PI3K signaling promotes formation of lipid-laden foamy macrophages at the spinal cord injury site.

After spinal cord injury (SCI), infiltrating macrophages undergo excessive phagocytosis of myelin and cellular debris, forming lipid-laden foamy macrophages. To understand their role in the cellular pathology of SCI, investigation of the foamy macrophage phenotype in vitro revealed a pro-inflammatory profile, increased reactive oxygen species (ROS) production, and mitochondrial dysfunction. Bioinformatic analysis identified PI3K as a regulator of inflammation in foamy macrophages, and inhibition of this pathway decreased their lipid content, inflammatory cytokines, and ROS production. Macrophage-specific inhibition of PI3K using liposomes significantly decreased foamy macrophages at the injury site after a mid-thoracic contusive SCI in mice. RNA sequencing and in vitro analysis of foamy macrophages revealed increased autophagy and decreased phagocytosis after PI3K inhibition as potential mechanisms for reduced lipid accumulation. Together, our data suggest that the formation of pro-inflammatory foamy macrophages after SCI is due to the activation of PI3K signaling, which increases phagocytosis and decreases autophagy.

Oral azacitidine modulates the bone marrow microenvironment in patients with acute myeloid leukaemia in remission: A subanalysis from the QUAZAR AML-001 trial.

Oral azacitidine (Oral-AZA) maintenance therapy improved relapse-free (RFS) and overall survival (OS) significantly versus placebo for AML patients in remission after intensive chemotherapy (IC) in the phase 3 QUAZAR AML-001 study. Immune profiling was performed on the bone marrow (BM) at remission and on-treatment in a subset of patients with the aim of identifying prognostic immune features and evaluating associations of on-treatment immune effects by Oral-AZA with clinical outcomes. Post-IC, increased levels of lymphocytes, monocytes, T cells and CD34 + CD117+ BM cells were prognostically favourable for RFS. CD3+ T-cell counts were significantly prognostic for RFS in both treatment arms. At baseline, high expression of the PD-L1 checkpoint marker was identified on a subset of CD34 + CD117+ BM cells; many of which were PD-L2+. High co-expression of T-cell exhaustion markers PD-1 and TIM-3 was associated with inferior outcomes. Oral-AZA augmented T-cell numbers during early treatment, increased CD4+:CD8+ ratios and reversed T-cell exhaustion. Unsupervised clustering analysis identified two patient subsets defined by T-cell content and expression of T-cell exhaustion markers that were enriched for MRD negativity. These results indicate that Oral-AZA modulates T-cell activity in the maintenance setting of AML, and these immune-mediated responses are associated with clinical outcomes.

Hematogenous Macrophages Contribute to Fibrotic Scar Formation After Optic Nerve Crush.

Although glial scar formation has been extensively studied after optic nerve injury, the existence and characteristics of traumatic optic nerve fibrotic scar formation have not been previously characterized. Recent evidence suggests infiltrating macrophages are involved in pathological processes after optic nerve crush (ONC), but their role in fibrotic scar formation is unknown. Using wild-type and transgenic mouse models with optic nerve crush injury, we show that macrophages infiltrate and associate with fibroblasts in the traumatic optic nerve lesion fibrotic scar. We dissected the role of hematogenous and resident macrophages, labeled with Dil liposomes intravenously administered, and observed that hematogenous macrophages (Dil+ cells) specifically accumulate in the center of traumatic fibrotic scar while Iba-1+ cells reside predominantly at the margins of optic nerve fibrotic scar. Depletion of hematogenous macrophages results in reduced fibroblast density and decreased extracellular matrix deposition within the fibrotic scar area following ONC. However, retinal ganglion cell degeneration and function loss after optic nerve crush remain unaffected after hematogenous macrophage depletion. We present new and previously not characterized evidence that hematogenous macrophages are selectively recruited into the fibrotic core of the optic nerve crush site and critical for this fibrotic scar formation.

Myelin and non-myelin debris contribute to foamy macrophage formation after spinal cord injury.

Tissue damage after spinal cord injury (SCI) elicits a robust inflammatory cascade that fails to resolve in a timely manner, resulting in impaired wound healing and cellular regeneration. This inflammatory response is partly mediated by infiltrating immune cells, including macrophages. As professional phagocytes, macrophages initially play an important role in debris clearance at the injury site, which would be necessary for proper tissue regeneration. After SCI, most macrophages become filled with lipid droplets due to excessive uptake of lipid debris, assuming a "foamy" phenotype that is associated with a proinflammatory state. Myelin has been assumed to be the main source of lipid that induces foamy macrophage formation after injury given its abundance in the spinal cord. This assumption has led to the widespread use of purified myelin treatment to model foamy macrophage formation in vitro. However, the assumption that myelin is necessary for foamy macrophage formation remains untested. To this end, we developed a novel foamy macrophage assay utilizing total spinal cord homogenate to include all sources of lipid present at the injury site. Using the myelin basic protein knockout (MBP KO, i.e., Shiverer) mice that lack myelin, we investigated lipid accumulation in foamy macrophages. Primary macrophages treated with myelin-deficient spinal cord homogenate still formed large lipid droplets typically observed in foamy macrophages, although to a lesser degree than cells treated with normal homogenate. Similarly, MBP KO mice subjected to contusive spinal cord injury also formed foamy macrophages that exhibited reduced lipid content and associated with improved histological outcomes and reduced immune cell infiltration. Therefore, the absence of myelin does not preclude foamy macrophage formation, indicating that myelin is not the only major source of lipid that contributes this pathology, even though myelin may alter certain aspects of its inflammatory profile.

TNFR2 Signaling Regulates the Immunomodulatory Function of Oligodendrocyte Precursor Cells.

Multiple sclerosis (MS) is a neuroimmune disorder characterized by inflammation, CNS demyelination, and progressive neurodegeneration. Chronic MS patients exhibit impaired remyelination capacity, partly due to the changes that oligodendrocyte precursor cells (OPCs) undergo in response to the MS lesion environment. The cytokine tumor necrosis factor (TNF) is present in the MS-affected CNS and has been implicated in disease pathophysiology. Of the two active forms of TNF, transmembrane (tmTNF) and soluble (solTNF), tmTNF signals via TNFR2 mediating protective and reparative effects, including remyelination, whereas solTNF signals predominantly via TNFR1 promoting neurotoxicity. To better understand the mechanisms underlying repair failure in MS, we investigated the cellular responses of OPCs to inflammatory exposure and the specific role of TNFR2 signaling in their modulation. Following treatment of cultured OPCs with IFNγ, IL1ß, and TNF, we observed, by RNA sequencing, marked inflammatory and immune activation of OPCs, accompanied by metabolic changes and dysregulation of their proliferation and differentiation programming. We also established the high likelihood of cell-cell interaction between OPCs and microglia in neuroinflammatory conditions, with OPCs able to produce chemokines that can recruit and activate microglia. Importantly, we showed that these functions are exacerbated when TNFR2 is ablated. Together, our data indicate that neuroinflammation leads OPCs to shift towards an immunomodulatory phenotype while diminishing their capacity to proliferate and differentiate, thus impairing their repair function. Furthermore, we demonstrated that TNFR2 plays a key role in this process, suggesting that boosting TNFR2 activation or its downstream signals could be an effective strategy to restore OPC reparative capacity in demyelinating disease.

Single-cell analysis of the cellular heterogeneity and interactions in the injured mouse spinal cord.

The wound healing process that occurs after spinal cord injury is critical for maintaining tissue homeostasis and limiting tissue damage, but eventually results in a scar-like environment that is not conducive to regeneration and repair. A better understanding of this dichotomy is critical to developing effective therapeutics that target the appropriate pathobiology, but a major challenge has been the large cellular heterogeneity that results in immensely complex cellular interactions. In this study, we used single-cell RNA sequencing to assess virtually all cell types that comprise the mouse spinal cord injury site. In addition to discovering novel subpopulations, we used expression values of receptor-ligand pairs to identify signaling pathways that are predicted to regulate specific cellular interactions during angiogenesis, gliosis, and fibrosis. Our dataset is a valuable resource that provides novel mechanistic insight into the pathobiology of not only spinal cord injury but also other traumatic disorders of the CNS.

Reactive Fibroblasts in Response to Optic Nerve Crush Injury.

Traumatic optic neuropathy leads to bidirectional degeneration of retinal ganglion cells and axons and results in optic nerve scaring, which inhibits the regeneration of damaged axons. Compared with its glial counterpart, the fibrotic response causing nerve scar tissue is poorly permissive to axonal regeneration. Using collagen1α1-GFP reporter mice, we characterize the development of fibrotic scar formation following optic nerve crush injury. We observe that perivascular collagen1α1 cells constitute a major cellular component of the fibrotic scar. We demonstrate that extracellular molecules and monocytes are key factors contributing to the pathogenesis of optic nerve fibrotic scar formation, with a previously unrecognized encapsulation of this scar. We also characterize the distribution of collagen1α1 cells in the retina after optic nerve crush injury based on in vivo and whole-mount retinal imaging. Our results identify collagen1α1 cells as a major component of fibrotic scarring following ONC and are a potential molecular target for promoting axonal regeneration after optic nerve injury.

Treatment of Uveitis and Outcomes of Glaucoma Drainage Implant Surgery: A Meta-Analysis.

PURPOSE: We performed a meta-analysis to evaluate the effect of uveitis treatment on glaucoma drainage implant surgical outcomes. METHODS: We included 16 articles in the meta-analysis. Two groups were defined based on medical therapy of uveitis: Group 1: poorly controlled uveitis, and Group 2: well-controlled uveitis including use of immunomodulatory medications. RESULTS: The two groups were similar in comparisons of follow-up time, age, gender, and etiology of uveitis. Meta-analysis demonstrated significantly greater success in Group 2 (95.1%) compared to Group 1 (81.6%) at 1 year after glaucoma drainage implant surgery (P = .001). The final success was significantly greater (P 0.014) in group 2 compared with group 1 (86.1% and 74.3%, respectively). CONCLUSION: Surgical success was significantly higher in uveitic glaucoma patients treated with more intensive immunosuppressive therapy before and after glaucoma drainage implant surgery. The level of control of uveitis perioperatively appears to influence glaucoma drainage implant surgery outcomes.

Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis.

Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ)-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications.

The origin, fate, and contribution of macrophages to spinal cord injury pathology.

Virtually all phases of spinal cord injury pathogenesis, including inflammation, cell proliferation and differentiation, as well as tissue remodeling, are mediated in part by infiltrating monocyte-derived macrophages. It is now clear that these infiltrating macrophages have distinct functions from resident microglia and are capable of mediating both harmful and beneficial effects after injury. These divergent effects have been largely attributed to environmental cues, such as specific cytokines, that influence the macrophage polarization state. In this review, we also consider the possibility that different macrophage origins, including the spleen, bone marrow, and local self-renewal, may also affect macrophage fate, and ultimately their function that contribute to the complex pathobiology of spinal cord injury.

Personalizing Gastric Cancer Screening With Predictive Modeling of Disease Progression Biomarkers.

Gastric cancer (GC) remains the third most common cause of cancer-related death worldwide. Infection with Helicobacter pylori is responsible for over 70% of GC incidence; colonization induces chronic inflammation, which can facilitate progression to intestinal metaplasia, dysplasia, and GC (Correa pathway). Although H. pylori eradication is a necessary first step in GC prevention, some patients continue to progress to advanced stage disease if substantial tissue damage has occurred or inflammation persists. This progression is often asymptomatic until cancer reaches stage IV, yet efficient, cost-effective screening protocols for patients who present with early stages of the Correa pathway do not exist. Given the high interpatient heterogeneity in progression time through this pathway, such screening protocols must necessarily be personalized. This requires the identification of reliable and longitudinally assessable biomarkers of patient-specific progression. Several gastric stem cell (GSC) markers including CD44, CD133, and Lgr5 are upregulated in GC. Here we show a significant stepwise increase in immunohistochemical staining for these markers in biopsies at different stages of the Correa pathway, suggesting GSC fraction to be a promising candidate biomarker for early detection of malignant transformation. We present a mathematical model capable of both simulating clinically observed increases in GSC fraction in longitudinal biopsy samples of individual patients, and forecasting patient-specific disease progression trajectories based only on characteristics identified from immunohistochemistry at initial presentation. From these forecasts, personalized screening schedules may be identified that would allow early stratification of high-risk patients, and potentially earlier detection of dysplasia or early-stage GC.

Congruence of multiple patient-related outcomes within a single day.

OBJECTIVE: Clinic-based collection of patient-reported outcome (PRO) quantifying symptom burden provide crucial information for effective care. We have pioneered point-of-care electronic assessment using the Edmonton Symptom Assessment Scale (ESAS) with direct linkage to the electronic medical record (EMR) which has been readily adopted by our oncology patients. As some patients may complete more than one ESAS per day in different clinics, the goal of the current analyses was to compare the within-patient congruence of ESAS assessments completed on the same day. METHODS: A total of 9621 ESAS records from 4021 patients of the Supportive Care Medicine and Radiation Oncology clinics between February and November 2017 were retrieved from the EMR. Patients completed the ESAS-r-CSS, which added sleep disturbance, constipation, and spiritual well-being domains to the standard ESAS-r. RESULTS: A total of 65 patients provided more than one ESAS report within the same day. The data were curated, removing those sporadic missing data and those with obvious technical error. This process left 130 samples for analysis. There was no statistical difference among different ESAS collection intervals for domains of tiredness, nausea, appetite, overall well-being, spiritual well-being, constipation, and difficulty sleeping, but there was a significant difference for pain, drowsiness, shortness of breath, depression, and anxiety. Repeat tests that occurred within 1 h of one another demonstrated higher congruence than those completed over longer periods. CONCLUSION: Patients reported significant worsening of several symptoms over the course of the day, with greatest concordance observed within smaller time periods.

Bromodomain and extraterminal domain-containing protein inhibition attenuates acute inflammation after spinal cord injury.

Inflammation is a major contributor to the secondary damage that occurs after spinal cord injury (SCI). The inflammatory response is coordinated by many different signaling modalities including the epigenetic modification of promoters and enhancers. Bromodomain and extraterminal domain-containing proteins (BETs; Brd2, Brd3, Brd4, BrdT) are epigenetic readers that bind acetylated histones to promote transcription of pro-inflammatory genes. BET inhibition is anti-inflammatory in animal models of cancer, rheumatoid arthritis, and coronary artery disease. However, the role of BETs in neuroinflammation remains largely unexplored. In this study, we investigated the role of BETs in promoting inflammation in neural cells and the ability of the BET inhibitor JQ1 to decrease inflammation acutely after SCI. Expression of BET mRNA was assessed via qPCR in purified primary mouse macrophages, astrocytes, neurons, oligodendrocytes, and microglia, as well as in naïve, sham-injured, and contusion-injured mouse spinal cord. Brd2, Brd3, and Brd4 mRNA were expressed in all purified primary neural cells and in the uninjured and injured mouse spinal cord. BET inhibition significantly attenuated proinflammatory signaling in all activated cell populations in vitro. To investigate the effects of BET modulation after SCI, the BET inhibitor JQ1 was injected intraperitoneally (30 mg/kg, bidaily) 3 h after spinal cord contusion in adult female C57BL/6 mice. By 3 days post-injury, BET inhibition significantly decreased pro-inflammatory cytokine expression and leukocyte recruitment to the injury site. However, this decrease did not lead to locomotor improvements or smaller lesion size. Taken together, our data implicate BETs as regulators of multiple key pro-inflammatory cytokines, and suggest that BETs can be pharmacologically inhibited to reduce inflammation acutely after SCI.

Neurofibromin level directs RAS pathway signaling and mediates sensitivity to targeted agents in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumor (MPNST) is a type of soft-tissue sarcoma strongly associated with dysfunction in neurofibromin; an inhibitor of the RAS pathway. We performed high-throughput screening of an array of FDA approved and promising agents in clinical development both alone and in combination at physiologically achievable concentrations against a panel of established MPNST cell line models. We found that drugs targeting a variety of factors in the RAS pathway can effectively lead to cell death in vitro with considerable drug combination synergy in regimens that target MEK or mTOR. We observed that the degree of relative sensitivity to chemotherapeutic agents was associated with the status of neurofibromin in these cell line models. Using a combination of agents that target MEK and mTORC1/2, we effectively silenced RAS/PI3K/MEK/mTOR signaling in vitro. Moreover, we employed RNAi against NF1 to establish that MPNST drug sensitivity is directly proportional to relative level of intracellular neurofibromin. Thus, two-drug combinations that target MEK and mTORC1/2 are most effective in halting the RAS signaling cascade, and the relative success of this and related small molecule interventions in MPNSTs may be predicated upon the molecular status of neurofibromin.

A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin.

BACKGROUND: Acute lymphoblastic leukemia (ALL) remains a major cause of death in children. AMP-activated protein kinase (AMPK) affects the unfolded protein response (UPR), leading to increased vulnerability to endoplasmic reticulum (ER) stress in ALL cells. In vitro, metformin causes ALL cell death via AMPK-mediated inhibition of the UPR. It was evaluated whether ER stress could be induced in relapsed ALL through a phase I study investigating the safety and feasibility of metformin in combination with relapse induction chemotherapy. PROCEDURE: Metformin was administered twice daily for 28 days in addition to vincristine, dexamethasone, PEG-asparaginase and doxorubicin (VXLD). Dose escalation of metformin was evaluated using a 3+3 design. Pharmacokinetics (PK), pharmacodynamic (PD) evaluation of the AMPK and ER stress/UPR pathways, and treatment response were assessed. RESULTS: Fourteen patients were enrolled; all were evaluable for toxicity. The recommended phase 2 dose (RP2D) was Dose level 2, 1,000 mg/m2 /day. A single dose-limiting toxicity (DLT), hypoglycemia with acidosis, was observed at the RP2D and two DLTs, diarrhea and acidosis, were observed at Dose Level 3. Nine patients were evaluable for response as defined by the protocol, receiving at least 85% of planned metformin doses. Five complete remissions, one partial response, and one stable disease were observed. PD evaluation showed induction of ER stress, activation of AMPK, and inhibition of the UPR. CONCLUSIONS: The VXLD with metformin was tolerable with a RP2D for metformin of 1,000 mg/m2 /day and yielded responses in a heavily pretreated population. ER stress was induced and toxicities attributable to metformin occurred in all dose levels.

Macrophage depletion and Schwann cell transplantation reduce cyst size after rat contusive spinal cord injury.

Schwann cell transplantation is a promising therapy for the treatment of spinal cord injury (SCI) and is currently in clinical trials. In our continuing efforts to improve Schwann cell transplantation strategies, we sought to determine the combined effects of Schwann cell transplantation with macrophage depletion. Since macrophages are major inflammatory contributors to the acute spinal cord injury, and are the major phagocytic cells, we hypothesized that transplanting Schwann cells after macrophage depletion will improve cell survival and integration with host tissue after SCI. To test this hypothesis, rat models of contusive SCI at thoracic level 8 were randomly subjected to macrophage depletion or not. In rat subjected to macrophage depletion, liposomes filled with clodronate were intraperitoneally injected at 1, 3, 6, 11, and 18 days post injury. Rats not subjected to macrophage depletion were intraperitoneally injected with liposomes filled with phosphate buffered saline. Schwann cells were transplanted 1 week post injury in all rats. Biotinylated dextran amine (BDA) was injected at thoracic level 5 to evalute axon regeneration. The Basso, Beattie, and Bresnahan locomotor test, Gridwalk test, and sensory test using von Frey filaments were performed to assess functional recovery. Immunohistochemistry was used to detect glial fibrillary acidic protein, neurofilament, and green fluorescent protein (GFP), and also to visulize BDA-labelled axons. The GFP labeled Schwann cell and cyst and lesion volumes were quantified using stained slides. The numbers of BDA-positive axons were also quantified. At 8 weeks after Schwann cell transplantation, there was a significant reduction in cyst and lesion volumes in the combined treatment group compared to Schwann cell transplantation alone. These changes were not associated, however, with improved Schwann cell survival, axon growth, or locomotor recovery. Although combining Schwann cell transplantation with macrophage depletion does improve histopathology of the injury site, the effect on axon growth and behavioral recovery appears no better than what can be achieved with Schwann cell transplants alone.

Improved Outcomes of Enhanced Recovery After Surgery (ERAS) Protocol for Radical Cystectomy with Addition of a Multidisciplinary Care Process in a US Comprehensive Cancer Care Center.

INTRODUCTION: Although enhanced recovery after surgery (ERAS) components include both anesthesia and surgical care processes, it is unclear whether a multidisciplinary approach to implementing ERAS care processes improves clinical outcomes. The addition of multidisciplinary care with anesthesiology-related components to an existing ERAS protocol for radical cystectomy at a US comprehensive cancer center provided an opportunity to compare short- and long-term outcomes. METHODS: We retrospectively compared the outcomes of 116 consecutive patients who underwent cystectomy after implementation of a multidisciplinary ERAS protocol with those of a historical control group of 143 consecutive patients who had been treated with a surgical ERAS protocol. Length of stay, return of bowel function, rate of blood transfusion, nausea, pain, and readmission rates were examined. RESULTS: Implementation of a multidisciplinary ERAS protocol was associated with better postsurgical symptom control, as indicated by lower rates of patient-reported nausea (P < .05). Multivariate Poisson regression analysis showed a decrease in estimated intraoperative transfusions (P ≤ .001) after adjusting for the effects of potential confounding variables. There were no statistically significant differences noted in length of stay, return of bowel function, 30- and 90-day complications, or readmissions. CONCLUSION: This is the first study to investigate the effects of adding anesthesia ERAS components to an existing surgical ERAS protocol for radical cystectomy. We found that with the addition of anesthesia-related interventions, there was a decrease in transfusions and nausea.

Single drug biomarker prediction for ER- breast cancer outcome from chemotherapy.

ER-negative breast cancer includes most aggressive subtypes of breast cancer such as triple negative (TN) breast cancer. Excluded from hormonal and targeted therapies effectively used for other subtypes of breast cancer, standard chemotherapy is one of the primary treatment options for these patients. However, as ER- patients have shown highly heterogeneous responses to different chemotherapies, it has been difficult to select most beneficial chemotherapy treatments for them. In this study, we have simultaneously developed single drug biomarker models for four standard chemotherapy agents: paclitaxel (T), 5-fluorouracil (F), doxorubicin (A) and cyclophosphamide (C) to predict responses and survival of ER- breast cancer patients treated with combination chemotherapies. We then flexibly combined these individual drug biomarkers for predicting patient outcomes of two independent cohorts of ER- breast cancer patients who were treated with different drug combinations of neoadjuvant chemotherapy. These individual and combined drug biomarker models significantly predicted chemotherapy response for 197 ER- patients in the Hatzis cohort (AUC = 0.637, P = 0.002) and 69 ER- patients in the Hess cohort (AUC = 0.635, P = 0.056). The prediction was also significant for the TN subgroup of both cohorts (AUC = 0.60, 0.72, P = 0.043, 0.009). In survival analysis, our predicted responder patients showed significantly improved survival with a >17 months longer median PFS than the predicted non-responder patients for both ER- and TN subgroups (log-rank test P-value = 0.018 and 0.044). This flexible prediction capability based on single drug biomarkers may allow us to even select new drug combinations most beneficial to individual patients with ER- breast cancer.

CONCORD biomarker prediction for novel drug introduction to different cancer types.

Many cancer therapeutic agents have shown to be effective for treating multiple cancer types. Yet major challenges exist toward introducing a novel drug used in one cancer type to different cancer types, especially when a relatively small number of patients with the other cancer type often benefit from anti-cancer therapy with the drug. Recently, many novel agents were introduced to different cancer types together with companion biomarkers which were obtained or biologically assumed from the original cancer type. However, there is no guarantee that biomarkers from one cancer can directly predict a therapeutic response in another. To tackle this challenging question, we have developed a concordant expression biomarker-based technique ("CONCORD") that overcomes these limitations. CONCORD predicts drug responses from one cancer type to another by identifying concordantly co-expressed biomarkers across different cancer systems. Application of CONCORD to three standard chemotherapeutic agents and two targeted agents demonstrated its ability to accurately predict the effectiveness of a drug against new cancer types and predict therapeutic response in patients.

Gene Expression Signature-Based Prediction of Lymph Node Metastasis in Patients With Endometrioid Endometrial Cancer.

OBJECTIVE: This study aimed to develop a prediction model for lymph node metastasis using a gene expression signature in patients with endometrioid-type endometrial cancer. METHODS: Newly diagnosed endometrioid-type endometrial cancer cases in which the patients had undergone lymphadenectomy during a surgical staging procedure were identified from a national dataset (N = 330). Clinical and pathologic data were extracted from patient medical records, and gene expression datasets of their tumors were used to create a 12-gene predictive model for lymph node metastasis. We used principal components analysis on a training set (n = 110) to develop multivariate logistic models to predict low-risk patients having a probability of lymph node metastasis of less than 4%. The model with the highest prediction performance was selected for an evaluation set (n = 112), which, in turn, was validated in an independent validation set (n = 108). RESULTS: The model applied to the evaluation set showed 100% sensitivity (90% confidence interval [CI], 74%-100%) and 42% specificity (90% CI, 34%-51%), which resulted in 100% negative predictive value (90% CI, 89%-100%). In the validation set, we confirmed that the model consistently showed 100% sensitivity (90% CI, 88%-100%), 42% specificity (90% CI, 32%-50%), and 100% negative predictive value (90% CI, 88%-100%). CONCLUSIONS: Our 12-gene signature model is a useful tool for the identification of patients with endometrioid-type endometrial cancer at low risk of lymph node metastasis, particularly given that it can be used to analyze histologic tissue before surgery and used to tailor surgical options.