Global Clinical Outcome Research Articles

Abstract PO1-16-01: Clinicopathological and global transcriptional complexity of estrogen receptor low positive breast cancers in a contemporary Swedish prospective population-based cohort

Abstract Background: Estrogen receptor (ER) expression is currently the most consequential biomarker for prognostic and therapeutic decision making in clinical management of early breast cancer. Endocrine therapy (ET) is an important part of standard of care in most cases with ER-positive disease, and an effective therapy for patients with endocrine-responsive tumors, decreasing the risk of recurrence and improving the rate of survival. Unfortunately, ET comes with frequently bothersome side-effects and tend to decrease quality of life. The threshold to define ER positivity as a marker of endocrine responsiveness is non-uniform between international and local guidelines. Among ER low positive tumors (ERlow ,1-10% expression) endocrine responsiveness is uncertain. Swedish national guidelines recommend a cut-off of ≥10% for ER positivity and ET prescriptions, thus patients with ERlow tumors are often exempted from adjuvant ET. This study explores the clinicopathological characteristics, global transcriptional complexity and clinical outcome of ERlow tumors to better understand their biology and response to therapy. Methods: 9138 patients diagnosed with early breast cancer between 2010 – 2021 in Sweden with available clinicopathological data and RNA sequencing data were included. Patients were classified according to ER expression: ERneg (< 1%; n=897), ERlow (1-10%, n=158) and ERhigh ( >10%, n=8083). Adjuvant ET was provided to 3.6%, 16.8% and 91.5% of patients with ERneg, ERlow, and ERhigh tumors, respectively. Clinicopathological characteristics, overall survival (OS) and global transcriptional profiles of ERlow tumors were compared with ERneg and ERhigh tumors, respectively. Results: Generally, ERlow and ERneg tumor pathological characteristics were more similar to each other but were significantly distinct compared to ERhigh tumors. However, among patients with HER2-negative disease only, significant differences related to tumor biology persisted between ERlow compared with ERneg tumors; ERlow was enriched with tumors displaying a lobular histology, NHG grades 1&2, PgRlow/high expression, low proliferation and Luminal & HER2-enriched molecular subtypes (p< 0.05 for all comparisons). Moreover, multivariable survival analyses revealed that the risk of dying was significantly lower for patients with ERlow tumors compared to patients with ERneg (p=0.005) or ERhigh tumors (p=0.011) in this cohort. The distribution of clinicopathological characteristics and overall survival between ERlow compared with ERneg or ERhigh tumors were similar among patients with HER2-positive tumors only. Global transcriptional comparisons identified only 42 genes to be differentially expressed between ERlow vs ERneg tumors (FDR< 0.05); but gene set enrichment analyses failed to identify any significantly enriched cancer-related processes/pathways within the queried databases. Conclusions: Identification of optimal therapies for all subsets of breast cancer is necessary in the pursuit of personalized medicine. These results confirm that ERneg and ERlow tumors are pathologically and transcriptionally distinct from ERhigh tumors. Although subtle differences exists in the underlying biology of ERlow compared to ERneg tumors, similar therapeutic management excluding ET for patients with ERlow and ERneg disease is recommended in the Swedish context. Omission of adjuvant ET did not seem to compromise overall survival for ERlow relative to ERneg or ERhigh tumors, urging the need for prospective studies investigating the true benefit of ET for ERlow tumors. Our results also raise reasonable clinical thoughts on the benefits of new treatment strategies such as cyclin-dependent kinase 4/6 inhibitors, immunotherapy and antibody-drug conjugates for patients with ERlow expressing tumors. Citation Format: Siker Kimbung, Srinivas Veerla, Anna Ehinger, Johan Vallon-Christersson, Martin Malmberg, Niklas Loman. Clinicopathological and global transcriptional complexity of estrogen receptor low positive breast cancers in a contemporary Swedish prospective population-based cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-01.

The impact of selection bias in the treatment for ruptured anterior communicating artery aneurysms: different results or different patients?

BackgroundAnterior communicating artery is one of the most frequent locations for the development of intracranial aneurysm. The availability and advances of different treatments modalities allows for case-specific selection, but potentially impacts our ability to assess equipoise among them. ObjectiveInvestigate and compare clinical and morphological variables among surgical and endovascular treatment groups with ruptured anterior communicating artery aneurysms. MethodsData from patients from a single university hospital treated for ruptured anterior communicating aneurysms after multidisciplinary discussion in a period from January 2009 to January 2020 were retrospectively reviewed. Demographics, clinical status, aneurysm morphologic features and in-hospital complications were registered for each treatment (endovascular coiling vs. microsurgical clipping). Clinical assessment was made from outpatient evaluation at 1-year follow-up. ResultsA total of 119 patients was obtained adding surgical (n = 80) and endovascular (n = 39) treatment groups. No significant changes between groups were detected regarding gender, age of treatment or other risk factors. Global complication rate (p = 0.335, p = 0.225, p = 0.428) and clinical outcome (p = 0.802) was similar among both groups. Univariate and multivariate analysis revealed statistically significant differences between endovascular and surgical treatment groups regarding dome orientation (p = 0.011), aneurysm height (p < 0.001) and maximum diameter (p < 0.001), aspect-ratio (p < 0.001), dome-to-neck ratio (p < 0.001) and dome diameter (p = 0.014). ConclusionsDespite similar clinical outcomes and rate of complications, morphological differences highlight the presence of a selection bias and high heterogeneity, which hampers inferential analysis when comparing both techniques.

Influence of the preoperative L5S1 disc state on lateral L2 to L5 fusion's outcomes at an average follow-up of 3,5years (minimum 2years).

The impact of pre-existing degeneration of a disc underlying a lumbar arthrodesis via lateral approach on long-term clinical outcome has, to our knowledge, not been studied. When performing arthrodesis between L2 and L5, its extension to L5S1 is challenging because it imposes a different surgical approach. Therefore, surgeon's temptation is to not include L5S1 in the fusion even in case of discopathy. Our objective was to study the influence of the preoperative L5S1 status on the clinical outcome of lumbar lateral interbody fusion (LLIF) using a pre-psoatic approach between L2 and L5 with a minimum follow-up of 2years. Patients who underwent LLIF from L2 to L5 between 2015 and 2020 were included in our study. We studied VAS, ODI, and global clinical outcome before surgery and at last follow-up. The L5-S1 disc was radiologically studied in preoperative imaging. Patients were included in two groups (A "with" and B :without" L5-S1 disc degeneration) to compare the clinical outcomes at last follow-up. Our primary objective was to evaluate the rate of L5-S1 disc revision surgery at last follow-up. 102 patients were included. 2 required L5-S1 disc surgery following overlying arthrodesis. Our results showed a significant improvement in the patients' clinical outcomes at the last follow-up (p < 0.0001). We did not find any significant difference on clinical criteria between groups A & B. A preop L5S1 disc degeneration does not seem to impact the final clinical outcomes after lumbar lateral interbody fusion at a minimal two years F.U. It should not be systematically involved in an overlying fusion.

Association between Resting Global Longitudinal Strain and Clinical Outcome of Patients Undergoing Stress Echocardiography

Reduced global longitudinal strain (GLS) of the left ventricle is associated with adverse prognosis in healthy subjects and in different cardiovascular conditions. Resting GLS may enable risk assessment independently from stress echocardiography (SE). We assessed whether there is an association of GLS measured at rest before SE with long-term outcome, independent of clinical parameters or reversible wallmotion abnormalities and Doppler coronary flow velocity reserve. Five hundred thirty patients who underwent SE for ischemia evaluation between 2010 and 2012 and who had rest images available were selected. Resting GLS was measured off-line (absolute value <15% was considered abnormal). Cox models were used to examine the association between clinical variables, ejection fraction, SE variables, and resting GLS with mortality and cardiac events (cardiac death and nonfatal myocardial infarction). The independent prognostic value of GLS over known rest and stress variables was assessed. Over a median follow-up of 7.5years, 137 patients died from any cause and 50 had a nonfatal myocardial infarction. Patients with resting GLS <15% had significantly lower event-free survival (log-rank P<.0001). Resting GLS was significantly associated with risk of all-cause death and hard cardiac events, after adjustment for clinical risk factors, reversible wall motion abnormalities, and coronary flow velocity reserve. Adding resting GLS into a model with clinical, rest, and stress imaging variables significantly increased the model C index (P=.031). In a large cohort of patients with suspected coronary artery disease referred for SE, resting GLS <15% was independently associated with mortality and hard cardiac events, incremental to SE data. Model discrimination including resting GLS measurement was comparable to discrimination including SE results.

Should L3 be selected as the lowest instrumented vertebra in patients with Lenke type 5C adolescent idiopathic scoliosis whose lowest end vertebra is L4?

L3 is most often selected as the lowest instrumented vertebra (LIV) to conserve mobile segments in fusion surgery; however, in cases with the lowest end vertebra (LEV) at L4, LIV selection as L3 could have a potential risk of correction loss and coronal decompensation. This study aimed to compare the clinical and radiographic outcomes depending on the LEV in adolescent idiopathic scoliosis (AIS) patients with Lenke type 5C curves. Data from 49 AIS patients with Lenke type 5C curves who underwent selective thoracolumbar/lumbar (TL/L) fusion to L3 as the LIV were retrospectively analyzed. The patients were classified according to their LEVs into L3 and L4 groups. In the L4 group, subanalysis was performed according to the upper instrumented vertebra (UIV) level toward the upper end vertebra (UEV and 1 level above the UEV [UEV+1] subgroups). Radiographic parameters and clinical outcomes were compared between these groups. Among 49 patients, 32 and 17 were in the L3 and L4 groups, respectively. The L4 group showed a lower TL/L curve correction rate and a higher subjacent disc angle postoperatively than the L3 group. Although no intergroup difference was observed in coronal balance (CB), the L4 group showed a significantly higher main thoracic (MT) and TL/L curve progression during the postoperative follow-up period than the L3 group. In the L4 group, the UEV+1 subgroup showed a higher absolute value of CB at 2 years than the UEV subgroup. In Lenke type 5C AIS patients with posterior selective TL/L fusion to L3 as the LIV, patients with their LEVs at L4 showed postoperative MT and TL/L curve progression; however, no significant differences were observed in global alignment and clinical outcome.

Global mean diffusivity: A radiomarker discriminating good outcome long term after traumatic brain injury.

Traumatic brain injury (TBI) is a chronic pathology responsible for cognitive disorders impacting outcome. Global clinical outcome several years after TBI may be associated with anatomical sequelae. Anatomical lesions are not well described because characterizing diffuse axonal injury and brain atrophy require using specific MRI sequences with quantitative measures. The best radiologic parameter to describe the lesions long term after TBI is not known. We aimed to first, assess the global volumetric and diffusion parameters related to long-term outcome after TBI and second, define the most discriminating parameter. In this observational study, we included 96 patients with severe TBI and 22 healthy volunteers. The mean delay after TBI was 63.2 months [range 31-119]. The Glasgow Outcome Scale Extended (GOS-E) was used to assess the global long-term clinical outcome. All patients underwent multimodal MRI with measures of brain volume, ventricle volume, global fractional anisotropy (FA) and global mean diffusivity (MD). All 96 participants had significant impairment in global FA, global MD, brain volume and ventricle volume as compared with the 22 controls (P<0.01). Only global MD significantly differed between the "good recovery" group (GOS-E score 7-8) and the other two groups: GOS-E scores 3-4 and 5-6. Brain volume significantly differed between the GOS-E 7-8 and 3-4 groups. Global MD was the most discriminating radiological parameter for the "good recovery" group versus other patients, long term after TBI. FA appeared less relevant at this time. Global atrophy was higher in patients than controls but lacked reliability to discriminate groups of patients. Global mean diffusivity seems a more promising radiomarker than global FA for discriminating good outcome long term after TBI. Further work is needed to understand the evolution of these long-term radiological parameters after TBI.

Transtubular Anterior Cervical Foraminotomy for the Treatment of Compressive Cervical Radiculopathy: Surgical Results and Complications in a Consecutive Series of Cases.

Study DesignThis was a retrospective review of patients with compressive cervical radiculopathy treated with a minimally invasive anterior cervical foraminotomy (ACF).PurposeThis study aimed to evaluate the results and complication rates of ACF in a consecutive series of patients and to report our clinical results of ACF as a minimally invasive technique in a series of 45 consecutive patients treated for compressive cervical radiculopathy.Overview of LiteratureACF is a motion-sparing procedure and an alternative to anterior cervical discectomy and fusion (ACDF) and posterior cervical foraminotomy for direct nerve root decompression in patients with compressive cervical radiculopathy.MethodsThe chart review recorded clinical and radiological features preoperatively and postoperatively and at follow-up (FU). The effect of prognostic factors was analyzed in relation to the clinical outcome.ResultsBetween January 2004 and October 2019, 45 patients (15 females and 30 males) with a mean age of 55.9 years (range, 28–78 years) underwent ACF for unilateral cervical radiculopathy. The global clinical outcome according to the MacNab scale was evaluated as excellent in 64.5% of patients (n=29), good in 28.9% (n=13), fair in 4.4% (n=2), and poor in 2.2% (n=1). The radiological FU was available for 73.3% (n=33). The statistical analysis revealed no influence of age, sex, operated level, and side on the clinical outcome. Only one patient (2.2%) exhibited spontaneous bone fusion at the operated level on FU after a right-sided C6–7 ACF with no clinical consequences. No patient presented with signs of delayed segmental instability. The overall reoperation rate of this series was 4.4%.ConclusionsACF is a feasible and low-cost alternative to ACDF in selected patients with cervical radiculopathy. The use of tubular retractors in ACF may confer an added advantage that creates a safe corridor for direct cervical root decompression yet minimizing surrounding soft tissue retraction and avoiding unnecessary bone removal.

Paediatric Brain Monitoring with Information Technology (KidsBrainIT) - ERA-NET NEURON Grant

Abstract The complete name of this ERA-NET NEURON Grant is “Paediatric Brain Monitoring with Information Technology (KidsBrainIT). Using IT Innovations to Improve Childhood Traumatic Brain Injury Intensive Care Management, Outcome, and Patient Safety”. The Project Coordinators are Ms. Dr. Tsz-Yan Milly Lo (Consultant Paediatric Intensivist and Research Lead in Paediatric Critical Care Medicine ) and Ian Piper from University of Edinburgh, UK and the partners are: Prof. Bart Depreitere and his team from Neurosurgery &amp; Intensive Care Research Group, University Hospitals Leuven, Belgium; Prof. Juan Sahuquillo and his team from Department of Neurosurgery, Vall d’Hebron University Hospital, Barcelona, Spain and the Romanian team with doctors CA Apetrei, C Gheorghita and A Tascu as principal investigators in three different hospitals. This material is based on the scientific project proposal with the basic project data. The aim of this grant is to test two clinically relevant hypotheses: after sustaining traumatic brain injury (TBI), paediatric patients with a longer period of measured cerebral perfusion pressure (CPP) maintained within the calculated optimal CPP (CPPopt) have an improved global clinical outcome and better tolerance against raised intracranial pressure (ICP). Paediatric TBI patients requiring intensive care are recruited from more contributing centres in 4 different countries. Their anonymised routinely collected bedside physiological monitoring data in minute-resolutions linking with anonmyised clinical and outcome data are exported and archived in the central KidsBrainIT data-bank. CPPopt is calculated and ICP dose-response analyses are performed on the KidsBrainIT dataset and their correlations with global outcome at 6 months are determined. The final aim of this study is to improve the treatments of the abnormal physiology insults: increase pressure from brain swelling (raised ICP) and brain perfusion pressure (CPP).

Spotlight on the December 12 issue

#### Notable in Neurology This issue features an article that discusses the possible compromising effect of continued drug shortages on patient care for neurologic conditions and another that validates optical coherence tomography as a multiple sclerosis monitoring tool. A featured article details the use of a composite motor, cognitive, and global functional clinical outcome measure in Huntington disease as an improved measure of clinical progression. ### Virtual Reality Training for Upper Extremity in Subacute Stroke (VIRTUES): A multicenter RCT![Graphic][1] Virtual reality (VR) is increasingly used … [1]: /embed/inline-graphic-1.gif

Motor, cognitive, and functional declines contribute to a single progressive factor in early HD.

To identify an improved measure of clinical progression in early Huntington disease (HD) using data from prospective observational cohort studies and placebo group data from randomized double-blind clinical trials. We studied Unified Huntington Disease Rating Scale (UHDRS) and non-UHDRS clinical measures and brain measures of progressive atrophy in 1,668 individuals with early HD followed up prospectively for up to 30 to 36 months of longitudinal clinical follow-up. The results demonstrated that a composite measure of motor, cognitive, and global functional decline best characterized clinical progression and was most strongly associated with brain measures of progressive corticostriatal atrophy. Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures.

Efficacy of Naltrexone for the Treatment of Alcohol Dependence in Latino Populations.

Naltrexone has been identified as a promising psychopharmacological treatment for alcohol dependence. Previous studies have suggested that its efficacy may vary based on ethnic background. The current study examined the efficacy of naltrexone in the treatment of alcohol dependence in Latino adults, a previously unexplored population. This was a secondary analysis of the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study. The overall COMBINE sample consisted of 1,383 adult participants who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for alcohol dependence, including 155 Latinos, who are the focus of this report. Consistent with the main trial, primary drinking outcomes, including percentage of days abstinent (PDA) and time to first heavy drinking day (TTHD), were examined. In addition, we examined the effects of naltrexone on a clinically relevant secondary outcome measure, global clinical outcome of alcohol consumption and alcohol-related problems. As seen with the subsample of African Americans from the COMBINE Study, results of the present analysis indicated that there were no significant effects of naltrexone on PDA and TTHD despite these significant effects in the original study. However, contrary to findings in the African American subsample, for Latino participants naltrexone was a significant predictor of a good global clinical outcome (i.e., abstinence or moderate drinking without problems). Naltrexone was not significantly associated with improvements in the primary drinking outcomes of PDA or TTHD at the end of treatment or at follow-up. However, Latinos appeared to benefit from naltrexone as demonstrated by improved ratings of global clinical outcome. These results indicate mixed findings for the efficacy of naltrexone among Latinos in the COMBINE Study.

Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from anationwide German registry (GRAID2)

The German Registry of Autoimmune Diseases2 (GRAID2) is aretrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62patients. In 19of these patients severe infections (30.6%) were documented, resulting in arate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.

Acute respiratory distress syndrome.

Since its first description, the acute respiratory distress syndrome (ARDS) has been acknowledged to be a major clinical problem in respiratory medicine. From July 2015 to July 2016 almost 300 indexed articles were published on ARDS. This review summarises only eight of them as an arbitrary overview of clinical relevance: definition and epidemiology, risk factors, prevention and treatment. A strict application of definition criteria is crucial, but the diverse resource-setting scenarios foster geographic variability and contrasting outcome data. A large international multicentre prospective cohort study including 50 countries across five continents reported that ARDS is underdiagnosed, and there is potential for improvement in its management. Furthermore, epidemiological data from low-income countries suggest that a revision of the current definition of ARDS is needed in order to improve its recognition and global clinical outcome. In addition to the well-known risk-factors for ARDS, exposure to high ozone levels and low vitamin D plasma concentrations were found to be predisposing circumstances. Drug-based preventive strategies remain a major challenge, since two recent trials on aspirin and statins failed to reduce the incidence in at-risk patients. A new disease-modifying therapy is awaited: some recent studies promised to improve the prognosis of ARDS, but mortality and disabling complications are still high in survivors in intensive care.

The Neurologic Assessment in Neuro-Oncology (NANO) scale: a tool to assess neurologic function for integration into the Response Assessment in Neuro-Oncology (RANO) criteria.

The Macdonald criteria and the Response Assessment in Neuro-Oncology (RANO) criteria define radiologic parameters to classify therapeutic outcome among patients with malignant glioma and specify that clinical status must be incorporated and prioritized for overall assessment. But neither provides specific parameters to do so. We hypothesized that a standardized metric to measure neurologic function will permit more effective overall response assessment in neuro-oncology. An international group of physicians including neurologists, medical oncologists, radiation oncologists, and neurosurgeons with expertise in neuro-oncology drafted the Neurologic Assessment in Neuro-Oncology (NANO) scale as an objective and quantifiable metric of neurologic function evaluable during a routine office examination. The scale was subsequently tested in a multicenter study to determine its overall reliability, inter-observer variability, and feasibility. The NANO scale is a quantifiable evaluation of 9 relevant neurologic domains based on direct observation and testing conducted during routine office visits. The score defines overall response criteria. A prospective, multinational study noted a >90% inter-observer agreement rate with kappa statistic ranging from 0.35 to 0.83 (fair to almost perfect agreement), and a median assessment time of 4 minutes (interquartile range, 3-5). The NANO scale provides an objective clinician-reported outcome of neurologic function with high inter-observer agreement. It is designed to combine with radiographic assessment to provide an overall assessment of outcome for neuro-oncology patients in clinical trials and in daily practice. Furthermore, it complements existing patient-reported outcomes and cognition testing to combine for a global clinical outcome assessment of well-being among brain tumor patients.

Assessing connectivity related injury burden in diffuse traumatic brain injury.

Many of the clinical and behavioral manifestations of traumatic brain injury (TBI) are thought to arise from disruption to the structural network of the brain due to diffuse axonal injury (DAI). However, a principled way of summarizing diffuse connectivity alterations to quantify injury burden is lacking. In this study, we developed a connectome injury score, Disruption Index of the Structural Connectome (DISC), which summarizes the cumulative effects of TBI-induced connectivity abnormalities across the entire brain. Forty patients with moderate-to-severe TBI examined at 3months postinjury and 35 uninjured healthy controls underwent magnetic resonance imaging with diffusion tensor imaging, and completed behavioral assessment including global clinical outcome measures and neuropsychological tests. TBI patients were selected to maximize the likelihood of DAI in the absence of large focal brain lesions. We found that hub-like regions, with high betweenness centrality, were most likely to be impaired as a result of diffuse TBI. Clustering of participants revealed a subgroup of TBI patients with similar connectivity abnormality profiles who exhibited relatively poor cognitive performance. Among TBI patients, DISC was significantly correlated with post-traumatic amnesia, verbal learning, executive function, and processing speed. Our experiments jointly demonstrated that assessing structural connectivity alterations may be useful in development of patient-oriented diagnostic and prognostic tools. Hum Brain Mapp 38:2913-2922, 2017. © 2017 Wiley Periodicals, Inc.

Abstract B25: Progressive epigenetic programming during B cell maturation yields a continuum of clonal disease phenotypes with distinct etiologies in chronic lymphocytic leukemia.

Abstract Knowledge of the cell-of-origin is essential for the full understanding of the causes of a malignant disease and for the rational design of targeted therapies. The B cell compartment is composed of a highly complex mixture of subtypes, each with distinct phenotypes and roles within the immune system. In chronic lymphocytic leukemia (CLL), heterogeneity in the biology and clinical course of the disease is thought to be linked to divergent cellular origins. We and others have previously shown that the epigenome of CLL, as measured by the global pattering of DNA methylation, is highly clonal and remarkably stable over time and thus represents a powerful approach to trace founder subtype populations. Here we combine epigenomic and transcriptomic analysis using next-generation sequencing approaches to compare CLL cells to highly purified and specific B cell subpopulations at various stages of maturation. We find that B cell maturation involves substantial unidirectional epigenetic programming that occurs as a continuum throughout the transition between naïve to fully-mature memory B cell subpopulations. Combining 258 CLL cases using Illumina 450K analysis reveals that all CLLs arise from a discrete window within the spectrum of B cell maturation that is more similar to mature B cells, with the majority of cases clustering at two distinct points correlating with unmutated IGHV versus highly mutated (&amp;lt;95% homology) IGHV genes; however, a significant number (~20%) of cases arise at various points between these two clusters. Next we show that using RNA-seq, broad differences in global expression patterns mirror the degree of epigenetic programming achieved by individual CLLs. Progressively further programming is paralleled by a transition from an aggressive to indolent expression pattern, indicated by the decrease in the expression levels of genes with known roles in promoting CLL cell survival, such as ZAP70, BTK, TCL1a, MCL1, miR-155 and others. Using DNA methylation and ChIP-seq data to compare the sequence and chromatin features of genomic regions that are programmed in normal B cell maturation versus CLL, reveals that although a myriad of transcription factors and pathways connected to immune cell function are involved in normal epigenetic programming in B cells, aberrant CLL-specific alterations involve excess activity of NFAT and EGR gene families and, paradoxically, a reduction of AP-1 activity. To further investigate the role of immediate-early genes, RNA-seq analysis of in vitro-activated CLL cells revealed a strong association between the degree of epigenetic programming and the specific inducibility of EGR2 and c-FOS, supporting a functional role of these genes in aberrant DNA methylation programming. Finally, in an independent clinically well-annotated cohort of 349 CLL cases, we demonstrate that the degree of epigenetic programming is significantly associated with time to treatment and overall survival in patients. Collectively, this work demonstrates that instead of a distinct cell(s)-of-origin, CLL is rather derived from a continuum of possible programming states, and that the degree of programming achieved by a particular CLL at the time of transformation dictates its global gene expression pattern and clinical outcome. Furthermore, a parallel assessment of B cell maturation with CLL development permits a refinement of the disease-specific, early molecular events, highlighting the dysregulation of particular transcription factors and pathways in the pathogenesis of aggressive versus indolent disease. Citation Format: Christopher C. Oakes, Marc Seifert, Assenov Yassen, Lei Gu, Martina Przekopowitz, Amy Ruppert, Andrius Serva, Sandra Koser, David Brocks, Daniel Lipka, Olga Bogatyrova, Daniel Mertens, Marc Zapatka, Peter Lichter, Hartmut Doehner, Ralf Kueppers, Thorsten Zenz, Stephan Stilgenbauer, John Byrd, Christoph Plass. Progressive epigenetic programming during B cell maturation yields a continuum of clonal disease phenotypes with distinct etiologies in chronic lymphocytic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B25.

Tratamiento de síntomas mixtos con antipsicóticos

Mixed states in bipolar disorder are highly prevalent, with a global worse clinical outcome and present difficulties in their diagnosis and treatment. Mood stabilizers may be insufficient for the treatment of these episodes, and addition of an antipsychotic may be required; use of antidepressants is discouraged. Efficacy data of antipsychotics in mixed episodes have been traditionally reported in conjunction with pure manic episodes. In this article, specific data concerning the efficacy of atypical antipsychotics when reported exclusively in mixed states are reviewed. Although all the atypical antipsychotics show efficacy on symptoms of manic polarity within mixed states, asenapine, olanzapine and ziprasidone show data regarding a greater efficacy on depressive symptoms. Further studies are required regarding the efficacy of these agents on mixed symptoms according to DSM-5.

FAME 2 global ischemic risk score and clinical outcome in patients with stable coronary disease receiving medical therapy alone

Purpose: We sought to investigate the relationship between global ischemia and clinical outcome in patients with stable coronary disease. Methods: This FAME 2 sub-analysis was conducted in 607 patients (pts) with at least one diseased major coronary artery, and receiving medical therapy (MT) alone (441 pts in the randomized trial and 166 pts with follow-up in the registry). We analyzed the rate of a composite of cardiovascular death, myocardial infarction, and ischemia-driven target lesion revascularization (MACE) in relation to a FAME 2 global ischemic risk score, defined as the sum of the individual risks of MACE for each target lesion and calculated as following: ∑1.3(1-FFRlesion)/0.05. Results: At least one MACE occurred in 95 pts (15.7%) at a median follow-up of 172 (80-284) days. Mean FAME 2 score was significantly higher in pts with MACE than in pts w/o MACE (16.2±18.7 vs. 9.4±12.1, p<0.0001). At multivariate Cox regression analysis (adjusted for age, hypertension, hypercholesterolemia, CCS class, silent ischemia and the number of vessel disease), FAME 2 score as a continuous variable was significantly associated with MACE (p=0.001, HR [95% CI]: 1.019 [0.008-0.030]). Kaplan-Meier analysis of 1-year MACE-free survival showed a significant difference between the three tertiles of the FAME 2 score (Log-rank 32.88, p<0.0001). Taking into account the localization of the stenotic segment, as weighted by the Leaman score, did not improve the predictive value of the FAME 2 score for MACE. Conclusions: The FAME 2 global ischemic risk score is an independent predictor of clinical outcome at 1-year follow-up. The data also suggest that, in the short term, the severity of ischemia (depth) is prognostically more important than its extent (breadth).

Prognostic role of immunohistochemical analysis of 5 mc in myelodysplastic syndromes

Aberrant DNA methylation at CpG islands within promoters is increasingly recognised as a common event in human cancers and has been associated with the silencing of important tumour suppressor genes. Epigenetic therapy using hypomethylating agents has demonstrated clinical effectiveness; the drugs azacitidine and decitabine have been approved for the treatment of MDS. We investigated the association between global DNA methylation and clinical outcome in MDS. We evaluated 134 MDS bone marrow trephine biopsies (BMTB) by immunohistochemistry and compared the results with those from an age-matched group of normal BMTB. Immunohistochemistry was performed on paraffin-embedded sections using the anti-5-methylcytosine (5mc) antibody. Our results showed that the 5mc immunostaining score (M-score) of patients with MDS was higher than those of normal controls and that overall survival significantly correlated with global DNA methylation, age and IPSS score. Therefore, we found that patients with high levels of methylation had a shorter median overall survival (OS) compared with patients with lower levels. These immunohistochemistry results were confirmed by analysing global DNA methylation on LINE-1 sequences using the COBRA method and pyrosequencing. This study reports that global DNA methylation detected by immunohistochemistry predicts OS in MDS.

The effects of drinking goal on treatment outcome for alcoholism.

It is well known to clinicians and researchers in the field of alcoholism that patients vary with respect to drinking goal. The objective in this study was to elucidate the contribution of drinking goal to treatment outcome in the context of specific behavioral and pharmacological interventions. Participants were 1,226 alcohol-dependent individuals enrolled in a large, multisite trial of combined behavioral intervention, acamprosate, and naltrexone. Drinking goal was coded as follows: (a) controlled drinking, (b) conditional abstinence, and (c) complete abstinence. Analysis revealed a main effect of drinking goal on percent days abstinent (p < .0001), days to relapse to heavy drinking (p < .0001), and global clinical outcome (p < .001). These results were such that a goal of complete abstinence was associated with the best outcomes, followed by conditional abstinence; controlled drinking was associated with the poorest outcomes. Conversely, a main effect of drinking goal was observed on drinks per drinking day (p < .01), such that controlled drinking was associated with fewer drinks per drinking day whereas complete abstinence was associated with the highest number of drinks per drinking day. Combined behavioral intervention performed better than medical management alone for participants whose drinking goal was not complete abstinence. These results suggest that drinking goal represents a highly predictive clinical variable and should be an integral part of the clinical assessment of patients with alcohol dependence. Assessment of patients' drinking goals may also help match patients to interventions best suited to address their goals and clinical needs.