Naltrexone modulates contextual processing in depression.

Context, the information surrounding an experience, can significantly alter the meaning and the affective responses to events. Yet the biological mechanisms through which context modulate experiences are not entirely understood. Here, we hypothesized that the µ-opioid system-extensively implicated in placebo effects, a clinical phenomenon thought to rely on contextual processing-modulates the effects of contextual information on emotional attributions in patients with depression. To test this hypothesis, 20 unmedicated patients with depression completed a randomized, double-blind, placebo-controlled, crossover study of one dose of 50 mg of naltrexone, or placebo immediately before completing two sessions of the Contextual Framing fMRI task. This task captures effects of valenced contextual cues (pleasant vs. unpleasant) on emotional attribution (the rating of subtle emotional faces: fearful, neutral, or happy). Behaviorally, we found that emotional attribution was significantly moderated by the interaction between contextual cues and subtle emotional faces, such that participants' ratings of valenced faces (fearful and happy), compared to neutral, were more negative during unpleasant, compared to pleasant context cues. At a neural level, context-induced blood-oxygen-level-dependent responses in the ventromedial prefrontal cortex, the dorsal anterior cingulate, the dorsolateral prefrontal cortex, and the lateral orbitofrontal cortex, significantly moderated the effects of context on emotional attribution, and were blunted by naltrexone. Furthermore, the effects of naltrexone on emotional attribution were partially abolished in more severely depressed patients. Our results provide insights into the molecular alterations underlying context representation in patients with depression, providing pivotal early data for future treatment studies.

[Children visiting as an integral part of patient- and family-centered care of adult critical care patients]. / Besuch von Kindern als integraler Bestandteil der patienten- und angehörigenzentrierten Betreuung von erwachsenen Intensivpatienten.

Children are relatives and should also be included even at the end of life. From the point of view of adult patients, involving children in this way means helpful assistance and care. From the point of view of children, who are often confronted for the first time with dying and death, integration facilitates the processing of an existentially threatening situation. Depending on certain factors and circumstances, children also carry a substantial burden. In addition to professional psychological support, they also need assistance from adult caregivers. Children are thus an integral part of patient- and family-centered care of adult intensive care patients.

Depressive symptoms and cerebral microvascular disease in adults with Type 1 diabetes mellitus.

AIM: To assess the prevalence of, and risk factors for, depressive symptoms, comparing a sample of middle-aged adults with and without juvenile-onset Type 1 diabetes mellitus, and to determine if depressive symptoms were associated with white matter hyperintensity volume among those with Type 1 diabetes. METHODS: Depressive symptoms and white matter hyperintensities were compared between adults (age range 30-65 years) with juvenile-onset Type 1 diabetes (n=130) and adults without Type 1 diabetes (n=133). The association of Type 1 diabetes with depression was computed before and after adjustment for white matter hyperintensities. Among the Type 1 diabetes group, the primary associations of interest were between depressive symptoms (Beck Depression Inventory score ≥10) and white matter hyperintensities (n=71), hyperglycaemia and physical activity. Associations between depressive symptoms and diabetes-related complications, cognitive impairment, smoking and self-reported disability were examined. Analyses were controlled for education, sex, age and antidepressant use. RESULTS: Depressive symptoms were more prevalent among those with vs those without Type 1 diabetes (28% vs 3%; P<0.001). White matter hyperintensities explained 40% of the association of Type 1 diabetes with depressive symptoms, while Type 1 diabetes had a direct effect of 68% on depressive symptoms. Among those with Type 1 diabetes, depressive symptoms were related to white matter hyperintensity volume, a 16-year average HbA1c ≥58 mmol/mol (7.5%), and lower physical activity levels. Associations with other characteristics were not significant. CONCLUSION: These findings suggest a cerebrovascular origin for depressive symptoms in adults with Type 1 diabetes, perhaps triggered by hyperglycaemia. Future longitudinal studies should investigate whether targeting hyperglycaemia and physical inactivity alleviates depressive symptoms, possibly by slowing the development of cerebral microvascular disease, in people with Type 1 diabetes.

Characterization or Monolithic Scintillation Detectors Etched with Laser Induced Optical Barriers.

Several groups are actively investigating the performance of monolithic (continuous) scintillation detectors using a variety of crystal thicknesses, photo-sensor configurations, and surface treatments. This work explores the performance of thick LYSO crystals that would be applicable to a whole-body PET system. The crystals were etched with laser induced optical barriers (LIOBs) to alter the behavior of the light spread within the crystal in order to improve the performance of the detector. We studied the behavior of the LIOBs in response to optical light using small cubes of LYSO with a variety of laser etching parameters to characterize the impact of the optical barriers. We demonstrated that the opacity of the etchings can be altered by varying the parameters of the laser etching, which influences the depth-dependent light response and spatial resolution in the thick crystal. We successfully etched several crystals, as large as 50×50×25-mm3 thick, with a fine grid of LIOBs, and achieved an average spatial resolution close to 3 mm (FWHM) with 511-keV gammas.

Impact of event positioning algorithm on performance of a whole-body PET scanner using one-to-one coupled detectors.

The advent of silicon photomultipliers (SiPMs) has introduced the possibility of increased detector performance in commercial whole-body PET scanners. The primary advantage of these photodetectors is the ability to couple a single SiPM channel directly to a single pixel of PET scintillator that is typically 4 mm wide (one-to-one coupled detector design). We performed simulation studies to evaluate the impact of three different event positioning algorithms in such detectors: (i) a weighted energy centroid positioning (Anger logic), (ii) identifying the crystal with maximum energy deposition (1st max crystal), and (iii) identifying the crystal with the second highest energy deposition (2nd max crystal). Detector simulations performed with LSO crystals indicate reduced positioning errors when using the 2nd max crystal positioning algorithm. These studies are performed over a range of crystal cross-sections varying from 1 × 1 mm2 to 4 × 4 mm2 as well as crystal thickness of 1 cm to 3 cm. System simulations were performed for a whole-body PET scanner (85 cm ring diameter) with a long axial FOV (70 cm long) and show an improvement in reconstructed spatial resolution for a point source when using the 2nd max crystal positioning algorithm. Finally, we observe a 30-40% gain in contrast recovery coefficient values for 1 and 0.5 cm diameter spheres when using the 2nd max crystal positioning algorithm compared to the 1st max crystal positioning algorithm. These results show that there is an advantage to implementing the 2nd max crystal positioning algorithm in a new generation of PET scanners using one-to-one coupled detector design with lutetium based crystals, including LSO, LYSO or scintillators that have similar density and effective atomic number as LSO.

Association between change in brain gray matter volume, cognition, and depression severity: Pre- and post- antidepressant pharmacotherapy for late-life depression.

Late-life depression (LLD) is associated with cognitive impairments and reduced gray matter volume (GMV); however the mechanisms underlying this association are not well understood. The goal of this study was to characterize changes in depression severity, cognitive function, and brain structure associated with pharmacologic antidepressant treatment for LLD. We administered a detailed neurocognitive battery and conducted structural magnetic resonance imaging (MRI) on 26 individuals with LLD, pre-/post-a 12-week treatment trial with venlafaxine. After calculating changes in cognitive performance, GMV, and depression severity, we calculated Pearson's correlations, performed permutation testing, and false discovery rate correction. We found that loss of GMV over 12 weeks in the superior orbital frontal gyrus was associated with less improvement in depression severity and that increased GMV in the same was associated with greater improvement in depression severity. We detected no associations between changes in cognitive performance and improvements in either depressive symptoms or changes in GMV.

Intrinsic functional connectivity in late-life depression: trajectories over the course of pharmacotherapy in remitters and non-remitters.

Previous studies in late-life depression (LLD) have found that patients have altered intrinsic functional connectivity in the dorsal default mode network (DMN) and executive control network (ECN). We aimed to detect connectivity differences across a treatment trial among LLD patients as a function of remission status. LLD patients (N=37) were enrolled into a 12-week trial of venlafaxine and underwent five functional magnetic resonance imaging resting state scans during treatment. Patients had no history of drug abuse, psychosis, dementia/neurodegenerative diseases or medical conditions with known effects on mood. We investigated whether there were differences in three networks: DMN, ECN and anterior salience network connectivity, as well as a whole brain centrality measure (eigenvector centrality). We found that remitters showed increases in ECN connectivity in the right precentral gyrus and decreases in DMN connectivity in the right inferior frontal gyrus and supramarginal gyrus. The ECN and DMN had regions (middle temporal gyrus and bilateral middle/inferior temporal/fusiform gyrus, respectively) that showed reversed effects (decreased ECN and increased DMN, respectively). Early changes in functional connectivity can occur after initial medication exposure. This study offers new data, indicating that functional connectivity changes differ depending on treatment response and can occur shortly after exposure to antidepressant medication.

Recent developments in time-of-flight PET.

While the first time-of-flight (TOF)-positron emission tomography (PET) systems were already built in the early 1980s, limited clinical studies were acquired on these scanners. PET was still a research tool, and the available TOF-PET systems were experimental. Due to a combination of low stopping power and limited spatial resolution (caused by limited light output of the scintillators), these systems could not compete with bismuth germanate (BGO)-based PET scanners. Developments on TOF system were limited for about a decade but started again around 2000. The combination of fast photomultipliers, scintillators with high density, modern electronics, and faster computing power for image reconstruction have made it possible to introduce this principle in clinical TOF-PET systems. This paper reviews recent developments in system design, image reconstruction, corrections, and the potential in new applications for TOF-PET. After explaining the basic principles of time-of-flight, the difficulties in detector technology and electronics to obtain a good and stable timing resolution are shortly explained. The available clinical systems and prototypes under development are described in detail. The development of this type of PET scanner also requires modified image reconstruction with accurate modeling and correction methods. The additional dimension introduced by the time difference motivates a shift from sinogram- to listmode-based reconstruction. This reconstruction is however rather slow and therefore rebinning techniques specific for TOF data have been proposed. The main motivation for TOF-PET remains the large potential for image quality improvement and more accurate quantification for a given number of counts. The gain is related to the ratio of object size and spatial extent of the TOF kernel and is therefore particularly relevant for heavy patients, where image quality degrades significantly due to increased attenuation (low counts) and high scatter fractions. The original calculations for the gain were based on analytical methods. Recent publications for iterative reconstruction have shown that it is difficult to quantify TOF gain into one factor. The gain depends on the measured distribution, the location within the object, and the count rate. In a clinical situation, the gain can be used to either increase the standardized uptake value (SUV) or reduce the image acquisition time or administered dose. The localized nature of the TOF kernel makes it possible to utilize local tomography reconstruction or to separate emission from transmission data. The introduction of TOF also improves the joint estimation of transmission and emission images from emission data only. TOF is also interesting for new applications of PET-like isotopes with low branching ratio for positron fraction. The local nature also reduces the need for fine angular sampling, which makes TOF interesting for limited angle situations like breast PET and online dose imaging in proton or hadron therapy. The aim of this review is to introduce the reader in an educational way into the topic of TOF-PET and to give an overview of the benefits and new opportunities in using this additional information.

Medical and ethical challenges in the case of a prenatally undiagnosed massive congenital brain tumor.

Fetal and neonatal brain tumors are rare. Prenatal ultrasound aids early tumor detection. Nonetheless, we encountered a preterm neonate born at 32 weeks gestation with a massive supratentorial glioma, which was undetected on ultrasound at 19-6/7 weeks gestation. The patient presented at birth with unanticipated massive macrocephaly. Resuscitation and stabilization were difficult, but the medical team felt that futility of care was not established and opted to transfer the baby to an academic center for further imaging and specialist consultations. Diagnosis of an extensive, inoperable tumor was confirmed and support withdrawn. Postmortem histologic examination and immunohistochemical stains identified the majority of tumor cells as glial in origin. This case report illustrates well how a severe and potentially fatal anomaly, which remained undetected prenatally, presented the medical team and family with multiple medical, ethical and emotional challenges at birth; decisions regarding futility of care in the neonatal transport setting are difficult.

MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors.

MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases (CRLs) through NAE inhibition causes accumulation of the CRL substrate c-Myc, which transactivates the PMAIP1 gene encoding Noxa, leading to increased Noxa protein, Bax and Bak activation, and subsequent apoptotic changes. Importantly, c-Myc knockdown diminishes Noxa induction; and Noxa siRNA diminishes MLN4924-induced killing. Because Noxa also neutralizes Mcl-1, an anti-apoptotic Bcl-2 paralog often upregulated in resistant AML, further experiments have examined the effect of combining MLN4924 with BH3 mimetics that target other anti-apoptotic proteins. In combination with ABT-199 or ABT-263 (navitoclax), MLN4924 exerts a synergistic cytotoxic effect. Collectively, these results provide new insight into MLN4924-induced engagement of the apoptotic machinery that could help guide further exploration of MLN4924 for AML.

Impact of detector design on imaging performance of a long axial field-of-view, whole-body PET scanner.

Current generation of commercial time-of-flight (TOF) PET scanners utilize 20-25 mm thick LSO or LYSO crystals and have an axial FOV (AFOV) in the range of 16-22 mm. Longer AFOV scanners would provide increased intrinsic sensitivity and require fewer bed positions for whole-body imaging. Recent simulation work has investigated the sensitivity gains that can be achieved with these long AFOV scanners, and has motivated new areas of investigation such as imaging with a very low dose of injected activity as well as providing whole-body dynamic imaging capability in one bed position. In this simulation work we model a 72 cm long scanner and prioritize the detector design choices in terms of timing resolution, crystal size (spatial resolution), crystal thickness (detector sensitivity), and depth-of-interaction (DOI) measurement capability. The generated list data are reconstructed with a list-mode OSEM algorithm using a Gaussian TOF kernel that depends on the timing resolution and blob basis functions for regularization. We use lesion phantoms and clinically relevant metrics for lesion detectability and contrast measurement. The scan time was fixed at 10 min for imaging a 100 cm long object assuming a 50% overlap between adjacent bed positions. Results show that a 72 cm long scanner can provide a factor of ten reduction in injected activity compared to an identical 18 cm long scanner to get equivalent lesion detectability. While improved timing resolution leads to further gains, using 3 mm (as opposed to 4 mm) wide crystals does not show any significant benefits for lesion detectability. A detector providing 2-level DOI information with equal crystal thickness also does not show significant gains. Finally, a 15 mm thick crystal leads to lower lesion detectability than a 20 mm thick crystal when keeping all other detector parameters (crystal width, timing resolution, and DOI capability) the same. However, improved timing performance with 15 mm thick crystals can provide similar or better performance than that achieved by a detector using 20 mm thick crystals.

Transfusion medicine on American television.

BACKGROUND: Television is a beloved American pastime and a frequent American export. As such, American television shapes how the global public views the world. OBJECTIVES: This study examines how the portrayal of blood transfusion and blood donation on American television may influence how domestic and international audiences perceive the field of transfusion medicine. MATERIALS AND METHODS: American television programming of the last quarter-century was reviewed to identify programmes featuring topics related to blood banking/transfusion medicine. The included television episodes were identified through various sources. RESULTS: Twenty-seven television episodes airing between 1991 and 2013 were identified as featuring blood bank/transfusion medicine topics. Although some accurate representations of the field were identified, most television programmes portrayed blood banking/transfusion medicine inaccurately. CONCLUSION: The way in which blood banking/transfusion medicine is portrayed on American television may assist clinicians in understanding their patient's concerns about blood safety and guide blood collection organisations in improving donor recruitment.

Combining Surface Treatments with Shallow Slots to Improve the Spatial Resolution Performance of Continuous, Thick LYSO Detectors for PET.

Positron emission tomography (PET) detectors based on continuous scintillation crystals can achieve very good performance and have a number of practical advantages compared to detectors based on a pixelated array of crystals. Our goal is to develop a thick continuous detector with high energy and spatial resolution, along with high γ-photon capture efficiency. We examine the performance of two crystal blocks: a 46 × 46 × 14 mm3 and a 48 × 48 × 25 mm3 block of LYSO (Lutetium Yttrium Orthosilicate). Using Maximum Likelihood (ML) positioning based upon the light response function (LRF) in the 14 mm thick crystal, we measure a spatial resolution of 3 mm in the central region of the crystal with degradation near the edges due to reflections off the crystal sides. We also show that we can match the spatial resolution achieved using a 14 mm thick crystal by using a 25 mm thick crystal with slots cut into the gamma entrance surface to narrow the LRF. We also find that we can improve the spatial resolution performance near the detector edges by reducing the reflectivity of the crystal sides, albeit with some loss in energy resolution.

Pulse granuloma involving Meckel's diverticulum: a case report and literature review.

Pulse granuloma is a rare, benign entity that most likely represents a reaction to vegetable material and is characterized by hyaline rings and foreign-body giant cells. We report a case of a pulse granuloma involving Meckel's diverticulum. The patient presented with abdominal pain and radiological findings consistent with Meckel's diverticulum. Microscopic examination of the resected tissue confirmed diagnosis of Meckel's diverticulum with small bowel mucosa. Peridiverticular foreign-body giant cells, hyaline rings and circular structures containing calcified basophilic granules were also identified, consistent with pulse granuloma. Pulse granulomas have been reported in a variety of locations, most commonly in the oral cavity. To the best of our knowledge, this is the first reported example of pulse granuloma in Meckel's diverticulum. Familiarity with pulse granuloma allows for the timely and accurate diagnosis of this entity, particularly in sites not previously described in the literature.

Study of PET scanner designs using clinical metrics to optimize the scanner axial FOV and crystal thickness.

The aim of this study is to understand the trade-off between crystal thickness and scanner axial field-of-view FOV (AFOV) for clinical PET imaging. Clinical scanner design has evolved towards 20-25 mm thick crystals and 16-22 cm long scanner AFOV, as well as time-of-flight (TOF) imaging. While Monte Carlo studies demonstrate that longer AFOV and thicker crystals will lead to higher scanner sensitivity, cost has prohibited the building of commercial scanners with >22 cm AFOV. In this study, we performed a series of system simulations to optimize the use of a given amount of crystal material by evaluating the impact on system sensitivity and noise equivalent counts (NEC), as well as image quality in terms of lesion detectability. We evaluated two crystal types (LSO and LaBr3) and fixed the total crystal volume used for each type (8.2 L of LSO and 17.1 L of LaBr3) while varying the crystal thickness and scanner AFOV. In addition, all imaging times were normalized so that the total scan time needed to scan a 100 cm long object with multiple bed positions was kept constant. Our results show that the highest NEC cm(-1) in a 35 cm diameter ×70 cm long line source cylinder is achieved for an LSO scanner with 10 mm long crystals and AFOV of 36 cm, while for LaBr3 scanners, the highest NEC cm(-1) is obtained with 20 mm long crystals and an AFOV of 38 cm. Lesion phantom simulations show that the best lesion detection performance is achieved in scanners with long AFOV (≥36 cm) and using thin crystals (≤10 mm of LSO and ≤20 mm of LaBr3). This is due to a combination of improved NEC, as well as improved lesion contrast estimation due to better spatial resolution in thinner crystals. Alternatively, for lesion detection performance similar to that achieved in standard clinical scanner designs, the long AFOV scanners can be used to reduce the total scan time without increasing the amount of crystal used in the scanner. In addition, for LaBr3 based scanners, the reduced lesion contrast relative to LSO based scanners requires improved timing resolution and longer scan times in order to achieve lesion detectability similar to that achieved in an LSO scanner with similar NEC cm(-1).

TOF PET offset calibration from clinical data.

In this paper, we present a timing calibration technique for time-of-flight positron emission tomography (TOF PET) that eliminates the need for a specialized data acquisition. By eliminating the acquisition, the process becomes fully automated, and can be performed with any clinical data set and whenever computing resources are available. It also can be applied retroactively to datasets for which a TOF offset calibration is missing or suboptimal. Since the method can use an arbitrary data set to perform a calibration prior to a TOF reconstruction, possibly of the same data set, one also can view this as reconstruction from uncalibrated data. We present a performance comparison with existing calibration techniques.

Subsyndromal depression and anxiety in older adults: health related, functional, cognitive and diagnostic implications.

Subsyndromal depression in later life is common in primary care. Comorbid anxiety disorders could exacerbate the negative effect of subsyndromal depression on functioning, health-related quality of life, comorbidity and/or cognition. We examined anxiety disorders co-existing with subsyndromal depression in participants ≥ age 50 in an NIH trial of Problem Solving Therapy for Primary Care for indicated prevention of major depression. There were 247 participants, with Centers for Epidemiologic Studies - Depression scores ≥ 11. Participants could have multiple psychiatric diagnoses: 22% of the sample had no DSM IV diagnosis; 39% of the sample had only 1 DSM IV diagnosis; 28% had 2 diagnoses; 6% had 3 DSM IV diagnoses; 4% had 4 DSM IV diagnoses; and 1% had 5 diagnoses. Furthermore, 34% of participants had a current comorbid DSM IV diagnosis of a syndromal anxiety disorder. We hypothesized that those with subsyndromal depression, alone relative to those with co-existing anxiety disorders, would report better health-related quality of life, less disability, less medical comorbidity and less cognitive impairment. However, there were no differences in quality of life based on the SF 12 nor in disability based on Late Life Function and Disability Instrument scores. There were no differences in medical comorbidity based on the Cumulative Illness Scale-Geriatrics scale scores nor in cognitive function based on the Executive Interview (EXIT), Hopkins Verbal Learning Test-Revised and Mini-Mental Status Exam. Our findings suggest that about one third of participants 50 years and older with subsyndromal depression have comorbid anxiety disorders; however, this does not appear to be associated with worse quality of life, functioning, disability, cognitive function or medical comorbidity.

DOI Determination by Rise Time Discrimination in Single-Ended Readout for TOF PET Imaging.

Clinical TOF PET systems achieve detection efficiency using thick crystals, typically of thickness 2-3cm. The resulting dispersion in interaction depths degrades spatial resolution for increasing radial positions due to parallax error. Furthermore, interaction depth dispersion results in time pickoff dispersion and thus in degraded timing resolution, and is therefore of added concern in TOF scanners. Using fast signal digitization, we characterize the timing performance, pulse shape and light output of LaBr3:Ce, CeBr3 and LYSO. Coincidence timing resolution is shown to degrade by ~50ps/cm for scintillator pixels of constant cross section and increasing length. By controlling irradiation depth in a scintillator pixel, we show that DOI-dependence of time pickoff is a significant factor in the loss of timing performance in thick detectors. Using the correlated DOI-dependence of time pickoff and charge collection, we apply a charge-based correction to the time pickoff, obtaining improved coincidence timing resolution of <200ps for a uniform 4×4×30mm3 LaBr3 pixel. In order to obtain both DOI identification and improved timing resolution, we design a two layer LaBr3[5%Ce]/LaBr3[30%Ce] detector of total size 4×4×30mm3, exploiting the dependence of scintillator rise time on [Ce] in LaBr3:Ce. Using signal rise time to determine interaction layer, excellent interaction layer discrimination is achieved, while maintaining coincidence timing resolution of <250ps and energy resolution <7% using a R4998 PMT. Excellent layer separation and timing performance is measured with several other commercially-available TOF photodetectors, demonstrating the practicality of this design. These results indicate the feasibility of rise time discrimination as a technique for measuring event DOI while maintaining sensitivity, timing and energy performance, in a well-known detector architecture.

Risk-based classification of leukemia by cytogenetic and multiplex molecular methods: results from a multicenter validation study.

Modern management of leukemia and selection of optimal treatment approaches entails the analysis of multiple recurrent cytogenetic abnormalities with independent diagnostic or prognostic value. We report the first multicenter validation of a multiplex molecular assay for 12 relevant fusion transcripts relative to cytogenetic methods. Performance was evaluated using a set of 280 adult and pediatric acute or chronic leukemias representative of the variety of presentations and pre-analytical parameters encountered in the clinical setting. The positive, negative and overall agreements were >98.5% with high concordance at each of the four sites. Positive detection of cases with low blast count or at relapse was consistent with a method sensitivity of 1%. There was 98.7% qualitative agreement with independent reference molecular tests. Apparent false negatives corresponded to rare alternative splicing isoforms not included in the panel. We further demonstrate that clinical sensitivity can be increased by adding those rare variants and other relevant transcripts or submicroscopic abnormalities. We conclude that multiplex RT-PCR followed by liquid bead array detection is a rapid and flexible method attuned to the clinical laboratory workflow, complementing standard cytogenetic methods and generating additional information valuable for the accurate diagnosis, prognosis and subsequent molecular monitoring of leukemia.

A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia.

This study of vosaroxin evaluated dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics (PK), clinical activity and pharmacodynamics in relapsed/refractory leukemia. Dosing was weekly (days 1, 8 and 15) or twice weekly (days 1, 4, 8 and 11). Seventy-three treated patients had a median age of 65 years, 85% had acute myeloid leukemia and 78% had refractory disease. Weekly schedule: 42 patients received 18-90 mg/m(2); MTD was 72 mg/m(2). Twice-weekly schedule: 31 patients received 9-50 mg/m(2); MTD was 40 mg/m(2). DLT was stomatitis; primary non-hematologic toxicity was reversible gastrointestinal symptoms and febrile neutropenia. Thirty-day all-cause mortality was 11%. Five patients had complete or incomplete remissions; median duration was 3.1 months. A morphologic leukemia-free state (bone marrow blast reduction to <5%) occurred in 11 additional patients. Antileukemic activity was associated with total dose or weekly time above 1 µmol/l plasma vosaroxin concentration (P<0.05). Vosaroxin exposure was dose proportional over 9-90 mg/m(2). The average terminal half-life was ~25 h and clearance was non-renal. No induction or inhibition of vosaroxin metabolism was evident. Vosaroxin-induced DNA damage was detected as increased intracellular γH2AX. Vosaroxin had an acceptable safety profile, linear PK and encouraging clinical activity in relapsed/refractory leukemia.