Traditional Endpoints Research Articles

Preclinical Investigations for Thrombectomy Devices—Does it Translate to Humans?

In the United States, 4 devices have received Food and Drug Administration clearance for intra-arterial mechanical removal of the embolus in a large vessel occlusion causing acute ischemic stroke (AIS). A number of other devices with similar indication are either beginning trials in the United States or are available for clinical use in the European Union. The goal of preclinical modeling for the intra-arterial treatment of AIS is to evaluate the safety and the efficacy of these devices quantitatively to predict how they will perform in patients, identify effective techniques for their use, or to optimize the design before introducing them into clinical trials. Safety studies should ascertain the potential for vascular trauma, propensity to generate distal emboli, and effect on the blood brain barrier, particularly in the case where the device is used to deliver energy for clot disruption. Efficacy metrics include the ability to restore flow through the occluded vessel (recanalization), the amount of flow restored to the distal territory (reperfusion), and the time needed to remove the embolus. Large animal models of stroke amenable to the study of endovascular mechanical thrombectomy are challenging because of the anatomy of the cerebrovasculature in commonly used laboratory animals.1 To date, most preclinical modeling uses large vessel occlusion in the extracranial circulation of the pig2–5 or dog,4,6 wherein the selected vessel is embolized with an autologous clot of varying composition. Notably, these are not models of AIS and, therefore, the traditional end points of infarct volume and neurological outcome are not applicable. Therefore, the end points of these studies are typically angiographic evidence of recanalization and pursuant damage to the vessel in which the device was operated. Importantly, the architecture of the extracranial vasculature with substantial perivascular support, external elastic lamina, and robust tunica media is …

Molecular characterization of toxicity mechanism of single-walled carbon nanotubes

Carbon nanotubes (CNTs) are one of widely used nanomaterials in industry and biomedicine. The potential impact of single-walled carbon nanotubes (SWCNTs) was evaluated using Caenorhabditis elegans (C. elegans) as a toxicological animal model. SWCNTs are extremely hydrophobic to form large agglomerates in aqueous solutions. Highly soluble amide-modified SWCNTs (a-SWCNTs) were therefore used in the present study so that the exact impact of SWCNTs could be studied. No significant toxicity was observed in C. elegans due to the amide modification. a-SWCNTs were efficiently taken up by worms and caused acute toxicity, including retarded growth, shortened lifespan and defective embryogenesis. The resulting toxicity was reversible since C. elegans could recover from a-SWCNT-induced toxicity once the exposure terminates. Chronic exposure to low doses of a-SWCNTs during all development stages could also cause a toxic accumulation in C. elegans. Genome-wide gene expression analysis was performed to investigate the toxic molecular mechanisms. Functional genomic analysis and molecular biology validation suggest that defective endocytosis, the decreased activity of the citrate cycle and the reduced nuclear translocation of DAF-16 transcription factor play key roles in inducing the observed a-SWCNT toxicity in worms. The present study presents an integrated approach to evaluating the toxicity of nanomaterials at the organism and molecular level for human and environmental health and demonstrates that traditional toxicological endpoints associated with functional genomic analysis can provide global and thorough insight into toxicity.

Use of calcium isotope tracers for screening potential treatments for osteoporosis

Determining the efficacy of novel osteoporosis therapies and preventive interventions (ie. dietary supplements) is costly and time consuming when using the traditional endpoints of bone mineral density (BMD) or fracture prevention. Calcium isotope tracers offer a relatively cheap and rapid technique to screen potential osteoporosis therapies in both humans and animals. We have developed methods to screen potential anti‐osteoporosis therapies using 41Ca in humans and 45Ca in rats. Following a single dose of the tracer and an equilibration period through one bone remodeling cycle (150d in humans and 30d in rats), the blood and urine clearance of tracer reflects bone turnover, and changes in urine tracer excretion in response to therapy measure changes in net bone turnover. Using this method, efficacy of potential anti‐osteoporosis therapies can be determined in as few as 50 days in humans and 10d in rats, and multiple therapies can be sequentially screened in the same individual. We have utilized this method to compare efficacy of antiresorptives, including bisphosphonates, estrogen, and soy isoflavones, in both humans (Weaver et al. 2009 J Clin Endocrinol Metab) and in rats and have recently confirmed that this method is also suitable for comparing anabolic therapies. These methods will be used in future planned studies to screen botanical products and drug/botanical combination therapies.Grant Funding Source: NIH, Purdue University

A protocol to determine valid in young cystic fibrosis patients

Measuring aerobic fitness (V˙O2max) via a maximal cardiopulmonary exercise test is an important clinical tool in cystic fibrosis. This study sought to establish: (1) the validity of traditional criteria to verify maximal efforts during a ramp cardiopulmonary exercise test; and (2) whether V˙O2 measured during an exhaustive cardiopulmonary exercise test represents a valid V˙O2max in paediatric patients, using a subsequent exhaustive supramaximal (Smax) exercise test. Cross-sectional. Fourteen patients (7-18 years; 10 males) completed an exhaustive ramp test to determine V˙O2max. Following 15-min recovery, Smax (110% ramp peak power output) was performed. Ramp test V˙O2peak was significantly higher than V˙O2 documented at traditional endpoint criteria, including a RER of 1.00 (0.99±0.47 L min(-1) vs. 1.83±0.78 L min(-1), p<0.001) and 1.10 (1.36±0.59 L min(-1) vs. 1.83±0.78 L min(-1), p<0.001), despite 100% of patients satisfying these two criteria. Only 23% and 75% of patients satisfied the 95% age-predicted heart rate (HR) maximum and 180 b min(-1) criteria. Whilst mean ramp and Smax V˙O2peak were not significantly different (1.83±0.78 L min(-1) vs. 1.82±0.67 L min(-1); p=0.88), at the individual level Smax elicited a 'meaningful' (>9%) increase in V˙O2peak (range 9.9-38.3%) compared with V˙O2peak from the ramp test in 3 of 14 cases (21.4%). Traditional criteria significantly underestimate V˙O2max in young cystic fibrosis patients. Conversely, Smax can confirm when 'true' V˙O2max is achieved. The use of Smax following cardiopulmonary exercise test represents an appropriate method to measure V˙O2max in young cystic fibrosis patients.

The role of chemistry in developing understanding of adverse outcome pathways and their application in risk assessment

The Adverse Outcome Pathway (AOP) conceptual framework has been presented as a logical sequence of events or processes within biological systems which can be used to understand adverse effects and refine the current risk assessment practice. This approach shifts the risk assessment focus from traditional apical endpoints to the development of a mechanistic understanding of a chemicals effect at a molecular and cellular level. In order to obtain this level of detail, chemistry in all its disciplines has a key role to play. Measurement techniques will be important in understanding chemical characterisation, free concentration and exposure at the site of interest. Such measurements will be vital in developing structure-based toxicological alerts and informing predictive models. This paper explores the areas where chemistry will be influential in the development of AOPs. In this paper we explore where chemistry will be influential in the development of AOP-based approaches to risk assessment.

A Review of Targeted Therapies Evaluated by the Pediatric Preclinical Testing Program for Osteosarcoma

Osteosarcoma, the most common malignant bone tumor of childhood, is a high-grade primary bone sarcoma that occurs mostly in adolescence. Standard treatment consists of surgery in combination with multi-agent chemotherapy regimens. The development and approval of imatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia in children and the fully human monoclonal antibody, anti-GD2, as part of an immune therapy for high-risk neuroblastoma patients have established the precedent for use of targeted inhibitors along with standard chemotherapy backbones. However, few targeted agents tested have achieved traditional clinical endpoints for osteosarcoma. Many biological agents demonstrating anti-tumor responses in preclinical and early-phase clinical testing have failed to reach response thresholds to justify randomized trials with large numbers of patients. The development of targeted therapies for pediatric cancer remains a significant challenge. To aid in the prioritization of new agents for clinical testing, the Pediatric Preclinical Testing Program (PPTP) has developed reliable and robust preclinical pediatric cancer models to rapidly screen agents for activity in multiple childhood cancers and establish pharmacological parameters and effective drug concentrations for clinical trials. In this article, we examine a range of standard and novel agents that have been evaluated by the PPTP, and we discuss the preclinical and clinical development of these for the treatment of osteosarcoma. We further demonstrate that committed resources for hypothesis-driven drug discovery and development are needed to yield clinical successes in the search for new therapies for this pediatric disease.

NCI-RTOG translational program strategic guidelines for the early-stage development of radiosensitizers.

The addition of chemotherapeutic agents to ionizing radiation has improved survival in many malignancies. Cure rates may be further improved by adding novel targeted agents to current radiotherapy or radiochemotherapy regimens. Despite promising laboratory data, progress in the clinical development of new drugs with radiation has been limited. To define and address the problems involved, a collaborative effort between individuals within the translational research program of the Radiation Oncology Therapy Group and the National Cancer Institute was established. We discerned challenges to drug development with radiation including: 1) the limited relevance of preclinical work, 2) the pharmaceutical industry's diminished interest, and 3) the important individual skills and institutional commitments required to ensure a successful program. The differences between early-phase trial designs with and without radiation are noted as substantial. The traditional endpoints for early-phase clinical trials-acute toxicity and maximum-tolerated dose-are of limited value when combining targeted agents with radiation. Furthermore, response rate is not a useful surrogate marker of activity in radiation combination trials.Consequently, a risk-stratified model for drug-dose escalation with radiation is proposed, based upon the known and estimated adverse effects. The guidelines discuss new clinical trial designs, such as the time-to-event continual reassessment method design for phase I trials, randomized phase II "screening" trials, and the use of surrogate endpoints, such as pathological response. It is hoped that by providing a clear pathway, this article will accelerate the rate of drug development with radiation.

Testing different brain metastasis grading systems in stereotactic radiosurgery: Radiation Therapy Oncology Group's RPA, SIR, BSBM, GPA, and modified RPA

The authors conducted validity testing of the 5 major reported indices for radiosurgically treated brain metastases- the original Radiation Therapy Oncology Group's Recursive Partitioning Analysis (RPA), the Score Index for Radiosurgery in Brain Metastases (SIR), the Basic Score for Brain Metastases (BSBM), the Graded Prognostic Assessment (GPA), and the subclassification of RPA Class II proposed by Yamamoto-in nearly 2500 cases treated with Gamma Knife surgery (GKS), focusing on the preservation of neurological function as well as the traditional endpoint of overall survival. The authors analyzed data from 2445 cases treated with GKS by the first author (T.S.), the primary surgeon. The patient group consisted of 1716 patients treated between January 1998 and March 2008 (the Chiba series) and 729 patients treated between April 2008 and December 2011 (the Tokyo series). The interval from the date of GKS until the date of the patient's death (overall survival) and impaired activities of daily living (qualitative survival) were calculated using the Kaplan-Meier method, while the absolute risk for two adjacent classes of each grading system and both hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model. For overall survival, there were highly statistically significant differences between each two adjacent patient groups characterized by class or score (all p values < 0.001), except for GPA Scores 3.5-4.0 and 3.0. The SIR showed the best statistical results for predicting preservation of neurological function. Although no other grading systems yielded statistically significant differences in qualitative survival, the BSBM and the modified RPA appeared to be better than the original RPA and GPA. The modified RPA subclassification, proposed by Yamamoto, is well balanced in scoring simplicity with respect to case number distribution and statistical results for overall survival. However, a new or revised grading system is necessary for predicting qualitative survival and for selecting the optimal treatment for patients with brain metastasis treated by GKS.

Gene Expression Patterns and Life Cycle Responses of Toxicant-Exposed Chironomids

Cellular stress responses are frequently presumed to be more sensitive than traditional ecotoxicological life cycle end points such as survival and growth. Yet, the focus to reduce test duration and to generate more sensitive end points has caused transcriptomics studies to be performed at low doses during short exposures, separately and independently from traditional ecotoxicity tests, making comparisons with life cycle end points indirect. Therefore we aimed to directly compare the effects on growth, survival, and gene expression of the nonbiting midge Chironomus riparius. To this purpose, we simultaneously analyzed life cycle and transcriptomics responses of chironomid larvae exposed to four model toxicants. We observed that already at the lowest test concentrations many transcripts were significantly differentially expressed, while the life cycle end points of C. riparius were hardly affected. Analysis of the differentially expressed transcripts showed that at the lowest test concentrations substantial and biologically relevant cellular stress was induced and that many transcripts responded already maximally at these lowest test concentrations. The direct comparison between molecular end life cycle responses after fourteen days of exposure revealed that gene expression is more sensitive to toxicant exposure than life cycle end points, underlining the potential of transcriptomics for ecotoxicity testing and environmental risk assessment.

Management of advanced lung cancer in resource-constrained settings: a perspective from India

Advanced lung cancer (LC) is an important cause of cancer-related morbidity and mortality in resource-constrained settings (RCSs). Cytological/pathological confirmation of diagnosis of LC is essential prior to treatment initiation for ruling out mimickers such as pulmonary tuberculosis. Accurate staging is necessary for optimal management, and investigations should be prioritized based on availability and cost–effectiveness. Platinum-based doublet chemotherapy remains the standard of care for advanced LC. Cost of therapy, lack of medical insurance and frequency of visits are important determinants of treatment regimen. EGF receptor mutation testing may not be readily available in RCSs and chemotherapy should be preferred for unselected patients with advanced non-small-cell lung cancer. Generic drugs may be more affordable than innovator brands. Treatment efficacy should be assessed with traditional end points (survival and objective response rates) as well as those relevant to RCSs (quality of life, toxicity profile and healthcare facility utilization). Issues related to LC treatment in first- and subsequent-line settings in RCSs are discussed in detail in this evidence-based review.

Endoscopic vein harvest of the lesser saphenous vein in the supine position: a unique approach to an old problem†

To obtain a suitable conduit from the lesser (short) saphenous system for use in coronary artery bypass surgery. We wanted to perform this while the patient was in the supine position as to not disrupt the standard operation, and at the same time, utilizing the endoscopic vein harvest technique with its obvious abilities to decrease vein harvest morbidity. We also theorized that through endoscopic techniques instead of the open technique we could harvest greater lengths of conduit, thus providing quality vein segments for additional grafts if needed. We were able to perform endoscopic vein harvest while in the supine position with one unique centrally located incision that has not been previously described. The lesser saphenous vein harvested in the described technique provided excellent conduit for our patients that were conduit poor. The endoscopic technique allowed increased length of harvested segments, by giving us the ability to travel under the gastrocnemius muscle with minimal morbidity as opposed to the open technique, where the traditional endpoint is the aforementioned muscle. Conduits were harvested successfully from 14 of 16 candidates. No wound infections or healing problems were experienced. Neurovascular integrity was maintained in all patients. Endoscopic vein harvest of the lesser saphenous vein with the patient in the supine position is safe, effective and affords conduits for a unique subset of patients undergoing coronary artery bypass grafting.

Brain imaging biomarkers for the Alzheimer’s Prevention Initiative

Alzheimer's disease (AD), the most common disabling impairment in older adults, takes an unacceptable toll on patients and families. With the growing number of people living to older ages, it is projected to afflict more than 100 million people around the world by 2050. While there is an urgent need, it takes too many cognitively normal (CN) individuals and too many years to evaluate presymptomatic AD treatments using traditional clinical endpoints. We and our colleagues have been using imaging techniques to detect the brain changes associated with the predisposition to AD in CN individuals with 2, 1 and 0 copies of the apolipoprotein E (APOE) e4 allele, the major late-onset AD susceptibility gene, and in CN presenilin 1 (PSEN1) mutation carriers and non-carriers from the world’s largest autosomal dominant early-onset AD kindred in Antioquia, Colombia; we developed several image-analysis techniques and a composite cognitive measure with improved power; and we estimated the sample sizes needed when using these endpoints. We recently proposed the Alzheimer’s Prevention Initiative (API) to help in the effort to launch an era in AD prevention research. The API will include preclinical AD treatment/biomarker development trials in individuals at increased genetic risk for early-onset and late-onset AD, an extremely large Colombian early-onset AD Prevention Registry; and an extremely large North American Alzheimer’s Prevention Registry to support several preclinical AD trials. The API’s first trial will test the anti-amyloid immunization therapy crenezumab in CN PSEN1 mutation carriers using the best established brain imaging and cerebrospinal fluid measurements and our composite cognitive measure as the primary clinical endpoint. It is intended to test an anti-amyloid agent in the preclinical treatment of AD, help determine the extent to which a treatment’s biomarker effects predict a clinical outcome, provide a better test of the amyloid hypothesis, and provide raw data and biological samples to the research community. With support from the U.S. National Institutes of Health, philanthropic funds from the Banner Alzheimer’s Institute, and Genentech, it is also intended to help provide a new paradigm for research collaboration in clinical trials. In this presentation, we will briefly introduce the crucial role of flourodeoxyglucose positron emission tomography (PET), amyloid PET, structural and functional MRI in the preclinical detection, tracking, and treatment of AD. We will present the novel image processing methods we have developed to help in this endeavor, as well as their implementation in the API’s preclinical treatment/biomarker development programs.

Factors influencing quality of life in adult patients with primary brain tumors

We performed a literature review with respect to factors influencing health-related quality of life (QOL) in adults with primary brain tumors. A comprehensive, peer-reviewed literature search was performed including studies examining QOL in adults with high-grade gliomas and low-grade gliomas and in routine neuro-oncology practice. The interpretation and implication of QOL domain scores may be different in high-grade, low-grade, and benign brain tumors. Several patient-related, treatment-related, and sociocultural factors influence QOL scores. Pretreatment baseline QOL domain scores have been shown to be a predictive parameter for survival function. Implementation of QOL scores in routine clinical practice is underused. QOL is an important outcome measure in the treatment of patients with brain tumors and should be incorporated as a surrogate end point along with traditional end points, such as disease-free and overall survival in most current trials.

Lack of interleukin-1 signaling results in perturbed early vein graft wall adaptations

Vein grafts fail as the result of wall maladaptations to surgical injury and hemodynamic perturbations. Interleukin-1 signaling has emerged as an important mediator of the vascular response to trauma and hemodynamically induced vascular lesions. We therefore hypothesized that interleukin-1 signaling drives early vein graft wall adaptations. Using interleukin-1 type I receptor knockout (IL-1RI(-/-)) and wild-type (B6129SF2/J) mice, we investigated morphologic changes 28 days after interposition isograft from donor inferior vena cava to recipient carotid artery, without (n = 19) or with (n = 13) outflow restriction. The impact of mouse strain on the response to vein arterialization also was evaluated between B6129SF2/J (n = 18) and C57BL/6J (n = 19) mice. No differences were observed in the traditional end points of intimal thickness and calculated luminal area, yet media+adventitia thickness of the vein graft wall of IL-1RI(-/-) mice was 44% to 52% less than wild-type mice, at the both proximal (P < .01, P < .01) and distal (P = .054, P < .01) portions of vein grafts, for both normal flow and low flow, respectively. Compared with the C57BL/6J strain, B6129SF2/J mice exhibited no difference in vein graft intimal thickness but 2-fold greater media+adventitia thickness (P < .01). When lacking IL-1 signaling, the vein graft wall adapts differently compared with the injured artery, showing typical intima hyperplasia although attenuated media+adventitia thickening. B6129SF2/J mice exhibit more media+adventitia response than C57BL/6J mice. The inflammatory networks that underlie the vein response to arterialization hold many roles in the adaptation of the total wall; thus, the utility of anti-inflammatory approaches to extend the durability of vein grafts comes into question.

Interactive toxicity of usnic acid and lipopolysaccharides in human liver HepG2 cells

Usnic acid (UA), a natural botanical product, is a constituent of some dietary supplements used for weight loss. It has been associated with clinical hepatotoxicity leading to liver failure in humans. The present study was undertaken to evaluate the interactive toxicity, if any, of UA with lipopolysaccarides (LPS), a potential contaminant of food, at low non-toxic concentrations. The human hepatoblastoma HepG2 cells were treated with the vehicle control and test agents, separately and in a binary mixture, for 24 h at 37°C in 5% CO2. After the treatment period, the cells were evaluated by the traditional biochemical endpoints of toxicity in combination with the toxicogenomic endpoints that included cytotoxicity, oxidative stress, mitochondrial injury and changes in pathway-focused gene expression profiles. Compared with the controls, low non-toxic concentrations of UA and LPS separately showed no effect on the cells as determined by the biochemical endpoints. However, the simultaneous mixed exposure of the cells to their binary mixture resulted in increased cytotoxicity, oxidative stress and mitochondrial injury. The pathway-focused gene expression analysis resulted in the altered expression of several genes out of 84 genes examined. Most altered gene expressions induced by the binary mixture of UA and LPS were different from those induced by the individual constituents. The genes affected by the mixture were not modulated by either UA or LPS. The results of the present study suggest that the interactions of low nontoxic concentrations of UA and LPS produce toxicity in HepG2 cells.

General population norms for the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI).

Metastatic renal cell cancer is associated with poor long-term survival and has no cure. Traditional clinical endpoints are best supplemented by patient-reported outcomes designed to assess symptoms and function. Normative data was obtained on the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy-Kidney Symptom Index (NFKSI) to aid in score interpretation and planning of future trials. General population data were obtained from 2000 respondents, who completed the 19-item NFKSI-19, as well the SF-36 (Short Form 36-item instrument) and the PROMIS-29 (29-item Patient Reported Outcomes Measurement Information System), both general health status measures. Basic demographic and self-reported comorbidity data were also collected. The sample was 50% female, 85.7% caucasian, with an equal distribution across age bands from 18 years to 75 years and older. Most respondents (62.8%) had more than a high school education and reported an Eastern Cooperative Oncology Group performance status of normal activity without symptoms (63.4%). Score distributions on the NFKSI-19, its subscales, and individual items are summarized. The NFKSI-19 and its subscales now have scores for the general US population, allowing comparability to generic questionnaires such as the SF-36 and PROMIS-29. These data can be used to guide treatment expectations and plan future comparative effectiveness research using the scales.

Quality of Life After Palliative Radiation Therapy for Patients With Painful Bone Metastases: Results of an International Study Validating the EORTC QLQ-BM22

Radiation therapy (RT) is an effective method of palliating painful bone metastases and can improve function and reduce analgesic requirements. In advanced cancer patients, quality of life (QOL) is the primary outcome of interest over traditional endpoints such as survival. The purpose of our study was to compare bone metastasis-specific QOL scores among patients who responded differently to palliative RT. Patients receiving RT for bone metastases across 6 countries were prospectively enrolled from March 2010-January 2011 in a trial validating the QLQ-BM22 and completed the QLQ-BM22 and the core measure (QLQ-C30) at baseline and after 1 month. Pain scores and analgesic intake were recorded, and response to RT was determined according to the latest published guidelines. The Kruskal-Wallis nonparametric and Wilcoxon rank sum tests compared changes in QOL among response groups. A Bonferroni-adjusted P<.003 indicated statistical significance. Of 79 patients who received palliative RT, 59 were assessable. Partial response, pain progression, and indeterminate response were observed in 22, 8, and 29 patients, respectively; there were no patients with a complete response. Patients across all groups had similar baseline QOL scores apart from physical functioning (patients who progressed had better initial functioning). One month after RT, patients who responded had significant improvements in 3 of 4 QLQ-BM22 domains (painful site, P<.0001; painful characteristic, P<.0001; and functional interference, P<.0001) and 3 QLQ-C30 domains (physical functioning, P=.0006; role functioning, P=.0026; and pain, P<.0001). Patients with progression in pain had significantly worse functional interference (P=.0007) and pain (P=.0019). Patients who report pain relief after palliative RT also have better QOL with respect to bone metastasis-specific issues. The QLQ-BM22 and QLQ-C30 are able to discriminate among patients with varying responses and are recommended for use in future bone metastasis clinical trials.

Clinically relevant graphical predictions from Bayesian joint longitudinal-survival models

Recent interest in understanding the effect of interventions on patient-reported outcomes as well as traditional clinical endpoints has led to an expansion of methods for simultaneous modeling of longitudinal and survival data in clinical trials. Such joint models link the multiple outcome measures using an underlying latent structure, typically a collection of individual-level random effects. They can estimate treatment effects separately on different aspects of a disease process, as well as illuminate associations among outcomes and individual variability. In communicating model output to clinicians and patients, it is challenging to convey a meaningful interpretation of multiple treatment effects, complex outcome associations, and important underlying assumptions. This paper presents graphical displays designed to make the output of Bayesian joint models accessible to non-technical audiences, while preserving important methodological features. We emphasize individual-level posterior predictions of longitudinal and survival outcomes, illustrating our methods using patient-reported symptom severity and survival in a clinical trial example.

Lactate as a hemodynamic marker in the critically ill

An early quantitative resuscitation strategy improves outcome in critically ill patients. The hemodynamic endpoints of such a strategy have been a topic of debate in the literature. This review focuses on the use of lactate as a marker for risk stratification, lactate clearance as a hemodynamic endpoint, and its use compared to mixed venous oxygenation as a resuscitation goal. Lactate clearance is associated with improved outcome across several cohorts of critically ill patients. Lactate levels and central venous oxygen saturations are frequently discordant. Targeting lactate clearance as part of a quantitative resuscitation strategy may be as effective as targeting central venous oxygen saturation. Resuscitation of the critically ill patient should be aimed at the reversal of tissue hypoxia. The use of lactate as a hemodynamic marker and resuscitation endpoint makes physiologic sense, and is supported by the recent data. The use of lactate clearance versus other traditional endpoints of resuscitation, such as mixed venous oxygen saturation, should be based on the clinical characteristics and response of the individual patient.

Multilevel Bayesian Models for Survival Times and Longitudinal Patient-Reported Outcomes With Many Zeros

Regulatory approval of new therapies often depends on demonstrating prolonged survival. Particularly when these survival benefits are modest, consideration of therapeutic benefits to patient-reported outcomes (PROs) may add value to the traditional biomedical clinical trial endpoints. We extend a popular class of joint models for longitudinal and survival data to accommodate the excessive zeros common in PROs, building hierarchical Bayesian models that combine information from longitudinal PRO measurements and survival outcomes. The model development is motivated by a clinical trial for malignant pleural mesothelioma, a rapidly fatal form of pulmonary cancer usually associated with asbestos exposure. By separately modeling the presence and severity of PROs, using our zero-augmented beta (ZAB) likelihood, we are able to model PROs on their original scale and learn about individual-level parameters from both presence and severity of symptoms. Correlations among an individual's PROs and survival are modeled using latent random variables, adjusting the fitted trajectories to better accommodate the observed data for each individual. This work contributes to understanding the impact of treatment on two aspects of mesothelioma: patients’ subjective experience of the disease process and their progression-free survival times. We uncover important differences between outcome types that are associated with therapy (periodic, worse in both treatment groups after therapy initiation) and those that are responsive to treatment (aperiodic, gradually widening gap between treatment groups). Finally, our work raises questions for future investigation into multivariate modeling, choice of link functions, and the relative contributions of multiple data sources in joint modeling contexts.