Recommendations for nomenclature and definition of cell products intended for human cardiovascular use.

Exogenous cell-based therapy has emerged as a promising new strategy to facilitate repair of hearts damaged by acute or chronic injury. However, the field of cell-based therapy is handicapped by the lack of standardized definitions and terminology, making comparisons across studies challenging. Even the term 'stem cell therapy' is misleading because only a small percentage of cells derived from adult bone marrow, peripheral blood, or adipose tissue meets the accepted haematopoietic or developmental definition of stem cells. Furthermore, cells (stem or otherwise) are dynamic biological products, meaning that their surface-marker expression, phenotypic and functional characteristics, and the products they secrete in response to their microenvironment can change. It is also important to point out that most surface markers are seldom specific for a cell type. In this article, we discuss the lack of consistency in the descriptive terminology used in cell-based therapies and offer guidelines aimed at standardizing nomenclature and definitions to improve communication among investigators and the general public.

A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial.

AIMS: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. METHODS AND RESULTS: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. CONCLUSIONS: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial.

BACKGROUND: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment. OBJECTIVES: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC. METHODS: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 × 108 allo-MSCs or vehicle transendocardially. Primary objectives were safety and feasibility. Secondary efficacy measures included cardiac function and structure measured by cardiac magnetic resonance imaging (CMR), functional capacity, quality of life (Minnesota Living with Heart Failure Questionnaire), and biomarkers. RESULTS: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the target dose of cells. Follow-up visits were well-attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-CMR compatible devices, CMR endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes. Secondary measures included 6-min walk test (p = 0.056) and Minnesota Living with Heart Failure Questionnaire score (p = 0.048), which tended to favor the allo-MSC group. CONCLUSIONS: In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible, and CMR was successfully performed in the majority of the HF patients with devices. This study lays the groundwork for phase 2 trials aimed at assessing efficacy of cell therapy in patients with AIC.

Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial.

OBJECTIVES: SENECA (StEm cell iNjECtion in cAncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC). BACKGROUND: AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium. METHODS: The study population is 36 cancer survivors with a diagnosis of AIC, left ventricular (LV) ejection fraction ≤40%, and symptoms of heart failure (NYHA class II-III) on optimally-tolerated medical therapy. Subjects must be clinically free of cancer for at least two years with a ≤ 30% estimated five-year risk of recurrence. The first six subjects participated in an open-label, lead-in phase and received 100 million allo-MSCs; the remaining 30 will be randomized 1:1 to receive allo-MSCs or vehicle via 20 transendocardial injections. Efficacy measures (obtained at baseline, 6 months, and 12 months) include MRI evaluation of LV function, LV volumes, fibrosis, and scar burden; assessment of exercise tolerance (six-minute walk test) and quality of life (Minnesota Living with Heart Failure Questionnaire); clinical outcomes (MACE and cumulative days alive and out of hospital); and biomarkers of heart failure (NT-proBNP). CONCLUSIONS: This is the first clinical trial using direct cardiac injection of cells for the treatment of AIC. If administration of allo-MSCs is found feasible and safe, SENECA will pave the way for larger phase II/III studies with therapeutic efficacy as the primary outcome.

Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit+ Cardiac Stem Cells As Regenerative Therapy for Heart Failure).

RATIONALE: Autologous bone marrow mesenchymal stem cells (MSCs) and c-kit+ cardiac progenitor cells (CPCs) are 2 promising cell types being evaluated for patients with heart failure (HF) secondary to ischemic cardiomyopathy. No information is available in humans about the relative efficacy of MSCs and CPCs and whether their combination is more efficacious than either cell type alone. OBJECTIVE: CONCERT-HF (Combination of Mesenchymal and c-kit+ Cardiac Stem Cells As Regenerative Therapy for Heart Failure) is a phase II trial aimed at elucidating these issues by assessing the feasibility, safety, and efficacy of transendocardial administration of autologous MSCs and CPCs, alone and in combination, in patients with HF caused by chronic ischemic cardiomyopathy (coronary artery disease and old myocardial infarction). METHODS AND RESULTS: Using a randomized, double-blinded, placebo-controlled, multicenter, multitreatment, and adaptive design, CONCERT-HF examines whether administration of MSCs alone, CPCs alone, or MSCs+CPCs in this population alleviates left ventricular remodeling and dysfunction, reduces scar size, improves quality of life, or augments functional capacity. The 4-arm design enables comparisons of MSCs alone with CPCs alone and with their combination. CONCERT-HF consists of 162 patients, 18 in a safety lead-in phase (stage 1) and 144 in the main trial (stage 2). Stage 1 is complete, and stage 2 is currently randomizing patients from 7 centers across the United States. CONCLUSIONS: CONCERT-HF will provide important insights into the potential therapeutic utility of MSCs and CPCs, given alone and in combination, for patients with HF secondary to ischemic cardiomyopathy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02501811.

Rationale and design for PACE: patients with intermittent claudication injected with ALDH bright cells.

Peripheral artery disease (PAD) is recognized as a public health issue because of its prevalence, functional limitations, and increased risk of systemic ischemic events. Current treatments for claudication, the primary symptom in patients with PAD, have limitations. Cells identified using cytosolic enzyme aldehyde dehydrogenase (ALDH) may benefit patients with severe PAD but has not been studied in patients with claudication. PACE is a randomized, double-blind, placebo-controlled clinical trial conducted by the Cardiovascular Cell Therapy Research Network to assess the safety and efficacy of autologous bone marrow-derived ALDH(br) cells delivered by direct intramuscular injections in 80 patients with symptom-limiting intermittent claudication. Eligible patients will have a significant stenosis or occlusion of infrainguinal arteries and a resting ankle-brachial index less than 0.90 and will be randomized 1:1 to cell or placebo treatment with a 1-year follow-up. The primary end points are the change in peak walking time and leg collateral arterial anatomy, calf muscle blood flow, and tissue perfusion as determined by magnetic resonance imaging at 6 months compared with baseline. The latter 3 measurements are new physiologic lower extremity tissue perfusion and PAD imaging-based end points that may help to quantify the biologic and mechanistic effects of cell therapy. This trial will collect important mechanistic and clinical information on the safety and efficacy of ALDH(br) cells in patients with claudication and provide valuable insight into the utility of advanced magnetic resonance imaging end points.

Implementation of cardovascular cell therapy network trials: challenges, innovation and lessons learned from experience in the CCTRN.

The cardiovascular cell therapy network was developed by the National Heart, Lung and Blood Institute to design and conduct clinical trials to advance the field of cardiovascular (CV) cell-based therapy. The Cardiovascular Cell Therapy Network successfully completed three clinical trials involving approximately 300 subjects across five centers and six satellites. Although the concept of a network within clinical trials research is not new, the knowledge gained in the implementation of such large-scale trials, particularly in novel therapeutic areas such as cell therapy is not often detailed in the literature. The purpose of this communication is to summarize key factors in achieving network goals and share the knowledge gained to promote success in future cardiovascular disease cell therapy trials and networks.

Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial.

CONTEXT: While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. OBJECTIVES: To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. DESIGN, SETTING, AND PATIENTS: A randomized, 2 × 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤ 45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. INTERVENTIONS: Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. MAIN OUTCOME MEASURES: The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. RESULTS: The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) vs the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P = .96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (−0.9% [95% CI, −6.6% to 4.9%], P = .76) or day 7 (1.1% [95% CI, −4.7% to 6.9%], P = .70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. CONCLUSION: Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00684021.

Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.

CONTEXT: Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. OBJECTIVE: To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. DESIGN, SETTING, AND PATIENTS: A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. INTERVENTION: Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). MAIN OUTCOME MEASURES: Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. RESULTS: Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. CONCLUSION: Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00824005.

Developing mechanistic insights into cardiovascular cell therapy: Cardiovascular Cell Therapy Research Network Biorepository Core Laboratory rationale.

Moderate improvements in cardiac performance have been reported in some clinical settings after delivery of bone marrow mononuclear cells to patients with cardiovascular disease. However, mechanistic insights into how these cells impact outcomes are lacking. To address this, the National Heart, Lung and Blood Institute (NHLBI) Cardiovascular Cell Therapy Research Network (CCTRN) established a Biorepository Core for extensive phenotyping and cell function studies and storing bone marrow and peripheral blood for 10 years. Analyzing cell populations and cell function in the context of clinical parameters and clinical outcomes after cell or placebo treatment empower the development of novel diagnostic and prognostics. Developing such biomarkers that define the safety and efficacy of cell therapy is a major Biorepository aim.

Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial.

CONTEXT: Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, because a substantial number of patients may not present for early cell delivery, the efficacy of autologous BMC delivery 2 to 3 weeks post-MI warrants investigation. OBJECTIVE: To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2 to 3 weeks following first MI. DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled trial (LateTIME) of the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network of 87 patients with significant LV dysfunction (LV ejection fraction [LVEF] ≤45%) following successful primary percutaneous coronary intervention (PCI) between July 8, 2008, and February 28, 2011. INTERVENTIONS: Intracoronary infusion of 150 × 10(6) autologous BMCs (total nucleated cells) or placebo (BMC:placebo, 2:1) was performed within 12 hours of bone marrow aspiration after local automated cell processing. MAIN OUTCOME MEASURES: Changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone between baseline and 6 months, measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volumes and infarct size. RESULTS: A total of 87 patients were randomized (mean [SD] age, 57 [11] years; 83% men). Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible. Change between baseline and 6 months in the BMC group vs placebo for mean LVEF (48.7% to 49.2% vs 45.3% to 48.8%; between-group mean difference, -3.00; 95% CI, -7.05 to 0.95), wall motion in the infarct zone (6.2 to 6.5 mm vs 4.9 to 5.9 mm; between-group mean difference, -0.70; 95% CI, -2.78 to 1.34), and wall motion in the border zone (16.0 to 16.6 mm vs 16.1 to 19.3 mm; between-group mean difference, -2.60; 95% CI, -6.03 to 0.77) were not statistically significant. No significant change in LV volumes and infarct volumes was observed; both groups decreased by a similar amount at 6 months vs baseline. CONCLUSION: Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs vs intracoronary placebo infusion, 2 to 3 weeks after PCI, did not improve global or regional function at 6 months. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00684060.

LateTIME: a phase-II, randomized, double-blinded, placebo-controlled, pilot trial evaluating the safety and effect of administration of bone marrow mononuclear cells 2 to 3 weeks after acute myocardial infarction.

A realistic goal for cardiac cell therapy may be to attenuate left ventricular remodeling following acute myocardial infarction to prevent the development of congestive heart failure. Initial clinical trials of cell therapy have delivered cells 1 to 7 days after acute myocardial infarction. However, many patients at risk of developing congestive heart failure may not be ready for cell delivery at that time-point because of clinical instability or hospitalization at facilities without access to cell therapy. Experience with cell delivery 2 to 3 weeks after acute myocardial infarction has not to date been explored in a clinical trial. The objective of the LateTIME study is to evaluate by cardiac magnetic resonance the effect on global and regional left ventricular function, between baseline and 6 months, of a single intracoronary infusion of 150 × 106 autologous bone marrow mononuclear cells (compared with placebo) when that infusion is administered 2 to 3 weeks after moderate-to-large acute myocardial infarction. The 5 clinical sites of the Cardiovascular Cell Therapy Research Network (CCTRN) will enroll a total of 87 eligible patients in a 2:1 bone marrow mononuclear cells-to-placebo patient ratio; these 87 will have undergone successful percutaneous coronary intervention of a major coronary artery and have left ventricular ejection fractions ≤0.45 by echocardiography. When the results become available, this study should provide insight into the clinical feasibility and appropriate timing of autologous cell therapy in high-risk patients after acute myocardial infarction and percutaneous coronary intervention.

Intramyocardial injection of autologous bone marrow mononuclear cells for patients with chronic ischemic heart disease and left ventricular dysfunction (First Mononuclear Cells injected in the US [FOCUS]): Rationale and design.

BACKGROUND: The increasing worldwide prevalence of coronary artery disease (CAD) continues to challenge the medical community. Management options include medical and revascularization therapy. Despite advances in these methods, CAD is a leading cause of recurrent ischemia and heart failure, posing significant morbidity and mortality risks along with increasing health costs in a large patient population worldwide. TRIAL DESIGN: The Cardiovascular Cell Therapy Research Network (CCTRN) was established by the National Institutes of Health to investigate the role of cell therapy in the treatment of chronic cardiovascular disease. FOCUS is a CCTRN-designed randomized, phase II, placebo-controlled clinical trial that will assess the effect of autologous bone marrow mononuclear cells delivered transendocardially to patients with left ventricular (LV) dysfunction and symptomatic heart failure or angina. All patients need to have limiting ischemia by reversible ischemia on single-photon emission computed tomography assessment. RESULTS: After thoughtful consideration of both statistical and clinical principles, we will recruit 87 patients (58 cell treated and 29 placebo) to receive either bone marrow-derived stem cells or placebo. Myocardial perfusion, LV contractile performance, and maximal oxygen consumption are the primary outcome measures. CONCLUSIONS: The designed clinical trial will provide a sound assessment of the effect of autologous bone marrow mononuclear cells in improving blood flow and contractile function of the heart. The target population is patients with CAD and LV dysfunction with limiting angina or symptomatic heat failure. Patient safety is a central concern of the CCTRN, and patients will be followed for at least 5 years.

Rationale and design for TIME: A phase II, randomized, double-blind, placebo-controlled pilot trial evaluating the safety and effect of timing of administration of bone marrow mononuclear cells after acute myocardial infarction.

Several previous studies have demonstrated that administration of autologous bone marrow-derived mononuclear cells (BMMNCs) improves cardiac function in patients after acute myocardial infarction (AMI). However, optimum timing of administration has not been investigated in a clinical trial. The Cardiovascular Cell Therapy Research Network was developed and funded by the National Heart, Lung, and Blood Institute to address important questions such as timing of cell delivery and to accelerate research in the use of cell-based therapies. The TIME trial is a randomized, phase II, double-blind, placebo-controlled clinical trial. The 5 member clinical sites of the Cardiovascular Cell Therapy Research Network will enroll 120 eligible patients with moderate-to-large anterior AMIs who have undergone successful percutaneous coronary intervention of the left anterior descending coronary artery and have a left ventricular (LV) ejection fraction

Reliability and validity of a questionnaire to measure colorectal cancer screening behaviors: does mode of survey administration matter?

Valid and reliable self-report measures of cancer screening behaviors are important for evaluating efforts to improve adherence to guidelines. We evaluated test-retest reliability and validity of self-report of the fecal occult blood test (FOBT), sigmoidoscopy (SIG), colonoscopy (COL), and barium enema (BE) using the National Cancer Institute colorectal cancer screening (CRCS) questionnaire. A secondary objective was to evaluate reliability and validity by mail, telephone, and face-to-face survey administration modes. Consenting men and women, 51 to 74 years old, receiving care at a multispecialty clinic for at least 5 years who had not been diagnosed with colorectal cancer were stratified by prior CRCS status and randomized to survey mode (n = 857). Within survey mode, respondents were randomized to complete a second survey at 2 weeks, 3 months, or 6 months. Comparing self-report with administrative and medical records, concordance estimates were 0.91 for COL, 0.85 for FOBT, 0.85 for SIG, and 0.92 for BE. Overall sensitivity estimates were 0.91 for COL, 0.82 for FOBT, 0.76 for SIG, and 0.56 for BE. Specificity estimates were 0.91 for COL, 0.86 for FOBT, 0.89 for SIG, and 0.97 for BE. Sensitivity and specificity varied little by survey mode for any test. Report-to-records ratio showed overreporting for SIG (1.1), COL (1.15), and FOBT (1.57), and underreporting for BE (0.82). Reliability at all time intervals was highest for COL; there was no consistent pattern according to survey mode. This study provides evidence to support the use of the National Cancer Institute CRCS questionnaire to assess self-report with any of the three survey modes.