Emerging EZH2 Inhibitors and Their Application in Lymphoma

Abstract

Purpose of Review

Enhancer of Zeste Homolog 2 (EZH2) is histone methyltransferase and catalyzes the methylation of histone 3 lysine 27, a mark of transcriptional repression. Various studies have elucidated the complex role of EZH2 in both normal biology and tumorigenesis. Here, we critically review the emerging role of EZH2 in malignancies, the development of small molecule inhibitors of EZH2, and their application in lymphoma.

Recent Findings

Activating mutations and overexpression of EZH2 are found in non-Hodgkin lymphoma (NHL). As a result, several EZH2 inhibitors have been developed and entered clinical investigation. Tazemetostat, first-in-class EZH2 inhibitor, demonstrated enhanced clinical activity in mutant follicular lymphoma and diffuse large B cell lymphoma.

Summary

With the early activity noted by tazemetostat in B cell lymphomas, the role of EZH2 inhibition in NHL is becoming more evident. This can be leveraged in future rationale combinations to enhance the activity of EZH2 inhibitors.

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Confidence Analysis of DEER Data and its Structural Interpretation with Ensemble-Biased Metadynamics

Given its ability to measure multicomponent distance distributions between electron-spin probes, Double Electron-Electron Resonance spectroscopy (DEER) has become a leading technique to assess the structural dynamics of biomolecules. However, methodologies to evaluate the statistical error of these distributions are not standard, often hampering a rigorous interpretation of the experimental results. Distance distributions are often determined from the experimental DEER data through a mathematical method known as Tikhonov regularization, but this approach makes rigorous error estimates difficult.

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Lipid-mediated interactions between the antimicrobial peptides magainin 2 and PGLa in bilayers

A synergistic enhancement of activities has been described for the amphipathic cationic antimicrobial peptides magainin 2 and PGLa when tested in antimicrobial assays or in biophysical experiments using model membranes. In the presence of magainin 2, PGLa changes from an in-planar alignment parallel to the membrane surface to a more transmembrane orientation when investigated in membranes made from fully saturated PC or PC/PG, but not when one of the fatty acyl chains is unsaturated. Such lipid-mediated changes in the membrane topology of polypeptide domains could provide an interesting mechanism for the regulation of membrane proteins.

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Effect of cytoskeleton elasticity on amoeboid swimming

Recently, it has been reported that the cells of the immune system, as well as dictyostelium amoebae, can swim in a bulk fluid by changing their shape repeatedly. We refer to this motion as the amoeboid swimming. Here, we explore how the propulsion and the deformation of the cell emerges as an interplay between the active forces that the cell employs to activate the shape changes, and the passive, visco–elastic response of the cell membrane, the cytoskeleton, and the surrounding environment. We introduce a model, in which the cell is represented by an elastic capsule enclosing a viscous liquid.

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A luminal loop of Wilson disease protein binds copper and is required for protein activity

The copper-transporting ATPase ATP7B is essential for loading of copper ions to copper-dependent enzymes in the secretory pathway; its inactivation results in Wilson disease. In contrast to copper ion uptake by the cytoplasmic domains, ATP7B-mediated copper ion release in the Golgi has not been explored yet. We here demonstrate that a luminal loop in ATP7B, rich in histidine/methionine residues, binds reduced copper (Cu(I)) ions and identified copper-binding residues play an essential role in ATP7B-mediated metal ion release.

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Biomembrane Adhesion to Substrates Topographically Patterned with Nanopits

We examine the adhesion of biomembranes to substrates topographically patterned with concave nanopits, and identify several universal features in the adhesion process. We find three distinct states, depending on whether the membrane remains flat above the nanopit, partially enters it, or completely adheres to it, and derive analytical conditions for the stability of these states valid for a very general class of nanopit shapes. Surprisingly, completely adhered states are always (meta)stable. We also show that the presence of many nanopits can increase or decrease the effective adhesiveness of a substrate, depending on the tension of the membrane and the strength of the membrane–substrate attraction.

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Charge interactions can dominate coupled folding and binding on the ribosome

Interactions between emerging nascent polypeptide chains and the ribosome can affect cotranslational protein folding. However, it has remained unclear how such interactions can affect the binding of nascent chains to their cellular targets. We thus investigated, on the ribosome, the interaction between the two intrinsically disordered proteins of opposite charge, ACTR and NCBD, which form a high-affinity complex in a coupled folding-and-binding reaction. Using fluorescence correlation spectroscopy and arrest-peptide-mediated force measurements in vitro and in vivo, we find that the ACTR-NCBD complex can form cotranslationally, but only with ACTR as the nascent chain and NCBD free in solution, not vice versa.

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Co-entangled actin-microtubule composites exhibit tunable nonlinear stiffness and power-law stress relaxation

We use optical tweezers microrheology and fluorescence microscopy to characterize the nonlinear mesoscale mechanics and mobility of in vitro co-entangled actin-microtubule composites. We create a suite of randomly-oriented, well-mixed networks of actin and microtubules by co-polymerizing varying ratios of actin and tubulin in situ. To perturb each composite far from equilibrium, we use optical tweezers to displace an embedded microsphere a distance greater than the lengths of the filaments at a speed much faster than their intrinsic relaxation rates.

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Nonlinear elasticity of the ECM fibers facilitates efficient inter-cellular communication

Biological cells embedded in fibrous matrices have been observed to form inter-cellular bands of dense and aligned fibers, through which they mechanically interact over long distances. Such matrix-mediated cellular interactions have been shown to regulate various biological processes. The current study aimed to explore the effects of elastic nonlinearity of the fibers contained in the extracellular matrix (ECM) on the transmission of mechanical loads between contracting cells. Based on our biological experiments, we developed a finite-element model of two contracting cells embedded within a fibrous network.

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Immunophenotypic and cytogenetic evolution patterns of the neoplastic plasma cells in multiple myeloma relapsed after stem cell transplant

Abstract

Multiple myeloma (MM) is a neoplasm characterized by proliferation of clonal plasma cells (PCs) and a combination of clinical manifestations. Flow cytometry is an important method for diagnosing and monitoring of MM. Cytogenetic profiling of neoplastic PCs provides important prognostic information. Although stem cell transplantation (SCT) has significantly improved the overall survival of patients with MM, most SCT recipients relapse. We have studied the immunophenotypic and cytogenetic dissimilarities in the neoplastic PCs before SCT and after relapse in patients with initial complete remission, and investigated a possible influence of such dissimilarities on the patients' survival. We retrospectively reviewed results of flow cytometric studies of bone marrow specimens from 46 patients with MM who underwent SCT, demonstrated a complete initial response, but subsequently relapsed. In nine of these patients, fluorescence in situ hybridization (FISH) studies were performed both pre-SCT and post-relapse. We have shown a significant flow cytometric and cytogenetic diversity of the neoplastic PCs in relapsed MM post-SCT. Such changes were detected in a considerable number of cases (47.8% and 44.4%, respectively). The most frequent cytogenetic changes indicate an emergence of possibly a more aggressive PC clone, known to be associated with worse prognosis and poorer outcome. Our study has demonstrated that the acquisition of immunophenotypic changes predicts worse overall survival.

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Toward a sensible single antigen bead cut-off based on kidney graft survival

Background There is no consensus in the literature on the interpretation of single antigen bead (SAB) positive for a specific HLA antibody. Methods To inform the debate, we studied the relationship between various SAB positivity algorithms and the impact of resulting donor-specific HLA antibody (DSA) positivity on long-term kidney graft survival in 3237 deceased-donor transplants. Results First, we showed that the interassay variability can be greatly reduced when working with signal-to-background ratios instead of absolute MFIs. Next, we determined pretransplant DSA using various MFI cut-offs, signal-to-background ratios (STBR) and combinations thereof. The impact of the various cut-offs was studied by comparing the graft survival between the DSA-positive and DSA-negative groups. We did not observe a strong impact of various cut-off levels on 10-year graft survival. A stronger relationship between the cut-off level and 1-year graft survival for DSA-positive transplants was found when using STBR, most pronounced for the bead of the same HLA-locus with lowest MFI taken as background. Conclusions With respect to pretransplant risk stratification, we propose a SBTR-6 (using the bead of the same HLA-locus with lowest MFI as background) cut-off of 15 combined with an MFI cut-off of 500, resulting in 8% and 21% lower 1- and 10-years graft survival, respectively, for 8% DSA positive transplants. Corresponding author: E-mail address: H.G.Otten@umcutrecht.nl. Corresponding author permanent address: Laboratory of Translational Immunology, University Medical Center Utrecht, F.03.821, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. Tel.: +31 88 75 57680 Disclosure The authors of this manuscript have no conflicts of interest to disclose. Authorship Participated in research design: BW, EK, AD, LP, HO Participated in writing of the paper: BW, EK, IJ, WA, LH, AvZ, MV, MLB, BH, AL, LB, CR, CV, ItB, AH, SH, DR, FC, HO Participated in the performance of the research: BW, EK, AD, LP Contributed new reagents or analytic tools: BW, EK, IJ, WA, AvdM, LH, MCB, ES, CH, FvR, AvZ, MV, MLB, AD, LP, MS, JS, BH, AL, LB, CR, MT, CV, LW, EvD, MG, MC, FvI, AN, NL, WS, KvdP, NvdW, ItB, FB, AH, PvdB, JdF, MB, SH, DR, FC, HO Participated in data analysis: BW, EK, HO Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Targeted Therapies for Brain Tumors: Will They Ever Deliver?

The strategy of using biologically targeted therapeutics for cancer has yet to translate into effective treatment of gliomas. The neuro-oncology community is beginning to recognize that phase 0 studies should be performed to account for the impact of the blood–brain barrier on the ability of a therapeutic to reach its target(s). Clin Cancer Res; 24(16); 3790–1. ©2018 AACR.

See related article by Sanai et al., p. 3820

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Renin-Angiotensin System Inhibitors to Mitigate Cancer Treatment-Related Adverse Events

Treatment-related side effects are a major clinical problem in cancer treatment. They lead to reduced compliance to therapy as well as increased morbidity and mortality. Well-known are the sequelae of chemotherapy on the heart, especially in childhood cancer survivors. Therefore, measures to mitigate the adverse events of cancer therapy may improve health and quality of life in patients with cancer, both in the short and long term. The renin–angiotensin system (RAS) affects all hallmarks of cancer, and blockage of the RAS is associated with an improved outcome in several cancer types. There is also increasing evidence that inhibition of the RAS might be able to alleviate or even prevent certain types of cancer treatment–related adverse effects. In this review, we summarize the potential of RAS inhibitors to mitigate cancer treatment–related adverse events, with a special emphasis on chemotherapy-induced cardiotoxicity, radiation injury, and arterial hypertension. Clin Cancer Res; 24(16); 3803–12. ©2018 AACR.

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Development and Validation of a Prostate Cancer Genomic Signature that Predicts Early ADT Treatment Response Following Radical Prostatectomy

Purpose: Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT.

Experimental Design: A training set consisting of 284 radical prostatectomy patients was established after 1:1 propensity score matching metastasis between adjuvant-ADT (a-ADT)-treated and no ADT–treated groups. An ADT Response Signature (ADT-RS) was identified from neuroendocrine and AR signaling–related genes. Two independent cohorts were used to form three separate data sets for validation (set I, n = 232; set II, n = 435; set III, n = 612). The primary endpoint of the analysis was postoperative metastasis.

Results: Increases in ADT-RS score were associated with a reduction in risk of metastasis only in a-ADT patients. On multivariable analysis, ADT-RS by ADT treatment interaction term remained associated with metastasis in both validation sets (set I: HR = 0.18, P_interaction = 0.009; set II: HR = 0.25, P_interaction = 0.019). In a matched validation set III, patients with Low ADT-RS scores had similar 10-year metastasis rates in the a-ADT and no-ADT groups (30.1% vs. 31.0%, P = 0.989). Among High ADT-RS patients, 10-year metastasis rates were significantly lower for a-ADT versus no-ADT patients (9.4% vs. 29.2%, P = 0.021). The marginal ADT-RS by ADT interaction remained significant in the matched dataset (P_interaction = 0.035).

Conclusions: Patients with High ADT-RS benefited from a-ADT. In combination with prognostic risk factors, use of ADT-RS may thus allow for identification of ADT-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early ADT after surgery. Clin Cancer Res; 24(16); 3908–16. ©2018 AACR.

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Adjuvant Therapy for Colon Cancer: Genes, Genes... and the Patient in the Center

Although molecular subtype–based stratification and genomic signatures of increasing complexity are becoming a new strategy to guide therapeutic decisions in stage II/III colon cancer, several prognostic factors that can be easily obtained from formalin-fixed paraffin-embedded (FFPE) specimens should be considered to create combined models that better define individual patients' needs. Clin Cancer Res; 24(16); 3787–9. ©2018 AACR.

See related article by Kandimalla et al., p. 3867

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Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by Ex Vivo-Expanded Autologous NK Cells

Purpose: Daratumumab and its use in combination with other agents is becoming a new standard of care for the treatment of multiple myeloma. We mechanistically studied how daratumumab acts on natural killer (NK) cells.

Experimental Design: Quantities of NK cells in peripheral blood and/or bone marrow of patients with multiple myeloma or healthy donors were examined by flow cytometry. NK-cell apoptosis and the associated mechanism were assessed by flow cytometry and immunoblotting. Patients' NK cells were expanded in vitro using feeder cells. Combination treatment of daratumumab and expanded NK cells was performed using an MM.1S xenograft animal model.

Results: CD38^–/low NK cells survived, whereas CD38⁺ NK cells were almost completely eliminated, in peripheral blood and bone marrow of daratumumab-treated multiple myeloma patients. NK-cell depletion occurred due to daratumumab-induced NK-cell fratricide via antibody-dependent cellular cytotoxicity. Consequently, CD38^–/low NK cells were more effective for eradicating multiple myeloma cells than were CD38⁺ NK cells in the presence of daratumumab. Blockade of CD38 with the F(ab)₂ fragments of daratumumab inhibited the antibody-mediated NK-cell fratricide. CD38^–/low NK cells displayed a significantly better potential for expansion than CD38⁺ NK cells, and the expanded NK cells derived from the former population were more cytotoxic than those derived from the latter against multiple myeloma cells. Therefore, infusion of ex vivo–expanded autologous NK cells from daratumumab-treated patients may improve the antibody therapy.

Conclusions: We unravel a fratricide mechanism for daratumumab-mediated NK-cell depletion and provide a potential therapeutic strategy to overcome this side effect in daratumumab-treated patients with multiple myeloma. Clin Cancer Res; 24(16); 4006–17. ©2018 AACR.

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Cross-talk between T Cells and Hematopoietic Stem Cells during Adoptive Cellular Therapy for Malignant Glioma

Purpose: Adoptive T-cell immunotherapy (ACT) has emerged as a viable therapeutic for peripheral and central nervous system (CNS) tumors. In peripheral cancers, optimal efficacy of ACT is reliant on dendritic cells (DCs) in the tumor microenvironment. However, the CNS is largely devoid of resident migratory DCs to function as antigen-presenting cells during immunotherapy. Herein, we demonstrate that cellular interactions between adoptively transferred tumor-reactive T cells and bone marrow–derived hematopoietic stem and progenitor cells (HSPCs) lead to the generation of potent intratumoral DCs within the CNS compartment.

Experimental Design: We evaluated HSPC differentiation during ACT in vivo in glioma-bearing hosts and HSPC proliferation and differentiation in vitro using a T-cell coculture system. We utilized FACS, ELISAs, and gene expression profiling to study the phenotype and function of HSPC-derived cells ex vivo and in vivo. To demonstrate the impact of HSPC differentiation and function on antitumor efficacy, we performed survival experiments.

Results: Transfer of HSPCs with concomitant ACT led to the production of activated CD86⁺CD11c⁺MHCII⁺ cells consistent with DC phenotype and function within the brain tumor microenvironment. These intratumoral DCs largely supplanted abundant host myeloid-derived suppressor cells. We determined that during ACT, HSPC-derived cells in gliomas rely on T-cell–released IFN to differentiate into DCs, activate T cells, and reject intracranial tumors.

Conclusions: Our data support the use of HSPCs as a novel cellular therapy. Although DC vaccines induce robust immune responses in the periphery, our data demonstrate that HSPC transfer uniquely generates intratumoral DCs that potentiate T-cell responses and promote glioma rejection in situ. Clin Cancer Res; 24(16); 3955–66. ©2018 AACR.

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T-cell Dysfunction in Glioblastoma: Applying a New Framework

A functional, replete T-cell repertoire is an integral component to adequate immune surveillance and to the initiation and maintenance of productive antitumor immune responses. Glioblastoma (GBM), however, is particularly adept at sabotaging antitumor immunity, eliciting severe T-cell dysfunction that is both qualitative and quantitative. Understanding and countering such dysfunction are among the keys to harnessing the otherwise stark potential of anticancer immune-based therapies. Although T-cell dysfunction in GBM has been long described, newer immunologic frameworks now exist for reclassifying T-cell deficits in a manner that better permits their study and reversal. Herein, we divide and discuss the various T-cell deficits elicited by GBM within the context of the five relevant categories: senescence, tolerance, anergy, exhaustion, and ignorance. Categorization is appropriately made according to the molecular bases of dysfunction. Likewise, we review the mechanisms by which GBM elicits each mode of T-cell dysfunction and discuss the emerging immunotherapeutic strategies designed to overcome them. Clin Cancer Res; 24(16); 3792–802. ©2018 AACR.

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Highlights of This Issue

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Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models.

Experimental Design: In a large set of patients with OCCC (n = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines (n = 17) and OCCC patient–derived xenografts (n = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055.

Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient–derived xenograft models.

Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Clin Cancer Res; 24(16); 3928–40. ©2018 AACR.

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Curation of the Pancreatic Ductal Adenocarcinoma Subset of the Cancer Genome Atlas Is Essential for Accurate Conclusions about Survival-Related Molecular Mechanisms

Purpose: Publicly available databases, for example, The Cancer Genome Atlas (TCGA), containing clinical and molecular data from many patients are useful in validating the contribution of particular genes to disease mechanisms and in forming novel hypotheses relating to clinical outcomes.

Experimental Design: The impact of key drivers of cancer progression can be assessed by segregating a patient cohort by certain molecular features and constructing survival plots using the associated clinical data. However, conclusions drawn from this straightforward analysis are highly dependent on the quality and source of tissue samples, as demonstrated through the pancreatic ductal adenocarcinoma (PDAC) subset of TCGA.

Results: Analyses of the PDAC-TCGA database, which contains mainly resectable cancer samples from patients in stage IIB, reveal a difference from widely known historic median and 5-year survival rates of PDAC. A similar discrepancy was observed in lung, stomach, and liver cancer subsets of TCGA. The whole transcriptome expression patterns of PDAC-TCGA revealed a cluster of samples derived from neuroendocrine tumors, which have a distinctive biology and better disease prognosis than PDAC. Furthermore, PDAC-TCGA contains numerous pseudo-normal samples, as well as those that arose from tumors not classified as PDAC.

Conclusions: Inclusion of misclassified samples in the bioinformatic analyses distorts the association of molecular biomarkers with clinical outcomes, altering multiple published conclusions used to support and motivate experimental research. Hence, the stringent scrutiny of type and origin of samples included in the bioinformatic analyses by researchers, databases, and web-tool developers is of crucial importance for generating accurate conclusions. Clin Cancer Res; 24(16); 3813–9. ©2018 AACR.

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Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice

Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed.

Experimental Design: Fibroblast activation protein (FAP)–specific CARs with different costimulatory domains, including CD28, -CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the -CD28 CAR was tested clinically in a patient with MPM.

Results: All the three CARs demonstrated FAP-specific functionality in vitro. Gene expression data indicated a distinct activity profile for the -CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the -CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the -CD28 CAR could be detected for up to 21 days and showed functionality.

Conclusions: Overall, anti-FAP--CD28/CD3 CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981–93. ©2018 AACR.

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Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients

Purpose: AZD1775 is a first-in-class Wee1 inhibitor with dual function as a DNA damage sensitizer and cytotoxic agent. A phase I study of AZD1775 for solid tumors suggested activity against brain tumors, but a preclinical study indicated minimal blood–brain barrier penetration in mice. To resolve this controversy, we examined the pharmacokinetics and pharmacodynamics of AZD1775 in patients with first-recurrence, glioblastoma.

Patients and Methods: Twenty adult patients received a single dose of AZD1775 prior to tumor resection and enrolled in either a dose-escalation arm or a time-escalation arm. Sparse pharmacokinetic blood samples were collected, and contrast-enhancing tumor samples were collected intraoperatively. AZD1775 total and unbound concentrations were determined by a validated LC/MS-MS method. Population pharmacokinetic analysis was performed to characterize AZD1775 plasma pharmacokinetic profiles. Pharmacodynamic endpoints were compared to matched archival tissue.

Results: The AZD1775 plasma concentration–time profile following a single oral dose in patients with glioblastoma was well-described by a one-compartment model. Glomerular filtration rate was identified as a significant covariate on AZD1775 apparent clearance. AZD1775 showed good brain tumor penetration, with a median unbound tumor-to-plasma concentration ratio of 3.2, and achieved potential pharmacologically active tumor concentrations. Wee1 pathway suppression was inferred by abrogation of G₂ arrest, intensified double-strand DNA breakage, and programmed cell death. No drug-related adverse events were associated with this study.

Conclusions: In contrast to recent preclinical data, our phase 0 study of AZD 1775 in recurrent glioblastoma indicates good human brain tumor penetration, provides the first evidence of clinical biological activity in human glioblastoma, and confirms the utility of phase 0 trials as part of an accelerated paradigm for drug development in patients with glioma. Clin Cancer Res; 24(16); 3820–8. ©2018 AACR.

See related commentary by Vogelbaum, p. 3790

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Metformin Targets Mitochondrial Glycerophosphate Dehydrogenase to Control Rate of Oxidative Phosphorylation and Growth of Thyroid Cancer In Vitro and In Vivo

Purpose: Mitochondrial glycerophosphate dehydrogenase (MGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin in the liver. There are no data on the expression and role of MGPDH as a metformin target in cancer. In this study, we evaluated MGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism.

Experimental Design: We analyzed MGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer–derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on MGPDH expression were determined by qRT-PCR and Western blot analysis. Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and MGPDH expression in metastatic thyroid cancer mouse models.

Results: We show for the first time that MGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that MGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of MGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high MGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth-inhibitory effects of metformin in vitro and in vivo.

Conclusions: Our study established MGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin. Clin Cancer Res; 24(16); 4030–43. ©2018 AACR.

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Andecaliximab/GS-5745 Alone and Combined with mFOLFOX6 in Advanced Gastric and Gastroesophageal Junction Adenocarcinoma: Results from a Phase I Study

Purpose: Matrix metalloproteinase-9 (MMP9) is implicated in protumorigenic processes. Andecaliximab (GS-5745, a monoclonal antibody targeting MMP9) was evaluated as monotherapy and in combination with mFOLFOX6.

Patients and Methods: Three dosages of andecaliximab monotherapy [200, 600, and 1800 mg i.v. every 2 weeks (q2w)] were investigated in patients with advanced solid tumors (n = 13 in a 3+3 design). After determining a recommended dose, patients with advanced HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma (n = 40) received 800 mg andecaliximab + mFOLFOX6 q2w. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed.

Results: Andecaliximab monotherapy demonstrated no dose-limiting toxicity (DLT) in any cohort, displaying target-mediated drug disposition at the lowest dose (200 mg) and linear pharmacokinetics at higher doses. Based on target engagement, recommended doses for further study are 800 mg q2w or 1,200 mg q3w. Maximal andecaliximab target binding, defined as undetectable andecaliximab-free MMP9 in plasma, was observed in the gastric/GEJ adenocarcinoma cohort. We observed no unusual toxicity, although there were four deaths on study not attributed to andecaliximab treatment. In first-line patients (n = 36), median progression-free survival (PFS) was 9.9 months [95% confidence interval (CI), 5–13.9 months], and the overall response rate (ORR) was 50%. Among all patients (n = 40), median PFS was 7.8 (90% CI, 5.5–13.9) months, and ORR was 48%, with a median duration of response of 8.4 months.

Conclusions: Andecaliximab monotherapy achieved target engagement without DLT. Andecaliximab + mFOLFOX6 showed encouraging clinical activity without additional toxicity in patients with HER2-negative gastric/GEJ adenocarcinoma. A phase III study evaluating mFOLFOX6 ± andecaliximab in this setting is ongoing. Clin Cancer Res; 24(16); 3829–37. ©2018 AACR.

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Identification and Validation of Radiographic Enhancement for Reliable Differentiation of CD117(+) Benign Renal Oncocytoma and Chromophobe Renal Cell Carcinoma

Purpose: The diagnostic differential for CD117/KIT(+) oncocytic renal tumor biopsies is limited to benign renal oncocytoma versus chromophobe renal cell carcinoma (ChRCC); however, further differentiation is often challenging and requires surgical resection. We investigated clinical variables that might improve preoperative differentiation of CD117(+) renal oncocytoma versus ChRCC to avoid the need for benign tumor resection.

Experimental Design: A total of 124 nephrectomy patients from a single institute with 133 renal oncocytoma or ChRCC tumors were studied. Patients from 2003 to 2012 comprised a retrospective cohort to identify clinical/radiographic variables associated with renal oncocytoma versus ChRCC. Prospective validation was performed among consecutive renal oncocytoma/ChRCC tumors resected from 2013 to 2017.

Results: Tumor size and younger age were associated with ChRCC, and multifocality with renal oncocytoma; however, the most reliable variable for ChRCC versus renal oncocytoma differentiation was the tumor:cortex peak early-phase enhancement ratio (PEER) using multiphase CT. Among 54 PEER-evaluable tumors in the retrospective cohort [19 CD117(+), 13 CD117(–), 22 CD117-untested], PEER classified each correctly as renal oncocytoma (PEER >0.50) or ChRCC (PEER ≤0.50), except for four misclassified CD117(–) ChRCC variants. Prospective study of PEER confirmed 100% accuracy of renal oncocytoma/ChRCC classification among 22/22 additional CD117(+) tumors. Prospective interobserver reproducibility was excellent for PEER scoring (intraclass correlation coefficient, ICC = 0.97) and perfect for renal oncocytoma/ChRCC assignment (ICC = 1.0).

Conclusions: In the largest clinical comparison of renal oncocytoma versus ChRCC to our knowledge, we identified and prospectively validated a reproducible radiographic measure that differentiates CD117(+) renal oncocytoma from ChRCC with potentially 100% accuracy. PEER may allow reliable biopsy-based diagnosis of CD117(+) renal oncocytoma, avoiding the need for diagnostic nephrectomy. Clin Cancer Res; 24(16); 3898–907. ©2018 AACR.

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Phase IB/II Study of Second-Line Therapy with Panitumumab, Irinotecan, and Everolimus (PIE) in KRAS Wild-Type Metastatic Colorectal Cancer

Purpose: Inhibition of mTOR in addition to EGFR may overcome resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC). This phase Ib/II study evaluated the safety and efficacy of the combination of irinotecan, panitumumab, and everolimus.

Patients and Methods: Patients with KRAS exon 2 wild-type (WT) mCRC following failure of fluoropyrimidine-based therapy received i.v. irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14-day cycle. The primary endpoint of the phase II study was response rate (RR). Secondary survival outcomes were calculated using the Kaplan–Meier method, and results were analyzed as intention to treat. A preplanned exploratory biomarker analysis was performed.

Results: Forty-nine patients were enrolled. Dose level 1 (irinotecan 200 mg/m², panitumumab 6 mg/kg, and everolimus 5 mg alternate day) was declared the MTD with no dose-limiting toxicities in six patients. Forty patients were treated at dose level 1: median age, 60 years (37–76); 65% male; 45% and 52.5%, respectively, with Eastern Cooperative Oncology Group values of 0/1. Median dose intensity was 85%. Grade 3 toxicities were diarrhea (23%), mucositis (18%), rash (13%), fatigue (8%), dehydration (5%), neutropenia (20%), febrile neutropenia (8%), hypomagnesemia (20%), and hypokalemia (8%). Grade 4 toxicities were hypomagnesemia (5%) and neutropenia (3%). RR was 48%, and stable disease was 43%. Median progression-free survival (PFS) was 5.6 months, and median overall survival (OS) was 10.8 months. Twenty-five patients were RAS/RAF WT and had an RR of 60%, median PFS of 6.4 months, and OS of 11.8 months.

Conclusions: The toxicity of the panitumumab, irinotecan, and everolimus regimen is as expected and manageable. The RR of 60% in all RAS/RAF WT supports further study of this combination. Clin Cancer Res; 24(16); 3838–44. ©2018 AACR.

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{Delta}Np63{gamma}/SRC/Slug Signaling Axis Promotes Epithelial-to-Mesenchymal Transition in Squamous Cancers

Purpose: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in head and neck squamous cell carcinoma (HNSCC) and its importance in tumor invasion.

Experimental Design: We use a three-dimensional invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the human papilloma virus-16, coupled with bioinformatic and IHC analysis of patient samples to investigate the role played by EMT in invasion and identify effectors and upstream regulatory pathways.

Results: We identify SNAI2 (Slug) as a critical effector of EMT-activated downstream of TP63 overexpression in HNSCC. Splice-form–specific depletion and rescue experiments further identify the Np63 isoform as both necessary and sufficient to activate the SRC signaling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in patients with HNSCC in The Cancer Genome Atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacologic inhibition of SRC.

Conclusions: Overexpression of Np63 modulates cell invasion by inducing targetable SRC-Slug–evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signaling. Clin Cancer Res; 24(16); 3917–27. ©2018 AACR.

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Cytokines Produced by Dendritic Cells Administered Intratumorally Correlate with Clinical Outcome in Patients with Diverse Cancers

Purpose: Dendritic cells (DC) initiate adaptive immune responses through the uptake and presentation of antigenic material. In preclinical studies, intratumorally injected activated DCs (aDCs; DCVax-Direct) were superior to immature DCs in rejecting tumors from mice.

Experimental Design: This single-arm, open-label phase I clinical trial evaluated the safety and efficacy of aDCs, administered intratumorally, in patients with solid tumors. Three dose levels (2 million, 6 million, and 15 million aDCs per injection) were tested using a standard 3 + 3 dose-escalation trial design. Feasibility, immunogenicity, changes to the tumor microenvironment after direct injection, and survival were evaluated. We also investigated cytokine production of aDCs prior to injection.

Results: In total, 39 of the 40 enrolled patients were evaluable. The injections of aDCs were well tolerated with no dose-limiting toxicities. Increased lymphocyte infiltration was observed in 54% of assessed patients. Stable disease (SD; best response) at week 8 was associated with increased overall survival. Increased secretion of interleukin (IL)-8 and IL12p40 by aDCs was significantly associated with survival (P = 0.023 and 0.024, respectively). Increased TNFα levels correlated positively with SD at week 8 (P < 0.01).

Conclusions: Intratumoral aDC injections were feasible and safe. Increased production of specific cytokines was correlated with SD and prolonged survival, demonstrating a link between the functional profile of aDCs prior to injection and patient outcomes. Clin Cancer Res; 24(16); 3845–56. ©2018 AACR.

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Combined HDAC and Bromodomain Protein Inhibition Reprograms Tumor Cell Metabolism and Elicits Synthetic Lethality in Glioblastoma

Purpose: Glioblastoma remains a challenge in oncology, in part due to tumor heterogeneity.

Experimental Design: Patient-derived xenograft and stem-like glioblastoma cells were used as the primary model systems.

Results: Based on a transcriptome and subsequent gene set enrichment analysis (GSEA), we show by using clinically validated compounds that the combination of histone deacetylase (HDAC) inhibition and bromodomain protein (BRD) inhibition results in pronounced synergistic reduction in cellular viability in patient-derived xenograft and stem-like glioblastoma cells. Transcriptome-based GSEA analysis suggests that metabolic reprogramming is involved with synergistic reduction of oxidative and glycolytic pathways in the combination treatment. Extracellular flux analysis confirms that combined HDAC inhibition and BRD inhibition blunts oxidative and glycolytic metabolism of cancer cells, leading to a depletion of intracellular ATP production and total ATP levels. In turn, energy deprivation drives an integrated stress response, originating from the endoplasmic reticulum. This results in an increase in proapoptotic Noxa. Aside from Noxa, we encounter a compensatory increase of antiapoptotic Mcl-1 protein. Pharmacologic, utilizing the FDA-approved drug sorafenib, and genetic inhibition of Mcl-1 enhanced the effects of the combination therapy. Finally, we show in orthotopic patient-derived xenografts of GBM, that the combination treatment reduces tumor growth, and that triple therapy involving the clinically validated compounds panobinostat, OTX015, and sorafenib further enhances these effects, culminating in a significant regression of tumors in vivo.

Conclusions: Overall, these results warrant clinical testing of this novel, efficacious combination therapy. Clin Cancer Res; 24(16); 3941–54. ©2018 AACR.

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Interferon Gamma Messenger RNA Signature in Tumor Biopsies Predicts Outcomes in Patients with Non-Small Cell Lung Carcinoma or Urothelial Cancer Treated with Durvalumab

Purpose: To identify a predictive biomarker for durvalumab, an anti–programmed death ligand 1 (PD-L1) mAb.

Experimental Design: RNA sequencing of 97 advanced-stage non–small cell lung carcinoma (NSCLC) biopsies from a nonrandomized phase Ib/II clinical trial (1108/NCT01693562) were profiled to identify a predictive signature; 62 locally advanced or metastatic urothelial cancer tumors from the same study were profiled to confirm predictive utility of the signature. Thirty NSCLC patients provided pre- and posttreatment tumors for messenger RNA (mRNA) analysis. NSCLC with ≥25% tumor cells and urothelial cancer with ≥25% tumor or immune cells stained for PD-L1 at any intensity were scored PD-L1 positive (PD-L1⁺). Kaplan–Meier and Cox proportional hazards analyses were used to adjust for gender, age, prior therapies, histology, ECOG status, liver metastasis, and smoking. Tumor mutation burden (TMB) was calculated using data from The Cancer Genome Atlas (TCGA).

Results: In the NSCLC discovery set, a four-gene IFN-positive (IFN⁺) signature comprising IFN, CD274, LAG3, and CXCL9 was associated with higher overall response rates, longer median progression-free survival, and overall survival compared with signature-low patients. IFN⁺-signature NSCLC patients had improved survival regardless of IHC PD-L1 status. These associations were replicated in a urothelial cancer cohort. The IFN⁺ signature was induced 2-fold (P = 0.003) by durvalumab after 8 weeks of therapy in patients with NSCLC, and baseline signature was associated with TMB but not survival in TCGA data.

Conclusions: The IFN⁺ mRNA signature may assist in identifying patients with improved outcomes with durvalumab, independent of PD-L1 assessed by IHC. Clin Cancer Res; 24(16); 3857–66. ©2018 AACR.

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Adherence to anti-vectorial prevention measures among travellers with chikungunya and malaria returning to Australia: comparative epidemiology

Compare the adoption and adherence to health protection behaviours prior to and during travel among international Australian travellers who return to Australia with notified chikungunya or malaria infection. T...

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Psychological features of abstinent heroin users before and after rehabilitation in Saint Petersburg, Russia

The objective of the study was to describe psychological features of abstinent heroin users undergoing rehabilitation in Saint Petersburg, Russia. Study subjects (n = 197) were recruited prospectively at the t...

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Dengue fever manifesting with tetany as the first presentation of primary hypoparathyroidism: a case report

Primary hypoparathyroidism is associated with diverse variety of symptomatology of hypocalcemia including seizures and tetany. We report a case of previously undiagnosed asymptomatic primary hypoparathyroidism...

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Gender of children and social provisions as predictors of unplanned pregnancies in Pakistan: a cross-sectional survey

Previous research indicates that attitudes to pregnancy and motherhood are influenced by social values, culture and religion. This study explores the relationship between social support and unwanted pregnancy ...

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Highlights from Recent Cancer Literature

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Kras and Tp53 Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer epidemiologically linked with liver injury, which has poorly understood incipient stages and lacks early diagnostics and effective therapies. While iCCA is conventionally thought to arise from the biliary tract, studies have suggested that both hepatocytes and biliary cells (cholangiocytes) may give rise to iCCA. Consistent with the plasticity of these cell lineages, primary liver carcinomas exhibit a phenotypic range from hepatocellular carcinoma (HCC) to iCCA, with intermediates along this spectrum. Here, we generated mouse models to examine the consequence of targeting mutant Kras and Tp53, common alterations in human iCCA, to different adult liver cell types. Selective induction of these mutations in the SOX9+ population, predominantly consisting of mature cholangiocytes, resulted in iCCA emerging from premalignant biliary intraepithelial neoplasia (BilIN). In contrast, adult hepatocytes were relatively refractory to these mutations and formed rare HCC. In this context, injury accelerated hepatocyte-derived tumorigenesis and promoted a phenotypic switch to iCCA. BilIN precursor lesions were absent in the hepatocyte-derived iCCA models, pointing toward distinct and direct emergence of a malignant cholangiocytic phenotype from injured, oncogenically primed hepatocytes. Tp53 loss enhanced the reprogramming of hepatocytes to cholangiocytes, which may represent a mechanism facilitating formation of hepatocyte-derived iCCA. Overall, our work shows iCCA driven by Kras and Tp53 may originate from both mature cholangiocytes and hepatocytes, and factors such as chronic liver injury and underlying genetic mutations determine the path of progression and resulting cancer phenotype.Significance: The histopathogenesis of biliary tract cancer, driven by Tp53 and Kras mutations, can be differentially impacted by the cell of origin within the mature liver as well by major epidemiologic risk factors. Cancer Res; 78(16); 4445–51. ©2018 AACR.

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Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations

Primary prostate cancer can have extensive microheterogeneity, but its contribution to the later emergence of metastatic castration-resistant prostate cancer (mCRPC) remains unclear. In this study, we microdissected residual prostate cancer foci in radical prostatectomies from 18 men treated with neoadjuvant-intensive androgen deprivation therapy (leuprolide, abiraterone acetate, and prednisone) and analyzed them for resistance mechanisms. Transcriptome profiling showed reduced but persistent androgen receptor (AR) activity in residual tumors, with no increase in neuroendocrine differentiation. Proliferation correlated negatively with AR activity but positively with decreased RB1 expression, and whole-exome sequencing (WES) further showed enrichment for RB1 genomic loss. In 15 cases where 2 or 3 tumor foci were microdissected, WES confirmed a common clonal origin but identified multiple oncogenic alterations unique to each focus. These findings show that subclones with oncogenic alterations found in mCRPC are present in primary prostate cancer and are selected for by neoadjuvant-intense androgen deprivation therapy. In particular, this study indicates that subclonal RB1 loss may be more common than previously appreciated in intermediate- to high-risk primary prostate cancer and may be an early event, independent of neuroendocrine differentiation, in the development of mCRPC. Comprehensive molecular analyses of primary prostate cancer may detect aggressive subclones and possibly inform adjuvant strategies to prevent recurrence.Significance: Neoadjuvant androgen deprivation therapy for prostate cancer selects for tumor foci with subclonal genomic alterations, which may comprise the origin of metastatic castration-resistant prostate cancer. Cancer Res; 78(16); 4716–30. ©2018 AACR.

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Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation

Translocations of retinoic acid receptor-α (RARA), typically PML–RARA, are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of RARA, we focused here on APL cases without RARA translocation to elucidate the molecular etiology of RARA-negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without RARA translocations. Four of five RARA-negative APL cases had translocations involving retinoic acid receptor-β (RARB) translocations, and TBL1XR1–RARB was identified as an in-frame fusion in three cases; one case had an RARB rearrangement detected by FISH, although the partner gene could not be identified. When transduced in cell lines, TBL1XR1–RARB homodimerized and diminished transcriptional activity for the retinoic acid receptor pathway in a dominant-negative manner. TBL1XR1–RARB enhanced the replating capacity of mouse bone marrow cells and inhibited myeloid maturation of human cord blood cells as PML–RARA did. However, the response of APL with RARB translocation to retinoids was attenuated compared with that of PML–RARA, an observation in line with the clinical resistance of RARB-positive APL to ATRA. Our results demonstrate that the majority of RARA-negative APL have RARB translocations, thereby forming a novel, distinct subgroup of APL. TBL1XR1–RARB as an oncogenic protein exerts effects similar to those of PML–RARA, underpinning the importance of retinoic acid pathway alterations in the pathogenesis of APL.Significance: These findings report a novel and distinct genetic subtype of acute promyelocytic leukemia (APL) by illustrating that the majority of APL without RARA translocations harbor RARB translocations. Cancer Res; 78(16); 4452–8. ©2018 AACR.

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Epithelial-Mesenchymal Transition in Human Prostate Cancer Demonstrates Enhanced Immune Evasion Marked by IDO1 Expression

Cancer invasion and metastasis are driven by epithelial–mesenchymal transition (EMT), yet the exact mechanisms that account for EMT in clinical prostate cancer are not fully understood. Expression of N-cadherin is considered a hallmark of EMT in clinical prostate cancer. In this study, we determined the molecular mechanisms associated with N-cadherin expression in patients with prostate cancer. We performed laser capture microdissection of matched N-cadherin–positive and -negative prostate cancer areas from patient samples (n = 8), followed by RNA sequencing. N-cadherin expression was significantly associated with an immune-regulatory signature including profound upregulation of indoleamine 2,3-dioxygenase (IDO1; log2-fold change = 5.1; P = 2.98E-04). Fluorescent immunostainings of patient samples confirmed expression of IDO1 protein and also its metabolite kynurenine in primarily N-cadherin–positive areas. N-cadherin–positive areas also exhibited a local decrease of intraepithelial cytotoxic (CD8+) T cells and an increase of immunosuppressive regulatory T cells (CD4+/FOXP3+). In conclusion, EMT in clinical prostate cancer is accompanied by upregulated expression of IDO1 and an increased number of regulatory T cells. These data indicate that EMT, which is an important step in tumor progression, can be protected from effective immune control in patients with prostate cancer.Significance: These findings demonstrate EMT is linked to an immunosuppressive environment in clinical prostate cancer, suggesting that patients with prostate cancer can potentially benefit from combinatorial drug therapy. Cancer Res; 78(16); 4671–9. ©2018 AACR.

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Aberrant FGFR Tyrosine Kinase Signaling Enhances the Warburg Effect by Reprogramming LDH Isoform Expression and Activity in Prostate Cancer

The acquisition of ectopic fibroblast growthfactor receptor 1 (FGFR1) expression is well documented in prostate cancer progression. How it contributes to prostate cancer progression is not fully understood, although it is known to confer a growth advantage and promote cell survival. Here, we report that FGFR1 tyrosine kinase reprograms the energy metabolism of prostate cancer cells by regulating the expression of lactate dehydrogenase (LDH) isozymes. FGFR1 increased LDHA stability through tyrosine phosphorylation and reduced LDHB expression by promoting its promoter methylation, thereby shifting cell metabolism from oxidative phosphorylation to aerobic glycolysis. LDHA depletion compromised, whereas LDHB depletion enhanced the tumorigenicity of prostate cancer cells. Furthermore, FGFR1 overexpression and aberrant LDH isozyme expression were associated with short overall survival and biochemical recurrence times in patients with prostate cancer. Our results indicate that ectopic FGFR1 expression reprograms the energy metabolism of prostate cancer cells, representing a hallmark change in prostate cancer progression.Significance: FGF signaling drives the Warburg effect through differential regulation of LDHA and LDHB, thereby promoting the progression of prostate cancer.Graphical Abstract: https://ift.tt/2MhXUN6. Cancer Res; 78(16); 4459–70. ©2018 AACR.

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Combined MR Imaging of Oxygen Consumption and Supply Reveals Tumor Hypoxia and Aggressiveness in Prostate Cancer Patients

The established role of hypoxia-induced signaling in prostate cancer growth, metastasis, and response to treatment suggests that a method to image hypoxia in tumors could aid treatment decisions. Here, we present consumption and supply-based hypoxia (CSH) imaging, an approach that integrates images related to oxygen consumption and supply into a single image. This integration algorithm was developed in patients with prostate cancer receiving hypoxia marker pimonidazole prior to prostatectomy. We exploited the intravoxel incoherent motion (IVIM) signal in diagnostic diffusion-weighted (DW) magnetic resonance (MR) images to generate separate images of the apparent diffusion coefficient (ADC) and fractional blood volume (fBV). ADC and fBV correlated with cell density (CD) and blood vessel density (BVD) in histology and whole-mount sections from 35 patients, thus linking ADC to oxygen consumption and fBV to oxygen supply. Pixel-wise plots of ADC versus fBV were utilized to predict the hypoxia status of each pixel in a tumor and to visualize the predicted value in a single image. The hypoxic fraction (HFDWI) of CSH images correlated strongly (R2 = 0.66; n = 41) with pimonidazole immunoscore (HSPimo); this relationship was validated in a second pimonidazole cohort (R2 = 0.54; n = 54). We observed good agreement between CSH images and pimonidazole staining in whole-mount sections. HFDWI correlated with tumor stage and lymph node status, consistent with findings for HSPimo. Moreover, CSH imaging could be applied on histologic CD and BVD images, demonstrating transferability to a histopathology assay. Thus, CSH represents a robust approach for hypoxia imaging in prostate cancer that could easily be translated into clinical practice.Significance: These findings present a novel imaging strategy that indirectly measures tumor hypoxia and has potential application in a wide variety of solid tumors and other imaging modalities.Graphical Abstract: https://ift.tt/2w9rmtt. Cancer Res; 78(16); 4774–85. ©2018 AACR.

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PDSS2 Deficiency Induces Hepatocarcinogenesis by Decreasing Mitochondrial Respiration and Reprogramming Glucose Metabolism

Glucose metabolic reprogramming from oxidative phosphorylation to glycolysis is one of the hallmarks of cancer development. Coenzyme Q10 (CoQ10) is essential for electron transport in the mitochondrial respiratory chain and for antioxidant defense. Here, we investigated the role of a key factor in CoQ10 synthesis, prenyldiphosphate synthase subunit 2 (PDSS2), in hepatocellular carcinoma (HCC) tumorigenesis. PDSS2 was frequently downregulated in HCC tissues and was significantly associated with poorer HCC prognosis (P = 0.027). PDSS2 downregulation was a prognostic factor independent of T status and stage (P = 0.028). Downregulation of CoQ10 was significantly correlated with downregulation of PDSS2 in HCC tumor tissues (R = 0.414; P < 0.001). Of the six different splicing isoforms of PDSS2, the five variants other than full-length PDSS2 showed loss of function in HCC. Reintroduction of full-length PDSS2 into HCC cells increased CoQ10 and mitochondrial electron transport complex I activity and subsequently induced a metabolic shift from aerobic glycolysis to mitochondrial respiration in cells. Reintroduction of PDSS2 also inhibited foci formation, colony formation in soft agar, and tumor formation in nude mice. Knockdown of PDSS2 induced chromosomal instability in the MIHA immortalized human liver cell line. Furthermore, knockdown of PDSS2 in MIHA induced malignant transformation. Overall, our findings indicate that PDSS2 deficiency might be a novel driving factor in HCC development.Significance: Downregulation of PDSS2 is a driving factor in hepatocellular carcinoma tumorigenesis. Cancer Res; 78(16); 4471–81. ©2018 AACR.

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Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers

Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this study, we treat mice bearing Hras-driven poorly differentiated and anaplastic thyroid cancers (Tpo-Cre/HrasG12V/p53flox/flox) with the FTI tipifarnib. Treatment caused sustained tumor regression and increased survival; however, early and late resistance was observed. Adaptive reactivation of RAS–MAPK signaling was abrogated in vitro by selective RTK (i.e., EGFR, FGFR) inhibitors, but responses were ineffective in vivo, whereas combination of tipifarnib with the MEK inhibitor AZD6244 improved outcomes. A subset of tumor-bearing mice treated with tipifarnib developed acquired resistance. Whole-exome sequencing of resistant tumors identified a Nf1 nonsense mutation and an activating mutation in Gnas at high allelic frequency, supporting the on-target effects of the drug. Cell lines modified with these genetic lesions recapitulated tipifarnib resistance in vivo. This study demonstrates the feasibility of targeting Ras membrane association in cancers in vivo and predicts combination therapies that confer additional benefit.Significance: Tipifarnib effectively inhibits oncogenic HRAS-driven tumorigenesis and abrogating adaptive signaling improves responses. NF1 and GNAS mutations drive acquired resistance to Hras inhibition, supporting the on-target effects of the drug. Cancer Res; 78(16); 4642–57. ©2018 AACR.

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Enhanced Glycolysis Supports Cell Survival in EGFR-Mutant Lung Adenocarcinoma by Inhibiting Autophagy-Mediated EGFR Degradation

Oncogenic EGFR is essential for the development and growth of non–small cell lung cancer (NSCLC), but the precise roles of EGFR in lung cancer metabolism remain unclear. Here, we show that EGFR mutation-mediated enhancement of glycolysis is critical for EGFR stability. EGFR knockdown significantly decreased levels of glycolytic pathway intermediates via transcriptional regulation of glycolytic genes. EGFR mutation-enhanced glycolysis was required for fueling the tricarboxylic acid cycle, a critical component of EGFR stability. Nonsustained ATP production enhanced reactive oxygen species accumulation and subsequent JNK-mediated activation of autophagy, which in turn induced EGFR degradation. Our data show that EGFR-mutant NSCLCs require EGFR mutation-enhanced glycolysis to maintain EGFR stability. This pathway may serve as an attractive therapeutic target for EGFR-mutant NSCLCs.Significance: Enhanced glycolysis by EGFR mutation is required for maintaining EGFR levels via inhibition of JNK-induced autophagy. This provides a promising rationale for use of JNK activators in patients with EGFR-mutated NSCLC. Cancer Res; 78(16); 4482–96. ©2018 AACR.

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CRISPR/Cas9-Mediated Knockout of DGK Improves Antitumor Activities of Human T Cells

The efficacy of T-cell therapy is inhibited by various tumor-associated immunosuppressive ligands and soluble factors. Such inhibitory signals turn specific T-cell signaling pathways on or off, impeding the anticancer functions of T cells. Many studies have focused on PD-1 or CTLA-4 blockade to invigorate T-cell functions through CD28/B7 signaling, but obtaining robust clinical outcomes remains challenging. In this study, we use CRISPR/Cas9 to potentiate T-cell function by increasing CD3 signaling via knockout of diacylglycerol kinase (DGK), an enzyme that metabolizes diacylglycerol to phosphatidic acid. Knockout of DGK augmented the effector functions of CAR-T cells in vitro via increased TCR signaling. DGK knockout from CAR-T cells rendered them resistant to soluble immunosuppressive factors such as TGFβ and prostaglandin E2 and sustained effector functions under conditions of repeated tumor stimulation. Moreover, DGK knockout caused significant regression of U87MGvIII glioblastoma tumors through enhanced effector functions in a xenograft mouse model. Collectively, our study shows that knockout of DGK effectively enhances the effector functions of CAR-T cells, suggesting that CRISPR/Cas9-mediated knockout of DGK could be applicable as part of a multifaceted clinical strategy to treat solid cancers.Significance: This novel study demonstrates efficient ablation of diacylglycerol kinase in human CAR-T cells that leads to improved antitumor immunity and may have significant impact in human cancer immunotherapy. Cancer Res; 78(16); 4692–703. ©2018 AACR.

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R-spondin3 Is Associated with Basal-Progenitor Behavior in Normal and Tumor Mammary Cells

R-spondin3 (RSPO3) is a member of a family of secreted proteins that enhance Wnt signaling pathways in diverse processes, including cancer. However, the role of RSPO3 in mammary gland and breast cancer development remains unclear. In this study, we show that RSPO3 is expressed in the basal stem cell–enriched compartment of normal mouse mammary glands but is absent from committed mature luminal cells in which exogenous RSPO3 impairs lactogenic differentiation. RSPO3 knockdown in basal-like mouse mammary tumor cells reduced canonical Wnt signaling, epithelial-to-mesenchymal transition-like features, migration capacity, and tumor formation in vivo. Conversely, RSPO3 overexpression, which was associated with some LGR and RUNX factors, highly correlated with the basal-like subtype among patients with breast cancer. Thus, we identified RSPO3 as a novel key modulator of breast cancer development and a potential target for treatment of basal-like breast cancers.Significance: These findings identify RSPO3 as a potential therapetuic target in basal-like breast cancers.Graphical Abstract: https://ift.tt/2nBHW1g. Cancer Res; 78(16); 4497–511. ©2018 AACR.

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CD271+ Cells Are Diagnostic and Prognostic and Exhibit Elevated MAPK Activity in SHH Medulloblastoma

The extensive heterogeneity both between and within the medulloblastoma subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH medulloblastoma subgroup. Here, we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH medulloblastoma using IHC analysis and transcriptome data across 763 primary tumors. RNA sequencing of CD271+ and CD271− cells revealed molecularly distinct, coexisting cellular subsets, both in vitro and in vivo. MAPK/ERK signaling was upregulated in the CD271+ population, and inhibiting this pathway reduced endogenous CD271 levels, stem/progenitor cell proliferation, and cell survival as well as cell migration in vitro. Treatment with the MEK inhibitor selumetinib extended survival and reduced CD271 levels in vivo, whereas, treatment with vismodegib, a well-known smoothened (SMO) inhibitor currently in clinical trials for the treatment of recurrent SHH medulloblastoma, had no significant effect in our models. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH medulloblastoma tumors and reveals a novel role for MEK inhibitors in targeting CD271+ SHH medulloblastoma cells.Significance: This study identifies CD271 as a specific and novel biomarker of SHH-type medulloblastoma and that targeting CD271+ cells through MEK inhibition represents a novel therapeutic strategy for the treatment of SHH medulloblastoma. Cancer Res; 78(16); 4745–59. ©2018 AACR.

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DDX3 Activates CBC-eIF3-Mediated Translation of uORF-Containing Oncogenic mRNAs to Promote Metastasis in HNSCC

Mutated or dysregulated DDX3 participates in the progression and metastasis of cancer via its multiple roles in regulating gene expression and cellular signaling. Here, we show that the high expression levels of DDX3 in head and neck squamous cell carcinoma (HNSCC) correlate with lymph node metastasis and poor prognosis and demonstrate that DDX3 is essential for the proliferation, invasion, and metastasis of oral squamous cell carcinoma (OSCC) cells. Microarray analyses revealed that DDX3 is required for the expression of a set of pro-metastatic genes, including ATF4-modulated genes in an aggressive OSCC cell line. DDX3 activated translation of ATF4 and a set of its downstream targets, all of which contain upstream open reading frames (uORF). DDX3 promoted translation of these targets, likely by skipping the inhibitory uORF. DDX3 specifically enhanced the association of the cap-binding complex (CBC) with uORF-containing mRNAs and facilitated recruitment of the eukaryotic initiation factor 3 (eIF3). CBC and certain eIF3 subunits contributed to the expression of metastatic-related gene expression. Taken together, our results indicate a role for the novel DDX3–CBC–eIF3 translational complex in promoting metastasis.Significance: The discovery of DDX3-mediated expression of oncogenic uORF-containing genes expands knowledge on translational control mechanisms and provides potential targets for cancer therapy.Graphical Abstract: https://ift.tt/2w8XSvZ Cancer Res; 78(16); 4512–23. ©2018 AACR.

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Influence of Smoking, Body Mass Index, and Other Factors on the Preventive Effect of Nonsteroidal Anti-Inflammatory Drugs on Colorectal Cancer Risk

Nonsteroidal anti-inflammatory drugs' (NSAID) use has consistently been associated with lower risk of colorectal cancer; however, studies showed inconsistent results on which cohort of individuals may benefit most. We performed multivariable logistic regression analysis to systematically test for the interaction between regular use of NSAIDs and other lifestyle and dietary factors on colorectal cancer risk among 11,894 cases and 15,999 controls. Fixed-effects meta-analyses were used for stratified analyses across studies for each risk factor and to summarize the estimates from interactions. Regular use of any NSAID, aspirin, or nonaspirin NSAIDs was significantly associated with a lower risk of colorectal cancer within almost all subgroups. However, smoking status and BMI were found to modify the NSAID–colorectal cancer association. Aspirin use was associated with a 29% lower colorectal cancer risk among never-smokers [odds ratios (OR) = 0.71; 95% confidence intervals (CI): 0.64–0.79], compared with 19% and 17% lower colorectal cancer risk among smokers of pack-years below median (OR, 0.81; 95% CI, 0.71–0.92) and above median (OR, 0.83; 95% CI, 0.74–0.94), respectively (P interaction = 0.048). The association between any NSAID use and colorectal cancer risk was also attenuated with increasing BMI (P interaction = 0.075). Collectively, these results suggest that obese individuals and heavy smokers are unlikely to benefit as much as other groups from the prophylactic effect of aspirin against colorectal cancer.Significance: Obesity and heavy smoking attenuate the benefit of aspirin use for colorectal cancer prevention. Cancer Res; 78(16); 4790–9. ©2018 AACR.

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Expression of Long Noncoding RNA YIYA Promotes Glycolysis in Breast Cancer

Long noncoding RNA (lncRNA) is yet to be linked to cancer metabolism. Here, we report that upregulation of the lncRNA LINC00538 (YIYA) promotes glycolysis, cell proliferation, and tumor growth in breast cancer. YIYA is associated with the cytosolic cyclin-dependent kinase CDK6 and regulated CDK6-dependent phosphorylation of the fructose bisphosphatase PFK2 (PFKFB3) in a cell-cycle–independent manner. In breast cancer cells, these events promoted catalysis of glucose 6-phosphate to fructose-2,6-bisphosphate/fructose-1,6-bisphosphate. CRISPR/Cas9-mediated deletion of YIYA or CDK6 silencing impaired glycolysis and tumor growth in vivo. In clinical specimens of breast cancer, YIYA was expressed in approximately 40% of cases where it correlated with CDK6 expression and unfavorable survival outcomes. Our results define a functional role for lncRNA in metabolic reprogramming in cancer, with potential clinical implications for its therapeutic targeting.Significance: These findings offer a first glimpse into how a long-coding RNA influences cancer metabolism to drive tumor growth. Cancer Res; 78(16); 4524–32. ©2018 AACR.

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From the Desk of the Editor

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Corylin inhibits LPS-induced inflammatory response and attenuates the activation of NLRP3 inflammasome in microglia

Inflammation has been found to be associated with many neurodegenerative diseases, including Parkinson's and dementia. Attenuation of microglia-induced inflammation is a strategy that impedes the progression o...

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Editorial Board

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Table of Contents

https://ift.tt/2MoBuc9

Methylomic analysis of ovarian cancers identifies tumor-specific alterations readily detectable in early precursor lesions

Purpose: High-grade serous ovarian carcinoma (HGSOC) typically remains undiagnosed until advanced stages when peritoneal dissemination has already occurred. Here, we sought to identify HGSOC-specific alterations in DNA methylation and assess their potential to provide sensitive and specific detection HGSOC at its earliest stages. Experimental Design: MethylationEPIC genome-wide methylation analysis was performed on a discovery cohort comprising 23 HGSOC, 37 non-HGSOC malignant and 36 cancer-free gynecologic tissue samples. The resulting data were processed using selective bioinformatic criteria to identify regions of high-confidence HGSOC-specific differential methylation. Quantitative methylation-specific real-time PCR (qMSP) assays were then developed for eight of the top performing regions and analytically validated in a cohort of 90 tissue samples. Lastly, qMSP assays were used to assess and compare methylation in 30 laser capture microdissected (LCM) fallopian tube epithelia samples obtained from cancer-free and serous tubal intraepithelial carcinoma (STIC) positive women. Results: Bioinformatic selection identified 91 regions of robust, HGSOC-specific hypermethylation, 23 of which exhibited an area under the receiver-operator curve (AUC) value ≥ 0.9 in the discovery cohort. Seven of eight genes demonstrated AUC values between 0.838 and 0.968 when analytically validated in a 90-patient cohort. A panel of the three top-performing genes (c17orf64, IRX2 and TUBB6) were able to perfectly discriminate HGSOC (AUC 1.0). Hypermethylation within these loci was found exclusively in LCM fallopian tube epithelia from women with STIC lesions, but not in cancer-free fallopian tubes. Conclusions: A panel of methylation biomarkers can be used to accurately identify HGSOC, even at precursor stages of the disease.

https://ift.tt/2PaD9Rc

Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer

Purpose: Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated. Experimental Design: Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects onin vitro and in vivophenotypes. Metabolomics was used to dissect the biochemical mechanisms that promote L-2-HG accumulation in RCC cells. Transcriptomic analysis was utilized to identify relevant targets of L-2-HG. Finally, bioinformatic and metabolomic analyses were used to assess the L-2-HG/L2HGDH axis as a function of patient outcome and cancer progression. Results: L2HGDH suppresses both in vitrocell migration and in vivotumor growth and these effects are mediated by L2HGDH's catalytic activity. Biochemical studies indicate that glutamine is the predominant carbon source for L-2-HG via the activity of malate dehydrogenase 2 (MDH2). Inhibition of the glutamine-MDH2 axis suppresses in vitrophenotypes in a L-2-HG dependent manner. Moreover, in vivogrowth of RCC cells with basal elevation of L-2-HG is suppressed by glutaminase inhibition. Transcriptomic and functional analyses demonstrate that the histone demethylase KDM6A is a target of L-2-HG in RCC. Finally, increased L-2-HG levels, L2HGDHcopy loss, and lower L2HGDH expression are associated with tumor progression and/or worsened prognosis in RCC patients. Conclusions: Collectively, our studies provide biochemical and mechanistic insight into the biology of this small molecule and provide new opportunities for treating L-2-HG driven kidney cancers.

https://ift.tt/2B8ifPA

A clinical and molecular Phase II trial of oral ENMD-2076 in ovarian clear cell carcinoma (OCCC): A study of the Princess Margaret Phase II Consortium

Purpose: Patients with recurrent ovarian clear cell carcinoma (OCCC) have limited effective options due to chemo-resistance. A phase II study was designed to assess the activity of ENMD-2076, an oral multi-target kinase selective against Aurora-A and VEGFR. Experimental design: This multi-center Phase II study included patients with recurrent OCCC who received prior platinum-based chemotherapy. Primary endpoints were objective response and 6-month progression free survival (PFS) rates. Correlative analyses include ARID1A and PTEN expression by immunohistochemistry and gene sequencing with a targeted custom capture next generation sequencing (NGS) panel. Results: 40 patients were enrolled with a median age of 54, 38 were evaluable. ENMD was well tolerated with main related grade 3 toxicities being hypertension (28%), proteinuria (10%) and diarrhea (10%). Best response was partial response for 3 patients (1 unconfirmed) and stable disease for 26 patients. The overall 6-month PFS rate was 22% and differed according to ARID1A expression (ARIDIA -ve vs ARID1A+ve; 33%vs 12%, p=0.023). PTEN positive expression was observed in 20/36 patients and there was no correlation with outcome. Median PFS in patients with PI3KCA wild-type vs PI3KCA-mutated group was 5 versus 3.7 months (p=0.049). Molecular profiling showed variants in PI3KCA (27%), ARID1A (26%) and TP53 (7%). The patient with the longest treatment duration (22 months) was PTEN wild type, diploid PTEN with putative bi-allelic inactivation of ARID1A. Conclusion: Single agent ENMD-2076 did not meet the pre-set bar for efficacy. Loss of ARID1A correlated with better PFS on ENMD-2076 and warrants further investigation as a potential predictive biomarker.

https://ift.tt/2nD1dj1

Kub5-Hera RPRD1B deficiency promotes "BRCAness" and vulnerability to PARP inhibition in BRCA-proficient Breast Cancers

Purpose: Identification of novel strategies to expand the use of PARP inhibitors beyond BRCA deficiency is of great interest in personalized medicine. Here, we investigated the unannotated role of Kub5-Hera^RPRD1B in homologous recombination (HR) repair and its potential clinical significance in targeted cancer therapy. Experimental Design: Functional characterization of K-H alterations on HR repair of double-strand breaks (DSB) were assessed by targeted gene silencing, plasmid reporter assays, immunofluorescence and Western blots. Cell survival with PARP inhibitors was evaluated through colony forming assays and statistically analyzed for correlation with K-H expression in various BRCA1/2 non-mutated breast cancers. Gene expression microarray/qPCR analyses, chromatin immunoprecipitation, and rescue experiments were used to investigate molecular mechanisms of action. Results: K-H expression loss correlates with Rucaparib LD₅₀ values in a panel of BRCA1/2 non-mutated breast cancers. Mechanistically, K-H^RPRD1B depletion promotes BRCAness, where extensive upregulation of poly(ADP-ribose) polymerase 1 (PARP1) activity was required for survival of breast cancer cells. PARP inhibition in these cells led to synthetic lethality that was rescued by wild-type K-H re-expression, but not by a mutant K-H (p.R106A) that weakly binds RNAPII. K-H mediates homologous recombination (HR) by facilitating recruitment of RNAPII to the promoter region of a critical DNA damage response and repair effector, cyclin-dependent kinase 1 (CDK1). Conclusions: Cancer cells with low K-H expression may have exploitable BRCAness properties that greatly expands use of PARP inhibitors beyond BRCA mutations. Our results suggest that aberrant K-H alterations may have vital translational implications in cellular responses/survival to DNA damage, carcinogenesis and personalized medicine.

https://ift.tt/2BdF70l

KMT2C mutations in diffuse type gastric adenocarcinoma promote epithelial-to-mesenchymal transition

Purpose: Lauren diffuse type gastric adenocarcinoma (DGA) is genomically stable. We identified lysine (K)-specific methyltransferase 2C (KMT2C) as a frequently mutated gene and examined its role in DGA progression. Experimental Design and Results: Whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy and identified lysine (K)-specific methyltransferase 2C (KMT2C) as mutated in 11 of 27 tumors (41%). This high frequency of KMT2C mutations in DGA has not been found in prior studies. KMT2C expression by immunohistochemistry in tumors from 135 DGA patients undergoing gastrectomy inversely correlated with more advanced tumor stage (p=0.023) and worse overall survival (p = 0.017). KMT2C shRNA knockdown in HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47-88 fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52-60%, and reduced cell invasion by 50-74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared to wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77-78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. Conclusions: KMT2C is frequently mutated in certain populations with DGA. KMT2C loss is associated with worse overall survival and promotes EMT.

https://ift.tt/2nEEh35

Validation of miR-31-3p Expression to Predict Cetuximab Efficacy When Used as First-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer

Purpose: MiR-31-3p expression has been shown to be associated with response to anti-EGFR therapy. We investigated the predictive role of this biomarker in the FIRE-3 study population, including its ability to differentiate outcomes between patients receiving anti-EGFR and anti-VEGF therapy. Experimental Design: MiR-31-3p expression was measured in primary tumors obtained from 340 RAS WT mCRC patients enrolled in the FIRE-3 Trial. This included 164 patients randomized to receive FOLFIRI plus cetuximab (FOLFIRI+Cetux) and 176 to FOLFIRI plus bevacizumab (FOLFIRI+Beva). Patients were divided into subgroups defined by low or high miR-31-3p expression using a pre-specified cut-off and by treatment arm. Analyses were performed to assess treatment efficacy by subgroup. Overall Survival (OS) and Progression Free Survival (PFS) were analyzed using Kaplan-Meier curves and Cox regression models. Investigator-assessed objective response (iOR), early tumor shrinkage at 6 weeks (ETS), and centrally-reviewed objective response (cOR) were analyzed using logistic regression models. The predictive value of miR-31-3p expression level was assessed through a treatment interaction test using multivariate models adjusted for potential confounding factors. Results: Low miR-31-3p expressers benefited from cetuximab compared to bevacizumab for PFS (HR=0.74 [0.55;1.00];P=0.05), OS (HR=0.61 [0.41;0.88];P<0.01), iOR (OR=4.0 [1.9;8.2];P<0.01), ETS (OR=4.0 [2.1;7.7];P<0.01) and cOR (OR=4.9 [2.3;10.5]:P<0.01) in multivariate analyses. There was no difference in outcomes for high expressers between treatment arms. MiR-31-3p expression level was predictive of treatment effect for PFS (P=0.03), OS (P=0.05), iOR (P=0.02), ETS (P=0.04) and cOR (P<0.01). Conclusion: MiR-31-3p expression level was validated as a predictive biomarker of cetuximab therapy efficacy for RAS WT mCRC patients.

https://ift.tt/2BiKlYm

Most Postmenopausal Bleeding Not Associated With Cancer

TUESDAY, Aug. 14, 2018 -- Most women with postmenopausal bleeding (PMB) will not be diagnosed with endometrial cancer, according to a review published online Aug. 6 in JAMA Internal Medicine. Megan A. Clarke, Ph.D., from the National Cancer...

https://ift.tt/2nG3KZQ

TBI Linked to Increased Suicide Risk

TUESDAY, Aug. 14, 2018 -- Individuals with medical contact for traumatic brain injury (TBI) have increased risk of suicide, according to a study published in the Aug. 14 issue of the Journal of the American Medical Association. Trine Madsen, Ph.D.,...

https://ift.tt/2MLsH0W

Triple Combo Blood Pressure Pill Can Improve BP Control

TUESDAY, Aug. 14, 2018 -- Treatment with a pill combining low doses of three antihypertensive drugs results in an increased proportion of patients with mild-to-moderate hypertension achieving their target blood pressure (BP), according to a study...

https://ift.tt/2MsCSdU

AMA Adopts New Policy on Housing for Homeless

TUESDAY, Aug. 14, 2018 -- The American Medical Association (AMA) calls for stable, affordable housing, without mandated therapy or service compliance, in order to improve housing stability and quality of life among individuals who are chronically...

https://ift.tt/2MLsESO

Zika, West Nile Cases Reported in Alabama

TUESDAY, Aug. 14, 2018 -- Multiple reports of Zika virus and West Nile virus are being investigated by Alabama health officials. People can get Zika virus from mosquito bites, sex, and blood transfusions, and a pregnant woman can pass it to her...

https://ift.tt/2MpncrK

Rab GTPases in Osteoclastic Endomembrane Systems

Osteoclasts (OCs) are bone-resorbing cells that maintain bone homeostasis. OC differentiation, survival, and activity are regulated by numerous small GTPases, including those of the Rab family, which are involved in plasma membrane delivery and lysosomal and autophagic degradation pathways. In resorbing OCs, polarized vesicular trafficking pathways also result in formation of the ruffled membrane, the resorbing organelle, and in transcytosis.

https://ift.tt/2KTNLRc

Gut Microbiome in BALB/c and C57BL/6J Mice Undergoing Experimental Thyroid Autoimmunity Associate with Differences in Immunological Responses and Thyroid Function

Horm Metab Res
DOI: 10.1055/a-0653-3766

Experimental models of hyperthyroid Graves' disease (GD) and Graves' orbitopathy (GO) are efficiently developed by genetic immunisation by electroporation with human thyrotropin hormone receptor (hTSHR) A-subunit plasmid in female BALB/c (H-2d) mice. We investigated susceptibility in C57BL/6 J (H-2b) animals to allow studies on disease mechanisms in transgenic and immune response gene knock-out mice. Higher numbers of female C57BL/6 J were positive for pathogenic thyroid stimulating antibodies, but induced hyperthyroidism remained at a low frequency compared to BALB/c animals. Assessment of hTSHR specific T cells showed reduced proliferation in C57BL/6 J animals accompanied with anti-inflammatory IL-10, with less pro-inflammatory IFN-γ compared to BALB/c. Whilst the orbital tissue from immune BALB/c mice showed inflammation and adipogenesis, in contrast C57BL/6 J animals showed normal pathology. We characterised the gut microbiota using 16 S ribosomal RNA gene sequencing to explore its possible pathogenic role in the model. Despite being housed under identical conditions, we observed significantly different organisation of the microbiota (beta-diversity) in the two strains. Taxonomic differences were also noted, with C57BL/6 J showing an enrichment of Operational Taxonomic Units (OTUs) belonging to the Paludibacter and Allobaculum, followed by Limibacter, Anaerophaga and Ureaplasma genera. A higher number of genera significantly correlating with clinical features was observed in C57BL/6 J compared to BALB/c; for example, Limibacter OTUs correlated negatively with thyroid-stimulating antibodies in C57BL/6 J mice. Thus, our data suggest gut microbiota may play a pivotal immunomodulatory role that differentiates the thyroid function and orbital pathology outcome in these two inbred strains undergoing experimental GO.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2Mo1d4w

Epidemiology of measles in the metropolitan setting, Addis Ababa, Ethiopia, 2005–2014: a retrospective descriptive surveillance data analysis

Measles is a highly infectious and serious respiratory viral disease which caused by a virus. It is a significant cause of illness and death worldwide. This data analysis was conducted to describe the trend an...

https://ift.tt/2KVeigR

Rapid and sensitive detection of Yersinia pestis by lateral-flow assay in simulated clinical samples

Yersinia pestis is a contributing agent to the epidemic disease, plague, which killed an estimated 200 million people during historical times. In this study, a rapid, cheap, sensitive, and specific technique, the...

https://ift.tt/2MjBOdb

C-reactive protein and procalcitonin to discriminate between tuberculosis, Pneumocystis jirovecii pneumonia, and bacterial pneumonia in HIV-infected inpatients meeting WHO criteria for seriously ill: a prospective cohort study

Tuberculosis, bacterial community-acquired pneumonia (CAP), and Pneumocystis jirovecii pneumonia (PJP) are the three commonest causes of hospitalisation in HIV-infected adults. Prompt diagnosis and treatment init...

https://ift.tt/2walQ9Y

Helcococcus ovis in a patient with an artificial eye: a case report and literature review

Helcococcus ovis, belonging to the genus of Helcococcu in Peptostreptococcaceae, is one kind of facultative anaerobic and gram-positive cocci, which was first isolated from a mixed infection in sheep in 1999. To ...

https://ift.tt/2MjBLhv

Myalgia caused by chronic myositis associated with plasmacytosis: a case report

Cutaneous and systemic plasmacytosis are skin disorders characterized by cutaneous polyclonal plasma cell infiltration accompanied by polyclonal hypergammaglobulinemia. Cutaneous plasmacytosis involvement is l...

https://ift.tt/2KS7wIT

CIDP, myasthenia gravis, and membranous glomerulonephritis – three autoimmune disorders in one patient: a case report

We present a patient fulfilling the electrophysiological criteria for definite chronic inflammatory demyelinating polyneuropathy (CIDP), antibody-positive myasthenia gravis (MG), and membranous glomerulonephri...

https://ift.tt/2Mef269

Clinical Impact of Post-Progression Survival on Overall Survival in Elderly Patients with Non-Small-Cell Lung Cancer Harboring Sensitive EGFR Mutations Treated with First-Line EGFR Tyrosine Kinase Inhibitors

Background/Aims: More than 50% of patients with lung cancer are aged #x3e; 65 years, and non-small-cell lung cancer (NSCLC) accounts for 85% of all cases of lung cancer among both elderly and adult patients. Subsequent therapies confound the capability to discern the effect of first-line chemotherapy on overall survival (OS). Therefore, using individual-level data, our study aimed to determine the relationships of progression-free survival (PFS) and post-progression survival (PPS) with OS after first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in elderly patients with NSCLC harboring sensitive EGFR mutations. Methods: Between April 2008 and December 2015, we analyzed 68 elderly patients with NSCLC harboring sensitive EGFR mutations and treated with first-line EGFR-TKI. The relationships of PFS and PPS with OS were analyzed at an individual level. Results: Linear regression analysis showed that PPS was more closely associated with OS (R² = 0.54) than PFS was (R² = 0.48). Best response at first-line treatment, performance status at the end of first-line treatment, and administration of EGFR-TKI rechallenge were significantly correlated with PPS. Conclusions: PPS has a stronger impact on OS than PFS does in elderly patients with NSCLC harboring sensitive EGFR mutations and treated with first-line EGFR-TKI. These results indicate that OS in this patient population may be influenced by treatments subsequent to first-line chemotherapy; however, this remains to be verified in prospective studies.
Chemotherapy 2018;63:181–189

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Primary peritoneal Epithelioid mesothelioma of clear cell type with a novel VHL gene mutation: a case report

Clear cell variant of epithelioid mesothelioma is an extremely rare tumor with only isolated cases reported so far in the peritoneum. Here, we report a case of peritoneal epithelioid mesothelioma, clear cell variant, in a 63-year-old female patient with a novel VHL gene mutation and an unusual indolent clinical course. The patient, who has no clinical history of asbestos exposure, presented with a 27.2 cm upper abdominal mass and a 5.5 cm liver lesion. Retrospective review of the patient's abdominal CT scan 4 years ago showed two small abdominal lesions that were felt clinically to represent hemangiomas.

https://ift.tt/2KSVD5g

Cancer mortality and incidence following external occupational radiation exposure: an update of the 3rd analysis of the UK national registry for radiation workers

https://ift.tt/2P9MhoZ

The growing importance of radiation worker studies

https://ift.tt/2KXiTiu

Persistent inequalities in unplanned hospitalisation among colon cancer patients across critical phases of their care pathway, England, 2011–13

https://ift.tt/2P6YSJI

Driver mutations of young lung adenocarcinoma patients with malignant pleural effusion

Genes, Chromosomes and Cancer, EarlyView.


https://ift.tt/2KTwZ4G

CIC‐NUTM1 fusion: A case which expands the spectrum of NUT‐rearranged epithelioid malignancies

Genes, Chromosomes and Cancer, EarlyView.


https://ift.tt/2P87n7p

A case of pediatric acute myeloid leukemia with t(11;16)(q23;q24) leading to a novel KMT2A‐USP10 fusion gene

Genes, Chromosomes and Cancer, EarlyView.


https://ift.tt/2KScS6U

Secondary Neutron Dose from a Dynamic Collimation System During Intracranial Pencil Beam Scanning Proton Therapy: A Monte Carlo Investigation

This study presents a unique application of Monte Carlo methods to study secondary neutron generation and dose equivalence distributions resulting from single field uniform dose and intensity modulated proton therapy treatments using a Dynamic Collimation System. Expected neutron doses are compared to aperture-collimated proton therapy techniques. The excess relative risk from an intracranial treatment plan's neutron dose distribution is compared against that of a traditional uncollimated intracranial proton therapy treatment using a graphite range shifter.

https://ift.tt/2KT00NJ

FDG / PET-CT based lymph node atlas in breast cancer patients

The aim of this study was to localize loco-regional lymph node metastases (LN) using FDG-PET datasets in 235 patients with 580 lymph nodes. A comprehensive LN atlas was created in this study comprising the largest number of lymph node metastases so far. Our quantitative data illustrate where lymph node metastases occur in different clinical situations and present areas at high risk (i.e "hot spots" of lymph node metastases). The ESTRO CTV and RTOG CTV do not provide coverage of the whole loco-regional lymphatic drainage. Whether target volumes that cover the whole loco-regional lymphatic drainage system are necessary and result in an improved oncological outcome is up to future studies to examine.

https://ift.tt/2nDoLnO

Knowledge-based planning for identifying high-risk stereotactic ablative radiotherapy treatment plans for lung tumors larger than 5cm

We retrospectively investigated the relationship between dosimetry and toxicity for Stereotactic ablative body radiotherapy (SABR) for lung tumors ≥5cm using a knowledge-based planning solution. This allowed to perform individualized treatment plan quality assurance and identified in nearly 50% of historical treatment plans from patients with grade≥3 toxicity where planning could have been improved.

https://ift.tt/2nDoMYU

NephroTalk: Evaluation of a Palliative Care Communication Curriculum for Nephrology Fellows

Nephrologists care for a medically complex population that faces difficult decisions around treatment options and end of life care. Yet communication training within nephrology fellowship is rare. Prior work suggests that communication training in nephrology can improve perceived preparedness to engage in difficult conversations, however it is unclear if this training results in improved clinical skills.

https://ift.tt/2KSL9Ts

Circulating Tumor Cells Dynamics in Pancreatic Adenocarcinoma Correlate With Disease Status: Results of the Prospective CLUSTER Study

Objectives: Previous retrospective studies demonstrated that circulating tumor cells (CTCs) subtypes correlate with overall survival in patients with pancreatic ductal adenocarcinoma (PDAC). Herein, we report results of a prospective observational study on CTCs dynamics to assess their clinical significance. Methods: The CLUSTER study is a prospective longitudinal study on PDAC CTCs dynamics (NCT02974764). Multiple peripheral blood samples were collected from 200 consecutively enrolled patients with presumed PDAC diagnosis. CTCs were isolated and characterized by immunofluorescence. Results: Two major CTCs subtypes were identified in PDAC patients: epithelial CTCs (eCTCs) and epithelial/mesenchymal CTCs (mCTCs). Patients who received neoadjuvant chemotherapy had significantly lower total CTCs (tCTCs, P = 0.007), eCTCs (P = 0.007), and mCTCs (P = 0.034), compared with untreated patients eligible for upfront resection. Surgical resection of the primary tumor resulted in significant reduction, but not disappearance, of CTCs burden across all cell subtypes (P

https://ift.tt/2MNLSHy

Validity of the Novel Taiwan Lymphoscintigraphy Staging and Correlation of Cheng Lymphedema Grading for Unilateral Extremity Lymphedema

Objective: The aim was to validate the new Taiwan Lymphoscintigraphy Staging, correlate it with Cheng Lymphedema Grading (CLG) and evaluate the treatment outcomes of unilateral extremity lymphedema. Background: No consensus has been reached for diagnosis and staging for patients with lymphedema among medical specialties. Methods: We included 285 patients with unilateral extremity lymphedema using lymphoscintigraphy. Lymphoscintigraphy was correlated to clinical symptoms and signs, and classified into normal lymphatic drainage, partial obstruction, and total obstruction. Inter- and intraobserver reliability of Taiwan Lymphoscintigraphy Staging, correlation between Taiwan Lymphoscintigraphy Staging and clinical findings were conducted. Patients were categorized in "surgical" (n = 154) or "nonsurgical" (n = 131) groups for outcome evaluation. Results: Lymphoscintigraphy found 11 patients (3.9%) with normal lymphatic drainage, 128 (44.9%) with partial obstruction, and 146 (51.2%) with total obstruction. Taiwan Lymphoscintigraphy Staging showed high interobserver agreement [intraclass correlation coefficient: 0.89 (95% confidence interval, 0.82–0.94)], and significantly correlated to computed tomography volumetric difference (r = 0.66, P

https://ift.tt/2MpPkLa

In the Next Issue

No abstract available

https://ift.tt/2vJIOWf

Ensuring Equity, Diversity, and Inclusion in Academic Surgery: An American Surgical Association White Paper

Objective: The leadership of the American Surgical Association (ASA) appointed a Task Force to objectively address issues related to equity, diversity, and inclusion with the discipline of academic surgery. Summary of Background Data: Surgeons and the discipline of surgery, particularly academic surgery, have a tradition of leadership both in medicine and society. Currently, we are being challenged to harness our innate curiosity, hard work, and perseverance to address the historically significant deficiencies within our field in the areas of diversity, equity, and inclusion. Methods: The ASA leadership requested members to volunteer to serve on a Task Force to comprehensively address equity, diversity, and inclusion in academic surgery. Nine work groups reviewed the current literature, performed primary qualitative interviews, and distilled available guidelines and published primary source materials. A work product was created and published on the ASA Website and made available to the public. The full work product was summarized into this White Paper. Results: The ASA has produced a handbook entitled: Ensuring Equity, Diversity, and Inclusion in Academic Surgery, which identifies issues and challenges, and develops a set of solutions and benchmarks to aid the academic surgical community in achieving these goals. Conclusion: Surgery must identify areas for improvement and work iteratively to address and correct past deficiencies. This requires honest and ongoing identification and correction of implicit and explicit biases. Increasing diversity in our departments, residencies, and universities will improve patient care, enhance productivity, augment community connections, and achieve our most fundamental ambition—doing good for our patients.

https://ift.tt/2vKlOpY

Long-term Quality of Life in Neonatal Surgical Disease

Objective: This prospective observational study was designed to assess Pediatric Quality of Life (PedsQL) after surgical treatment for congenital diaphragmatic hernia (CDH), esophageal atresia/tracheoesophageal fistula (EA/TEF), Hirschsprung disease (HD), gastroschisis (GAS), omphalocele (OMP), and necrotizing enterocolitis (NEC). Summary of Background Data: Improvements in neonatal and surgical care have led to increased survival for many newborn conditions. Quality of life in these patients is seldom explored in a longitudinal manner. We hypothesized that age-adjusted physical and psychosocial scores would improve over time, but with diagnosis-dependent variation. Methods: Data were collected from 241 patients (CDH = 52; EA/TEF = 62; HD = 46; GAS = 32; OMP = 26; NEC = 23) in an institutional Clinical Outcomes Registry (COR) from 2012 to 2017. Aggregate physical, psychosocial, and overall PedsQL scores were determined for each diagnosis. Spline regression models were created to model scores as a function of age. Results: Physical scores trended up for all diagnoses except CDH and NEC beyond age 10. Psychosocial scores trended up for all diagnoses except NEC and EA/TEF beyond age 10. Beyond age 12, CDH, GAS, and HD patients had overall scores within the normal range, while NEC, OMP, and EA/TEF patients had scores similar to children with chronic medical illness. Conclusion: Variation exists in long-term PedsQL scores after neonatal surgery for selected, complex disease. Beyond age 12, quality of life is significantly impaired in NEC, moderately impaired in OMP and EA/TEF, and within normal range for CDH, HD, and GAS patients at the population level. These data are relevant to prenatal and perioperative discussions with patients and families.

https://ift.tt/2MurzSA

Decreased Risk of Delirium With Use of Regional Analgesia in Geriatric Trauma Patients With Multiple Rib Fractures

Objective: The aim of this study was to examine the risk of delirium in geriatric trauma patients with rib fractures treated with systemic opioids compared with those treated with regional analgesia (RA). Summary of Background Data: Delirium is a modifiable complication associated with increased morbidity and mortality. RA may reduce the need for opioid medications, which are associated with delirium in older adults. Methods: Cohort study of patients ≥65 years admitted to a regional trauma center from 2011 to 2016. Inclusion factors were ≥ 3 rib fractures, blunt trauma mechanism, and admission to intensive care unit (ICU). Exclusion criteria included head AIS ≥3, spine AIS ≥3, dementia, and death within 24 hours. The primary outcome was delirium positive ICU days, defined using the CAM-ICU assessment. Delirium incident rate ratios (IRRs) and 95% confidence intervals (95% CIs) were estimated using generalized linear mixed models with Poisson distribution and robust standard errors. Results: Of the 144 patients included in the study, 27 (19%) received Acute Pain Service consultation and RA and 117 (81%) received opioid-based systemic analgesia. Patients with RA had more severe chest injury than those without. The risk of delirium decreased by 24% per day per patient with use of RA (IRR 0.76, 95% CI 0.61 to 0.96). Individual opioid use, as measured in daily morphine equivalents (MEDs), was significantly reduced after initiation of RA (mean difference −7.62, 95% CI −14.4 to −0.81). Conclusion: Although use of RA techniques in geriatric trauma patients with multiple rib fractures was associated with higher MED, opioid use decreased after RA initiation and Acute Pain Service consultation, and the risk of delirium was lower.

https://ift.tt/2vKlFTs