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Abstract Patients with chronic liver disease (CLD) often present with significant frailty, sarcopenia, and impaired immune function. However, the mechanisms driving the development of these age-related phenotypes are not fully understood. To determine whether accelerated biological aging may play a role in CLD, epigenetic, transcriptomic, and phenotypic assessments were performed on the skeletal muscle tissue and immune cells of CLD patients and age-matched healthy controls. Accelerated biological aging of the skeletal muscle tissue of CLD patients was detected, as evidenced by an increase in epigenetic age compared with chronological age (mean +2.2 ± 4.8 years compared with healthy controls at −3.0 ± 3.2 years, p = 0.0001). Considering disease etiology, age acceleration was significantly greater in both the alcohol-related (ArLD) (p = 0.01) and nonalcoholic fatty liver disease (NAFLD) (p = 0.0026) subgroups than in the healthy control subgroup, with no age acceleration observed in the immune-mediated subgroup or healthy control subgroup (p = 0.3). The skeletal muscle transcriptome was also enriched for genes associated with cellular senescence. Similarly, blood cell epigenetic age was significantly greater than that in control individuals, as calculated using the PhenoAge (p

Background Mobile stroke units have been shown to deliver faster patient care and improve clinical outcomes. However, costs associated with staffing limit their use to densely populated cities. Using the Melbourne mobile stroke unit, we aim to evaluate the safety, timeliness, and resource efficiency of a telemedicine model, where the neurologist assesses a patient remotely, via telemedicine, compared with an onboard neurologist model. We hypothesize that, without compromising patient safety, the telemedicine model will provide timely care and superior resource efficiency. Methods Using a prospective, randomized, blinded end‐point controlled design, 270 participants consecutively assessed on the Melbourne mobile stroke unit over ≈12 months will be assigned into 2 arms: (1) telemedicine neurologist assessment (intervention) versus (2) onboard assessment (comparator). Enrollment is based on prospectively designated randomized days of neurologist review onboard versus telemedicine. The primary outcome will be the odds that a randomly selected participant in the telemedicine arm will have a better outcome than a randomly selected participant in the onboard arm, measured using a desirability‐of‐outcome ranking, an outcome measure that includes, in order of importance: (1) safety, (2) scene‐to‐treatment‐decision time metrics, and (3) resource usage. All participants within each arm will be compared with those in the other, resulting in a “win/tie/loss” distribution for telemedicine compared with the onboard model. Conclusions The study will establish whether use of a telemedicine neurologist delivers superior resource efficiency without compromising patient care. This would enable the broader use of mobile stroke units, particularly relevant to regions with limited access to neurologists, thus improving equity in access to time‐critical, lifesaving stroke care. Registration URL: clinicaltrials.gov; Unique Identifier: NCT05991310.

Abstract Sarcopenia is associated with reduced quality of life and increased mortality in patients with end stage liver disease (ESLD). Historically, sarcopenia identification in ESLD utilised L3 skeletal muscle index (SMI). There are few data on muscle quality and function within lower limb muscle groups with high functional relevance. The aim of this prospective case–control study was to evaluate the quadriceps muscle in patients with ESLD. Muscle mass and quality were evaluated using MRI (quadriceps anatomical cross sectional area (ACSA), quadriceps volume index, L3 SMI, quadriceps intermuscular adipose tissue (IMAT)), mid‐arm muscle circumference (MAMC) and ultrasonography (vastus lateralis (VL) thickness and quadriceps ACSA). Muscle strength/function was assessed by handgrip strength, peak quadriceps isokinetic torque and chair rise time. Thirty‐nine patients with ESLD (55 years, 61% male, 48% alcoholic related liver disease (ArLD), 71% Child–Pugh B/C) and 18 age/sex‐matched healthy control participants (HC) were studied. Quadriceps mass was significantly reduced in ESLD versus HC (−17%), but L3 SMI and MAMC were unchanged. Quadriceps IMAT percentage was increased in ESLD (+103%). Handgrip strength (−15%), peak isokinetic torque (−29%), and chair rise time (+56%) were impaired in ESLD. Ultrasound measures of VL thickness (r = 0.56, r = 0.57, r = 0.42) and quadriceps ACSA (r = 0.98, r = 0.86, r = 0.67) correlated to MRI quadriceps ACSA, quadriceps volume and L3 SMI, respectively. Quadriceps muscle mass, quality, and function were impaired in patients with ESLD, whereas conventional assessments of muscle (L3 SMI and MAMC) highlighted no differences between ESLD and HC. Full evaluation of lower limb muscle health is essential in ESLD in order to accurately assess sarcopenia and target future interventions.

Background: Ageing is associated with alterations to skeletal muscle oxidative metabolism that may be influenced by physical activity status, although the mechanisms underlying these changes have not been unraveled. Similarly, the effect of resistance exercise training (RET) on skeletal muscle mitochondrial regulation is unclear.Methods: Seven endurance-trained masters athletes ([MA], 74 ± 3 years) and seven untrained older adults ([OC]. 69 ± 6 years) completed a single session of knee extension RET (6 x 12 repetitions, 75% 1-RM, 120-s intra-set recovery). Vastus lateralis muscle biopsies were collected pre-RET, 1 h post-RET, and 48h post-RET. Skeletal muscle biopsies were analyzed for citrate synthase (CS) enzyme activity, mitochondrial content, and markers of mitochondrial quality control via immunoblotting.Results: Pre-RET CS activity and protein content were ∼45% (p < .001) and ∼74% greater in MA compared with OC (p = .006). There was a significant reduction (∼18%) in CS activity 48 h post-RET (p < .05) in OC, but not MA. Pre-RET abundance of individual and combined mitochondrial electron transport chain (ETC) complexes I-V were significantly greater in MA compared with OC, as were markers of mitochondrial fission and fusion dynamics (p-DRP-1Ser616, p-MFFSer146, OPA-1 & FIS-1, p < .05 for all). Moreover, MA displayed greater expression of p-AMPKThr172, PGC1α, TFAM, and SIRT-3 (p < .05 for all). Notably, RET did not alter the expression of any marker of mitochondrial content, biogenesis, or quality control in both OC and MA.Conclusion: The present data suggest that long-term aerobic exercise training supports superior skeletal muscle mitochondrial density and protein content into later life, which may be regulated by greater mitochondrial quality control mechanisms and supported via superior fission-fusion dynamics. However, a single session of RET is unable to induce mitochondrial remodelling in the acute (1h post-RET) and delayed (48 h post-RET) recovery period in OC and MA.

Abstract Background Several chronic inflammatory diseases co-exist with and accelerate sarcopenia (reduction in muscle strength, function and mass) and negatively impact on both morbidity and mortality. There is currently limited research on the extent of sarcopenia in such conditions, how to accurately assess it and whether there are generic or disease-specific mechanisms driving sarcopenia. Therefore, this study aims to identify potential mechanisms driving sarcopenia within chronic inflammatory disease via a multi-modal approach; in an attempt to help define potential interventions for future use. Methods This prospective cohort study will consist of a multi-modal assessment of sarcopenia and its underlying mechanisms. Recruitment will target three chronic inflammatory diseases: chronic liver disease (CLD) (n=50), with a subset of NAFLD (n=20), inflammatory bowel disease (IBD) (n=50) and rheumatoid arthritis (RA) (n=50) both before and after therapeutic intervention. In addition, 20 age and sex matched healthy individuals will be recruited for comparison. Participants will undergo 4 assessment visits at weeks 0, 2, 12 and 24. Visits will consist of the following assessments: blood tests, anthropometrics, functional assessment, quadriceps muscle imaging, actigraphy, quality of life questionnaires, food diary collection and muscle biopsy of the vastus lateralis (at weeks 2 and 24 only). In addition, stool and urine samples will be collected for future microbiome and metabolomics analysis. Discussion This is the first study to use a multi-modal assessment model to phenotype sarcopenia in these chronic inflammatory diseases. We hope to identify generic as well as disease-specific mechanisms driving sarcopenia. We appreciate that these cohorts do require separate standards of care treatments which limit comparison between groups. Ethics and dissemination The study is approved by the Health Research Authority - West Midlands Solihull Research Ethics Service Committee Authority (REC reference: 18/WM/0167). Recruitment commenced in January 2019 and will continue until July 2021. The study was halted in March 2020 and again in January 2021 with the COVID-19 pandemic. The findings will be disseminated through peer-reviewed publications and conference presentations. All data will be stored on a secure server. Trial registration ClinicalTrials.gov Identifier: NCT04734496

Abstract Bed rest (BR) results in significant impairments in skeletal muscle metabolism. Mitochondrial metabolism is reportedly highly sensitive to disuse, with dysregulated fission‐fusion events and impaired oxidative function previously reported. The effects of clinically relevant short‐term BR (≤5 days) on mitochondrial protein expression are presently unclear, as are the effects of exercise prehabilitation as a potential counteractive intervention. The present study examined the effects of a 5‐day period of BR and short‐term resistance exercise prehabilitation (ST‐REP) on mitochondrial‐protein content. Ten older men (71 ± 4 years) underwent 5 days of BR, completing four sessions of high‐volume unilateral resistance exercise prehabilitation over 7 days beforehand. Muscle biopsies were obtained from the vastus lateralis in the non‐exercised control and exercised legs, both pre‐ and post‐prehabilitation and pre‐ and post‐BR, to determine changes in citrate synthase enzyme activity and the expression of key proteins in the mitochondrial electron transport chain and molecular regulators of fission‐fusion dynamics, biosynthesis, and mitophagy. We observed no significant effect of either BR or ST‐REP on citrate synthase protein content, enzyme activity, or ETC complex I‐V protein content. Moreover, we observed no significant changes in markers of mitochondrial fission and fusion (p‐DRP1S616, p‐DRP1S637, p‐DRP1S616/S637 ratio, p‐MFFS146, Mitofillin, OPA1, or MFN2 (p > 0.05 for all). Finally, we observed no differences in markers of biosynthesis (p‐AMPKT172, p‐ACCS79, PGC1a, TFAM) or mitophagy‐related signaling (ULK‐1, BNIP3/NIX, LC3B I/II) (p > 0.05 for all). In contrast to previous longer‐term periods of musculoskeletal disuse (i.e., 7–14 days), a clinically relevant, 5‐day period of BR resulted in no significant perturbation in muscle mitochondrial protein signaling in healthy older adults, with no effect of ST‐REP in the week prior to BR. Accordingly, disuse‐induced muscle atrophy may precede alterations in mitochondrial content.

Abstract The protein supplement industry is expanding rapidly and estimated to have a multi-billion market worth. Recent research has centred on understanding how the manufacturing processes of protein supplements may impact muscle recovery and remodeling. The hydrolysed forms of protein undergo a further heating extraction process during production which may contribute to amino acids (AA) appearing in circulation at a slightly quicker rate, or greater amplitude, than the intact form. Whilst the relative significance of the rate of aminoacidemia to muscle protein synthesis is debated, it has been suggested that protein hydrolysates, potentially through the more rapid delivery and higher proportion of di-, tri- and smaller oligo-peptides into circulation, are superior to intact non-hydrolysed proteins and free AAs in promoting skeletal muscle protein remodeling and recovery. However, despite these claims, there is currently insufficient evidence to support superior muscle anabolic properties compared with intact non-hydrolysed proteins and/or free AA controls. Further research is warranted with appropriate protein controls, particularly in populations consuming insufficient amounts of protein, to support and/or refute an important muscle anabolic role of protein hydrolysates. The primary purpose of this review is to provide the reader with a current perspective on the potential anabolic effects of protein hydrolysates in individuals wishing to optimise recovery from, and maximise adaptation to, exercise training.

Abstract Background Poor recovery from periods of disuse accelerates age‐related muscle loss, predisposing individuals to the development of secondary adverse health outcomes. Exercise prior to disuse (prehabilitation) may prevent muscle deterioration during subsequent unloading. The present study aimed to investigate the effect of short‐term resistance exercise training (RET) prehabilitation on muscle morphology and regulatory mechanisms during 5 days of bed rest in older men. Methods Ten healthy older men aged 65–80 years underwent four bouts of high‐volume unilateral leg RET over 7 days prior to 5 days of inpatient bed rest. Physical activity and step‐count were monitored over the course of RET prehabilitation and bed rest, whilst dietary intake was recorded throughout. Prior to and following bed rest, quadriceps cross‐sectional area (CSA), and hormone/lipid profiles were determined. Serial muscle biopsies and dual‐stable isotope tracers were used to determine integrated myofibrillar protein synthesis (iMyoPS) over RET prehabilitation and bed rest phases, and acute postabsorptive and postprandial myofibrillar protein synthesis (aMyoPS) rates at the end of bed rest. Results During bed rest, daily step‐count and light and moderate physical activity time decreased, whilst sedentary time increased when compared with habitual levels (P

IntroductionEnd stage liver disease (ESLD) is associated with loss of muscle mass and function, known as sarcopenia, which can increase the risk of complications of ESLD, hospitalization and mortality. Therefore, the accurate assessment of muscle mass is essential to evaluate sarcopenia in ESLD. However, manual segmentation of muscle volume (MV) can be laborious on cross-sectional imaging, due to the number of slices that require analysis. This study aimed to investigate the impact of reducing the number of slices required for MV estimation. Further, we aimed to compare two equations utilized in estimating MV (cylindrical and truncated cone).MethodsThirty eight ESLD patients (23 males; 54.8 ± 10.7 years) were recruited from the Queen Elizabeth University Hospital Birmingham. A 3T MRI scan was completed of the lower limbs. Quadriceps MV was estimated utilizing 1-, 2-, 3-, and 4 cm slice intervals with both cylindrical and truncated cone equations. Absolute and relative error (compared to 1 cm slice interval) was generated for 2-, 3-, and 4 cm slice intervals. L3 skeletal muscle index (SMI) was also calculated in 30 patients.ResultsRelative error increased with slice interval using the cylindrical (0.45 vs. 1.06 vs. 1.72%) and truncated cone equation (0.27 vs. 0.58 vs. 0.74%) for 2, 3, and 4 cm, respectively. Significantly, the cylindrical equation produced approximately twice the error compared to truncated cone, with 3 cm (0.58 vs. 1.06%, P < 0.01) and 4 cm intervals (0.74 vs. 1.72%, P < 0.001). Finally, quadriceps MV was significantly correlated to L3 SMI (r2 = 0.44, P < 0.0001).ConclusionThe use of the truncated equation with a 4 cm slice interval on MRI offers an efficient but accurate estimation of quadricep muscle volume in ESLD patients.

mTORC1 is an important regulator of muscle mass. Here, the authors show that the PHD1 controls muscle mass in a hydroxylation-independent manner. PHD1 prevents the degradation of leucine sensor LRS during oxygen and amino acid depletion to ensure effective mTORC1 activation in response to leucine.

IntroductionSarcopenia is present in many chronic disease states including decompensated end stage liver disease (ESLD) and non-cirrhotic non-alcoholic fatty liver disease (NAFLD). Sarcopenia in ESLD can negatively impact quality of life and increase mortality. Despite this, very little is understood about the mechanisms of sarcopenia in these conditions. One key reason for this is the reluctance to undertake percutaneous muscle biopsies due to the perceived increased risks. ESLD can induce thrombocytopaenia and coagulopathy which significantly increases the risk of bleeding. In addition, patients with either NAFLD or ESLD often have co-morbidities that would require additional care and risk assessment. Thus, the aim of this study was to establish an effective and safe protocol for the implementation of percutaneous muscle biopsies in patients with NAFLD and ESLD.MethodsA total of 47 patients with ESLD and 9 patients with non-cirrhotic NAFLD were recruited from the Liver Unit, Queen Elizabeth Hospital (Birmingham, United Kingdom). A total of 71 percutaneous vastus lateralis biopsies were attempted over two study visits. A vigorous safety screening occurred prior to and during each visit and a strict protocol was followed to mitigate against complications and risk.ResultsA total of 85% of patients consented to the muscle biopsy at either visit (48/56). A total of 9% of consented biopsies could not occur due to medical considerations, including high international normalised ratio (INR) (n = 3) and the use of aspirin (n = 4). Muscle tissue was obtained from 90% of attempts, with a mean average yield (wet weight tissue) of 98.1 ± 52.9 mg.ConclusionPercutaneous muscle biopsies are both feasible and yield sufficient tissue in an ESLD population. The procedure is effective for obtaining muscle tissue whilst also safe, with only one adverse event. This study provides evidence for the successful use of muscle biopsies in this population, even in consideration of disease specific complications, medications, and comorbidities.

Sarcopenia is of important clinical relevance for loss of independence in older adults. The prevalence of obesity in combination with sarcopenia (“sarcopenic-obesity”) is increasing at a rapid rate. However, whilst the development of sarcopenia is understood to be multi-factorial and harmful to health, the role of obesity from a protective and damaging perspective on skeletal muscle in aging, is poorly understood. Specifically, the presence of obesity in older age may be accompanied by a greater volume of skeletal muscle mass in weight-bearing muscles compared with lean older individuals, despite impaired physical function and resistance to anabolic stimuli. Collectively, these findings support a potential paradox in which obesity may protect skeletal muscle mass in older age. One explanation for these paradoxical findings may be that the anabolic response to weight-bearing activity could be greater in obese vs. lean older individuals due to a larger mechanical stimulus, compensating for the heightened muscle anabolic resistance. However, it is likely that there is a complex interplay between muscle, adipose, and external influences in the aging process that are ultimately harmful to health in the long-term. This narrative briefly explores some of the potential mechanisms regulating changes in skeletal muscle mass and function in aging combined with obesity and the interplay with sarcopenia, with a particular focus on muscle morphology and the regulation of muscle proteostasis. In addition, whilst highly complex, we attempt to provide an updated summary for the role of obesity from a protective and damaging perspective on muscle mass and function in older age. We conclude with a brief discussion on treatment of sarcopenia and obesity and a summary of future directions for this research field.

Sarcopenia is a common complication affecting liver disease patients, yet the underlying mechanisms remain unclear. We aimed to elucidate the cellular mechanisms that drive sarcopenia progression using an in vitro model of liver disease. C2C12 myotubes were serum and amino acid starved for 1-h and subsequently conditioned with fasted ex vivo serum from four non-cirrhotic non-alcoholic fatty liver disease patients (NAFLD), four decompensated end-stage liver disease patients (ESLD) and four age-matched healthy controls (CON) for 4- or 24-h. After 4-h C2C12 myotubes were treated with an anabolic stimulus (5 mM leucine) for 30-min. Myotube diameter was reduced following treatment with serum from ESLD compared with CON (−45%) and NAFLD (−35%; p < 0.001 for both). A reduction in maximal mitochondrial respiration (24% and 29%, respectively), coupling efficiency (~12%) and mitophagy (~13%) was identified in myotubes conditioned with NAFLD and ESLD serum compared with CON (p < 0.05 for both). Myostatin (43%, p = 0.04) and MuRF-1 (41%, p = 0.03) protein content was elevated in myotubes treated with ESLD serum compared with CON. Here we highlight a novel, experimental platform to further probe changes in circulating markers associated with liver disease that may drive sarcopenia and develop targeted therapeutic interventions.

Much reading research has found that informative parafoveal masks lead to a reading benefit for native speakers (see, Schotter et al., 2012). However, little reading research has tested the impact of uninformative parafoveal masks during reading. Additionally, parafoveal processing research is primarily restricted to native speakers. In the current study we manipulated the type of uninformative preview using a gaze contingent boundary paradigm with a group of L1 English speakers and a group of late L2 English speakers (L1 German). We were interested in how different types of uninformative masks impact on parafoveal processing, whether L1 and L2 speakers are similarly impacted, and whether they are sensitive to parafoveally viewed language-specific sub-lexical orthographic information. We manipulated six types of uninformative masks to test these objectives: an Identical, English pseudo-word, German pseudo-word, illegal string of letters, series of X’s, and a blank mask. We found that X masks affect reading the most with slight graded differences across the other masks, L1 and L2 speakers are impacted similarly, and neither group is sensitive to sub-lexical orthographic information. Overall these data show that not all previews are equal, and research should be aware of the way uninformative masks affect reading behavior. Additionally, we hope that future research starts to approach models of eye-movement behavior during reading from not only a monolingual but also from a multilingual perspective.

Objectives: Sub-optimal dietary protein consumption may partially underlie the age-related loss of muscle mass and function (sarcopenia). Specifically, dose, timing, source and distribution of dietary protein across the day might influence muscle anabolism in individuals from across the lifespan.Design: The present study aimed to assess daily and meal-specific protein intake, protein source and protein intake pattern in 40 young (23.8 ± 4.3 years), 40 middle-aged (51.6 ± 4.1 years), and 40 old (77.4 ± 7.4 years) individuals using 3-day weighed food diaries.Results: Old individuals consumed on average 83.4 ± 24.6 g of daily protein, which was significantly lower compared with young but not middle-aged individuals who consumed, respectively, 105.1 ± 43.0 g and 97.0 ± 31.1 g of daily protein (P = 0.013). No significant difference in daily protein intake was found with middle-aged individuals. Dietary protein intake pattern was uneven across meals for all groups (P < 0.001 for all). Sources of protein consumption were similar between groups except at lunch where old individuals ingested lower quality proteins compared with middle aged and young individuals.Conclusion: Although total daily protein intake was sufficient in the majority of participants, per-meal protein intake and protein distribution contend the current knowledge regarding optimal protein intakes. Increasing protein intake, especially at breakfast and lunch, could mitigate age-related muscle loss.

Abstract Objectives To describe the difficulties of obtaining muscle samples using a Bergstrom needle technique in a frail older adult population. The data were obtained from a study primarily investigating immunosenescence in frailty. An intended research technique was skeletal muscle biopsy in a small subset of participants to investigate muscle morphology and local inflammatory factors. Results Forty healthy older adults and 37 frail older adults were considered for a Bergstrom needle muscle biopsy. Of these, 17.5% of healthy older adults and 94.6% of the frail older adults had single or multiple participant factors resulting in a contra-indication to muscle biopsy. 40.7% of healthy older female participants were at risk of a failed muscle biopsy due to low muscle mass. Considering only muscle mass muscle biopsy would have been successful in 18.7% of the frail older women and 21.4% of the frail older men. In this population, muscle biopsy was not feasible because of contra-indications in the majority of participants. This questions whether a biopsy sample obtained from frail older individuals, is actually representative of this population and supports the need to disclose biopsy failure rate in this population.

The prevalence of Type 2 diabetes (T2D) is increasing, which creates a large economic burden. Diet is a critical factor in the treatment and management of T2D; however, there are a large number of dietary approaches and a general lack of consensus regarding the efficacy of each. Therefore, the purpose of this narrative review is twofold: (1) to critically evaluate the effects of various dietary strategies on diabetes management and treatment, such as Mediterranean diet, plant-based diet, low-calorie and very low-calorie diets, intermittent fasting, low-carbohydrate and very low-carbohydrate diets, and low glycemic diets and (2) to examine several purported supplements, such as protein, branched-chain amino acids, creatine, and vitamin D to improve glucose control and body composition. This review can serve as a resource for those wanting to evaluate the evidence supporting the various dietary strategies and supplements that may help manage T2D.

BackgroundAn impaired muscle anabolic response to exercise and protein nutrition is thought to underpin age-related muscle loss, which may be exacerbated by aspects of biological aging that may not be present in older individuals who have undertaken long-term high-level exercise training, or master athletes (MA). The aim of this study was to compare rested-state and exercise-induced rates of integrated myofibrillar protein synthesis (iMyoPS) and intracellular signaling in endurance trained MA and healthy age-matched untrained individuals (Older Controls).MethodsIn a parallel study design, iMyoPS rates were determined over 48 h in the rested-state and following a bout of unaccustomed resistance exercise (RE) in OC (n = 8 males; 73.5 ± 3.3 years) and endurance-trained MA (n = 7 males; 68.9 ± 5.7 years). Intramuscular anabolic signaling was also determined. During the iMyoPS measurement period, physical activity was monitored via accelerometry and dietary intake was controlled.ResultsAnthropometrics, habitual activity, and dietary intake were similar between groups. There was no difference in rested-state rates of iMyoPS between OC (1.47 ± 0.06%⋅day–1) and MA (1.46 ± 0.08%⋅day–1). RE significantly increased iMyoPS above rest in both OC (1.60 ± 0.08%⋅day–1, P < 0.01) and MA (1.61 ± 0.08%⋅day–1, P < 0.01), with no difference between groups. AktThr308 phosphorylation increased at 1 h post-RE in OC (P < 0.05), but not MA. No other between-group differences in intramuscular signaling were apparent at any time-point.ConclusionWhile our sample size is limited, these data suggest that rested-state and RE-induced iMyoPS are indistinguishable between MA and OC. Importantly, the OC retain a capacity for RE-induced stimulation of skeletal muscle remodeling.

Preserving skeletal muscle mass and functional capacity is essential for healthy ageing. Transient periods of disuse and/or inactivity in combination with sub-optimal dietary intake have been shown to accelerate the age-related loss of muscle mass and strength, predisposing to disability and metabolic disease. Mechanisms underlying disuse and/or inactivity-related muscle deterioration in the older adults, whilst multifaceted, ultimately manifest in an imbalance between rates of muscle protein synthesis and breakdown, resulting in net muscle loss. To date, the most potent intervention to mitigate disuse-induced muscle deterioration is mechanical loading in the form of resistance exercise. However, the feasibility of older individuals performing resistance exercise during disuse and inactivity has been questioned, particularly as illness and injury may affect adherence and safety, as well as accessibility to appropriate equipment and physical therapists. Therefore, optimising nutritional intake during disuse events, through the introduction of protein-rich whole-foods, isolated proteins and nutrient compounds with purported pro-anabolic and anti-catabolic properties could offset impairments in muscle protein turnover and, ultimately, the degree of muscle atrophy and recovery upon re-ambulation. The current review therefore aims to provide an overview of nutritional countermeasures to disuse atrophy and anabolic resistance in older individuals.

Maintaining adequate daily protein intake is important to maintain muscle mass throughout the lifespan. In this regard, the overnight period has been identified as a window of opportunity to increase protein intake in the elderly. However, it is unknown whether pre-sleep protein intake affects next-morning appetite and, consequently, protein intake. Therefore, the purpose of the current study was to investigate the effects of a pre-sleep protein drink on next-morning appetite, energy intake and metabolism. Twelve older individuals (eight males, four females; age: 71.3 ± 4.2 years) took part in a single-blind randomised cross-over study. After a standardised dinner, participants consumed either a 40-g protein drink, isocaloric maltodextrin drink, or placebo water control before bedtime. Next-morning appetite, energy intake, resting metabolic rate (RMR), respiratory exchange rate (RER), and plasma acylated ghrelin, leptin, glucose, and insulin concentrations were assessed. No between-group differences were observed for appetite and energy intake at breakfast. Furthermore, RMR, RER, and assessed blood markers were not significantly different between any of the treatment groups. Pre-sleep protein intake does not affect next-morning appetite and energy intake and is therefore a viable strategy to increase daily protein intake in an older population.

The branch chain amino acid leucine is a potent stimulator of protein synthesis in skeletal muscle. Leucine rapidly enters the cell via the L-Type Amino Acid Transporter 1 (LAT1); however, little is known regarding the localisation and distribution of this transporter in human skeletal muscle. Therefore, we applied immunofluorescence staining approaches to visualise LAT1 in wild type (WT) and LAT1 muscle-specific knockout (mKO) mice, in addition to basal human skeletal muscle samples. LAT1 positive staining was visually greater in WT muscles compared to mKO muscle. In human skeletal muscle, positive LAT1 staining was noted close to the sarcolemmal membrane (dystrophin positive staining), with a greater staining intensity for LAT1 observed in the sarcoplasmic regions of type II fibres (those not stained positively for myosin heavy-chain 1, Type II—25.07 ± 5.93, Type I—13.71 ± 1.98, p < 0.01), suggesting a greater abundance of this protein in these fibres. Finally, we observed association with LAT1 and endothelial nitric oxide synthase (eNOS), suggesting LAT1 association close to the microvasculature. This is the first study to visualise the distribution and localisation of LAT1 in human skeletal muscle. As such, this approach provides a validated experimental platform to study the role and regulation of LAT1 in human skeletal muscle in response to various physiological and pathophysiological models.

We report the first neural recording during ecstatic meditations called jhanas and test whether a brain reward system plays a role in the joy reported. Jhanas are Altered States of Consciousness (ASC) that imply major brain changes based on subjective reports: (1) external awareness dims, (2) internal verbalizations fade, (3) the sense of personal boundaries is altered, (4) attention is highly focused on the object of meditation, and (5) joy increases to high levels. The fMRI and EEG results from an experienced meditator show changes in brain activity in 11 regions shown to be associated with the subjective reports, and these changes occur promptly after jhana is entered. In particular, the extreme joy is associated not only with activation of cortical processes but also with activation of the nucleus accumbens (NAc) in the dopamine/opioid reward system. We test three mechanisms by which the subject might stimulate his own reward system by external means and reject all three. Taken together, these results demonstrate an apparently novel method of self-stimulating a brain reward system using only internal mental processes in a highly trained subject.

PURPOSE: To investigate the mechanisms underpinning modifications in glucose homeostasis and insulin sensitivity 24 h after a bout of resistance exercise (RE) with or without protein ingestion. METHODS: Twenty-four healthy males were assigned to a control (CON; n = 8), exercise (EX; n = 8) or exercise plus protein condition (EX+PRO; n = 8). Muscle biopsy and blood samples were obtained at rest for all groups and immediately post-RE (75% 1RM, 8×10 repetitions of leg-press and extension exercise) for EX and EX+PRO only. At 24 h post-RE (or post-resting biopsy for CON), a further muscle biopsy was obtained. Participants then consumed an oral glucose load (OGTT) containing 2 g of [U-¹³C] glucose during an infusion of 6, 6-[²H₂] glucose. Blood samples were obtained every 10 min for 2 h to determine glucose kinetics. EX+PRO ingested an additional 25 g of intact whey protein with the OGTT. A final biopsy sample was obtained at the end of the OGTT. RESULTS: Fasted plasma glucose and insulin were similar for all groups and were not different immediately post- and 24 h post-RE. Following RE, muscle glycogen was 26±8 and 19±6% lower in EX and EX+PRO, respectively. During OGTT, plasma glucose AUC was lower for EX and EX+PRO (75.1±2.7 and 75.3±2.8 mmol·L⁻¹∶120 min, respectively) compared with CON (90.6±4.1 mmol·L⁻¹∶120 min). Plasma insulin response was 13±2 and 21±4% lower for EX and CON, respectively, compared with EX+PRO. Glucose disappearance from the circulation was ∼12% greater in EX and EX+PRO compared with CON. Basal 24 h post-RE and insulin-stimulated PAS-AS160/TBC1D4 phosphorylation was greater for EX and EX+PRO. CONCLUSIONS: Prior RE improves glycemic control and insulin sensitivity through an increase in the rate at which glucose is disposed from the circulation. However, co-ingesting protein during a high-glucose load does not augment this response at 24 h post-exercise in healthy, insulin-sensitive individuals.

Abstract Background Postnatal depression (PND) is under-diagnosed and most women do not access effective help. We aimed to evaluate comparative management of (PND) following screening with the Edinburgh Postnatal Depression Scale, using three best-practice care pathways by comparing management by general practitioners (GPs) alone compared to adjunctive counselling, based on cognitive behavioural therapy (CBT), delivered by postnatal nurses or psychologists. Methods This was a parallel, three-group randomised controlled trial conducted in a primary care setting (general practices and maternal & child health centres) and a psychology clinic. A total of 3,531 postnatal women were screened for symptoms of depression; 333 scored above cut-off on the screening tool and 169 were referred to the study. Sixty-eight of these women were randomised between the three treatment groups. Results Mean scores on the Beck Depression Inventory (BDI-II) at entry were in the moderate-to-severe range. There was significant variation in the post-study frequency of scores exceeding the threshold indicative of mild-to-severe depressive symptoms, such that more women receiving only GP management remained above the cut-off score after treatment (p = .028). However, all three treatment conditions were accompanied by significant reductions in depressive symptoms and mean post-study BDI-II scores were similar between groups. Compliance was high in all three groups. Women rated the treatments as highly effective. Rates of both referral to the study (51%), and subsequent treatment uptake (40%) were low. Conclusions Data from this small study suggest that GP management of PND when augmented by a CBT-counselling package may be successful in reducing depressive symptoms in more patients compared to GP management alone. The relatively low rates of referral and treatment uptake, suggest that help-seeking remains an issue for many women with PND, consistent with previous research. Trial Registration The study is registered at ClinicalTrials.gov, Trial Registration Number NCT01002027.

Abstract Background Given that the prevalence of antenatal and postnatal depression is high, with estimates around 13%, and the consequences serious, efforts have been made to identify risk factors to assist in prevention, identification and treatment. Most risk factors associated with postnatal depression have been well researched, whereas predictors of antenatal depression have been less researched. Risk factors associated with early parenting stress have not been widely researched, despite the strong link with depression. The aim of this study was to further elucidate which of some previously identified risk factors are most predictive of three outcome measures: antenatal depression, postnatal depression and parenting stress and to examine the relationship between them. Methods Primipara and multiparae women were recruited antenatally from two major hoitals as part of the beyondblue National Postnatal Depression Program 1. In this subsidiary study, 367 women completed an additional large battery of validated questionnaires to identify risk factors in the antenatal period at 26–32 weeks gestation. A subsample of these women (N = 161) also completed questionnaires at 10–12 weeks postnatally. Depression level was measured by the Beck Depression Inventory (BDI). Results Regression analyses identified significant risk factors for the three outcome measures. (1). Significant predictors for antenatal depression: low self-esteem, antenatal anxiety, low social support, negative cognitive style, major life events, low income and history of abuse. (2). Significant predictors for postnatal depression: antenatal depression and a history of depression while also controlling for concurrent parenting stress, which was a significant variable. Antenatal depression was identified as a mediator between seven of the risk factors and postnatal depression. (3). Postnatal depression was the only significant predictor for parenting stress and also acted as a mediator for other risk factors. Conclusion Risk factor profiles for antenatal depression, postnatal depression and parenting stress differ but are interrelated. Antenatal depression was the strongest predictor of postnatal depression, and in turn postnatal depression was the strongest predictor for parenting stress. These results provide clinical direction suggesting that early identification and treatment of perinatal depression is important.

Abstract Background Information on clinical acceptability is needed when making cost-utility decisions about health screening implementation. Despite being in use for two decades, most data on the clinical acceptability of the Edinburgh Postnatal Depression Scale (EPDS) come from qualitative reports, or include relatively small samples of depressed women. This study aimed to measure acceptability in a survey of a relatively large, community sample with a high representation of clinically depressed women. Methods Using mail, telephone and face-to-face interview, 920 postnatal women were approached to take part in a survey on the acceptability of the EPDS, including 601 women who had screened positive for depression and 245 who had received DSM-IV diagnoses of depression. Acceptability was measured on a 5-point Likert scale of comfort ranging from "Not Comfortable", through "Comfortable" to "Very Comfortable". Results The response rate was just over half for postal surveys (52%) and was 100% for telephone and face-to-face surveys (432, 21 and 26 respondents for postal, telephone and face-to-face surveys respectively) making 479 respondents in total. Of these, 81.2% indicated that screening with the EPDS had been in the range of "Comfortable" to "Very Comfortable". The other 18.8 % rated screening below the "Comfortable" point, including a small fraction (4.3%) who rated answering questions on the EPDS as "Not Comfortable" at the extreme end of the scale. Comfort was inversely related to EPDS score, but the absolute size of this effect was small. Almost all respondents (97%) felt that screening was desirable. Conclusion The EPDS had good acceptability in this study for depressed and non-depressed women. Women's views on the desirability of postnatal depression screening appear to be largely independent of personal level of comfort with screening. These results should be useful to policy-makers and are broadly supportive of the Edinburgh Postnatal Depression Scale as a suitable tool for universal perinatal depression screening.

Introduction: TRC102 potentiates the activity of cancer therapies that induce base excision repair (BER) including antimetabolite and alkylating agents. TRC102 rapidly and covalently binds to apurinic/apyrimidinic (AP) sites generated during BER, and TRC102-bound DNA causes topoisomerase II-dependent irreversible strand breaks and apoptosis. This study assessed the safety, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of TRC102 alone and in combination with pemetrexed., Purpose: Patients with advanced solid tumors received oral TRC102 daily for 4 days. Two weeks later, patients began standard-dose pemetrexed on day 1 in combination with oral TRC102 on days 1 to 4. The pemetrexed-TRC102 combination was repeated every 3 weeks until disease progression., Methods: Twenty-eight patients were treated with TRC102 at 15, 30, 60 or 100 mg/m(2)/d. The MTD was exceeded at 100 mg/m(2)/d due to grade 3 anemia in 50 % of patients. TRC102 exposure increased in proportion to dose with a mean t1/2 of 28 h. A pharmacodynamic assay confirmed that TRC102 binds to pemetrexed-induced AP sites at all doses studied. Stable disease or better was achieved in 15 of 25 patients evaluable for response (60 %), including one patient with recurrent metastatic oropharyngeal carcinoma that expressed high levels of thymidylate synthase, who achieved a partial response and was progression free for 14 months., Conclusions: When administered with pemetrexed, the maximum tolerated dose of oral TRC102 is 60 mg/m(2)/d for 4 days. Randomized controlled studies are planned to evaluate the clinical benefit of adding TRC102 to pemetrexed and other agents that induce BER.

Purpose: TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors., Patients and Methods: Patients received escalating doses of intravenous TRC105 until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design., Results: Fifty patients were treated with escalating doses of TRC105. The maximum tolerated dose (MTD) was exceeded at 15 mg/kg every week because of dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concentrations that saturate CD105 receptors were maintained at 10 mg/kg weekly (the MTD) and 15 mg/kg every 2 weeks. Common adverse events including anemia, telangiectasias, and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase Ib and phase II studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%), including two ongoing responses at 48 and 18 months., Conclusion: TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 weeks, with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clinical activity was seen in a refractory patient population. Ongoing clinical trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, breast, and hepatocellular cancer., (©2012 AACR.)

Metastatic breast cancer is incurable. The goal of this study was to develop a positron emission tomography (PET)/near-infrared fluorescent (NIRF) probe for imaging CD105 expression in breast cancer experimental lung metastasis. TRC105, a chimeric anti-CD105 antibody, was dual-labeled with a NIRF dye (IRDye 800CW) and (89)Zr to yield (89)Zr-Df-TRC105-800CW. Luciferase-transfected 4T1 murine breast cancer cells were injected intravenously into female mice to establish the tumor model. Bioluminescence imaging (BLI) was carried out to noninvasively monitor the lung tumor burden. PET imaging revealed that 4T1 lung tumor uptake of (89)Zr-Df-TRC105-800CW was 8.7 ± 1.4, 10.9 ± 0.5, and 9.7 ± 1.1% ID/g at 4, 24, and 48 h postinjection (n = 4), with excellent tumor contrast. Biodistribution studies, blocking, control studies with (89)Zr-Df-cetuximab-800CW, ex vivo BLI/PET/NIRF imaging, and histology all confirmed CD105 specificity of the tracer. Broad clinical potential of TRC105-based agents was shown in many tumor types, which also enabled early detection of small metastasis and intraoperative guidance for tumor removal.

Purpose: High tumor microvessel density correlates with a poor prognosis in multiple solid tumor types. The clinical gold standard for assessing microvessel density is CD105 immunohistochemistry on paraffin-embedded tumor specimens. The goal of this study was to develop an (89)Zr-based PET tracer for noninvasive imaging of CD105 expression., Methods: TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to p-isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS) and labeled with (89)Zr. FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and Df-TRC105. PET imaging, biodistribution, blocking, and ex-vivo histology studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the pharmacokinetics and tumor-targeting of (89)Zr-Df-TRC105. Another chimeric antibody, cetuximab, was used as an isotype-matched control., Results: FACS analysis of HUVECs revealed no difference in CD105 binding affinity between TRC105 and Df-TRC105, which was further validated by fluorescence microscopy. (89)Zr labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of (89)Zr-Df-TRC105 was 6.1 ± 1.2, 14.3 ± 1.2, 12.4 ± 1.5, 7.1 ± 0.9, and 5.2 ± 0.3 %ID/g at 5, 24, 48, 72, and 96 h after injection, respectively (n = 4), higher than all organs starting from 24 h after injection, which provided excellent tumor contrast. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking experiments, control studies with (89)Zr-Df-cetuximab, and ex-vivo histology all confirmed the in vivo target specificity of (89)Zr-Df-TRC105., Conclusion: We report here the first successful PET imaging of CD105 expression with (89)Zr as the radiolabel. Rapid, persistent, CD105-specific uptake of (89)Zr-Df-TRC105 in the 4T1 tumor was observed.

CD105 (endoglin) is an independent marker for poor prognosis in more than 10 solid tumor types. The goal of this study was to develop a CD105-specific agent for both positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging, which has potential clinical applications in the diagnosis and imaged-guided resection of solid tumors. TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to a NIRF dye (800CW) and p-isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS) before (89)Zr-labeling. Another chimeric antibody, cetuximab, was used as an isotype-matched control. FACS analysis revealed no difference in CD105 binding affinity/specificity between TRC105 and Df-TRC105-800CW. Serial PET imaging revealed that the 4T1 tumor uptake of (89)Zr-Df-TRC105-800CW was 6.3 ± 1.9, 12.3 ± 1.3, and 11.4 ± 1.1 %ID/g at 4, 24, and 48 h post-injection (p.i.) respectively (n = 3), higher than all organs starting from 24 h p.i., which provided excellent tumor contrast. Tumor uptake as measured by both in vivo and ex vivo NIRF imaging had a linear correlation with the %ID/g values obtained from PET, corroborated by biodistribution studies. Blocking experiments, control studies with (89)Zr-Df-cetuximab-800CW, and histology all confirmed the CD105 specificity of (89)Zr-Df-TRC105-800CW. In conclusion, herein we report dual-modality PET and NIRF imaging of CD105 expression in a breast cancer model, where CD105-specific uptake of (89)Zr-Df-TRC105-800CW in the tumor was observed.

Purpose: Angiogenesis is an indispensable process during tumor development. The currently accepted standard method for quantifying tumor angiogenesis is to assess microvessel density (MVD) based on CD105 staining, which is an independent prognostic factor for survival in patients with most solid tumor types. The goal of this study is to evaluate tumor angiogenesis in a mouse model by near-infrared fluorescence (NIRF) imaging of CD105 expression., Methods: TRC105, a human/murine chimeric anti-CD105 monoclonal antibody, was conjugated to an NIRF dye (IRDye 800CW; Ex: 778 nm; Em: 806 nm). FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and 800CW-TRC105. In vivo/ex vivo NIRF imaging, blocking studies, and ex vivo histology were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of 800CW-TRC105 to target tumor angiogenesis. Another chimeric antibody, cetuximab, was used as an isotype-matched control., Results: FACS analysis of human umbilical vein endothelial cells (HUVECs) revealed no difference in CD105 binding affinity between TRC105 and 800CW-TRC105, which was further validated by fluorescence microscopy. 800CW conjugation of TRC105 was achieved in excellent yield (> 85%), with an average of 0.4 800CW molecules per TRC105. Serial NIRF imaging after intravenous injection of 800CW-TRC105 revealed that the 4T1 tumor could be clearly visualized as early as 30 min post-injection. Quantitative region of interest (ROI) analysis showed that the tumor uptake peaked at about 16 h post-injection. Based on ex vivo NIRF imaging at 48 h post-injection, tumor uptake of 800CW-TRC105 was higher than most organs, thus providing excellent tumor contrast. Blocking experiments, control studies with 800CW-cetuximab and 800CW, as well as ex vivo histology all confirmed the in vivo target specificity of 800CW-TRC105., Conclusion: This is the first successful NIRF imaging study of CD105 expression in vivo. Fast, prominent, persistent, and CD105-specific uptake of the probe during tumor angiogenesis was observed in a mouse model. 800CW-TRC105 may be used in the clinic for imaging tumor angiogenesis within the lesions close to the skin surface, tissues accessible by endoscopy, or during image-guided surgery.

Purpose: Overexpression of CD105 (endoglin) correlates with poor prognosis in many solid tumor types. Tumor microvessel density (MVD) assessed by CD105 staining is the current gold standard for evaluating tumor angiogenesis in the clinic. The goal of this study was to develop a positron emission tomography (PET) tracer for imaging CD105 expression., Methods: TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with (64)Cu. FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and DOTA-TRC105. PET imaging, biodistribution, blocking, and ex vivo histology studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of (64)Cu-DOTA-TRC105 to target tumor angiogenesis. Another chimeric antibody, cetuximab, was used as an isotype-matched control., Results: FACS analysis of human umbilical vein endothelial cells (HUVECs) revealed no difference in CD105 binding affinity between TRC105 and DOTA-TRC105, which was further validated by fluorescence microscopy. (64)Cu labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of the tracer was 8.0 ± 0.5, 10.4 ± 2.8, and 9.7 ± 1.8%ID/g at 4, 24, and 48 h post-injection, respectively (n = 3), higher than most organs at late time points which provided excellent tumor contrast. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking experiments, control studies with (64)Cu-DOTA-cetuximab, as well as ex vivo histology all confirmed the in vivo target specificity of (64)Cu-DOTA-TRC105., Conclusion: This is the first successful PET imaging study of CD105 expression. Fast, prominent, persistent, and CD105-specific uptake of the tracer in the 4T1 tumor was observed. Further studies are warranted and currently underway.

Optimizing the in vivo stability of positron emission tomography (PET) tracers is of critical importance to cancer diagnosis. In the case of (64)Cu-labeled monoclonal antibodies (mAb), in vivo behavior and biodistribution is critically dependent on the performance of the bifunctional chelator used to conjugate the mAb to the radiolabel. This study compared the in vivo characteristics of (64)Cu-labeled TRC105 (a chimeric mAb that binds to both human and murine CD105), through two commonly used chelators: 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Flow cytometry analysis confirmed that chelator conjugation of TRC105 did not affect its CD105 binding affinity or specificity. PET imaging and biodistribution studies in 4T1 murine breast tumor-bearing mice revealed that (64)Cu-NOTA-TRC105 exhibited better stability than (64)Cu-DOTA-TRC105 in vivo, which resulted in significantly lower liver uptake without compromising the tumor targeting efficiency. In conclusion, this study confirmed that NOTA is a superior chelator to DOTA for PET imaging with (64)Cu-labeled TRC105.

Purpose: A previous Southwest Oncology Group (SWOG) study (S9429) demonstrated efficacy and tolerability of concurrent chemoradiotherapy in poor-risk stage III non-small-cell lung cancer (NSCLC). This study evaluated adding consolidation paclitaxel after chemoradiotherapy for a similar patient cohort., Patients and Methods: Patients with histologically/cytologically determined stage III NSCLC were eligible based on performance status (PS) 2 and either low albumin or weight loss more than 10%, poor pulmonary function, or comorbidities precluding cisplatin use. Treatment was carboplatin 200 mg/m2 days 1, 3, 29, and 31, and etoposide 50 mg/m2 days 1 through 4, and 29 to 32. Beginning day 1, thoracic radiation was delivered at 1.8 Gy in 25 fractions plus 16-Gy boost (total dose, 61 Gy). Patients without disease progression received paclitaxel 175 mg/m2 every 21 days for three cycles., Results: Characteristics of 87 eligible patients were age 51 to 82 years; 57% PS 0 to 1, 43% PS 2; and 51% stage IIIA, 49% stage IIIB. Toxicities of concurrent chemoradiotherapy included grade 3 esophagitis (7%) and grade 3/4 neutropenia (43%). Fifty-four assessable patients received paclitaxel consolidation. Four treatment-related deaths occurred during chemoradiotherapy and four occurred during consolidation. Overall response rate was 53%. Median progression free- and overall survival were 6.1 and 10.2 months, respectively. One- and 2-year survival rates were 43% and 25%., Conclusion: Compared with a previous SWOG trial in a similar patient population, the addition of consolidation paclitaxel after chemoradiotherapy resulted in increased toxicity without a survival advantage. More PS 2 patients (43% v 18%) enrolled onto S9712, which may explain increased toxicity and lack of benefit. The optimal chemoradiotherapy approach for poor-risk patients remains to be defined.

Purpose: This multicenter, dose-escalation study evaluates the safety, pharmacokinetics, and efficacy of galiximab (anti-CD80 monoclonal antibody) in patients with relapsed or refractory follicular lymphoma., Patients and Methods: Patients had follicular lymphoma that had relapsed or failed to respond to primary therapy; the majority (90%) presented with stage III or IV disease. Four weekly intravenous infusions of galiximab were administered at doses of 125, 250, 375, or 500 mg/m2., Results: Thirty-seven patients received galiximab treatment and were evaluated for safety; 35 were assessable for response. Antibody infusions were safe and well tolerated with no dose-limiting toxicities. A total of 22 (60%) of 37 patients experienced adverse events related to galiximab. All but one of the events were grade 1 or 2; the most common were fatigue, nausea, and headache. Cytopenias were rare; only one patient experienced anemia and febrile neutropenia, which were unrelated to galiximab and resolved after treatment. No patient developed antigaliximab antibody formation. The mean serum half-life ranged from 13 to 24 days. The overall response rate was 11% (two complete responses and two partial responses). Time to best response was delayed (months 3, 6, 9, and 12). Twelve patients (34%) maintained stable disease. Nearly half of all patients (49%) had a decrease in indicator lesions. Two responders remain on study without progression (22 and 24.4 months)., Conclusion: The favorable safety profile of galiximab and evidence of single-agent biologic activity and dose-dependent pharmacokinetics support further evaluation of galiximab as a treatment for follicular lymphoma, possibly in combination with other lymphoma therapies.

Zevalin (ibritumomab tiuxetan; IDEC Pharmaceuticals Corporation, San Diego, CA, USA) was approved by the United States Food and Drug Administration on February 19, 2002, following 9 years of clinical development. Six clinical studies supported the Zevalin Biologics License Application. The Zevalin regimen is indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), and for those with follicular NHL refractory to Rituxan (rituximab, MabThera; IDEC Pharmaceuticals Corporation, San Diego, CA and Genentech, South San Francisco, CA). In the year following FDA approval, approximately 1300 patients were treated in clinical trials or with the commercially available product.

Purpose: To test the concept of taxane sequencing in combined-modality therapy, this phase II trial (S9504) evaluated consolidation docetaxel after concurrent chemoradiotherapy in patients with pathologically documented stage IIIB non-small-cell lung cancer (NSCLC). Results were compared with those of the predecessor study (S9019) with identical eligibility, staging criteria, and treatment, excepting docetaxel consolidation., Patients and Methods: Treatment consisted of cisplatin 50 mg/m2 on days 1, 8, 29, and 36, etoposide 50 mg/m2 on days 1 through 5 and 29 through 33, and concurrent thoracic radiotherapy (total dose of 61 Gy). Consolidation docetaxel started 4 to 6 weeks after chemoradiotherapy at an initial dose of 75 mg/m2., Results: Stage subsets (tumor-node-metastasis system) in 83 eligible patients were as follows: T4N0/1, 31 patients (37%); T4N2, 22 patients (27%), and T1-3N3, 30 patients (36%). Concurrent chemoradiotherapy was generally well tolerated, but two patients died from probable radiation-associated pneumonitis. Neutropenia during consolidation docetaxel was common (57% with grade 4) and most frequent during escalation to 100 mg/m2. Median progression-free survival was 16 months, median survival was 26 months, and 1-, 2-, and 3-year survival rates were 76%, 54%, and 37%, respectively. Brain metastasis was the most common site of failure. In S9019, median survival was 15 months and 1-, 2-, and 3-year survival rates were 58%, 34%, and 17%, respectively., Conclusion: Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB NSCLC is feasible and generally tolerable, and results compare favorably with the predecessor trial S9019. Nevertheless, this study remains hypothesis-generating and does not provide definitive evidence of the benefit of this approach. Phase III trials evaluating the S9504 regimen have been initiated to validate these results.

This was a 30-patient Phase II trial of reduced-dose (90)Y ibritumomab tiuxetan (Zevalin) RIT for patients with low-grade, follicular, or transformed B-cell NHL and mild thrombocytopenia. Patients were given an imaging dose of (111)In-labeled ibritumomab tiuxetan for dosimetry measurements. One week later, patients were administered a therapeutic dose of 0.3 mCi/kg (11 MBq/kg) (90)Y ibritumomab tiuxetan. Both (111)In- and (90)Y-labeled ibritumomab tiuxetan doses were preceded by an infusion of 250 mg/m(2) rituximab (Rituxan, MabThera) an unlabeled chimeric anti-CD20 antibody, to clear peripheral blood B cells and improve biodistribution of the radiolabeled antibody. For all 30 patients, normal organ and red marrow radiation absorbed doses were well below protocol-defined limits of 2000 cGy and 300 cGy, respectively. Median radiation absorbed doses were 48 cGy to red marrow (range: 6.5-95 cGy), 393 cGy to liver (range: 92-1581 cGy), 522 cGy to spleen (range: 165-1711 cGy), 162 cGy to lungs (41-295 cGy), and 14 cGy to kidneys (0.03-65 cGy). Though most correlative analyses were negative, certain analyses demonstrated a statistically significant correlation between the severity or duration of thrombocytopenia and pharmacokinetic or dosimetric parameters. These correlations were not consistent across the total patient population, and therefore, could not be exploited to predict hematologic toxicity.

Zevalin (ibritumomab tiuxetan) radioimmunotherapy is a novel treatment for non-Hodgkin's lymphoma (NHL). The Zevalin regimen includes 5 mCi (111)In-labeled Zevalin on Day 1, followed by serial anterior and posterior planar gamma images for imaging or dosimetry. On Day 8, patients receive 0.4 mCi/kg (90)Y Zevalin for radioimmunotherapy. Both Zevalin doses are preceded by 250 mg/m(2) rituximab to clear peripheral B cells and improve biodistribution of the radiolabeled antibody. In a 143-patient, Phase III, randomized study, the Zevalin regimen produced a significantly higher overall response rate than rituximab for relapsed or refractory, low-grade, follicular, or transformed NHL (80% versus 56%, p = 0.02). Fifteen patients from the Zevalin arm of this study were randomly selected for additional radiation dosimetry. (90)Y residence times were calculated from (111)In image analysis data. MIRDOSE3.1 radiation absorbed dose estimates to normal tissues were highest for spleen, testes, and liver, with considerably lower doses reaching heart, lung, intestines, red marrow, and kidneys. Radiation absorbed doses to organs and marrow were within a safe range following administration of 0.4 mCi/kg (90)Y Zevalin.

Background: Kaposi's sarcoma (KS) is the most common neoplastic apoptosis manifestation of acquired immunodeficiency syndrome. Toremifene is known to upregulate transforming growth factor beta-1 (TGF-beta1), which is a growth-inhibitory factor for KS. We investigated the in vitro effect of toremifene on KS cells., Methods: MTT assay was used to measure the growth of four KS cell lines and a human umbilical vein endothelial (HUVE) cell line after incubation with toremifene. Reverse transcription polymerase chain reaction and ELISA were used to measure the level of TGF-beta1., Results: The IC(50) for the KS cells ranged from 2.2 to 3.2 microM, and 80% of the growth inhibition occurred within 24 h. Toremifene enhanced TGF-beta1 mRNA expression, and the level of TGF-beta1 increased from 103 to 473 pg/ml after 48 h of incubation. Toremifene had no effect on the growth of HUVE cells., Conclusion: Toremifene has a specific antiproliferative effect on KS cells. The stimulation of TGF-beta1 production may play a role in the antiproliferative process., (Copyright 2002 S. Karger AG, Basel)

Clinical trials have documented the single-agent efficacy of radioimmunotherapy (RIT) in lymphoma, and several combination therapy studies are now in progress. RIT agents are currently becoming generally available for clinical use in lymphoma therapy. Solid tumors, which are notoriously less responsive to any single agent, have demonstrated clinically useful responses, albeit temporary, and multimodality studies have been instituted. However, a sincere debate continues regarding the basic parameters to be used to define appropriate therapeutic dosing when using this modality in clinical cancer care. It is a good time to reevaluate relevant dose response information from preclinical and clinical RIT. Preclinical studies have demonstrated abundant evidence of dose response in tumor and normal tissue in homogenous model systems; however, substantive variation occurs between the dose responses of tumors with low and variable (or shed) antigen expression, as well as between histologically different tumor models. Clinical studies of various heavily pretreated patient populations given several very different RIT pharmaceuticals have led to disparate conclusions regarding patient dosing methods and dosimetric predictions of toxicity and efficacy. Single-study data on previously untreated lymphoma patients with similar histology has demonstrated a correlation of imaging dosimetry with toxicity and tumor response. High-dose therapy with bone marrow support has also demonstrated a high tumor response rate and nonmarrow normal organ toxicities that correlate with the calculated dose to those organs from imaging. In iodine-131 ((131)I)--anti-CD20 studies, (131)I was demonstrated to have variable excretion, and estimated total-body radiation dose from tracer study proved a predictive surrogate for marrow toxicity. Yttrium-90 ((90)Y)--anti-CD20, which has little (90)Y excretion from the body, demonstrated the injected dose per body weight to be more predictive of marrow toxicity than indium-111 ((111)In) tracer dosimetry methods in heavily pretreated patients, and showed maximal safety with standard mCi/kg therapy dosing. Variations in clinical RIT choices, dosing methods, and dosimetry methods emphasize the need to review the relevant information to date. Future clinical trial designs, the sophistication of dosimetry, treatment planning, and clinical treatment decisions should all be focused on achieving the best benefit-risk relationship for each patient., (Copyright 2002 American Cancer Society.)

Unlabelled: Radiation dosimetry studies were performed in patients with non-Hodgkin's lymphoma (NHL) treated with 90Y Zevalin (90yttrium ibritumomab tiuxetan, IDEC-Y2B8) on a Phase III open-label prospectively randomized multicenter trial. The trial was designed to evaluate the efficacy and safety of 90Y Zevalin radioimmunotherapy compared to rituximab (Rituxan, MabThera) immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed NHL. An important secondary objective was to determine if radiation dosimetry prior to 90Y Zevalin administration is required for safe treatment in this patient population., Methods: Patients randomized into the Zevalin arm were given a tracer dose of 5 mCi (185 MBq) (111)In Zevalin (111indium ibritumomab tiuxetan) on Day 0, evaluated with dosimetry, and then administered a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) 90Y Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve Zevalin biodistribution. Following administration of (111)In Zevalin, serial anterior and posterior whole-body scans were acquired and blood samples were obtained. Residence times for 90Y were estimated for major organs, and the MIRDOSE3 computer software program was used to calculate organ-specific and total body radiation absorbed dose. Patients randomized into the rituximab arm received a standard course of rituximab immunotherapy (375 mg/m(2) weekly x 4)., Results: In a prospectively defined 90 patient interim analysis, the overall response rate was 80% for Zevalin vs. 44% for rituximab. For all patients with Zevalin dosimetry data (N=72), radiation absorbed doses were estimated to be below the protocol-defined upper limits of 300 cGy to red marrow and 2000 cGy to normal organs. The median estimated radiation absorbed doses were 71 cGy to red marrow (range: 18-221 cGy), 216 cGy to lungs (94-457 cGy), 532 cGy to liver (range: 234-1856 cGy), 848 cGy to spleen (range: 76-1902 cGy), 15 cGy to kidneys (0.27-76 cGy) and 1484 cGy to tumor (range: 61-24274 cGy). Toxicity was primarily hematologic, transient, and reversible. The severity of hematologic nadir did not correlate with estimates of effective half-life (half-life) or residence time of 90Y in blood, or radiation absorbed dose to the red marrow or total body., Conclusion: 90Y Zevalin administered to NHL patients at non-myeloablative maximum tolerated doses delivers acceptable radiation absorbed doses to uninvolved organs. Lack of correlation between dosimetric or pharmacokinetic parameters and the severity of hematologic nadir suggest that hematologic toxicity is more dependent on bone marrow reserve in this heavily pre-treated population. Based on these findings, it is safe to administer 90Y Zevalin in this defined patient population without pre-treatment (111)In-based radiation dosimetry.

Purpose: To assess the acute toxicity of three-dimensional conformal radiotherapy (3D-CRT) in prostate cancer patients eligible for implant monotherapy., Methods and Materials: Between December 1991 and June 1998, 198 prostate cancer patients were treated with 3D-CRT at the University of California Davis Medical Center. Fifty-two of these patients had a prostate-specific antigen (PSA) level /= Grade 3, e.g., hourly nocturia, gross hematuria, diarrhea requiring parenteral support, narcotics for pain control, or catheterization for acute urinary retention, was observed., Conclusion: Although relatively high doses of radiation are delivered to prostate cancers with 3D-CRT compared with conventional radiotherapy, 3D-CRT is surprisingly well-tolerated. No patients in the cohort eligible for implant monotherapy experienced acute toxicity >/= Grade 3.