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The aim of this study is to assess international guidelines implementation concerning thromboprophylaxis strategy in myeloma patients treated with immunomodulatory drugs. This retrospective study includes multiple myeloma patients treated with immunomodulatory drugs between 2014 and 2017 in the Hematology department of a teaching hospital (Hospices Civils de Lyon, France) and followed by the multidisciplinary care plan for cancer outpatients ONCORAL (ONCological care for outpatients with ORAL anticancer drugs). Data from immunomodulatory drugs administration, thromboprophylaxis strategy and thrombotic events were collected from medical files. Adherence to 2010 International Myeloma Working Group (IMWG) guidelines was assessed. 213 patients received at least one immunomodulatory drug: lenalidomide (60.9%), pomalidomide (24.0%) and thalidomide (15.1%). About two third of treatment lines (66.2%) were in accordance with IMWG recommendations. Among the others, 30.5% and 69.5% had thromboprophylaxis, respectively, superior or inferior to IMWG recommendations. 37 venous thrombotic events and 4 arterial thromboembolisms (one patient experienced both a stroke and deep venous thrombosis simultaneously) were reported. Thromboprophylaxis was systematically performed in myeloma patients treated with immunomodulatory drugs in this real-life retrospective cohort. However, the choice of anticoagulant or anti-platelet agent remains debatable, as adherence to existing guidelines was variable.

This paper presents the results of a proteomics analysis of mouse brain nerve tissue cells after a single local effect of a proton beam with an energy of 1 GeV at an absorbed dose of 3 Gy. Electrophoretic methods of protein separation as well as mass spectrometric and immune detection methods were used in the work. It was found that on day 31 after irradiation, the number of detected proteoforms and expressed genes almost doubled: 7754 proteoforms and 1591 genes after irradiation against 3652 proteoforms and 996 genes before irradiation. The data obtained indicate the plasticity of the nervous tissue response to the action of proton radiation. Especially noteworthy are changes in the profiles of proteoforms of such regulatory proteins as 14-3-3, cofilin-1, neuromodulin, and gamma-enolase that are involved in the reorganization of the cytoskeleton of nerve cells and regenerative processes.

Summary Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.

Purpose To investigate paediatric orthopaedists’ cast practices for early onset scoliosis regarding patient selection, cast application, radiographic evaluation, treatment cessation and adjunctive bracing. Methods A casting survey was distributed to all paediatric orthopaedists in Children's Spine and Growing Spine Study Groups (n = 92). Questions included physician and patient characteristics, technique, treatment, outcomes, radiographic measurements and comparison to other treatments. A total of 55 orthopaedists (60%) responded, and descriptive statistics were calculated on the subset who cast (n = 45). Results A majority of respondents use cast treatment for idiopathic and syndromic scoliosis patients, but not for neuromuscular or congenital scoliosis patients. Major curve angle ranked most important in orthopaedists’ decision to commence cast treatment, in comparison with rib-vertebra angle difference or clinical observations. The major curve angle threshold to initiate casting was a median of 30° (20° to 70°), and the minimum patient age was median ten months (3 to 24). First in-cast and out-of-cast radiographs are taken standing, supine, awake, under anesthesia and/or in traction. In all, 58% consistently cast over or under the arm, while 44% vary position by patient. Respondents were divided about the use of a brace after cast treatment: 22% do not prescribe a brace, 31% always do and 36% do in some patients. Conclusions Future multicentre research studies must standardize radiographic practices and consider age and major curve angle at cast initiation and termination, scoliosis aetiology, shoulder position and treatment duration. Practices need to be aligned or compared in these areas in order to distinguish what makes for the best cast treatment possible. Level of Evidence V, Expert opinion

Amplification of the locus encoding the oncogenic transcription factor MYCN is a defining feature of high-risk neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of MYCN perturbation in neuroblastoma. At oncogenic levels, MYCN associates with E-box binding motifs in an affinity-dependent manner, binding to strong canonical E-boxes at promoters and invading abundant weaker non-canonical E-boxes clustered at enhancers. Loss of MYCN leads to a global reduction in transcription, which is most pronounced at MYCN target genes with the greatest enhancer occupancy. These highly occupied MYCN target genes show tissue-specific expression and are linked to poor patient survival. The activity of genes with MYCN-occupied enhancers is dependent on the tissue-specific transcription factor TWIST1, which co-occupies enhancers with MYCN and is required for MYCN-dependent proliferation. These data implicate tissue-specific enhancers in defining often highly tumor-specific ‘MYC target gene signatures’ and identify disruption of the MYCN enhancer regulatory axis as a promising therapeutic strategy in neuroblastoma. This study investigates the effects of MYCN on the chromatin and transcriptional landscape of neuroblastoma. The authors find that, at oncogenic levels, MYCN binds to canonical E-boxes at promoters and invades enhancers, leading to transcriptional amplification.

Summary Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.

Summary Background Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT. Methods In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age ( vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5–60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010–020150–34). Findings Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4–74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI −5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, −1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5–26·6; p Interpretation This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated. Funding Merck & Co., Inc.

Wilms tumor is the most common childhood renal cancer. To identify mutations that predispose to Wilms tumor, we are conducting exome sequencing studies. Here we describe 11 different inactivating mutations in the REST gene (encoding RE1-silencing transcription factor) in four familial Wilms tumor pedigrees and nine non-familial cases. Notably, no similar mutations were identified in the ICR1000 control series (13/558 versus 0/993; P < 0.0001) or in the ExAC series (13/558 versus 0/61,312; P < 0.0001). We identified a second mutational event in two tumors, suggesting that REST may act as a tumor-suppressor gene in Wilms tumor pathogenesis. REST is a zinc-finger transcription factor that functions in cellular differentiation and embryonic development. Notably, ten of 11 mutations clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these mutations compromise REST transcriptional repression. These data establish REST as a Wilms tumor predisposition gene accounting for ∼2% of Wilms tumor.

Triple-negative breast cancer (TNBC) is a collection of diseases with distinct clinical behaviors and heterogeneous molecular features. Such clinical and genetic heterogeneity has called into question whether there are common pathogenic mechanisms (and potential therapeutic targets) driving the TNBC subtype of breast cancer. Herein, we present evidence of a novel tumor suppressor network that is frequently compromised in TNBC, and a broadly-effective strategy to target this pathway for TNBC therapeutic intervention. Using an unbiased genetic screen, we identified a tumor suppressor network governing tumor survival of TNBCs in vitro and in vivo. We define the tyrosine phosphatase PTPN12 as a core component in this network. PTPN12 is a potent suppressor of mammary epithelial cell survival and transformation, and PTPN12 function is compromised in more than 70% of human TNBCs. Notably, the tumorigenic and metastatic potential of PTPN12-deficient TNBCs is severely impaired by restoring PTPN12, suggesting that strategies to mimic PTPN12 function have substantive therapeutic potential. Using integrative proteomic, genetic, and pharmacologic approaches, we demonstrate that PTPN12 suppresses TNBC survival by inhibiting multiple oncogenic receptor tyrosine kinases (TKs) including MET, PDGFRβ, and others. Frequent inactivation of PTPN12 in human TNBC unleashes these oncogenic TKs in a concerted manner. Importantly, combination inhibitors targeting these PTPN12-regulated TKs significantly impair TNBC cell survival and confer robust tumor regression across a panel of 18 patient-derived xenograft ("PDX") models of human TNBC. This suggests that TNBCs are broadly dependent on a distinct combination of proto-oncogenic tyrosine kinases constrained by PTPN12. Collectively, these data identify PTPN12 as a commonly inactivated tumor suppressor in TNBC and provide a rationale for combinatorially targeting select receptor tyrosine kinases in TNBC and other cancers based on their defects in tyrosine phosphatase activity. Citation Format: Thomas F Westbrook, Amritha Nair, Tingting Sun, Kristen L Karlin, Jessica Kessler, Ilenia Migliaccio, Don X Nguyen, Ronald J Bernardi, Alex Renwick, Chad J Creighton, Noah Dephoure, Steven P Gygi, Chad A Shaw, Richard Gibbs, David Wheeler, Rachel Schiff, James G Christensen, David J Shields, C Kent Osborne, Stephen J Elledge, Susan G Hilsenbeck, Michael T Lewis. A broad spectrum therapeutic strategy for TNBC revealed by a new pathway that coordinates oncogenic RTKs [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-01.

SummaryDefining the molecular networks that drive breast cancer has led to therapeutic interventions and improved patient survival. However, the aggressive triple-negative breast cancer subtype (TNBC) remains recalcitrant to targeted therapies because its molecular etiology is poorly defined. In this study, we used a forward genetic screen to discover an oncogenic network driving human TNBC. SCYL1, TEX14, and PLK1 (“STP axis”) cooperatively trigger degradation of the REST tumor suppressor protein, a frequent event in human TNBC. The STP axis induces REST degradation by phosphorylating a conserved REST phospho-degron and bridging REST interaction with the ubiquitin-ligase βTRCP. Inhibition of the STP axis leads to increased REST protein levels and impairs TNBC transformation, tumor progression, and metastasis. Expression of the STP axis correlates with low REST protein levels in human TNBCs and poor clinical outcome for TNBC patients. Our findings demonstrate that the STP-REST axis is a molecular driver of human TNBC.

Resume Introduction Le diagnostic de paralysie faciale a frigore, frequemment porte en cas de paralysie faciale peripherique d’installation brutale, doit etre neanmoins evoque avec prudence en particulier en cas de douleur intense associee, et doit faire eliminer un processus expansif de la base du crâne, notamment du rocher. Observation Nous rapportons le cas d’un patient de 43 ans qui a presente une paralysie faciale peripherique de debut rapidement progressif. Les examens radiologiques ont permis de mettre en evidence une tumeur du rocher, dont l’aspect radiologique pouvait faire evoquer plusieurs diagnostics, tels qu’une tumeur glomique ou une lesion secondaire. L’examen histologique a finalement etabli le diagnostic de plasmocytome. Discussion La localisation de cette lesion au rocher n’a ete que rarement decrite et les caracteristiques radiologiques sont tres peu specifiques. Des examens simples, tels que la recherche d’un composant monoclonal, les radiographies de squelette et le myelogramme, peuvent orienter vers le diagnostic soit de plasmocytome solitaire (lesion isolee, myelogramme normal), qui devra etre confirme par une biopsie, soit de myelome multiple (lesions osteolytiques, myelogramme envahi), et dans ce dernier cas dispenser d’une analyse histologique.

SUMMARY Down syndrome (DS, trisomy 21) is associated with developmental abnormalities and increased leukemia risk. To reconcile chromatin alterations with transcriptome changes, we performed paired exogenous spike-in normalized RNA and chromatin immunoprecipitation sequencing in DS models. Absolute normalization unmasks global amplification of gene expression associated with trisomy 21. Overexpression of the nucleosome binding protein HMGN1 (encoded on chr21q22) recapitulates transcriptional changes seen with triplication of a Down syndrome critical region on distal chromosome 21, and HMGN1 is necessary for B cell phenotypes in DS models. Absolute exogenous-normalized chromatin immunoprecipitation sequencing (ChIP-Rx) also reveals a global increase in histone H3K27 acetylation caused by HMGN1. Transcriptional amplification downstream of HMGN1 is enriched for stage-specific programs of B cells and B cell acute lymphoblastic leukemia, dependent on the developmental cellular context. These data offer a mechanistic explanation for DS transcriptional patterns and suggest that further study of HMGN1 and RNA amplification in diverse DS phenotypes is warranted., Graphical Abstract, In Brief How trisomy 21 contributes to Down syndrome phenotypes, including increased leukemia risk, is not well understood. Mowery et al. use per-cell normalization approaches to reveal global transcriptional amplification in Down syndrome models. HMGN1 overexpression is sufficient to induce these alterations and promotes lineage-associated transcriptional programs, signaling, and B cell progenitor phenotypes.

Since 1975 proton beam of PNPI synchrocyclotron with fixed energy of 1000 MeV is used for the stereotaxic proton therapy of different head brain diseases. 1300 patients have been treated during this time. The advantage of high energy beam (1000 MeV) is low scattering of protons in the irradiated tissue. This factor allows to form the dose field with high edge gradients (20%/mm) that is especially important for the irradiation of the intra-cranium targets placed in immediate proximity to the life critical parts of the brain. Fixation of the 6 0mm diameter proton beam at the isodose centre with accuracy of ±1.0 mm, two-dimensional rotation technique of the irradiation provide a very high ratio of the dose in the irradiation zone to the dose at the object's surface equal to 200:1. The absorbed doses are: 120-150 Gy for normal hypophysis, 100-120 Gy for pituitary adenomas and 40-70 Gy for arterio-venous malformation at the rate of absorbed dose up to 50 Gy/min. In the paper the dynamics and the efficiency of 1000 MeV proton therapy treatment of the brain deceases are given. At present time the feasibility study is in progress with the goal to create a proton therapy on Bragg peak by means of the moderation of 1000 MeV proton beam in the absorber down to 200 MeV, energy required for radiotherapy of deep seated tumors.

Nat. Genet. 47, 1471–1474 (2015); published online 9 November 2015; corrected after print 8 February 2016 In the version of this article initially published, the authors failed to acknowledge funding from the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS FoundationTrust and University College London to Neil Sebire.

c-MYC (MYC) hyperactivation is one of the most common drivers of human breast cancer and correlates with poor prognosis. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. Like other classic oncogenes, hyperactivation of MYC leads to collateral stresses onto breast cancer cells, suggesting that tumors harbor unique vulnerabilities arising from oncogenic activation of MYC. Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We demonstrate that core components of the spliceosome and its catalytic activity are required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces global changes in mRNA metabolism and increases the burden on the core spliceosome to process pre-mRNA. In primary human breast cancers, MYC hyperactivation is associated with altered splicing efficiency. In contrast to normal mammary epithelium, partial inhibition of the spliceosome in MYC-hyperactivated breast cancers leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of essential cell processes. Importantly, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing and that components of the spliceosome are therapeutic entry points for aggressive MYC-driven breast cancers. Citation Format: Tiffany Hsu, Lukas Simon, Nicholas Neill, richard marcotte, Azin Sayad, Kristen Karlin, Chandraiah Lagisetti, Thomas Cooper, Thomas Webb, Benjamin Neel, Chad Shaw, Thomas (“Trey”) Westbrook. The spliceosome is a therapeutic vulnerability in MYC-driven breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr PR02.