Primary Treatment Target Research Articles

Clinical review on triglycerides.

Hypertriglyceridaemia is a common clinical problem. Epidemiologic and genetic studies have established that triglyceride-rich lipoproteins (TRL) and their remnants as important contributors to ASCVD while severe hypertriglyceridaemia raises risk of pancreatitis. While low-density lipoprotein is the primary treatment target for lipid lowering therapy, secondary targets that reflect the contribution of TRL such as apoB and non-HDL-C are recommended in the current guidelines. Reduction of severely elevated triglycerides is important to avert or reduce the risk of pancreatitis. Here we discuss interventions for hypertriglyceridaemia, including diet and lifestyle, established treatments such as fibrates and omega-3 fatty acid preparations and emerging therapies, including various biological agents.

TMOD-34. A RADIOMIC SIGNATURE OF INFILTRATION IN PERITUMORAL EDEMA PREDICTS SUBSEQUENT RECURRENCE IN GLIOBLASTOMA

Abstract BACKGROUND The malignant parenchyma in glioblastoma extends beyond the enhancing borders of tumor on postcontrast T1-weighted magnetic resonance imaging (MRI), which is the primary target of treatment. Such non-enhancing tumor invasion into the peri-tumoral edema (PED) is, however, not usually distinguishable on conventional MRI. The aim of this study was to evaluate pre-operative MRI in the PED to assess whether areas of tumor infiltration and early recurrence can be detected. METHODS A cohort of 90 de novo glioblastoma patients from a single institution (Penn) was selected. All included patients had preoperative multi-parametric MRI (mpMRI;T1,T1Gd,T2,T2-FLAIR,ADC), underwent initial gross-total-resection followed by standard chemoradiation, and had pathologically-confirmed recurrence. An extensive panel of handcrafted features, including shape, volume, intensity distributions, texture, was extracted from mpMRI scans. Predictive modeling for estimation of PED infiltration was performed using sequential feature selection approach designed with a support vector machine classifier and through a Leave-one-out cross-validation approach in the Penn cohort. Generalizability of the model was evaluated by applying it on a cohort of 20 patients from a second institution (Case), and predicted probability distributions in PED were compared in both the cohorts. RESULTS Spatial probability maps, representing the likelihood of tumor infiltration and eventual recurrence, were binarized at 50% cutoff, and compared with actual recurrence on post-recurrence scans. The cross-validated accuracy of our model within Penn cohort was 81.35% (odds-ratio=3.62, sensitivity/specificity=78.26/81.35). The model trained on the Penn cohort, when applied on the Case cohort, produced almost similar intensity distribution in the PED, suggesting that the method has potential for robust performance across institutions. The comparison of intensity distributions revealed higher ADC and T2-FLAIR in non-recurrent regions compared to recurrent ones. CONCLUSION Multi-parametric pattern analysis of mpMRI across multiple institutions generates similar, accurate estimates of spatial extent and patterns of recurrence in PED, which may guide strategies for treatment intensification in glioblastoma.

Abstract 249: ERBB2 and beta-1-Adrenergic Receptor Cross-talk Underlies Cardiac Dysfunction

ERBB2 is a member of the EGFR growth factor receptor family and a primary target for anti-cancer treatment in patients diagnosed with breast cancer. ERBB2 targeting is known to cause cardiotoxicity, resulting in cardiac dilation while, less is understood about the underlying mechanisms. Studies have shown a direct co-relationship between beta2-adrenergic receptors (β2ARs) and ERBB2 in the cardiac hypertrophy wherein increased ERBB2 expression is associated with elevated β2ARs. Given the key role of β1ARs in cardiac function, we assessed potential cross-talk between ERBB2 and β1ARs. Towards this end, we have used a transgenic mouse model of cardiomyocyte-specific overexpression of microRNA-7 (miR-7 Tg) that abrogates ERBB2 expression in the adult cardiomyocytes and associated with cardiac dilation. Radio-ligand binding in miR-7 Tg hearts showed selective increase in β1AR density with no changes in the β2ARs. In contrast, cardiomyocyte-specific overexpression of ERBB2 results cardiac hypertrophy and is associated with significant increase in β2AR density with no changes in β1ARs. These observations show that ERBB2 expression may differentially regulate β1AR versus β2AR providing a unique role for ERBB2 in cardiac physiology. Further, ERBB2 expression is elevated in an age-dependent manner in C57BL6 mice that may account for hypertrophic response. Consistently, miR-7 Tg mice have age-dependent cardiac dilation consistent with the loss in the ERBB2 expression. To test for such a role, C57BL6 mice were administered vehicle, AG1875 (EGFR inhibitor) or AG825 (ERBB2 inhibitor) for two weeks to assess for changes in cardiac function. Administration of AG825 resulted significant cardiac dysfunction and dilation compared to AG1875 or vehicle controls, conferring the idea that inhibition of ERBB2 and not EGFR that mediates deleterious remodeling. Proteomic analysis showed dramatic differences in the associated proteins following AG825 compared to vehicle or AG1478 and our presentation will elucidate the results on how homeostatic ERBB2 signaling and expression is key for cardiac function and how chemotherapeutic inhibition of ERBB2 underlies deleterious pathways leading to cardiotoxicity.

Suboptimal lipid levels in clinical practice among Portuguese adults with dyslipidemia under lipid-lowering therapy: Data from the DISGEN-LIPID study

IntroductionCardiovascular disease (CVD) is the leading cause of morbidity and mortality in Portugal. Hypercholesterolemia has a causal role in atherosclerotic CVD. Guidelines recommend that cardiovascular (CV) risk reduction should be individualized and treatment goals identified. Low-density lipoprotein cholesterol (LDL-C) is the primary treatment target. MethodsDISGEN-LIPID was a cross-sectional observational study conducted in 24 centers in Portugal in dyslipidemic patients aged ≥40 years, on lipid-lowering therapy (LLT) for at least three months and with an available lipid profile in the previous six months. ResultsA total of 368 patients were analyzed: 48.9% men and 51.1% women (93.9% postmenopausal), of whom 73% had a SCORE of high or very high CV risk. One quarter had a family history of premature CVD; 31% had diabetes; 26% coronary heart disease; 9.5% cerebrovascular disease; and 4.1% peripheral arterial disease. Mean baseline lipid values were total cholesterol (TC) 189 mg/dl, LDL-C 116 mg/dl, high-density lipoprotein cholesterol (HDL-C) 53.5 mg/dl, and triglycerides (TG) 135 mg/dl. Women had higher TC (p<0.001), LDL-C (non-significant) and HDL-C (p<0.001), and lower TG (p=0.002); 57% of men and 63% of women had LDL-C>100 mg/dl (p=0.28), and 58% of men and 47% of women had LDL-C>70 mg/dl (p=0.933). ConclusionThese observational data show that, despite their high-risk profile, more than half of patients under LLT, both men and women, did not achieve the recommended target levels for LDL-C, and a large proportion also had abnormal HDL-C and/or TG. This is a renewed opportunity to improve clinical practice in CV prevention.

Abstract 1015: Molecular dissection of androgen receptor signaling in prostatic endothelial, epithelial, and stromal cells

Abstract Introduction and objectives: Androgen receptor (AR) is involved in development prostate cancer (CaP), and is a primary target for treatment of CaP. Androgen deprivation therapy (ADT) inhibits AR signaling by reducing AR ligands and/or blocking AR-ligand binding. ADT induces apoptosis of both endothelial cells and epithelial cells of human prostate, with apoptosis of endothelial cells preceding the apoptosis of epithelial cells. Further, the AR response to stimulation by androgen also differs between the 2 cell types. The current understanding of AR signaling was gained predominantly using CaP cell lines and samples prepared from whole tissue specimens. The present study sought to delineate AR signaling specifically in endothelial, epithelial, and stromal cells isolated from fresh clinical prostate tissue specimens and primary xenografts of human prostate tissue. Our results reveal the potentially different roles of AR signaling in different human prostate cell compartments, how AR regulates normal differentiated cell functions, and the biological consequences of ADT. Methods: Prostate tissue remnants were transplanted to male nude mice that were castrated and implanted with a sustained delivery device to maintain testosterone at human plasma levels. Endothelial and epithelial cells of both fresh prostate tissue and prostate tissue xenografts were isolated sequentially using magnetic beads conjugated with an antibody specific to epithelial cell or endothelial cell surface markers; the remaining cell fraction was defined as stromal cells. Transcriptomes were obtained using RNASeq, and were analyzed for differential expression of AR-regulated genes, AR co-regulators, and androgen metabolism enzymes. Results: Antibody-mediated cell type-specific enrichment isolated effectively the 3 cell types from the prostate from 16 patients. Among 1263 AR-regulated genes, 399, 313, and 223 were predominantly expressed in epithelial, endothelial or stromal cells, respectively. Among 179 AR co-regulators, 26, 26, and 18 were expressed predominantly in epithelial, endothelial or stromal cells, respectively. Among 128 potential androgen metabolic enzyme genes, 42, 15, and 12 were expressed predominantly in epithelial, endothelial or stromal cells, respectively. Conclusions: Differences in expression of genes associated with AR-mediated trans-regulation were apparent between the different cell types of prostate, whereas, the difference in expression of androgen metabolism genes was less striking. Therefore, the organ level outcome of ADT can only be understood by determining the response of the different cell types in CaP tissue. Citation Format: Nelson T. Gross, Jianming Wang, Gary Smith, Yue Wu. Molecular dissection of androgen receptor signaling in prostatic endothelial, epithelial, and stromal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1015.

Editor's Note: Genomic and Molecular Characterization of Malignant Peripheral Nerve Sheath Tumor Identifies the IGF1R Pathway as a Primary Target for Treatment.

Editor's Note: Genomic and Molecular Characterization of Malignant Peripheral Nerve Sheath Tumor Identifies the IGF1R Pathway as a Primary Target for Treatment.

Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance

Ischemic stroke is caused by a thromboembolic occlusion of cerebral arteries. Treatment is focused on fast and efficient removal of the occluding thrombus, either via intravenous thrombolysis or via endovascular thrombectomy. Recanalization, however, is not always successful and factors contributing to failure are not completely understood. Although the occluding thrombus is the primary target of acute treatment, little is known about its internal organization and composition. The aim of this study, therefore, was to better understand the internal organization of ischemic stroke thrombi on a molecular and cellular level. A total of 188 thrombi were collected from endovascularly treated ischemic stroke patients and analyzed histologically for fibrin, red blood cells (RBC), von Willebrand factor (vWF), platelets, leukocytes and DNA, using bright field and fluorescence microscopy. Our results show that stroke thrombi are composed of two main types of areas: RBC-rich areas and platelet-rich areas. RBC-rich areas have limited complexity as they consist of RBC that are entangled in a meshwork of thin fibrin. In contrast, platelet-rich areas are characterized by dense fibrin structures aligned with vWF and abundant amounts of leukocytes and DNA that accumulate around and in these platelet-rich areas. These findings are important to better understand why platelet-rich thrombi are resistant to thrombolysis and difficult to retrieve via thrombectomy, and can guide further improvements of acute ischemic stroke therapy.

Statins in Ischemic Stroke Prevention: What Have We Learned in the Post-SPARCL (The Stroke Prevention by Aggressive Reduction in Cholesterol Levels) Decade?

We describe the current status of lipid-lowering therapies for ischemic stroke prevention. The SPARCL trial published in 2006 has been a landmark study in vascular neurology. The trial demonstrated that high-dose atorvastatin prevents recurrent stroke, and led the AHA/ASA to recommend statin therapy for patients with stroke or TIA of atherosclerotic origin. Recently, the J-STARS study demonstrated that therapy with low-dose pravastatin reduced atherothrombotic infarction incidence among patients with prior ischemic stroke. Besides, several trials have shown improved stroke outcomes with non-statin lipid-lowering medications: IMPROVE-IT with ezetimibe on top of simvastatin and PCSK9 inhibitors-FOURIER with evocolumab and ODYSSEY-OUTCOMES with alirocumab-on top of statin therapy. LDL-cholesterol remains the primary lipid treatment target for reduction of stroke risk. Randomized trials have shown that each reduction of 40mg/dL in the level of LDL-cholesterol reduces the stroke risk by approximately one quarter, and further, reductions in LDL-cholesterol levels have shown to produce additional reductions in stroke risk. Currently, we have evidence of benefit for adding non-statin lipid-modifying therapies to statins to reduce stroke risk. Surely, these novel strategies to reduce residual lipidic risk will provide future benefits on stroke prevention.

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature.

Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein–coupled receptors (GPCRs) called somatostatin receptor (SST)1–5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.

Nouvelles recommandations sur la prise en charge des dyslipidémies: Comparaison des recommandations françaises de la HAS et des recommandations européennes ESC/EAS

Total cardiovascular risk estimation using a system such as SCORE is recommended for adults>40years of age without evidence of cardiovascular disease, diabetes, chronic kidney disease, severe hypertension or familial hypercholesterolemia. Before treatment, a full lipid profile is recommended, fasting in French guidelines, fasting or non-fasting in European guidelines. LDL-C has to be used as the primary target for treatment. For patients with elevated triglycerides, non-HDL-C level is also recommended as the secondary goal for treatment. In patients at very high and high cardiovascular risk, LDL-C goals are respectively below<0.70g/L and<1.0g/L. For subjects at very high and high cardiovascular risk, French guidelines do not mention that a≥50% reduction in LDL-C should be achieved. Statins are the treatment of choice to reach LDL-C goals. If the goal is not reached on maximally tolerated dose of statin, combination with another LDL lowering drug, mainly ezetimibe, is recommended. Fibrates are mainly proposed for patients with severe hypertriglyceridemia (TG>5g/L after lifestyle changes).

Simultaneous upper and lower limb abobotulinumtoxinA injections and guided self-rehabilitation contracts in spastic hemiparesis: Baseline data from the engage study

Guided self-rehabilitation contracts (GSC) are a diary-based and antagonist-targeting strategy, in which therapists identify muscles against which to prescribe patients daily, home-based self-stretching and active training programmes. Patients record a diary of exercises performed between visits. The ENGAGE study assesses effects of abobotulinumtoxinA (aboBoNT-A) on voluntary movements, following co-injection of upper (UL) and lower limbs (LL), alongside GSC in patients with chronic hemiparesis resulting from acquired brain injury. An interim analysis of ENGAGE baseline data is presented here. International phase 3b/4, prospective, single-arm, open-label study ( NCT02969356 ). Patients, stratified with UL or LL as primary treatment target (PTT), receive two consecutive injections of aboBoNT-A 1500 U, together with personalised GSC. Primary efficacy endpoint is the proportion of responders (improvement in composite active range of motion [CX A ] of ≥ 35° or 5° in UL or LL, respectively) in the PTT at Cycle 2 Week 6. Baseline data were analysed for 157 patients (data cut-off December 2017). Baseline characteristics are presented in Table 1 ; 91% of patients had experienced stroke; mean time since brain injury was 79.5 months. PTT split was 52% versus 48% for UL and LL, respectively. Twenty-seven percent of patients were naïve to botulinum toxin (BoNT) for both UL and LL spasticity (34% UL-naïve; 58% LL-naïve), and 74% were naïve to GSC. Baseline BoNT doses administered are shown in Table 2 . Degree of CX A in UL or LL at baseline are presented in Table 3 . The ENGAGE study will provide insights into the safety and efficacy of the combination of GSC with aboBoNT-A, simultaneously injected into UL and LL, in adults with spastic hemiparesis.

Antihypertensive therapy in chronic kidney disease: what targets and how to reach them

Antihypertensive therapy in chronic kidney disease: what targets and how to reach them Abstract. The primary treatment target for lowering cardiovascular risk in chronic renal failure (as well as in the general hypertensive population) is to lower sitting office blood pressure. Since the physiological nocturnal blood pressure drop ("dipping") is frequently absent or even reversed in chronic renal failure (occasionally causing nocturnal blood pressures to be higher than at daytime), 24 hour blood pressure monitoring needs to be liberally used. Systolic office blood pressures should be 130 to 139 mm Hg, diastolic 80 to 89 mm Hg, and 24 hour blood pressures 10 mm Hg lower. In kidney diseases with relevant proteinuria (> 0.5 - 1.0 g / 24 h) and in diabetics with microalbuminuria (> 30 mg / 24 h), proteinuria reduction is an important second treatment goal, because this slows progressive loss of renal function. If there still is relevant proteinuria or (in diabetics, microalbuminuria) after reaching "cardiovascular" blood pressure goals, further lowering of blood pressure below 130 mm Hg systolic should be attempted, if tolerated. Orthostasis, syncope and diastolic blood pressures < 70 mm Hg must by all means be avoided. In addition, there is no demonstrable benefit of lowering systolic blood pressure < 130 mm Hg if eGFR is < 20 ml / min / 1.73 m2. Since intake and excretion of sodium chloride play a central role in the pathogenesis of hypertension in renal failure, habitual salt overconsumers (taking more than approximately 9 g NaCl / 24 h) need to reduce their intake. For the same reason, diuretics are mandatory components of antihypertensive treatment in chronic renal failure, even if there are no signs of volume expansion at all. At eGFRs < 30 ml / min / 1.73 m2, thiazide type diuretics should replaced or supplemented by loop diuretics (e. g. torasemide). SGLT2 inhibitors are adjuvant diuretics in diabetics with an eGFR > 30 ml / min / 1.73 m2. ACE inhibitors or angiotensin 2 receptor antagonists are only mandatory if proteinuria exceeds 0.5 to 1.0 g / 24 h (or in diabetics with microalbuminuria), but not generally in chronic renal failure. At least two antihypertensive drugs are almost always required; at least one should be taken in the evening.

Patterns and Predictors of Tic Suppressibility in Youth With Tic Disorders.

Tic suppression is the primary target of tic disorder treatment, but factors that influence voluntary tic inhibition are not well understood. Several studies using the Tic Suppression Task have demonstrated significant inter-individual variability in tic suppressibility but have individually been underpowered to address correlates of tic suppression. The present study explored patterns and clinical correlates of reward-enhanced tic suppression in youth with tic disorders using a large, pooled dataset. Individual-level data from nine studies using the Tic Suppression Task were pooled, yielding a sample of 99 youth with tic disorders. Analyses examined patterns of tic suppressibility and the relationship between tic suppressibility and demographic and clinical characteristics. A large majority of youth demonstrated a high degree of tic suppression, but heterogeneous patterns of tic suppressibility were also observed. Better tic suppressibility was related to older age and more frequent tics but unrelated to other clinical variables, including presence of psychiatric comorbidity, psychotropic medication status, tic and premonitory urge severity, and self-rated tic suppressibility. The mechanisms underlying the observed heterogeneity in reward-enhanced tic suppressibility warrant further investigation. The Tic Suppression Task is a promising method for testing mechanistic hypotheses related to tic suppression.

Astragaloside IV inhibits ventricular remodeling and improves fatty acid utilization in rats with chronic heart failure.

Chronic heart failure (CHF) is the end-stage of many cardiovascular diseases and severely affects the patients’ lifespan. Inhibiting ventricular remodeling is thus a primary treatment target for CHF patients. Astragaloside IV (AS-IV) can improve cardiac function and protect myocardial cells. The study aims to investigate the effects of AS-IV on ventricular remodeling and explore its role in regulating energy metabolism using a rat CHF model. Sprague–Dawley rats were divided into five groups (n=20 per group): CHF + benazepril hydrochloride (Benazepril HCL), CHF + low-dose (30 mg.kg−1.day−1) AS-IV, CHF + high-dose (60 mg.kg−1.day−1) AS-IV, and a sham control group. After 8 weeks of treatment, the cardiac structure and functional parameters were measured. Morphological changes in the myocardial tissue in five groups were evaluated. Protein and mRNA expression of peroxisome proliferator-activated receptor α (PPARα), medium-chain acyl-CoA dehydrogenase (MCAD), and muscle carnitine palmitoyl transferase-1 (MCPT1) were also analyzed. Our results showed that the left ventricular mass index (LVMI), collagen volume fraction (CVF), and free fatty acid (FFA) concentration of CHF group rats increased when compared with sham control group, while the protein and mRNA expressions of PPARα, MCAD, and MCPT1 decreased in CHF. Importantly, treatment with AS-IV (CHF + AS-IV group) showed improved heart function and structure, increased expression of PPARα, MCAD, and MCPT1 and improved FFA utilization in comparison with CHF group. In conclusion, our study shows that AS-IV inhibits ventricular remodeling, improves cardiac function, and decreases FFA concentration of CHF model rats. Our findings suggest a therapeutic potential of using AS-IV in CHF.

Using Contact Patterns to Inform HIV Interventions in Persons Who Inject Drugs in Northern Vietnam.

Population mixing patterns can greatly inform allocation of HIV prevention interventions such as treatment as prevention or preexposure prophylaxis. Characterizing contact patterns among subgroups can help identify the specific combinations of contact expected to result in the greatest number of new infections. Baseline data from an intervention to reduce HIV-related risk behaviors in male persons who inject drugs (PWID) in the Northern Vietnamese province of Thai Nguyen were used for the analysis. Egocentric network data were provided by PWID who reported any drug-injection equipment sharing in the previous 3 months. Age-dependent mixing was assessed to explore its epidemiological implications on risk of HIV transmission risk (among those HIV-infected) and HIV acquisition risk (among those not infected) in PWID. A total of 1139 PWID collectively reported 2070 equipment-sharing partnerships in the previous 3 months. Mixing by age identified the 30-34 and 35-39 years age groups as the groups from whom the largest number of new infections was transmitted, making them primary targets for treatment as prevention. Among the uninfected, 25-29, 30-35, and 35-39 years age groups had the highest HIV acquisition rate, making them the primary targets for preexposure prophylaxis. Collection and analysis of contact patterns in PWID is feasible and can greatly inform infectious disease dynamics and targeting of appropriate interventions. Results presented also provide much needed empirical data on mixing to improve mathematical models of disease transmission in this population.

Core psychopathology in anorexia nervosa and bulimia nervosa: A network analysis.

The cognitive-behavioral theory of eating disorders (EDs) proposes that shape and weight overvaluation are the core ED psychopathology. Core symptoms can be statistically identified using network analysis. Existing ED network studies support that shape and weight overvaluation are the core ED psychopathology, yet no studies have estimated AN core psychopathology and concerns exist about the replicability of network analysis findings. The current study estimated ED symptom networks among people with anorexia nervosa (AN) and bulimia nervosa (BN) and among a combined group of people with AN and BN. Participants were girls and women with AN (n = 604) and BN (n = 477) seeking residential ED treatment. ED symptoms were assessed with the Eating Disorder Examination-Questionnaire (EDE-Q); 27 of the EDE-Q items were included as nodes in symptom networks. Core symptoms were determined by expected influence and strength values. In all networks, desiring weight loss, restraint, shape and weight preoccupation, and shape overvaluation emerged as the most important symptoms. In addition, in the AN and combined networks, fearing weight gain emerged as an important symptom. In the BN network, weight overvaluation emerged as another important symptom. Findings support the cognitive-behavioral premise that shape and weight overvaluation are at the core of AN psychopathology. Our BN and combined network findings provide a high degree of replication of previous findings. Clinically, findings highlight the importance of considering shape and weight overvaluation as a severity specifier and primary treatment target for people with EDs.

S203. COMPENSATORY COGNITIVE APPROACHES TO IMPROVING FUNCTIONING IN PSYCHOSIS: SYSTEMATIC REVIEW AND META-ANALYSIS

BackgroundCognitive impairments in domains such as attention, memory, processing speed and executive functions are a central feature of psychotic disorders that have significant negative consequences for daily functioning, including activities of daily living, social and vocational roles. Compensatory approaches aim to minimise the impact of cognitive impairment on daily functioning through the use of aids or strategies to reduce cognitive load, in much the same way as glasses reduce the impact of vision impairment. The primary treatment target is real world community functioning and functional capacity, rather than cognition. There is now a need to synthesise the available evidence in this field so that treatment recommendations and future research directions can be better informed. A large body of research into compensatory approaches to cognition in psychosis exists, but this has never been comprehensively synthesised. The aim of this systematic review and meta-analysis is to examine the effects of compensatory approaches for cognitive deficits in psychotic disorders on i) functional outcomes and ii) other outcomes such as symptoms and quality of life.MethodsA systematic review and meta-analysis was conducted according to PRISMA guidelines. PsycINFO and MEDLINE electronic databases were searched from inception to October 2017 using multiple terms for ‘psychosis’, ‘cognition’ and ‘compensatory’. All papers retrieved from this search were double-screened and final inclusion/exclusion was determine by consensus. Data were double-extracted and risk of bias rated by two independent authors. Meta-analysis only included randomised-controlled trials. Standardised Mean Differences (SMD) were calculated to produce a single summary estimate using the random-effects model with 95% Confidence Intervals using Comprehensive Meta-Analysis (CMA) software. When means or standard deviations were not reported in the original articles, SMDs were calculated from data provided by the study authors.Results2192 articles were identified via electronic and manual searches. Forty-two papers describing 40 independent studies were included in the review: case studies (n=4), case series (n=2), uncontrolled single arm pilot studies (n=5), within-subjects designs (n=1), quasi-randomised trials (n=2), and randomised controlled trials (n=26). The types of compensatory interventions included environmental adaptation and supports, internal and external self-management strategies, and errorless learning. Compensatory interventions were associated with improvements in global functioning post intervention (N=1,449; SMD=0.506; 95%CI=0.347, 0.665; p<.001). Improvements in global symptoms (N=849; SMD=-0.297; 95%CI=-0.484, -0.111; p=.002) and positive symptoms (N=784; SMD=-0.227; 95%CI=-0.416, -0.038; p=.018) were also found. Compensatory interventions were not associated with improvements in negative symptoms (N=736; SMD=-0.162; 95%CI=-0.382, 0.058; p=.150). The heterogeneity of findings was low.DiscussionCompensatory approaches are effective for improving functioning in psychosis, with a medium effect size. General symptoms and positive symptoms appear to benefit from compensatory approaches, but compensatory approaches are not effective for improving negative symptoms. Future analyses will examine the durability of effects, effects of study quality and moderating factors such as pure vs. partially compensatory, treatment intensity/length, mode of delivery (group vs. individual), baseline functioning level and age of participants.

Dialectical Behavior Therapy Is Effective for the Treatment of Suicidal Behavior: A Meta-Analysis

Dialectical Behavior Therapy (DBT) prioritizes suicidal behavior and other self-directed violence as the primary treatment targets, and has been demonstrated to reduce self-directed violence in clinical trials. This paper synthesizes findings from controlled trials that assessed self-directed violence and suicidality, including suicide attempts, non-suicidal self-injury (NSSI), suicidal ideation, and accessing psychiatric crisis services. Eighteen controlled trials of DBT were identified. Random effects meta-analyses demonstrated that DBT reduced self-directed violence (d = -.324, 95% CI = -.471 to -.176), and reduced frequency of psychiatric crisis services (d = -.379, 95% CI = -.581 to -.176). There was not a significant pooled effect of DBT with regard to suicidal ideation (d = -.229, 95% CI = -.473 to .016). Our findings may reflect the prioritization of behavior over thoughts within DBT, and offer implications for clinical practice and future research concerning the implementation of DBT for acute suicidality.

Anti-Trop2 blockade enhances the therapeutic efficacy of ErbB3 inhibition in head and neck squamous cell carcinoma

ErbB3 has been widely implicated in treatment resistance, but its role as a primary treatment target is less clear. Canonically ErbB3 requires EGFR or ErbB2 for activation, whereas these two established treatment targets are thought to signal independently of ErbB3. In this study, we show that ErbB3 is essential for tumor growth of treatment-naive HNSCC patient-derived xenografts. This ErbB3 dependency occurs via ErbB3-mediated control of EGFR activation and HIF1α stabilization, which require ErbB3 and its ligand neuregulin-1. Here, we show that ErbB3 antibody treatment selects for a population of ErbB3-persister cells that express high levels of the transmembrane protein Trop2 that we previously identified as an inhibitor of ErbB3. Co-treatment with anti-ErbB3 and anti-Trop2 antibodies is synergistic and produces a greater anti-tumor response than either antibody alone. Collectively, these data both compel a revision of ErbB-family signaling and delineate a strategy for its effective inhibition in HNSCC.

The Complementary Role of Imaging and Tumor Biomarkers in Gynecological Cancers: An Update of the Literature

Gynecological tumors, including endometrial, cervical and ovarian cancer, have increased in incidence over time. The widespread introduction of screening programs and advances in diagnostic imaging methods has lead to a progressive increase in gynecological cancer detection. Accurate diagnosis and proper monitoring of disease remain the primary target for a successful treatment. In the last years, knowledge about cancer biomarkers has considerably increased providing great opportunities for improving cancer detection and treatment. In addition, in the last few years there has been an important development of imaging techniques. Nowadays, a multimodal approach including the evaluation of serum tumor biomarkers combined with imaging techniques, seems to be the best strategy for assessing tumor presence, spread, recurrence, and/or the response to treatment in female cancer patients In this review we provide an overview of the application of biomarkers combined with novel imaging methods and highlight their roles in female cancer diagnosis and follow-up.