Treatment Options for Paediatric Anaplastic Large Cell Lymphoma (ALCL): Current Standard and beyond.

Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL), remains one of the most curable cancers in the paediatric setting; multi-agent chemotherapy cures approximately 65-90% of patients. Over the last two decades, major efforts have focused on improving the survival rate by intensification of combination chemotherapy regimens and employing stem cell transplantation for chemotherapy-resistant patients. More recently, several new and 'renewed' agents have offered the opportunity for a change in the paradigm for the management of both chemo-sensitive and chemo-resistant forms of ALCL. The development of ALK inhibitors following the identification of the EML4-ALK fusion gene in Non-Small Cell Lung Cancer (NSCLC) has opened new possibilities for ALK-positive ALCL. The uniform expression of CD30 on the cell surface of ALCL has given the opportunity for anti-CD30 antibody therapy. The re-evaluation of vinblastine, which has shown remarkable activity as a single agent even in the face of relapsed disease, has led to the consideration of a revised approach to frontline therapy. The advent of immune therapies such as checkpoint inhibition has provided another option for the treatment of ALCL. In fact, the number of potential new agents now presents a real challenge to the clinical community that must prioritise those thought to offer the most promise for the future. In this review, we will focus on the current status of paediatric ALCL therapy, explore how new and 'renewed' agents are re-shaping the therapeutic landscape for ALCL, and identify the strategies being employed in the next generation of clinical trials

A natural histone H2A variant lacking the Bub1 phosphorylation site and regulated depletion of centromeric histone CENP-A foster evolvability in Candida albicans.

Eukaryotes have evolved elaborate mechanisms to ensure that chromosomes segregate with high fidelity during mitosis and meiosis, and yet specific aneuploidies can be adaptive during environmental stress. Here, we identify a chromatin-based system required for inducible aneuploidy in a human pathogen. Candida albicans utilizes chromosome missegregation to acquire tolerance to antifungal drugs and for nonmeiotic ploidy reduction after mating. We discovered that the ancestor of C. albicans and 2 related pathogens evolved a variant of histone 2A (H2A) that lacks the conserved phosphorylation site for kinetochore-associated Bub1 kinase, a key regulator of chromosome segregation. Using engineered strains, we show that the relative gene dosage of this variant versus canonical H2A controls the fidelity of chromosome segregation and the rate of acquisition of tolerance to antifungal drugs via aneuploidy. Furthermore, whole-genome chromatin precipitation analysis reveals that Centromere Protein A/ Centromeric Histone H3-like Protein (CENP-A/Cse4), a centromeric histone H3 variant that forms the platform of the eukaryotic kinetochore, is depleted from tetraploid-mating products relative to diploid parents and is virtually eliminated from cells exposed to aneuploidy-promoting cues. We conclude that genetically programmed and environmentally induced changes in chromatin can confer the capacity for enhanced evolvability via chromosome missegregation

Resistance to Targeted Agents Used to Treat Paediatric ALK-Positive ALCL.

Non-Hodgkin lymphoma (NHL) is the third most common malignancy diagnosed in children. The vast majority of paediatric NHL are either Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma (LL). Multi-agent chemotherapy is used to treat all of these types of NHL, and survival is over 90% but the chemotherapy regimens are intensive, and outcomes are generally poor if relapse occurs. Therefore, targeted therapies are of interest as potential solutions to these problems. However, the major problem with all targeted agents is the development of resistance. Mechanisms of resistance are not well understood, but increased knowledge will facilitate optimal management strategies through improving our understanding of when to select each targeted agent, and when a combinatorial approach may be helpful. This review summarises currently available knowledge regarding resistance to targeted therapies used in paediatric anaplastic lymphoma kinase (ALK)-positive ALCL. Specifically, we outline where gaps in knowledge exist, and further investigation is required in order to find a solution to the clinical problem of drug resistance in ALCL

Spin-orbit misalignment in the HD80606 planetary system

We recently reported the photometric and spectroscopic detection of the primary transit of the 111-day-period, eccentric extra-solar planet HD80606 b, at Observatoire de Haute-Provence, France (Moutou et al. 2009). The whole egress of the primary transit and a section of its central part were observed, allowing the measurement of the planetary radius, and evidence for a spin-orbit misalignment through the observation of the Rossiter-McLaughlin anomaly. The ingress having not been observed for this long-duration transit, uncertainties remained in the parameters of the system. We present here a refined, combined analysis of our photometric and spectroscopic data, together with further published radial velocities, ground-based photometry, and Spitzer photometry around the secondary eclipse, as well as new photometric measurements of HD 80606 acquired at Mount Hopkins, Arizona, just before the beginning of the primary transit. Although the transit is not detected in those new data, they provide an upper limit for the transit duration, which narrows down the possible behaviour of the Rossiter-McLaughlin anomaly in the unobserved part of the transit. We analyse the whole data with a Bayesian approach using a Markov-chain Monte Carlo integration on all available information. We find R_p = 0.98 +- 0.03 R_Jup for the planetary radius, and a total primary transit duration of 11.9 +- 1.3 hours from first to fourth contact. Our analysis reinforces the hypothesis of spin-orbit misalignment in this system (alignment excluded at >95 % level), with a positive projected angle between the planetary orbital axis and the stellar rotation (median solution lambda ~ 50 degrees). As HD80606 is a component of a binary system, the peculiar orbit of its planet could result from a Kozai mechanism.Comment: accepted for Publication in Astronomy & Astrophysics, submitted 11 May 200

Patient-derived xenograft models of ALK+ ALCL reveal preclinical promise for therapy with brigatinib

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood–brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.</p

Erratum to:Effects of a physical activity and nutrition program in retirement villages: a cluster randomised controlled trial

Abstract Background This cluster randomised controlled trial aimed to determine if a 6- month home-based intervention could improve the physical activity and dietary behaviours of adults aged 60 to 80 years living in retirement villages located in Perth, Western Australia. Methods Participants (n = 363) from 38 retirement villages were recruited into the trial and allocated to the intervention (n = 197: 17 sites) or control (n = 166: 21 sites) group and were blinded. Previously validated instruments-Fat and Fibre Barometer and International Physical Activity Questionnaire, along with anthropometric measures (weight, height, waist and hip circumferences) and blood pressure were collected at baseline and 6 -month time period. Comparisons between intervention and control groups were undertaken pre- and post- intervention using univariate chi-square and t-tests. Multi-level mixed regression analyses were then conducted to ascertain the effects of the intervention on changes in the outcome variables over time and between groups. Results A total of 139 (70.5%) intervention and 141 (84.9%) control group participants completed the program and post-test assessments. The intervention group demonstrated significant increases in time (80 min more per week on average) devoted to moderate-intensity physical activity, engagement in strength exercises (from 23.7% to 48.2%), frequency of fruit consumed as well as fat avoidance and fibre intake scores, in addition to a 0.5 kg mean reduction in weight post program, whereas no apparent changes were observed in the control group. Mixed regression results further confirmed statistically significant improvements in weight loss (p < 0.05), engagement in strength exercises (p < 0.001) and fruit intake (p = 0.012) by the intervention participants at post-test relative to their controls. Conclusions Retirement offers a time to reassess lifestyle, and adopt positive health enhancing physical activity and dietary behaviours. This intervention was successful in improving weight, engagement in strength exercises, increasing levels of moderate-intensity physical activity and consumption of fruit among retirement village residents. Further investigation is needed on how to better engage retirement village managers in such programs. Trial registration Australia and New Zealand Clinical Trial Registry (ACTRN12612001168842) registered November 2, 2012

BRG1 and NPM-ALK Are Co-Regulated in Anaplastic Large-Cell Lymphoma; BRG1 Is a Potential Therapeutic Target in ALCL.

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL

Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer\u27s Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer’s disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ1-40, Aβ1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology

Cardiac Angiogenic Imbalance Leads to Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is an often fatal disease that affects pregnant women who are near delivery, and it occurs more frequently in women with pre-eclampsia and/or multiple gestation. The aetiology of PPCM, and why it is associated with pre-eclampsia, remain unknown. Here we show that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-$1\alpha$, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble FLT1 (sFLT1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by subclinical cardiac dysfunction, the extent of which correlates with circulating levels of sFLT1. Exogenous sFLT1 alone caused diastolic dysfunction in wild-type mice, and profound systolic dysfunction in mice lacking cardiac PGC-$1\alpha$. Finally, plasma samples from women with PPCM contained abnormally high levels of sFLT1. These data indicate that PPCM is mainly a vascular disease, caused by excess anti-angiogenic signalling in the peripartum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM

Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma: Long Term Results of the International ALCL99 Trial

With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern; a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern; and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively (p 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments