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We propose a design for dose finding for cytotoxic agents in completely or partially ordered groups of patients. By completely ordered groups, we mean that prior to the study, there is clinical information that would indicate that for a given dose, the groups can be ordered with respect to the probability of toxicity at that dose. With partially ordered groups, at a given dose, only some of the groups can be ordered with respect to the probability of toxicity at that dose. The method we propose includes elements of the parametric model used in the continual reassessment method combined with the Hwang-Peddada order-restricted estimation procedure. We evaluate the operating characteristics of these designs in a family of dose-toxicity curves representing complete and partial orders. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We propose a new design for dose finding for cytotoxic agents in two ordered groups of patients. By ordered groups, we mean that prior to the study there is clinical information that would indicate that for a given dose one group would be more susceptible to toxicities than patients in the other group. The designs are evaluated relative to two previously proposed designs for ordered groups over a range of scenarios generated randomly from a family of dose-toxicity curves. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Introduction: Generic health-related quality-of-life (HRQOL) patient-reported outcome measures have been used in patients with chronic immune-mediated polyneuropathies. We have created a disease-specific HRQOL instrument.Methods: The chronic acquired polyneuropathy patient-reported index (CAP-PRI) was developed and validated in multiple steps. Items were initially generated through patient and specialist input. The performance of the preliminary 20 items was analyzed via a prospective, 5-center study involving chronic immune-mediated polyneuropathy patients.Results: Data analysis suggested modification to a 15-item scale with 3 response categories rather than 5. The final CAP-PRI was validated in another prospective, 5-center study. The CAP-PRI appeared to be a unidimensional outcome measure that fit the Rasch model in our multicenter cohort. It correlated appropriately with outcome measures commonly used in this patient population.Conclusions: The CAP-PRI is a simple disease-specific HRQOL measure that appears to be useful for clinical care and possibly also for clinical trials. Muscle Nerve 54: 9-17, 2016. [ABSTRACT FROM AUTHOR]

Existing statistical methodology on dose finding for combination chemotherapies has focused on toxicity considerations alone in finding a maximum tolerated dose combination to recommend for further testing of efficacy in a phase II setting. Recently, there has been increasing interest in integrating phase I and phase II trials in order to facilitate drug development. In this article, we propose a new adaptive phase I/II method for dual-agent combinations that takes into account both toxicity and efficacy after each cohort inclusion. The primary objective, both within and at the conclusion of the trial, becomes finding a single dose combination with an acceptable level of toxicity that maximizes efficacious response. We assume that there exist monotone dose-toxicity and dose-efficacy relationships among doses of one agent when the dose of other agent is fixed. We perform extensive simulation studies that demonstrate the operating characteristics of our proposed approach, and we compare simulated results to existing methodology in phase I/II design for combinations of agents. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In studies of combinations of agents in phase I oncology trials, the dose-toxicity relationship may not be monotone for all combinations, in which case the toxicity probabilities follow a partial order. The continual reassessment method for partial orders (PO-CRM) is a design for phase I trials of combinations that leans upon identifying possible complete orders associated with the partial order. This article addresses some practical design considerations not previously undertaken when describing the PO-CRM. We describe an approach in choosing a proper subset of possible orderings, formulated according to the known toxicity relationships within a matrix of combination therapies. Other design issues, such as working model selection and stopping rules, are also discussed. We demonstrate the practical ability of PO-CRM as a phase I design for combinations through its use in a recent trial designed at the University of Virginia Cancer Center. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The time-to-event continual reassessment method (TITE-CRM) was proposed to handle the problem of long trial duration in Phase 1 trials as a result of late-onset toxicities. Here, we implement the TITE-CRM in dose-finding trials of combinations of agents. When studying multiple agents, monotonicity of the dose-toxicity curve is not clearly defined. Therefore, the toxicity probabilities follow a partial order, meaning that there are pairs of treatments for which the ordering of the toxicity probabilities is not known at the start of the trial. A CRM design for partially ordered trials (PO-CRM) was recently proposed. Simulation studies show that extending the TITE-CRM to the partial order setting produces results similar to those of the PO-CRM in terms of maximum tolerated dose recommendation yet reduces the duration of the trial. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We assessed the performance of items from the Quantitative Myasthenia Gravis (QMG), MMT (Manual Muscle Test), and MG-ADL (Myasthenia Gravis - Activities of Daily Living) scales, using data from two recently completed treatment trials of generalized MG. Items were selected that were relevant to manifestations of MG, meaningful to both the physician and the patient, and responsive to clinical change. After the 10 items were chosen, they were weighted based on input from MG experts from around the world, considering factors such as quality of life, disease severity, risk, prognosis, validity, and reliability. The MG Composite is easy to administer, takes less than 5 minutes to complete, and requires no equipment. Weighting of the response options of the 10 items should result in ordinal scores that better represent MG status and are more responsive to meaningful clinical change. To better determine its suitability for clinical use and for treatment trials, the MG Composite will be tested prospectively at several academic medical centers and will be used as a secondary measure of efficacy in pending clinical trials of MG. Muscle Nerve 38: 1553-1562, 2008 [ABSTRACT FROM AUTHOR]

We describe the process whereby a recently developed myasthenia gravis (MG)-specific quality-of-life (QOL) instrument was reduced from 60 items to 15 items while maintaining potential usefulness in the clinic and in prospective treatment trials. In data from a recently completed prospective trial of mycophenolate mofetil (MMF) in MG, the MG-QOL15 correlated as highly as the 60-item MG-QOL for physical and social domains of the 36-item health survey of the Medical Outcomes Study Short Form (SF-36). Correlation coefficients for the MG-QOL15 were similar to the 60-item MG-QOL for the Quantitative Myasthenia Gravis (QMG), MG-specific Manual Muscle Testing (MG-MMT), and the MG-specific Activities of Daily Living (MG-ADL) scores at week 0 and for change in scores from week 0 to week 12 in the MMF trial. Using the physician global impression at week 12 of the trial as the 'gold standard,' the MG-QOL15 demonstrated high sensitivity. Because the MG-QOL15 instrument can be quickly and easily administered and interpreted, it is a potential QOL measure for treatment trials and the clinical evaluation of patients with MG. Muscle Nerve, 2008 [ABSTRACT FROM AUTHOR]

ABSTRACTObjectives: To explore whether serum prostate specific antigen (PSA) decline can be used as a prognostic factor for survival among patients with androgen-independent prostate cancer (AIPC) who are treated with a secondary hormonal therapy, megestrol acetate. Materials and Methods: One hundred forty-nine patients were randomized with equal probability to either low-dose (160 mg/day) or high-dose (640 mg/day) megestrol acetate. Patients were stratified on performance status (0–1, or 2) and on disease measurability (measurable, or evaluable disease). Results: Patients with high pretreatment PSA (≥95 ng/ml) had worse survival times than patients with low PSA (<95), with a hazard ratio of 1.6 (p = 0.003). The median survival times for patients with a ≥50% reduction in PSA at 8 weeks and those patients without a 50% reduction were 15 and 11 months, respectively (p = 0.763). A landmark analysis at 8 weeks showed that a PSA decline was significantly associated with survival. The survival time for patients whose PSA dropped below the pretreatment levels (median = 15 months) were significantly longer than for patients who did not have a decline in PSA (median = 9 months, p = 0.031). Similar significant results were observed between PSA reduction and survival when landmark analyses were performed at 12 and 16 weeks. PSA changes during the first 45 days after the initiation of therapy were significantly related to survival. The median survival time for patients whose PSA doubled during the first 45 days after treatment and for patients whose PSA did not double during the first 45 days were 10 and 14 months, respectively (p = 0.020). Conclusions: PSA decline is significantly associated with longer survival times in prostate patients treated with secondary hormonal manipulation. Longer survival time is observed among the following AIPC patients: 1) those whose pretreatment PSA were <95 ng/ml: 2) those whose PSA decline was >0% from baseline; and... [ABSTRACT FROM AUTHOR]

Toxicity probability interval designs have received increasing attention as a dose-finding method in recent years. In this study, we compared the two-stage, likelihood-based continual reassessment method (CRM), modified toxicity probability interval (mTPI), and the Bayesian optimal interval design (BOIN) in order to evaluate each method's performance in dose selection for phase I trials. We use several summary measures to compare the performance of these methods, including percentage of correct selection (PCS) of the true maximum tolerable dose (MTD), allocation of patients to doses at and around the true MTD, and an accuracy index. This index is an efficiency measure that describes the entire distribution of MTD selection and patient allocation by taking into account the distance between the true probability of toxicity at each dose level and the target toxicity rate. The simulation study considered a broad range of toxicity curves and various sample sizes. When considering PCS, we found that CRM outperformed the two competing methods in most scenarios, followed by BOIN, then mTPI. We observed a similar trend when considering the accuracy index for dose allocation, where CRM most often outperformed both mTPI and BOIN. These trends were more pronounced with increasing number of dose levels. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Adaptive, model-based, dose-finding methods, such as the continual reassessment method, have been shown to have good operating characteristics. One school of thought argues in favor of the use of parsimonious models, not modeling all aspects of the problem, and using a strict minimum number of parameters. In particular, for the standard situation of a single homogeneous group, it is common to appeal to a one-parameter model. Other authors argue for a more classical approach that models all aspects of the problem. Here, we show that increasing the dimension of the parameter space, in the context of adaptive dose-finding studies, is usually counter productive and, rather than leading to improvements in operating characteristics, the added dimensionality is likely to result in difficulties. Among these are inconsistency of parameter estimates, lack of coherence in escalation or de-escalation, erratic behavior, getting stuck at the wrong level, and, in almost all cases, poorer performance in terms of correct identification of the targeted dose. Our conclusions are based on both theoretical results and simulations. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Despite several new therapeutic options for acute myeloid leukemia (AML), disease relapse remains a significant challenge. We have previously demonstrated that augmenting ceramides can counter various drug‐resistance mechanisms, leading to enhanced cell death in cancer cells and extended survival in animal models. Using a nanoscale delivery system for ceramide (ceramide nanoliposomes, CNL), we investigated the effect of CNL within a standard of care venetoclax/cytarabine (Ara‐C) regimen. We demonstrate that CNL augmented the efficacy of venetoclax/cytarabine in in vitro, ex vivo, and in vivo models of AML. CNL treatment induced non‐apoptotic cytotoxicity, and augmented cell death induced by Ara‐C and venetoclax. Mechanistically, CNL reduced both venetoclax (Mcl‐1) and cytarabine (Chk1) drug‐resistant signaling pathways. Moreover, venetoclax and Ara‐C augmented the generation of endogenous pro‐death ceramide species, which was intensified with CNL. Taken together, CNL has the potential to be utilized as an adjuvant therapy to improve outcomes, potentially extending survival, in patients with AML. [ABSTRACT FROM AUTHOR]

The majority of methods for the design of phase I trials in oncology are based upon a single course of therapy, yet in actual practice, it may be the case that there is more than one treatment schedule for any given dose. Therefore, the probability of observing a dose-limiting toxicity may depend upon both the total amount of the dose given, as well as the frequency with which it is administered. The objective of the study then becomes to find an acceptable combination of both dose and schedule. Past literature on designing these trials has entailed the assumption that toxicity increases monotonically with both dose and schedule. In this article, we relax this assumption for schedules and present a dose-schedule finding design that can be generalized to situations in which we know the ordering between all schedules and those in which we do not. We present simulation results that compare our method with other suggested dose-schedule finding methodology. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Health-related quality of life (HRQOL) estimates can play an important role in patient care by providing information about the patient's perception of impairment and disability and the degree to which the patient tolerates disease manifestations. The 15-item myasthenia gravis quality of life scale (MG-QOL15) is an HRQOL evaluative instrument specific to patients with myasthenia gravis (MG) that was designed to be easy to administer and interpret. In this multicenter study we demonstrate the construct validity of the MG-QOL15 in the practice setting. To assess the construct validity, score distributions were examined for test items in different MG patient groups that represent the clinical spectrum of the disease. For example, patients in remission more frequently scored test items as normal than did patients in other groups. Patients with lower (better) MG composite scores also more frequently scored items as normal than did patients with higher (worse) scores. There was also appropriate correlation between the MG-QOL15 and the other MG-specific scales studied. The study findings shed light on what troubles MG patients. The MG-QOL15 has construct validity in the clinical practice setting and represents an efficient and valuable tool for assessing HRQOL for patients with MG. Muscle Nerve, 2010 [ABSTRACT FROM AUTHOR]

This paper studies the notion of coherence in interval‐based dose‐finding methods. An incoherent decision is either (a) a recommendation to escalate the dose following an observed dose‐limiting toxicity or (b) a recommendation to deescalate the dose following a non–dose‐limiting toxicity. In a simulated example, we illustrate that the Bayesian optimal interval method and the Keyboard method are not coherent. We generated dose‐limiting toxicity outcomes under an assumed set of true probabilities for a trial of n=36 patients in cohorts of size 1, and we counted the number of incoherent dosing decisions that were made throughout this simulated trial. Each of the methods studied resulted in 13/36 (36%) incoherent decisions in the simulated trial. Additionally, for two different target dose‐limiting toxicity rates, 20% and 30%, and a sample size of n=30 patients, we randomly generated 100 dose‐toxicity curves and tabulated the number of incoherent decisions made by each method in 1000 simulated trials under each curve. For each method studied, the probability of incurring at least one incoherent decision during the conduct of a single trial is greater than 75%. Coherency is an important principle in the conduct of dose‐finding trials. Interval‐based methods violate this principle for cohorts of size 1 and require additional modifications to overcome this shortcoming. Researchers need to take a closer look at the dose assignment behavior of interval‐based methods when using them to plan dose‐finding studies. [ABSTRACT FROM AUTHOR]

Abstract: Although many studies around the world hope to measure or improve developmental progress in children to promote community flourishing and productivity, growth is sometimes used as a surrogate because cognitive skills are more difficult to measure. Our objective was to assess how childhood measures of anthropometry correlate with measures of child development in low‐income settings with high prevalence of poor nutrition and enteric disease, to inform studies considering growth outcomes in the absence of direct child developmental skill assessment. Children from the MAL‐ED study were followed from birth to 24 months of age in field sites in 8 low‐ and middle‐income countries across 3 continents. Monthly weight, length, and head circumference measurements were performed. At 24 months, the Bayley Scales of Infant and Toddler Development was administered. We correlated cognitive measures at 24 months with anthropometric measurements from birth to 2 years comparing 3 constructs: absolute attained monthly measures, summative difference in measures from the mean growth curve, and rate of change in measures. Growth faltering at multiple time periods is related to Bayley cognitive outcomes at 24 months. Birthweight, overall growth by 18–24 months, and rate of growth in the 6‐ to 18‐month period were most associated with 24‐month developmental scores. In this study, head circumference measurements, compared with length, was more closely linked to cognitive scores at 24 months. Notably, all studies between growth and cognitive outcomes exhibited low r2 values (0.001–0.049). Anthropometric measures, particularly head circumference, were related to cognitive development, although explaining a low percent of variance. When feasible, direct measures of child development may be more useful. [ABSTRACT FROM AUTHOR]

The MG-QOL15 is helpful in informing the clinician about the patient's perception of the extent of and dissatisfaction with myasthenia gravis (MG)-related dysfunction. The aims of this study were to determine the usefulness of the MG-QOL15 for following individuals with MG and to guide clinical researchers who plan to use the MG-QOL15. We assessed sensitivity and specificity for detecting clinical change and evaluated test-retest reliability. Sensitivities and specificities of various cut-points of change in scores are presented. Also presented are means and standard deviations of MG-QOL15 scores for all patients and for subgroups of patients. The test-retest reliability coefficient was 98.6%. The MG-QOL15 has an acceptable longitudinal construct validity. We consider this instrument to be most useful for informing the clinician about the patient's perception and tolerance of MG-related dysfunction. More objective measures, such as the MG Composite, should also be used to follow disease severity. Muscle Nerve, 2011 [ABSTRACT FROM AUTHOR]

Two recent randomized, controlled trials failed to demonstrate a benefit of mycophenolate mofetil (MMF) over prednisone in the treatment of myasthenia gravis (MG). We reviewed our experience with MMF in MG to determine whether these trials may have been unsuccessful because of their short duration and the unpredicted benefit of prednisone. We reviewed outcomes and prednisone dosage for all our acetylcholine-receptor (AChR)-antibody positive MG patients treated with MMF alone or with prednisone for at least 3 months. The percentage of patients with a desirable outcome (MG-specific Manual Muscle Test score <4 or Myasthenia Gravis Foundation of America post-invention status of minimal manifestations or better) began to increase after 6 months; 80% of those followed for >24 months had a desirable outcome. Prednisone dose decreased after 12 months; after 25 months, 54.5% of patients took no prednisone and 75% took <7.5 mg/day. This retrospective analysis provides class IV evidence that MMF begins to improve AChR-positive MG after 6 months, both with prednisone and as monotherapy. Muscle Nerve 41: 593-598, 2010 [ABSTRACT FROM AUTHOR]

The article discusses a study on integrin adjunct therapy for the treatment of melanoma. It mentions that multivalent integrin binding reagents are able to mimic adhesion to extracellular matrices by clustering the integrins. It mentions the development of pentavalent fibronectin in the binding region of integrins and also mentions assessment of entry and stability of the fibrinectin in blood of mice.