Pelvic Organ Prolapse in Female Patients Presenting to Transitional Urology Care Clinic.

PURPOSE: Patients with congenital genitourinary abnormalities are growing into adulthood and their expectations, especially in the areas of sexual function and fertility are creating unforeseen challenges for health care providers. We review the incidence and management of pelvic organ prolapse at our Transitional Urology Clinic. MATERIALS AND METHODS: This study is a retrospective chart review of the presentation and treatment of patients with clinically bothersome pelvic organ prolapse seen at our tertiary Transitional Urology Clinic during 2012 to 2015. RESULTS: Seven patients with a mean age of 22.8 years presented to our clinic with clinically bothersome prolapse. Four patients had myelomeningocele, 2 had sacral agenesis and 1 had bladder exstrophy. All were on self-catheterization. Three patients were sexually active and 1 had an intact uterus and desired fertility. Bothersome symptoms included vaginal bulge in 6 cases, difficult vaginal intercourse in 1 and difficult catheterization in 1. For the leading edge of Bp (anterior compartment) prolapse the median POP-Q (Pelvic Organ Prolapse Quantification System) stage was 3 (range 1 to 3), for Bp (posterior compartment) prolapse it was 1 (range 0 to 3) and for C (vaginal vault or cervical) prolapse it was 2 (range 1 to 3). Management included pessary in 1 case, hysterectomy with bilateral uterosacral ligament suspension in 4, sacrocolpopexy in 1 and observation in 1. Mean followup was 17.6 months (range 1 to 92). One of the 5 patients treated with surgical intervention had recurrence in the anterior compartment and vaginal vault. CONCLUSIONS: Females with congenital genitourinary anomalies present with pelvic organ prolapse at a much younger age and a more advanced stage. There is a paucity of literature on the epidemiology, presentation and management of pelvic organ prolapse in this patient population.

Increased expression of CYP24A1 correlates with advanced stages of prostate cancer and can cause resistance to vitamin D3-based therapies.

A major limitation of exogenous vitamin D3 administration for the treatment of prostate cancer is the marginal, if any, clinical efficacy. We dissected the basis for the resistance to the vitamin D3 antitumor properties and specifically examined the effect of its major catabolic enzyme, CYP24A1, in prostate cancer. Local CYP24A1 expression levels and the effect of selective modulation were analyzed using tissue microarrays from needle core biopsy specimens and xenograft-bearing mouse models. CYP24A1 mRNA was elevated in malignant human prostate tissues compared to benign lesions. High CYP24A1 protein levels were seen in poorly differentiated and highly advanced stages of prostate cancer and correlated with parallel increase in the tumor proliferation rate. The use of CYP24A1 RNAi enhanced the cytostatic effects of vitamin D3 in human prostate cancer cells. Remarkably, subcutaneous and orthotopic xenografts of prostate cancer cells harboring CYP24A1 shRNA resulted in a drastic reduction in tumor volume when mice were subjected to vitamin D3 supplementation. CYP24A1 may be a predictive marker of vitamin D3 clinical efficacy in patients with advanced prostate cancer. For those with up-regulated CYP24A1, combination therapy with RNAi targeting CYP24A1 could be considered to improve clinical responsiveness to vitamin D3.

The Single-Incision Sling to Treat Female Stress Urinary Incontinence: A Dynamic Computational Study of Outcomes and Risk Factors.

Dynamic behaviors of the single-incision sling (SIS) to correct urethral hypermobility are investigated via dynamic biomechanical analysis using a computational model of the female pelvis, developed from a female subject's high-resolution magnetic resonance (MR) images. The urethral hypermobility is simulated by weakening the levator ani muscle in the pelvic model. Four positions along the posterior urethra (proximal, midproximal, middle, and mid-distal) were considered for sling implantation. The α-angle, urethral excursion angle, and sling-urethra interaction force generated during Valsalva maneuver were quantitatively characterized to evaluate the effect of the sling implantation position on treatment outcomes and potential complications. Results show concern for overcorrection with a sling implanted at the bladder neck, based on a relatively larger sling-urethra interaction force of 1.77 N at the proximal implantation position (compared with 0.25 N at mid-distal implantation position). A sling implanted at the mid-distal urethral location provided sufficient correction (urethral excursion angle of 23.8 deg after mid-distal sling implantation versus 24.4 deg in the intact case) with minimal risk of overtightening and represents the optimal choice for sling surgery. This study represents the first effort utilizing a comprehensive pelvic model to investigate the performance of an implanted sling to correct urethral hypermobility. The computational modeling approach presented in the study can also be used to advance presurgery planning, sling product design, and to enhance our understanding of various surgical risk factors which are difficult to obtain in clinical practice.

Emotional intelligence and spiritual well-being: implications for spiritual care.

Understanding factors that influence spiritual well-being may improve nurses' spiritual caregiving. This study examined relationships between emotional intelligence (EI) and spiritual well-being (SWB) in undergraduate and graduate nursing students. Using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) and the spiritual well-being scale (SWBS) relationships were found between managing emotion and spiritual well-being, and managing emotion and existential well-being. Implications for education and practice are discussed.

Pain Related to Intradetrusor BotulinumtoxinA: A Randomized Clinical Trial.

IMPORTANCE: OnabotulinumtoxinA (BTX-A) is an effective treatment for overactive bladder (OAB), but few studies have been done to evaluate injection techniques. OBJECTIVE: The primary objective was to evaluate procedural discomfort between 2 commonly used injection techniques for BTX-A. STUDY DESIGN: This was a single-blinded, randomized clinical trial of women undergoing injection of 100 U BTX-A for idiopathic OAB. Patients were randomized to 5 mL/5 injection or 10 mL/10 injection groups. Bladder pain was assessed by a validated Numeric Pain Rating Scale. Overactive bladder symptoms were assessed with a standardized questionnaire (Overactive Bladder Questionnaire Short Form). Patient satisfaction, treatment efficacy, and adverse events were assessed at 30 days after procedure. RESULTS: One hundred eight patients were randomized to 52 in the 5 mL/5 injection arm and 56 in the 10 mL/10 injection arm. Mean procedural pain scores were 3.2 (±2.3) in the 5 mL/5 injection group versus 3.6 (±2.1) in the 10 mL/10 injection group (P = 0.21). No difference was found when categorizing pain scores into ordinal outcomes of low (P = 0.55), medium (P = 0.70), and high (P = 1.0) or a binary outcome of low (P = 0.55) versus medium + high (P = 0.55). Multivariate analyses did not effect statistical significance between the 2 groups for the ordinal outcome (odds ratio = 1.86; 95% confidence interval = 0.77 = 4.52; P = 0.17) or the binary outcome (odds ratio = 1.81; 95% confidence interval = 0.68-4.77; P = 0.28). No difference was observed between overall patient satisfaction, global impression of improvement, Overactive Bladder Questionnaire Short Form scores, or adverse outcomes. CONCLUSIONS: Procedural discomfort related to BTX-A injection for idiopathic OAB was not different between 2 injection protocols. Overall satisfaction was high for both groups, and there was no difference in symptom scores or adverse events.

LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models.

The HGF/MET signaling pathway regulates a wide variety of normal cellular functions that can be subverted to support neoplasia, including cell proliferation, survival, apoptosis, scattering and motility, invasion, and angiogenesis. MET over-expression (with or without gene amplification), aberrant autocrine or paracrine ligand production, and missense MET mutations are mechanisms that lead to activation of the MET pathway in tumors and are associated with poor prognostic outcome. We report here preclinical development of a potent, orally bioavailable, small-molecule inhibitor LY2801653 targeting MET kinase. LY2801653 is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a dissociation constant (Ki) of 2 nM, a pharmacodynamic residence time (Koff) of 0.00132 min(-1) and t1/2 of 525 min. LY2801653 demonstrated in vitro effects on MET pathway-dependent cell scattering and cell proliferation; in vivo anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4) and MET over-expressed (H441) xenograft models; and in vivo vessel normalization effects. LY2801653 also maintained potency against 13 MET variants, each bearing a single-point mutation. In subsequent nonclinical characterization, LY2801653 was found to have potent activity against several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2 and against the serine/threonine kinases MKNK1/2. The potential value of MET and other inhibited targets within a number of malignancies (such as colon, bile ducts, and lung) is discussed. LY2801653 is currently in phase 1 clinical testing in patients with advanced cancer (trial I3O-MC-JSBA, NCT01285037).

Partnering with those we serve: using experiential learning activities to support community nursing practice.

The concept of community is multidimensional and may include geographical boundaries and/or the shared interests of its members. Community nursing practice involves nurses, patients, and families who collaborate to address health issues and to promote positive health initiatives. Informed by community health theorists, experiential learning activities provide the structure to promote partnering in community nursing practice to achieve outcomes that benefit those who serve and those who are served.

Prospective Evaluation of Intradetrusor Injections of OnabotulinumtoxinA in Adults With Spinal Dysraphism.

OBJECTIVE: To prospectively evaluate the effectiveness of OnabotulinumtoxinA (BTX-A) on neurogenic overactive bladder (nOAB) in adults with congenital spinal dysraphism (CSD). METHODS: We conducted a prospective, nonrandomized pilot study of 24 adults with CSD and neurogenic overactive bladder. Patients were evaluated with baseline video-urodynamics (UDS) and validated questionnaires, underwent injection 200U BTX-A, and then underwent repeat evaluation with questionnaires and UDS 1-3 months postinjection. A high-risk subgroup was separately analyzed based on adverse clinical characteristics (ie, decrease bladder compliance, vesicoureteral reflux, hydronephrosis, chronic kidney disease). RESULTS: BTX-A injection improved patient recorded outcome measures seen in both I-QOL Score total (67.9 vs 75.5, P = .007) and Neurogenic Bladder Symptom Score total (38.0 vs 29.0, P = .001). On UDS, BTX-A injection significantly improved end filling pressure (16.0 vs 8.8, P = .036) and also improved bladder compliance (mL/cm H2O) (89.38 vs 135.81, P = .445). High-risk patients were found to have similar improvements in most subjective questionnaire scoring, a significant decrease in end filling pressures, and improved bladder compliance on UDS. CONCLUSION: BTX-A can be used as an effective treatment in adults with CSD. We found that BTX-A significantly improved quality of life from patient reported outcome measurements as well as improving end filling pressures and bladder compliance. These improvements were seen even within our high-risk subgroup. Further studies are needed to evaluate long-term efficacy and appropriate follow-up of this at-risk population.

Population regulation by enemies of the grass Brachypodium sylvaticum: demography in native and invaded ranges.

The enemy-release hypothesis (ERH) states that species become more successful in their introduced range than in their native range because they leave behind natural enemies in their native range and are thus "released" from enemy pressures in their introduced range. The ERH is popularly cited to explain the invasive properties of many species and is the underpinning of biological control. We tested the prediction that plant populations are more strongly regulated by natural enemies (herbivores and pathogens) in their native range than in their introduced range with enemy-removal experiments using pesticides. These experiments were replicated at multiple sites in both the native and invaded ranges of the grass Brachypodium sylvaticum. In support of the ERH, enemies consistently regulated populations in the native range. There were more tillers and more seeds produced in treated vs. untreated plots in the native range, and few seedlings survived in the native range. Contrary to the ERH, total measured leaf damage was similar in both ranges, though the enemies that caused it differed. There was more damage by generalist mollusks and pathogens in the native range, and more damage by generalist insect herbivores in the invaded range. Demographic analysis showed that population growth rates were lower in the native range than in the invaded range, and that sexually produced seedlings constituted a smaller fraction of the total in the native range. Our removal experiment showed that enemies regulate plant populations in their native range and suggest that generalist enemies, not just specialists, are important for population regulation.

Management of Recurrent Urinary Tract Infections in Women: How Providers Can Improve the Patient Experience.

OBJECTIVE: To provide guidance to providers on how to improve the patient experience for women with recurrent urinary tract infections (rUTIs). METHODS: The recently updated 2019 American Urological Association (AUA) guidelines for recurrent uncomplicated acute cystitis and other contemporary publications pertaining to recurrent UTIs in women were reviewed. These data were used to summarize practice-based methodology to formulate recommendations with an emphasis on education to enhance the patient experience. RESULTS: We summarize the guideline-based management of patients with rUTI and augment this with a patient-focused perspective to provide recommendations for how to best counsel patients regarding evaluation, treatment using antibiotic stewardship practices, and a comprehensive prevention plan. We focus on patient education as the foundation for successful provider-patient relationships as well as patient compliance with care pathways. CONCLUSION: rUTIs are costly, time-consuming, and painful for patients. For providers, rUTIs represent a frustrating aspect of clinical care facing the balance of antibiotic stewardship with effective treatment and patient expectations with limited data supporting nonantibiotic therapies. Urologists have the skills and knowledge to provide this patient population with competent and compassionate care. By investing in these patients, being responsive to their concerns and offering education, patients will have a better overall experience with this chronic condition.

Inhibition of Sphingosine Phosphate Receptor 1 Signaling Enhances the Efficacy of VEGF Receptor Inhibition.

Inhibition of VEGFR signaling is an effective treatment for renal cell carcinoma, but resistance continues to be a major problem. Recently, the sphingosine phosphate (S1P) signaling pathway has been implicated in tumor growth, angiogenesis, and resistance to antiangiogenic therapy. S1P is a bioactive lipid that serves an essential role in developmental and pathologic angiogenesis via activation of the S1P receptor 1 (S1P1). S1P1 signaling counteracts VEGF signaling and is required for vascular stabilization. We used in vivo and in vitro angiogenesis models including a postnatal retinal angiogenesis model and a renal cell carcinoma murine tumor model to test whether simultaneous inhibition of S1P1 and VEGF leads to improved angiogenic inhibition. Here, we show that inhibition of S1P signaling reduces the endothelial cell barrier and leads to excessive angiogenic sprouting. Simultaneous inhibition of S1P and VEGF signaling further disrupts the tumor vascular beds, decreases tumor volume, and increases tumor cell death compared with monotherapies. These studies suggest that inhibition of angiogenesis at two stages of the multistep process may maximize the effects of antiangiogenic therapy. Together, these data suggest that combination of S1P1 and VEGFR-targeted therapy may be a useful therapeutic strategy for the treatment of renal cell carcinoma and other tumor types.

Procedure Choice in Primary Versus Recurrent Prolapse: A Study of Fellowship-Trained Surgeons.

OBJECTIVE: This retrospective study describes procedures of choice in management of patients with primary prolapse compared with recurrence prolapse patients by fellowship-trained surgeons. METHODS: Surgically managed primary and recurrent prolapse cases from 2012 to 2015 at Houston Methodist Hospital were reviewed. Baseline characteristics, compartment defects, and stage were compared. Mean interval from the index surgeries to management of prolapse recurrence was recorded. In recurrence cases, mesh complaints were noted if present. Primary outcome was the procedure type used to manage cases of recurrence and primary prolapse. Logistic regression was used to determine odds ratio (OR) for the procedure of choice in recurrence and primary repairs of prolapse. RESULTS: Of 386 cases reviewed, 379 met criteria for inclusion; 25.8% of repairs were for recurrence. Recurrence patients were significantly older than primary cases (mean, 63.6 vs 60.5; P = 0.03) and had been postmenopausal for longer (P = 0.004). Median time interval to surgical management of recurrence was 8 years. Thirty percent of recurrence patients treated previously by mesh had mesh complaints. There was no difference in the distribution of defects or stage. Sacrocolpopexy was more frequently used to manage recurrent prolapse (OR, 2.6334; P < 0.0005). Vaginal mesh repairs showed no difference in utilization. Uterosacral ligament fixation (OR, 0.347; P = 0.002) was used more often in primary prolapse. Anterior colporrhaphy (OR, 0.398; P = 0.0005) and uterosacral ligament fixation (OR, 0.347; P = 0.002) were performed less in recurrence cases. CONCLUSION: Fellowship-trained urogynecologists at this institution utilize sacrocolpopexy mesh more frequently in recurrent prolapse, and uterosacral ligament fixation was used more frequently in primary prolapse cases.

Abemaciclib Is Active in Preclinical Models of Ewing Sarcoma via Multipronged Regulation of Cell Cycle, DNA Methylation, and Interferon Pathway Signaling.

PURPOSE: Ewing sarcoma (ES) is a rare and highly malignant cancer that occurs in the bone and surrounding tissue of children and adolescents. The EWS/ETS fusion transcription factor that drives ES pathobiology was previously demonstrated to modulate cyclin D1 expression. In this study, we evaluated abemaciclib, a small-molecule CDK4 and CDK6 (CDK4 and 6) inhibitor currently under clinical investigation in pediatric solid tumors, in preclinical models of ES. EXPERIMENTAL DESIGN: Using Western blot, high-content imaging, flow cytometry, ELISA, RNA sequencing, and CpG methylation assays, we characterized the in vitro response of ES cell lines to abemaciclib. We then evaluated abemaciclib in vivo in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models of ES as either a monotherapy or in combination with chemotherapy. RESULTS: Abemaciclib induced quiescence in ES cell lines via a G1 cell-cycle block, characterized by decreased proliferation and reduction of Ki-67 and FOXM1 expression and retinoblastoma protein (RB) phosphorylation. In addition, abemaciclib reduced DNMT1 expression and promoted an inflammatory immune response as measured by cytokine secretion, antigen presentation, and interferon pathway upregulation. Single-agent abemaciclib reduced ES tumor volume in preclinical mouse models and, when given in combination with doxorubicin or temozolomide plus irinotecan, durable disease control was observed. CONCLUSIONS: Collectively, our data demonstrate that the antitumor effects of abemaciclib in preclinical ES models are multifaceted and include cell-cycle inhibition, DNA demethylation, and immunogenic changes.

Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors.

Merestinib is an oral multi-kinase inhibitor targeting a limited number of oncokinases including MET, AXL, RON and MKNK1/2. Here, we report that merestinib inhibits neurotrophic receptor tyrosine kinases NTRK1/2/3 which are oncogenic drivers in tumors bearing NTRK fusion resulting from chromosomal rearrangements. Merestinib is shown to be a type II NTRK1 kinase inhibitor as determined by x-ray crystallography. In KM-12 cells harboring TPM3-NTRK1 fusion, merestinib exhibits potent p-NTRK1 inhibition in vitro by western blot and elicits an anti-proliferative response in two- and three-dimensional growth. Merestinib treatment demonstrated profound tumor growth inhibition in in vivo cancer models harboring either a TPM3-NTRK1 or an ETV6-NTRK3 gene fusion. To recapitulate resistance observed from type I NTRK kinase inhibitors entrectinib and larotrectinib, we generated NIH-3T3 cells exogenously expressing TPM3-NTRK1 wild-type, or acquired mutations G595R and G667C in vitro and in vivo. Merestinib blocks tumor growth of both wild-type and mutant G667C TPM3-NTRK1 expressing NIH-3T3 cell-derived tumors. These preclinical data support the clinical evaluation of merestinib, a type II NTRK kinase inhibitor (NCT02920996), both in treatment naïve patients and in patients progressed on type I NTRK kinase inhibitors with acquired secondary G667C mutation in NTRK fusion bearing tumors.

Outcomes in Pelvic Organ Prolapse Surgery in Women Using Chronic Antithrombotic Therapy.

INTRODUCTION: Chronic antithrombotic therapy is common among patients requiring surgery for pelvic organ prolapse because of age and comorbidities. The impact of chronic anticoagulation on postoperative complications in pelvic organ prolapse surgery has not been investigated. This study aims to determine if patients on chronic antithrombotic therapy are at increased risk for postoperative complications. METHODS: This retrospective cohort study included women having prolapse surgery from 2012 to 2015, identified by Current Procedural Terminology codes, excluding patients undergoing concomitant major nonurogynecologic procedures. Baseline characteristics were compared and all procedures performed, operative duration, estimated blood loss, and length of hospitalization. Complications (blood transfusion, intensive care unit admission, reoperation, readmission, hematoma, thromboembolic event, and infection) were compared in women on chronic antithrombotic therapy and controls. Logistic regression determined odds ratio (OR) for complications in patients on chronic antithrombotics. Complications were graded by the Clavien-Dindo classification. RESULTS: A total of 388 charts were reviewed, and 386 patients met inclusion criteria. Twenty-one of the 386 patients were on chronic antithrombotic therapy. Chronic antithrombotic therapy increased overall complications (OR, 6.8; P < 0.0005), blood transfusion (OR, 165; P < 0.001), intensive care unit admission (OR, 19.10; P < 0.004), hospital readmission (OR, 20.7; P < 0.0005), vaginal hematoma (OR, 554.1; P < 0.001), infection (OR, 22.44; P < 0.004), and complications that required specific additional follow-up (OR, 9.42; P < 0.0005). There were no thromboembolic events. Antithrombotic therapy did not significantly increase reoperation rates (OR, 3.8; P = 0.275). Findings were maintained when adjusting for covariates of age and body mass index. CONCLUSIONS: Postoperative surgical complications after prolapse repair procedures are increased in patients who use chronic antithrombotic medication, the majority of cases are successfully managed conservatively.

The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma.

Purpose: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G2-M cell-cycle checkpoints. We evaluated prexasertib (LY2606368), a small-molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on the preclinical models of neuroblastoma.Experimental Design: We evaluated the antiproliferative activity of prexasertib in a panel of cancer cell lines; neuroblastoma cell lines were among the most sensitive. Subsequent Western blot and immunofluorescence analyses measured DNA damage and DNA repair protein activation. Prexasertib was investigated in several cell line-derived xenograft mouse models of neuroblastoma.Results: Within 24 hours, single-agent prexasertib promoted γH2AX-positive double-strand DNA breaks and phosphorylation of DNA damage sensors ATM and DNA-PKcs, leading to neuroblastoma cell death. Knockdown of CHK1 and/or CHK2 by siRNA verified that the double-strand DNA breaks and cell death elicited by prexasertib were due to specific CHK1 inhibition. Neuroblastoma xenografts rapidly regressed following prexasertib administration, independent of starting tumor volume. Decreased Ki67 and increased immunostaining of endothelial and pericyte markers were observed in xenografts after only 6 days of exposure to prexasertib, potentially indicating a swift reduction in tumor volume and/or a direct effect on tumor vasculature.Conclusions: Overall, these data demonstrate that prexasertib is a specific inhibitor of CHK1 in neuroblastoma and leads to DNA damage and cell death in preclinical models of this devastating pediatric malignancy. Clin Cancer Res; 23(15); 4354-63. ©2017 AACR.

Inhibition of CXCR4 by LY2624587, a Fully Humanized Anti-CXCR4 Antibody Induces Apoptosis of Hematologic Malignancies.

SDF-1 and CXCR4 are a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. Overexpression of CXCR4 is a hallmark of many hematological malignancies including acute myeloid leukemia, chronic lymphocytic leukemia and non-Hodgkin's lymphoma, and generally correlates with a poor prognosis. In this study, we developed a humanized anti-CXCR4 monoclonal antibody, LY2624587 as a potent CXCR4 antagonist that was advanced into clinical study for cancer. LY2624587 blocked SDF-1 binding to CXCR4 with an IC50 of 0.26 nM, and inhibited SDF-1-induced GTP binding with a Kb of 0.66 nM. In human lymphoma U937 and leukemia CCRF-CEM cells expressing endogenous CXCR4, LY2624587 inhibited SDF-1-induced cell migration with IC50 values of 3.7 and 0.26 nM, respectively. This antibody also inhibited CXCR4 and SDF-1 mediated cell signaling including activation of MAPK and AKT in tumor cells expressing CXCR4. Bifocal microscopic and flow cytometry analyses revealed that LY2624587 mediated receptor internalization and caused CXCR4 down-regulation on the cell surface. In human hematologic cancer cells, LY2624587 caused dose dependent apoptosis in vitro and in vivo. In mouse xenograft models developed with human leukemia and lymphoma cells expressing high levels of CXCR4, LY2624587 exhibited dose-dependent tumor growth inhibition and provided significant survival benefit in a disseminated lymphoma model. Collectively, we have demonstrated that CXCR4 inhibition by LY2624587 has the potential for the treatment of human hematological malignancies.

Stromal-Based Signatures for the Classification of Gastric Cancer.

Treatment of metastatic gastric cancer typically involves chemotherapy and monoclonal antibodies targeting HER2 (ERBB2) and VEGFR2 (KDR). However, reliable methods to identify patients who would benefit most from a combination of treatment modalities targeting the tumor stroma, including new immunotherapy approaches, are still lacking. Therefore, we integrated a mouse model of stromal activation and gastric cancer genomic information to identify gene expression signatures that may inform treatment strategies. We generated a mouse model in which VEGF-A is expressed via adenovirus, enabling a stromal response marked by immune infiltration and angiogenesis at the injection site, and identified distinct stromal gene expression signatures. With these data, we designed multiplexed IHC assays that were applied to human primary gastric tumors and classified each tumor to a dominant stromal phenotype representative of the vascular and immune diversity found in gastric cancer. We also refined the stromal gene signatures and explored their relation to the dominant patient phenotypes identified by recent large-scale studies of gastric cancer genomics (The Cancer Genome Atlas and Asian Cancer Research Group), revealing four distinct stromal phenotypes. Collectively, these findings suggest that a genomics-based systems approach focused on the tumor stroma can be used to discover putative predictive biomarkers of treatment response, especially to antiangiogenesis agents and immunotherapy, thus offering an opportunity to improve patient stratification. Cancer Res; 76(9); 2573-86. ©2016 AACR.