Issue 1 2009J. Curtis Nickel OBJECTIVE To report a multicentre, community based open-label study designed to assess the efficacy and safety of intravesical sodium chondroitin sulphate in the treatment of patients with the clinical diagnosis of interstitial cystitis (IC). Chondroitin sulphate is a naturally occurring glycosaminoglycan (GAG) in the bladder mucus layer and changes in this GAG have been implicated in the pathogenesis of IC, and small single-centre studies have suggested that intravesical chondroitin sulphate may have efficacy in IC. PATIENTS AND METHODS Patients with IC were treated with sodium chondroitin sulphate (Uracyst®, Stellar Pharmaceuticals Inc., London ON, Canada) solution 2.0% via urinary catheter weekly for 6 weeks and then monthly for 16 weeks for a total of 10 treatments. The primary efficacy endpoint was the percentage of responders to treatment as indicated by a marked or moderate improvement on a seven-point patient Global Response Assessment (GRA) scale at week 10 (4 weeks after the initial six treatments) compared with baseline. A major secondary efficacy endpoint (durability) was the percentage of responders on the GRA scale after 10 treatments. Additional secondary efficacy objectives were differences from baseline in Patient Symptom/Problem Index scores over the course of the treatment compared with baseline. RESULTS In all, 47% of the 53 enrolled patients with long standing moderately severe IC (mean [sd, range] diagnosis of IC 3.0 [3.4, 0.1,16] years; duration of symptoms 9.2 [9.2, 1,39] years; baseline symptom score 14.2 [3.2]) were responders at week 10. At 24 weeks, 60% were responders. There was a statistically and clinically significant decrease in the mean (sd) symptom and bother scores from baseline at 10 weeks and 24 weeks, at 9.0 (4.3) and 8.1 (5.0), respectively (P < 0.001). There were no significant safety issues during the study. CONCLUSIONS This multicentre community based real-life clinical practice study suggests that intravesical chondroitin sulphate may have an important role in the treatment of IC and validates the rationale for a randomized placebo-controlled trial. [source] High-dose ifosfamide with mesna and granuloctye,colony-stimulating factor (recombinant human G-CSF) in patients with unresectable malignant mesotheliomaCANCER, Issue 2 2003A Southwest Oncology Group study Abstract BACKGROUND The current study was conducted to assess the activity and toxicity of high-dose ifosfamide and mesna with recombinant human granulocyte,colony-stimulating factor (rhG-CSF), given in an outpatient setting, in the treatment of patients with unresectable malignant mesothelioma. METHODS Between September 1994 and September 1996, 41 patients with histologically verified, unresectable malignant mesothelioma were registered, 38 of whom were analyzable (2 were ineligible and 1 was nonanalyzable). Patients received intravenous ifosfamide at a dose of 2.8 g/m2 over 3 hours (total dose of 14 g/m2), plus mesna at a dose of 0.56 g/m2 prior to and at 4 hours and 8 hours after ifosfamide infusion daily for 5 days every 21 days. rhG-CSF at a dose of 5 ,g/kg/day was administered subcutaneously on days 6,15. RESULTS Response assessment could be determined adequately in 21 patients. Two patients obtained responses; 1 was a confirmed partial response (3%; 95% confidence interval [95% CI], 0,14%) and 1 was an unconfirmed response (3%; 95% CI, 5,14%). Eleven patients had stable disease (29%), 7 patients developed disease progression (18%), 1 patient had an early death (3%), and 17 patients had inadequate assessment (45%). At the time of last follow-up, 36 of the 38 eligible patients had developed disease progression, with a median progression-free survival of 5 months (95% CI, 3,7 months) and 34 patients had died with a median survival of 7 months (95% CI, 6,9 months). Twenty-four patients (63%) and 7 patients (18%), respectively, had Grade (according to Southwestern Oncology Group Toxicity Criteria) 4 hematologic toxicities and Grade 4 nonhematological toxicities. There was one treatment-related death, the result of infection, pulmonary edema, and renal failure. CONCLUSIONS This regimen demonstrated a low overall objective response rate with substantial toxicity, and in the opinion of the authors does not warrant further investigation in the treatment of patients with unresectable malignant mesothelioma. Cancer 2003;98:331,6. © 2003 American Cancer Society. DOI 10.1002/cncr.11512 [source] A multiinstitutional, concurrent chemoradiation trial of strontium-89, estramustine, and vinblastine for hormone refractory prostate carcinoma involving boneCANCER, Issue 6 2002Wallace Akerley M.D. Abstract BACKGROUND Estramustine phosphate (EMP) and vinblastine have radiosensitizing properties and significant activity against hormone refractory prostate carcinoma. Strontium-89 is a palliative agent that acts as a selective radiation source for bone metastasis. The combination of EMP, vinblastine, and strontium-89 was developed to exploit the potential for radiosynergy. PATIENTS AND METHODS Forty-four patients at the Brown Oncology Group affiliated hospitals were treated with oral EMP 600 mg/m2 daily on Weeks 1,4 and 7,10, vinblastine 4 mg/m2 intravenously once each week on Weeks 1,4 and 7,10, and strontium-89 2.2 MBq/kg on Day 1. Courses were repeated every 12 weeks. Response assessment was based on a change in the serum prostate specific antigen (PSA) levels, correlated with change in measurable disease and bone scan appearance. RESULTS A greater than or equal to 50% decline in PSA for at least 6 weeks was observed in 21 patients (48%, 95% confidence interval, 33,62%). Median duration of response was 23 weeks (range, 6,70.8 weeks). The median survival was 13 months with 1- and 2-year survival rates of 55% and 25%, respectively. After completion of protocol therapy, a retrospective review showed that only nine patients received subsequent palliative external beam radiation after progression. CONCLUSIONS The addition of strontium-89 to the regimen of EMP and vinblastine can be delivered safely and in repeated doses, provides effective palliation, and may decrease the need for future radiation therapy. A randomized trial is necessary to quantify these effects. Cancer 2002;94:1654,60. © 2002 American Cancer Society. DOI 10.1002/cncr.10437 [source] Principles of risk assessment for determining the safety of chemicals: Recent assessment of residual solvents in drugs and di(2-ethylhexyl) phthalateCONGENITAL ANOMALIES, Issue 2 2004Ryuichi Hasegawa ABSTRACT Risk assessment of chemicals is essential for the estimation of chemical safety, and animal toxicity data are typically used in the evaluation process, which consists of hazard identification, dose,response assessment, exposure assessment, and risk characterization. Hazard identification entails the collection of all available toxicity data and assessment of toxicity endpoints based on findings for repeated dose toxicity, carcinogenicity or genotoxicity and species-specificity. Once a review is compiled, the allowable lifetime exposure level of a chemical is estimated from a dose,response assessment based on several measures. For non-carcinogens and non-genotoxic carcinogens, the no-observed-adverse-effect-level (NOAEL) is divided by uncertainty factors (e.g. with environmental pollutants) or safety factors (e.g. with food additives) to derive a tolerable daily intake (TDI) or acceptable daily intake (ADI), respectively. These factors include interspecies and individual differences, duration of exposure, quality of data, and nature of toxicity such as carcinogenicity or neurotoxicity. For genotoxic carcinogens, low dose extrapolation is accomplished with mathematical modeling (e.g. linearized multistage model) from the point of departure to obtain exposure levels that will be associated with an excess lifetime cancer risk of a certain level. Data for levels of chemicals in food, water and air, are routinely used for exposure assessment. Finally, risk characterization is performed to ensure that the established ,safe' level of exposure exceeds the estimated level of actual exposure. These principles have led to the evaluation of several existing chemicals. To establish a guideline for residual solvents in medicine, the permitted daily exposure (PDE), equivalent to TDI, of N,N-dimethylformamide was derived on the basis of developmental toxicity (malformation) and of N-methylpyrrolidone on the basis of the developmental neurotoxicity. A TDI for di(2-ethylhexyl)phthalate was derived from assessment of testicular toxicity. [source] TK/TD dose,response modeling of toxicityENVIRONMETRICS, Issue 5 2007Munni Begum Abstract In environmental cancer risk assessment of a toxic chemical, the main focus is in understanding induced target organ toxicity that may in turn lead to carcinogenicity. Mathematical models based on systems of ordinary differential equations with biologically relevant parameters are tenable methods for describing the disposition of chemicals in target organs. In evaluation of a toxic chemical, dose,response assessment often addresses only toxicodynamics (TD) of the chemical, while its toxicokinetics (TK) do not enter into consideration. The primary objective of this research is to integrate both TK and TD in evaluation of toxic chemicals while performing dose,response assessment. Population models, with hierarchical setup and nonlinear predictors, for TK concentration and TD effect measures are considered. A one-compartment model with biologically relevant parameters, such as organ volume, uptake rate and excretion rate, or clearance, is used to derive the TK predictor while a two parameter Emax model is used as a predictor for TD measures. Inference of the model parameters with nonnegative and assay's Limit of Detection (LOD) constraints was carried out by Bayesian approaches using Markov Chain Monte Carlo (MCMC) techniques. Copyright © 2006 John Wiley & Sons, Ltd. [source] Clinical impact of, and prognostic stratification by, F-18 FDG PET/CT in head and neck mucosal squamous cell carcinomaHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 11 2007Caroline A. Connell FRANZCR Abstract Background The aim of this study was to determine prospectively the incremental value of positron emission tomography/computed tomography (PET/CT) over conventional assessment (clinical examination and CT/MRI imaging). Methods All patients undergoing 18F-fluorodeoxyglucose (FDG)-PET/CT for primary head and neck mucosal squamous cell carcinoma between January 2002 and December 2003 (inclusive) were included in this study provided they had undergone contemporaneous conventional assessment of the head and neck region and had 12 months minimum follow-up. Results Seventy-six patients underwent 100 PET/CT scans. The majority of patients (74%) were treated with definitive (chemo)radiotherapy. Median follow-up time was 28 months. PET/CT led to a TNM classification alteration in 34% (12/35), a change in radiotherapy planning technique and/or dose in 29% (10/35), and altered treatment response assessment in 43% (13/30). A complete metabolic response was predictive of overall survival (p = .037). Conclusion Our results support incorporation of PET/CT into the management paradigm of head and neck mucosal squamous cell carcinoma. © 2007 Wiley Periodicals, Inc. Head Neck 2007 [source] Impact of 18F-fluorodeoxyglucose positron emission tomography in the staging and treatment response assessment of extra-pulmonary small-cell cancerJOURNAL OF MEDICAL IMAGING AND RADIATION ONCOLOGY, Issue 2 2010DL Gregory Summary The aim of this study was to retrospectively evaluate the value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in extrapulmonary small-cell cancer (EPSCC). Patients with EPSCC who underwent PET for staging or response assessment between 1996 and 2007 were identified from a database. Patient records were reviewed. PET-based, and conventional staging and restaging results were compared. The binary staging classification of limited disease (LD) versus extensive disease (ED) was used. Patients with LD had tumours that could be encompassed within a tolerable radiation therapy (RT) volume. Of 33 eligible patients, 12 had staging PET scans, 11 had restaging scans and 10 had both. All known gross disease sites were FDG-avid. PET and conventional stage groupings were concordant in 21 of 22 cases. One patient was appropriately upstaged from LD to ED by PET. PET detected additional disease sites, without causing upstaging in three further patients. Restaging PET scans identified previously unrecognised persistent or progressive disease in 4 of 21 cases. In four further cases, persistent FDG uptake after treatment was either false positive (n = 2) or of uncertain (n = 2) aetiology. PPV was 100% for staging and 82% for restaging. In 8 of 43 imaging episodes (19%), PET appropriately influenced management in five cases by changing treatment intent from radical to palliative, and in three cases by altering the RT volume. PET has incremental value compared to conventional imaging for staging EPSCC, and may also be useful for restaging after therapy. PET influenced patient management in 19% of 43 imaging episodes. [source] 18F-fluoro-2-deoxy-D-glucose positron emission tomography and positron emission tomography/computed tomography imaging of malignant pleural mesothelioma§JOURNAL OF MEDICAL IMAGING AND RADIATION ONCOLOGY, Issue 2 2009RM Subramaniam Summary Malignant pleural mesothelioma (MPM) is the most common primary pleural tumor and its incidence is rising. Its diagnosis, staging and response assessment are challenging for imaging. Integrated positron emission tomography (PET)/CT increases the accuracy of overall staging in patients with mesothelioma and improves the selection of patients for curative surgical resection. It is particularly useful in identifying occult distant metastases. It may be used to predict prognosis and to assess the metabolic response to therapy. [source] The size of the disease relevant IgE antibody fraction in relation to ,total-IgE' predicts the efficacy of anti-IgE (Xolair®) treatmentALLERGY, Issue 10 2009S. G. O. Johansson Background:, Some patients with allergic asthma treated with anti-IgE (Xolair®) do not become symptom free. Better criteria for response assessment than allergy skin tests or IgE determination are needed. The impact of the size of the disease relevant allergen-specific IgE antibody fraction, i.e. the percentage of IgE antibody of total IgE, was evaluated in cat allergic patients treated with the recommended doses of Xolair®. Results were measured as changes in basophil allergen threshold sensitivity (CD-sens). Methods:, In a double-blind placebo controlled trial 20 patients with a high (>3.8%) and 18 with a low (<1%) percentage of IgE antibodies to cat were given Xolair® for 16 weeks and the change in CD-sens was compared to 11 and 10 patients, respectively, in each group receiving placebo. Results:, The CD-sens dropped significantly in both the high (P < 0.001) and low (P < 0.001) group on Xolair® but did not change significantly after placebo. For Xolair® -treated patients, at the end of the trial there was a highly significant (P < 0.001) difference in CD-sens between the high group, where no patients, and the low group, where 13/18 patients, had become negative. Conclusions:, The currently recommended doses of Xolair® very efficiently eliminate IgE antibodies if the IgE antibody fraction is <1% of total IgE but has not enough effect on allergen sensitivity if the fraction is >3,4%. Further studies will show if increased doses of Xolair® would help also these patients, who seem to represent about 1/3 of the patient population. [source] The relationship between subjective and objective assessments of sacral neuromodulation effectiveness in patients with urgency-frequency,NEUROUROLOGY AND URODYNAMICS, Issue 8 2008Kenneth M. Peters Abstract Aims Global response assessment (GRA) has been used to evaluate patients' perceptions of treatment effectiveness. However, few studies have scrutinized the relationship between GRAs and objective voiding diary outcomes data. This study explores the relationship between self-reported symptom-specific GRA responses and objective changes in frequency, urgency and pelvic pain in patients with urgency-frequency with or without pelvic pain after implantation of a prosthetic sacral nerve stimulation device. Methods Patients scheduled for a staged procedure were enrolled in a prospective, observational, longitudinal study. Post implantation, patietns were grouped into "responders" or "non-responders" based on their answers to symptom-specific GRAs at three and six months. Treatment responders were defined as those reporting "moderately" or "markedly improved" on a 7-point scale, and all others were considered non-responders. Pre- and post-implant changes in mean 24-hour voiding frequency, voided volume, urgency and pelvic pain scores as recorded on voiding diaries were compared between groups using paired t-test. Results At three months, responders demonstrated corresponding statistically significant improvement in voiding frequency (P,<,0.001), average voided volume (P,=,0.003), urgency (P,=,0.022) and pelvic pain (P,=,0.039). At six months, responders demonstrated statistically significant improvements in frequency (P,=,0.025) and urgency (P,=,0.006). None of the symptom changes were statistically significant in treatment non-responders. Conclusions The GRA non-responders groups' perceptions of treatment response agreed with their objective changes in bothersome symptoms and responders' changes agreed with their perception of improvement in the majority of symptoms. Further study is needed to standardize the GRA, and explore its potential for use in clinical practice. Neurourol. Urodynam. 27:775,778, 2008, © 2008 Wiley-Liss, Inc. [source] Phase II study of bryostatin 1 and vincristine for aggressive non-Hodgkin lymphoma relapsing after an autologous stem cell transplant,AMERICAN JOURNAL OF HEMATOLOGY, Issue 8 2009Paul M. Barr Bryostatin 1, isolated from a marine bryozoan, enhances the efficacy of cytotoxic agents through modulation of the protein kinase C pathway and is active in combination with vincristine for diffuse large B-cell lymphoma. Further, the apoptotic frequency of peripheral blood T lymphocytes as determined by flow cytometry may predict which patients will respond to this combination. We tested the efficacy and safety of bryostatin 1 50 ,g/m2 given over 24 hr and vincristine 1.4 mg/m2 on days 1 and 15 every 28 days in aggressive B-cell non-Hodgkin lymphoma (NHL) relapsing after autologous stem cell transplantation. End points included tumor response, toxicity, and survival. Responses were correlated with an increase in apoptotic frequency of CD5+ cells by flow cytometry using annexin V staining. Fourteen patients were enrolled with 13 being evaluable for a response. The overall response rate was 31% with two patients achieving a complete response. The most common toxicities were Grade 3 lymphopenia (seven patients), Grade 3 to 4 neutropenia (two patients), and Grade 3 hypophosphatemia (two patients). Median progression-free and overall survivals for all patients were 5.7 and 21.4 months, respectively. One patient demonstrated an increase in T-cell apoptotic frequency, also achieving a complete response. Bryostatin 1 and vincristine have efficacy in select patients with aggressive NHL. Future investigations of agents targeting the protein kinase C pathway may benefit from early response assessment using flow cytometry to evaluate T-cell apoptosis. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source] Radiation exposure from work-related medical X-rays at the Portsmouth Naval Shipyard,AMERICAN JOURNAL OF INDUSTRIAL MEDICINE, Issue 3 2005Robert D. Daniels BS Abstract Background Previous analyses suggest that worker radiation dose may be significantly increased by routine occupational X-ray examinations. Medical exposures are investigated for 570 civilian workers employed at the Portsmouth Naval Shipyard (PNS) at Kittery, Maine. The research objective was to determine the radiation exposure contribution of work-related chest X-rays (WRX) relative to conventional workplace radiation sources. Methods Methods were developed to estimate absorbed doses to the active (hematopoietic) bone marrow from X-ray examinations and workplace exposures using data extracted from worker dosimetry records (8,468) and health records (2,453). Dose distributions were examined for radiation and non-radiation workers. Results Photofluorographic chest examinations resulted in 82% of the dose from medical sources. Radiation workers received 26% of their collective dose from WRX and received 66% more WRX exposure than non-radiation workers. Conclusions WRX can result in a significant fraction of the total dose, especially for radiation workers who were more likely to be subjected to routine medical monitoring. Omission of WRX from the total dose is a likely source of bias that can lead to dose category misclassification and may skew the epidemiologic dose,response assessment for cancers induced by the workplace. Am. J. Ind. Med. 47:206,216, 2005. Published 2005 Wiley-Liss, Inc. [source] Vinorelbine, doxorubicin, and prednisone in androgen-independent prostate cancerCANCER, Issue 5 2006Lester S. Borden Jr. MD Abstract BACKGROUND. Ultimately, patients with metastatic prostate cancer progress on androgen ablation therapy. The investigation of new chemotherapeutic regimens for the treatment of androgen-independent prostate cancer (AIPC) is essential. The authors conducted a Phase II trial with vinorelbine, doxorubicin, and daily prednisone (NAP) to investigate the antitumor activity and palliative response of this regimen in patients with AIPC. METHODS. Forty-six patients entered this Phase II combination chemotherapy trial. Patients were treated with both vinorelbine and doxorubicin at doses of 20 mg/m2 on Days 1, 8, and 15 every 28 days and prednisone 5 mg twice daily. Endpoints included prostate-specific antigen (PSA) response and palliation, as measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) instrument, the Brief Pain Inventory Scale, and a narcotic analgesic log. RESULTS. The median follow-up for all 46 patients was 13.4 months. Fifty-two percent of patients had impaired performance status at baseline. One responding patient remained on NAP and was progression-free at 11.5 months. Thirty-nine patients progressed, 3 patients died prior to response assessment, and 3 patients refused therapy. The median overall survival was 57 weeks (95% confidence interval [95% CI], 36,76 weeks), and the median time to disease progression was 17 weeks (range, 11,24 weeks). The PSA response among the 36 patients who completed 3 cycles of NAP was 42% (95% CI, 26,59%). There was a statistically significant improvement in quality of life measured both by the FACT-General instrument (P = .03) and the FACT-P instrument (P = .0006) over the 3 months compared with baseline measurements. Pain medicine use also improved: The median morphine equivalents among patients who were taking pain medications at the time of study enrollment showed a substantial decline after 1 cycle of treatment that was maintained. Pain (as assessed by the Brief Pain Inventory) improved compared with baseline pain at the 2nd-month assessment (worst pain, P = .08; least pain, P = .02; and average pain, P = .003). Overall, the regimen was tolerated well. The most common side effects were mild fatigue and gastrointestinal complaints (all of which were Grade 1 or 2 [according to Version 2.0 of the Expanded Common Toxicity Criteria]). Seventeen patients (37%) experienced Grade 3 or 4 neutropenia. Five patients (11%) developed a cardiac ejection fraction of <50% during treatment and had doxorubicin discontinued. No patients developed clinical congestive heart failure. CONCLUSIONS. The NAP combination produced substantive palliation and a moderate response rate in men with AIPC. Cancer 2006. © American Cancer Society. [source] A critical reappraisal of treatment response criteria in systemic mastocytosis and a proposal for revisionsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2010A. Pardanani Abstract Mast cell disease (MCD) is a hematopoietic stem cell neoplasm that is associated with infiltration of one or more organs with cytologically abnormal mast cells (MC). MCD is frequently but not always associated with a KIT mutation and, in some cases, is associated with clonal expansion of non-MC lineage cells. In adults, there is almost always MC infiltration of the bone marrow, which is a cardinal feature of systemic mastocytosis (SM). While, as members of the wider community of physician scientists, we recognize the contribution of the current consensus treatment response criteria for SM, as individuals with more than average clinical experience in SM, we would like to point out their limitations and engage in a constructive discussion that will hopefully lead to a consideration for revisions. We present here an alternative proposal for treatment response assessments we believe is more objective, reproducible, and importantly, SM-subtype specific, given the recent progress in our understanding of the natural history of this disease. We believe this proposal is timely given the prospects for new clinical trials in SM, and the related regulatory aspects of new drug approval that are currently not adequately addressed. The intent of this exercise is not to undermine the complexity of the disease or previous work by other investigators, but to come up with ideas for response criteria that are more practical and consider meaningful patient outcome. [source] | ||||||||||