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The Carillon Mitral Contour System has been studied in 3 nonrandomized trials in patients with symptomatic congestive heart failure and functional mitral regurgitation. The REDUCE FMR study is a uniquely designed, double-blind trial evaluating the impact of the Carillon device on reducing regurgitant volume, as well as assessing the safety and clinical efficacy of this device. Carillon is a coronary sinus-based indirect annuloplasty device. Eligible patients undergo an invasive venogram to assess coronary sinus vein suitability for the Carillon device. If the venous dimensions are suitable, they are randomized on a 3:1 basis to receive a device or not. Patients and assessors are blinded to the treatment assignment. The primary end point is the difference in regurgitant volume at 1 year between the implanted and nonimplanted groups. Other comparisons include clinical parameters such as heart failure hospitalizations, 6-minute walk test, Kansas City Cardiomyopathy Questionnaire (KCCQ), and other echocardiographic parameters. An exercise echo substudy will also be included. [ABSTRACT FROM AUTHOR]

Objectives This study sought to investigate the association of exercise intolerance in type 2 diabetes (T2DM) with skeletal muscle capillary blood flow (CBF) reserve. Background Exercise intolerance in T2DM strongly predicts adverse prognosis, but associations with muscle blood flow independent of cardiac dysfunction are undefined. Methods In 134 T2DM patients without cardiovascular disease, left ventricular function and contrast-enhanced ultrasound of the quadriceps (for CBF; i.e., product of capillary blood volume and velocity) were assessed at rest and immediately following treadmill exercise for peak oxygen uptake (V o 2peak ). Left ventricular systolic and diastolic functional reserve indexes were derived from changes in systolic and early diastolic color tissue Doppler velocities. Cardiac index reserve and its constituents (stroke volume and chronotropic indexes) and left ventricular filling pressure (ratio of early diastolic mitral inflow and annular velocities) were also measured. Results V o 2peak correlated with muscle CBF reserve ( β = 0.16, p = 0.005) independent of cardiac index reserve and clinical covariates. This was explained by higher muscle capillary blood velocity reserve ( β = 0.18, p = 0.002), rather than blood volume reserve (p > 0.10) in patients with higher V o 2peak . A concurrent association of V o 2peak with cardiac index reserve ( β = 0.20, p < 0.001) appeared to reflect chronotropic index ( β = 0.15, p = 0.012) rather than stroke volume index reserve (p > 0.10), although the systolic functional reserve index was also identified as an independent correlate ( β = 0.16, p = 0.028). No associations of V o 2peak with diastolic functional reserve were identified (p > 0.10). Conclusions V o 2peak is associated with muscle CBF reserve in T2DM, independent of parallel associations with cardiac functional reserve. This is consistent with a multifactorial basis for exercise intolerance in T2DM. [ABSTRACT FROM AUTHOR]

IGF-1R inhibitors arrived in the clinic accompanied by optimism based on preclinical activity of IGF-1R targeting, and recognition that low IGF bioactivity protects from cancer. This was tempered by concerns about toxicity to normal tissue IGF-1R and cross-reactivity with insulin receptor (InsR). In fact, toxicity is not a show-stopper; the key issue is efficacy. While IGF-1R inhibition induces responses as monotherapy in sarcomas and with chemotherapy or targeted agents in common cancers, negative Phase 2/3 trials in unselected patients prompted the cessation of several Pharma programs. Here, we review completed and on-going trials of IGF-1R antibodies, kinase inhibitors and ligand antibodies. We assess candidate biomarkers for patient selection, highlighting the potential predictive value of circulating IGFs/IGFBPs, the need for standardized assays for IGF-1R, and preclinical evidence that variant InsRs mediate resistance to IGF-1R antibodies. We review hypothesis-led and unbiased approaches to evaluate IGF-1R inhibitors with other agents, and stress the need to consider sequencing with chemotherapy. The last few years were a tough time for IGF-1R therapeutics, but also brought progress in understanding IGF biology. Even failed studies include patients who derived benefit; they should be investigated to identify features distinguishing the tumors and host environment of responders from non-responders. We emphasize the importance of incorporating biospecimen collection into trial design, and wording patient consents to allow post hoc analysis of trial material as new data become available. Such information represents the key to unlocking the potential of this approach, to inform the next generation of trials of IGF signalling inhibitors. [ABSTRACT FROM AUTHOR]

Objective Autonomic dysfunction may contribute to the etiology and exercise intolerance of subclinical diabetic heart disease. This study sought the efficacy of exercise training for improvement of peak oxygen uptake (VO2peak) and cardiac autonomic function in type 2 diabetic patients with non-ischemic subclinical left-ventricular (LV) dysfunction. Materials/Methods Forty-nine type 2 diabetic patients with early diastolic tissue Doppler velocity > 1 standard deviation below the age-based mean entered an exercise intervention (n = 24) or usual care (n = 25) for 6-months (controlled, pre-/post- design). Co-primary endpoints were treadmill VO2peak and 5-min heart-rate variability (by the coefficient of variation of normal RR intervals [CVNN]). Autonomic function was additionally assessed by resting heart-rate (for sympathovagal balance estimation), baroreflex sensitivity, cardiac reflexes, and exercise/recovery heart-rate profiles. Echocardiography was performed for LV function (systolic/diastolic tissue velocities, myocardial deformation) and myocardial fibrosis (calibrated integrated backscatter). Results VO2peak increased by 11% during the exercise intervention (p = 0.001 vs.--1% in controls), but CVNN did not change (p = 0.23). Reduction of resting heart-rate in the intervention group (p < 0.05) was associated with an improvement in the secondary endpoint of heart-rate variability total spectral power (p < 0.05). However, baroreflex sensitivity, cardiac reflexes, and exercise/recovery heart-rate profiles showed no significant benefit. No effects on LV function were observed despite favorable reduction of calibrated integrated backscatter in the intervention group (p < 0.05). Conclusions The exercise intolerance of subclinical diabetic heart disease was amenable to improvement by exercise training. Despite a reduction in resting heart-rate and potential attenuation of myocardial fibrosis, no other cardiac autonomic or LV functional adaptations were detected. [ABSTRACT FROM AUTHOR]

Abstract: Background: The development of predictive biomarkers for IGF targeted anti-cancer therapeutics remains a critical unmet need. The insulin receptor A isoform (InsR-A) has been identified as a possible biomarker candidate but quantification of InsR-A in widely available formalin fixed paraffin embedded (FFPE) tissues is complicated by its similarities with the metabolic signaling insulin receptor isoform B (InsR-B). In the present study, qPCR based assays specific for InsR-A, InsR-B and IGF-1R were developed for use in FFPE tissues and tested for feasible use in clinical archived FFPE estrogen receptor (ER)+and ER− breast cancer tumors. Design: FFPE compatible primer sets were designed with amplicon sizes of less than 60 base pairs and validated for target specificity, assay repeatability and amplification efficiency. FFPE tumors from ER+ (n=83) and ER−(n=64) primary untreated breast cancers, and ER+ hormone refractory (HR ER+) (n=61) breast cancers were identified for feasibility testing. The feasible use of InsR-A and InsR-B qPCRs were tested using all tumor groups and the feasibility of IGF-1R qPCR was determined using HR ER+ tumors. Results: All qPCR assays were highly reproducible with amplification efficiencies between 96-104% over a 6 log range with limits of detection of 4 or 5 copies per reaction. Greater than 90% of samples were successfully amplified using InsR-A, InsR-B or IGF-1R qPCR primer sets and greater than 88% of samples tested amplified both InsR isoforms or both isoforms and IGF-1R. InsR-A was the predominant isoform in 82% ER+, 68% ER− and 100% HR ER+ breast cancer. Exploratory analyses demonstrated significantly more InsR-A expression in ER+ and HR ER+ groups compared to InsR-B (ER+ p<0.05, HR ER+ p<0.0005) and both groups had greater InsR-A expression when compared to ER− tumors (ER+ p<0.0005, HR ER+ p<0.05). IGF-1R expression of HR ER+ tumors was lower than InsR-A (p<0.0005) but higher than InsR-B (p<0.0005). The InsR-B expression of HR ER+ tumors was significantly reduced compared other tumor subgroups (ER+ and ER−, p<0.0005) and lead to a significant elevation of HR ER+ InsR-A: InsR-B ratios (ER+ and ER−, p<0.0005). Conclusions: The validated, highly sensitive InsR-A and InsR-B qPCR based assays presented here are the first to demonstrate the feasible amplification of InsR isoforms in FFPE tissues. Quantification data generated from this feasibility study indicating InsR-A is more predominant than InsR-B in breast cancer support the use of these assays for further investigation of InsR-A and InsR-B as predictive biomarkers for IGF targeted therapeutics. [Copyright &y& Elsevier]

Malignant melanoma presents a substantial clinical challenge. Current diagnostic methods are limited in their ability to diagnose early disease and accurately predict individual risk of disease progression and outcome. The lack of adequate approaches to properly define disease subgroups precludes rational treatment design and selection. Better tools are urgently needed to provide more accurate and personalized melanoma patient management. Recent progress in the understanding of the molecular aberrations that underlie melanoma oncogenesis will likely advance the diagnosis, prognosis, and treatment of melanoma. The emerging pattern of molecular complexity in melanoma tumors mirrors the clinical diversity of the disease and highlights the notion that melanoma, like other cancers, is not a single disease but a heterogeneous group of disorders that arise from complex molecular changes. Understanding of molecular aberrations involving important cellular processes, such as cellular signaling networks, cell cycle regulation, and cell death, will be essential for better diagnosis, accurate assessment of prognosis, and rational design of effective therapeutics. Defining an individual patient's unique tumor characteristics may lead to personalized prediction of outcomes and selection of therapy. We review the emerging molecular landscape of melanoma and its implications for better management of patients with melanoma. [ABSTRACT FROM AUTHOR]

Background: Left ventricular opacification (LVO) improves image quality at stress echocardiography (SE). We examined whether routine use of LVO adds incremental benefit and is cost-effective for diagnosis of coronary artery disease (CAD). Methods: Contrast pharmacologic and/or exercise SE was performed in 135 patients (81 men; 56 ± 10 years) undergoing coronary angiography. Observers sequentially interpreted first standard, then LVO images; a positive SE was defined by resting or inducible wall motion abnormality in ≥2 segments. Coronary artery disease (75 patients, 119 territories) was defined as >50% stenosis. Three cost-effectiveness models were studied, and a sensitivity analysis was performed. Results: Left ventricular opacification increased the sensitivity of SE (80%-91%; P = .03), including single-vessel CAD (65%-87%; P = .04), with no significant change in specificity (72%-77%; P = NS). Left ventricular opacification was of benefit to 14% of patients, unrelated to resting image quality. Use of LVO in all patients added 59% to the cost of the procedure (P < .001), at a cost of $1069 per additional correct diagnosis. In a cost-effectiveness model based on cardiac outcomes after SE, LVO resulted in an increase in total cost of $1069. A 3.7% improvement in sensitivity resulted in a negative cost to identify CAD, but even 15% to 20% improvements in specificity failed to balance the cost of contrast for exclusion of CAD. Conclusions: Left ventricular opacification adds significant incremental diagnostic benefit to standard SE, especially single-vessel CAD. Despite improved sensitivity, the use of contrast in all patients was not cost-effective when analyzed with a model based on previously published patient outcomes. [Copyright &y& Elsevier]

Background: Exercise training improves functional capacity in patients with systolic dysfunction (SD), but the role of exercise training in diastolic dysfunction (DD) is unclear. We compared the responses of patients with exercise intolerance and SD or DD to 16 weeks of exercise training. Methods: Fifty-one patients with SD and DD were enrolled in exercise training, which was completed in 24 patients with SD (22 men, 62 ± 8 years old, ejection fraction <35%) and 18 patients with DD (9 men, 65 ± 5 years old, ejection fraction >45%). Peak VO 2 , quality of life (Minnesota Living with Heart Failure and Hare-Davis questionnaires), and echocardiographic measures (ejection fraction, systolic and diastolic tissue velocity, and filling pressure) were performed at baseline and after 16 weeks of training. Results: Patients with SD and those with DD showed similar baseline peak VO 2 (11.9 ± 2.5 vs 12.5 ± 4.1 mL/[kg min], P = .55) and E/E′ ratio (21 ± 13 vs 14.4 ± 15, P = .07), but different systolic velocity (3.4 ± 1.0 vs 5.5 ± 1.7 cm/s, P < .001), diastolic velocity (3.9 ± 1.5 vs 5.1 ± 1.8 cm/s, P = .05), and ejection fraction (26 ± 8% vs 55 ± 9%, P < .001). Baseline quality of life scores were worse in patients with SD. There was a similar increment in peak VO 2 in SD (24%, P = .001) and DD (30%, P < .001) after exercise training, but this did not correlate with improved diastolic parameters. Quality of life scores improved in both SD and DD, although SD scores remained significantly worse. Conclusions: In patients with exercise limitation attributed to DD, the improvement in peak VO 2 and quality of life with exercise training is similar to those with SD, but unrelated to changes in diastolic function. [Copyright &y& Elsevier]

Background: Although multiple risk factor intervention (MRFI) is recommended to reduce the increased morbidity and mortality of cardiovascular disease (CVD) in chronic kidney disease (CKD), its efficacy is unknown. We studied the efficacy of a MRFI program in CKD. Methods: This randomized controlled study of 200 patients with stage 4 or 5 CKD compared a physician-supervised, nurse-driven MRFI clinic (focused on dyslipidemia, hyperhomocysteinemia, blood pressure [BP], anemia, and hyperphosphatemia) with conventional care in CKD. One hundred eleven subjects completed 2 years of follow-up (median follow-up 674 days [interquartile range {IQR} 348-719 days]). Outcome measures were atheroma burden (carotid intimamedia thickness [IMT]) and endothelial function (brachial artery reactivity [BAR]). Results: The MRFI group showed significant improvements, compared with usual care, in serum low-density lipoprotein cholesterol (−30.9 mg/dL vs −12.7 mg/dL, P = .001), homocysteine (−6.95 vs −0.67 μmol/L, P < .001), systolic BP (−6.9 vs −0.2 mm Hg, P = .049), and diastolic BP (−4.8 vs −1.0 mm of Hg, P = .043). No significant changes were seen in serum phosphate or hemoglobin level. Despite observed improvements in risk factors, no differences from baseline were demonstrated for IMT (−0.00 vs −0.01 mm, P = .533) or BAR (0.09% vs 0.22%, P = .834). Forty-two patients reached a composite end point of CVD death, acute coronary syndrome, revascularization, nonfatal stroke, and amputation and this was similar between groups (23 vs 19 events, P = .475). Conclusions: A MRFI program was not associated with improvement in vascular structure or function in stage 4 or 5 patients with CKD. [Copyright &y& Elsevier]

Background: Exercise training (ExT) improves exercise capacity in chronic heart failure, but the results of home-based training have been variable. We sought the predictors of favorable outcome using a telemonitoring approach. Methods: Exercise capacity and quality of life (QOL) were assessed in 30 patients (28 men, age 64 ± 8 years) with symptomatic chronic heart failure and left ventricular ejection fraction ≤35% (28% ± 9%) undergoing 8 months of home ExT. Patients were provided with heart rate monitors and exercise diaries after undergoing 4 months of hospital-based ExT. Weekly telephone contact was established and heart rate data were downloaded bimonthly. Changes in peak oxygen consumption per unit time (V˙o 2) and QOL were compared between the 15 most and 15 least adherent patients defined by the number of hours per week at >60% maximum heart rate, observed during heart-rate monitoring. Results: Peak V˙o 2 increased by 26% (P < .001) after 4 months of hospital ExT, but this increase had fallen to 8% (P = .07) at 12 months; only adherent patients (n = 15) showed persistent improvement of peak V˙o 2 at 12 months (P = .02). Improvement in peak V˙o 2 at 12 months was associated with baseline peak V˙o 2 (r = −0.61, P < .001) and hours logged on the heart rate monitor (r = 0.47, P = .01). Quality of life improvements were sustained at 12 months for the Minnesota Living with Heart Failure Questionnaire and Hare-Davis Depression Questionnaire. Nevertheless, QOL improvements achieved during the outpatient program were lost or attenuated at 12 months in nonadherent patients but were maintained in adherent patients. Conclusions: Telemonitoring is feasible for following adherence to home ExT. Ongoing adherence is critical in obtaining sustained benefit from ExT in heart failure. [Copyright &y& Elsevier]

Abstract: Prostaglandins (PGs) play a central role in primate parturition by their actions on uterine contractility and on cervical ripening. Rhesus monkey placentation is hemochorial and the endocrine events surrounding parturition are qualitatively similar to human pregnancy. Although there is an increase in PG production before the onset of labor, little is known about the cellular localization of the PGH synthase (PGHS) or the 15-hydroxy PG dehydrogenase (PGDH) in the fetal membranes of nonhuman primates and whether it changes at term in spontaneous labor or during preterm labor associated with infection. Placental corticotropin releasing hormone (CRH) and the glucocorticoid receptor (GR) have also been implicated as mediators in parturition by virtue of their roles in PG production. We utilized immunohistochemical methods to localize the inducible isoform PGHS-2, PGDH, GR and CRH in rhesus monkey amnion, chorion and attached decidua. Tissues were obtained at cesarean section during late pregnancy, in spontaneous labor at term and in premature labor induced by Group B streptococcal intraamniotic infection. Specific staining for immunoreactive (ir)-PGHS-2 was observed in amnion epithelial and mesenchymal cells and to a lesser extent in chorion and decidua. In contrast, ir-PGDH was localized primarily to the extravillous trophoblast layer of chorion. GR was localized to both the cytoplasm and nucleus of amnion epithelial cells, subepithelial fibroblasts, chorion trophoblasts and in decidua. Immunostaining for CRH was found in amnion and in scattered decidual cells but was most intense in the chorion trophoblast layer. There was no demonstrable change in this overall pattern of immunostaining in association with the onset of labor at term except for a decrease in staining for ir-PGDH in chorion. Experimental Group B streptococcal chorioamnionitis resulted in preterm labor and extensive necrosis of extravillous trophoblast cells with subsequent loss of chorionic ir-PGDH and relative sparing of ir-PGHS-2 in amnion epithelium which favors the net production of PGs. The expression pattern of these effectors in the rhesus monkey fetal membranes points to a functional role of PGs and glucocorticoids in the process of term and preterm parturition which is similar to that in human pregnancy. [Copyright &y& Elsevier]

Objective: The purpose of this study was to examine the roles of intrauterine infection, inflammation, and spontaneous labor on the expression of matrix metalloproteinase-9 in fetal membranes and amniotic fluid of late pregnant rhesus monkeys.Study Design: Pregnant rhesus monkeys with timed gestations were chronically catheterized to allow serial sampling of amniotic fluid before and during experimentally induced intrauterine inflammation. Six animals received group B streptococci into the chorionic-decidual space, and 4 animals received intra-amniotic interleukin-1 beta infusions (10 microg). Three additional animals were serially sampled by amniocentesis through late pregnancy until spontaneous term labor. Amniotic fluid samples were examined by zymography for matrix metalloproteinase-9 and -2 and Western immunoblot for matrix metalloproteinase-9 and -2 and tissue inhibitors of metalloproteinase-1 and -2. Fetal membranes were obtained at cesarean delivery during labor (before rupture), formalin fixed, and embedded in paraffin for immunocytochemistry of matrix metalloproteinase-9 and in situ hybridization of matrix metalloproteinase-9 messenger RNA. Tissues from 2 additional animals were collected as age-matched non-labor controls.Results: In amniotic fluid, the 92-kd latent matrix metalloproteinase-9 was detectable in late pregnancy and increased dramatically, followed by the appearance of the 83-kd active form before spontaneous term delivery. Amniotic fluid matrix metalloproteinase-2 levels (both latent and active forms) remained relatively constant throughout pregnancy and in labor. Both bacteria and interleukin-1 beta rapidly increased the signal of latent matrix metalloproteinase-9 without a consistent increase in the active form before the onset of labor. Chorionic-decidual inoculation of group B streptococci was followed by the expression of latent matrix metalloproteinase-9 before the appearance of group B streptococci in amniotic fluid or the onset of labor. Matrix metalloproteinase-2 increased to a new steady-state level or remained unchanged after group B streptococci inoculation or interleukin-1 beta infusion, respectively. Amniotic fluid tissue inhibitors of metalloproteinase-1 declined and tissue inhibitors of metalloproteinase-2 remained unchanged during early group B streptococci infection, after interleukin-1 beta infusion and on the day of spontaneous term labor. However, both tissue inhibitors of metalloproteinase-1 and -2 levels increased after preterm labor that was induced by group B streptococci. Immunocytochemistry localized matrix metalloproteinase-9 protein to amnion and chorion epithelial and mesenchymal cells and decidual stromal cells. Granular matrix metalloproteinase-9 staining was observed in the connective tissue layer of inflamed fetal membranes. In situ hybridization for messenger RNA confirmed the production of matrix metalloproteinase-9 by amnion and chorion.Conclusion: Bacterial- and interleukin-1 beta-induced preterm labor and spontaneous term labor are preceded and accompanied by progressive increases in amniotic fluid matrix metalloproteinase-9 (92 kd) in rhesus monkeys. Amniotic fluid matrix metalloproteinase-9 may serve as a clinical marker for the onset of both preterm and term labor. [ABSTRACT FROM AUTHOR]

Examines whether blockade of prostaglandin synthesis with indomethacin prevents interleukin 1beta-induced increases in uterine contractions in a nonhuman primate model. Increase in concentrations of amniotic fluid leukocytes and cytokines after interleukin 1beta infusion in both the presence and absence of indomethacin.

Studies the inhibition and augmentation of progesterone production during pregnancy on the parturition in rhesus monkeys. Reduction by epostane of maternal and fetal progesterone levels; Inducement of preterm labor and delivery due to progesterone withdrawal; Failure of exogenous progesterone to prevent parturition at term.

Describes the temporal and quantitative relationships among intrauterine infection, fetal-placental steroid biosynthesis, and preterm labor in a nonhuman primate model. Infection of rhesus monkeys; Infection-associated preterm parturition with increases in fetal adrenal steroid biosynthesis; Accompaniment of fetal stress by placental dysfunction.

Many proliferative, invasive, and immune tolerance mechanisms that support normal human pregnancy are also exploited by malignancies to establish a nutrient supply and evade or edit the host immune response. In addition to the shared capacity for invading through normal tissues, both cancer cells and cells of the developing placenta create a microenvironment supportive of both immunologic privilege and angiogenesis. Systemic alterations in immunity are also detectable, particularly with respect to a helper T cell type 2 polarization evident in advanced cancers and midtrimester pregnancy. This review summarizes the similarities between growth and immune privilege in cancer and pregnancy and identifies areas for further investigation. Our PubMed search strategy included combinations of terms such as immune tolerance, pregnancy, cancer, cytokines, angiogenesis, and invasion. We did not place any restrictions on publication dates. The knowledge gained from analyzing similarities and differences between the physiologic state of pregnancy and the pathologic state of cancer could lead to identification of new potential targets for cancer therapeutic agents. [ABSTRACT FROM AUTHOR]

Background: Epithelial ovarian cancer (EOC) mortality rates have remained unchanged in 30years. The most common EOC subtype, high-grade serous ovarian carcinoma (HG-SOC), can be divided into four subgroups on the basis of molecular characteristics. The C5 subgroup is defined by MYCN pathway activation and carries a poor prognosis. The commonly used EOC cell lines are poor models of HG-SOC, whereas patient-derived xenografts (PDX) retain pathological and immunohistochemical features of primary tumour, providing a valuable preclinical resource for therapeutic exploration. Methods: Fourteen "C5-like" HG-SOC PDX were generated from tumour tissue transplanted into NOD/SCIDIL2R&#947null mice. Three were from a consecutive cohort of HG-SOC PDX identified by qRT-PCR of the MYCN pathway and the rest from a separate cohort by gene expression analysis. Molecular analysis done included qRT-PCR for MYCN, HMGA2, LIN28B, and sequencing of DNA repair genes. In-vivo response to cisplatin (intraperitoneal on days 1, 8, and 18) is underway, because platinum response provides prognostic information. Tumour volume is measured twice weekly and mice with tumours larger than 0.7cm³ are euthanised. PDX are deemed sensitive if response is maintained for 100 or more days; resistant if they had stable disease or relapsed in less than 100days; and refractory if they progressed on treatment. Investigation of in vivo response to compounds targeting the MYCN pathway is underway and each response is considered in light of molecular phenotype. Findings: Preliminary data revealed six "C5-like" PDX overexpressed LIN28B and eight overexpressed MYCN. Three overexpressed CCNE1 (drug resistance marker) and three PDX harboured mutations in DNA repair genes (marker of platinum sensitivity). Two PDX were sensitive to cisplatin, two were resistant, four were refractory, and one showed mixed response. Interpretation: This cohort of "C5-like" HG-SOC PDX depicts molecular complexity and treatment response heterogeneity. Use of these molecularly annotated PDX to demonstrate novel effective therapies targeting the MYCN pathway will inform clinical trial design. [ABSTRACT FROM AUTHOR]