Background and Purpose— A safe and effective tissue plasminogen activator (tPA) dose for childhood stroke has not been established. This article describes a Bayesian outcome-adaptive method for determining the best dose of an experimental agent and explains how this method was used to design a dose-finding trial for tPA in childhood. Methods— The method assigns doses to successive cohorts of patients on the basis of each dose’s desirability, quantified in terms of the tradeoff between efficacy and toxicity. The tradeoff function is constructed from several pairs of equally desirable (efficacy, toxicity) probabilities specified by the physicians planning the trial. Each cohort’s dose is chosen adaptively, based on dose-outcome data from the patients treated previously in the trial, to optimize the efficacy-toxicity tradeoff. Application of the method to design the tPA trial is described, including a computer simulation study to establish design properties. A hypothetical cohort-by-cohort example is given to illustrate how the method works during trial conduct. Results and Conclusions— Because only a dose that is both safe and efficacious may be selected and the method combines phase I and phase II by integrating efficacy and toxicity to choose doses, it avoids the more time-consuming and expensive conventional approach of conducting a phase I trial based on toxicity alone followed by a phase II trial based on efficacy alone. This is especially useful in settings with low accrual rates, such as trials of tPA for pediatric acute ischemic stroke.
Objective:
To determine the maximum tolerable dose (MTD) of Photofrin in pediatric subjects.
Background: The principle behind PDT is light-mediated activation of a photosensitizer that is selectively accumulated in the target tissue, causing tumor-cell destruction through singlet-oxygen production. Transfer and translation of captured light energy into chemical reaction in the presence of molecular oxygen produces singlet oxygen or superoxide, and induces cell damage through direct and indirect cytotoxicity.
Design/Methods:
This phase I study includes pediatric subjects with brain tumors that are deemed refractory to conventional therapy. The subjects are individuals with either supratentorial or infratentorial brain tumors.
A minimum number 3 pediatric subjects will be required for each dose level (Dose Escalation Scheme - Laser 240 J/cm2)
Dose Level of Photofrin - 0.5 mg kg−1, 1.3 mg kg−1, 2.0 mg kg−1, 3.0 mg kg−1.
MTD is defined as the Photofrin dose that precedes the dose level used with a subgroup of subjects that exhibits a greater than 33% DLT occurrence.
Dose Limiting Toxicity(DLT) is defined as any of the following events that are at least possibly, probably, or definitely attributable to experimental - intervention: Neurotoxicity, Photosensitivity, ocular sensitivity, any other toxicity of CTCAE grade 4 or higher.
Results: 3 patients were enrolled in this phase I study (Patient #1-15 year old boy with high risk medulloblastoma. Patient #2-28 month old boy with grade 2/3 ependymoma and Patient #3-5 year old boy with anaplastic 4th ventricular ependymoma). Patient 1 followed at 31 days and patient 2 at 13 days post PDT did not reveal any dose related toxicity related to PDT. (Patient 3 is currently undergoing the procedure at the time of submission)
Conclusions: This is first ever phase I trial to be conducted on pediatric patients with brain tumors to determine the maximum tolerable dose of Photofrin.
Study Supported by the Bleser Endowed Chair in Neurology, the Baumann Research Endowment, and a Pinnacle Biologics Grant (to Dr. Whelan). Disclosure: Dr. Parachuri has nothing to disclose. Dr. Katyayan has nothing to disclose. Dr. Whelan has nothing to disclose.
Lymphomatoid granulomatosis is a vasocentric lymphoreticular proliferative disease. Some patients go on to develop frank neoplasia. Central nervous system involvement with lymphomatoid granulomatosis has been reported previously in the literature. We are presenting a childhood case evaluated with magnetic resonance imaging and x-ray computerized tomography who developed severe tissue destruction with pleomorphic cellular infiltrate and oligoclonal light chains. This report adds information regarding neuroimaging as well as immunopathology data relevant to the basic biology of this disease.
Phenylhydrazine-induced anemia in the domestic cat results in an increase in minor, high oxygen affinity hemoglobin B components and an accompanying decrease in the major, low affinity B component. This change is accompanied by an unusually large increase in erythrocytic adenosine triphosphate and 2,3-diphosphoglycerate, a slight decrease in the oxygen affinity of whole blood, and a large decrease in the Hill constant.
Similar to functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS) detects the changes of hemoglobin species inside the brain, but via differences in optical absorption. Within the near-infrared spectrum, light can penetrate biological tissues and be absorbed by chromophores, such as oxyhemoglobin and deoxyhemoglobin. What makes fNIRS more advantageous is its portability and potential for long-term monitoring. This paper reviews the basic mechanisms of fNIRS and its current clinical applications, the limitations toward more widespread clinical usage of fNIRS, and current efforts to improve the temporal and spatial resolution of fNIRS toward robust clinical usage within subjects. Oligochannel fNIRS is adequate for estimating global cerebral function and it has become an important tool in the critical care setting for evaluating cerebral oxygenation and autoregulation in patients with stroke and traumatic brain injury. When it comes to a more sophisticated utilization, spatial and temporal resolution becomes critical. Multichannel NIRS has improved the spatial resolution of fNIRS for brain mapping in certain task modalities, such as language mapping. However, averaging and group analysis are currently required, limiting its clinical use for monitoring and real-time event detection in individual subjects. Advances in signal processing have moved fNIRS toward individual clinical use for detecting certain types of seizures, assessing autonomic function and cortical spreading depression. However, its lack of accuracy and precision has been the major obstacle toward more sophisticated clinical use of fNIRS. The use of high-density whole head optode arrays, precise sensor locations relative to the head, anatomical co-registration, short-distance channels, and multi-dimensional signal processing can be combined to improve the sensitivity of fNIRS and increase its use as a wide-spread clinical tool for the robust assessment of brain function.
Near-IR light treatment modifies cellular function, promotes cell survival, and improves outcomes in laboratory and mouse models of Parkinson's disease.
This review presents current research on the use of far-red to near-infrared (NIR) light treatment in various in vitro and in vivo models. Low-intensity light therapy, commonly referred to as "photobiomodulation," uses light in the far-red to near-infrared region of the spectrum (630–1000 nm) and modulates numerous cellular functions. Positive effects of NIR–light-emitting diode (LED) light treatment include acceleration of wound healing, improved recovery from ischemic injury of the heart, and attenuated degeneration of injured optic nerves by improving mitochondrial energy metabolism and production. Various in vitro and in vivo models of mitochondrial dysfunction were treated with a variety of wavelengths of NIR-LED light. These studies were performed to determine the effect of NIR-LED light treatment on physiologic and pathologic processes. NIRLED light treatment stimulates the photoacceptor cytochrome c oxidase, resulting in increased energy metabolism and production. NIR-LED light treatment accelerates wound healing in ischemic rat and murine diabetic wound healing models, attenuates the retinotoxic effects of methanol-derived formic acid in rat models, and attenuates the developmental toxicity of dioxin in chicken embryos. Furthermore, NIR-LED light treatment prevents the development of oral mucositis in pediatric bone marrow transplant patients. The experimental results demonstrate that NIR-LED light treatment stimulates mitochondrial oxidative metabolism in vitro, and accelerates cell and tissue repair in vivo. NIR-LED light represents a novel, noninvasive, therapeutic intervention for the treatment of numerous diseases linked to mitochondrial dysfunction.
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