Cancers, Vol. 10, Pages 69: Nano-Pulse Stimulation Ablates Orthotopic Rat Hepatocellular Carcinoma and Induces Innate and Adaptive Memory Immune Mechanisms that Prevent Recurrence

Cancers, Vol. 10, Pages 69: Nano-Pulse Stimulation Ablates Orthotopic Rat Hepatocellular Carcinoma and Induces Innate and Adaptive Memory Immune Mechanisms that Prevent Recurrence

Cancers doi: 10.3390/cancers10030069

Authors: Brittany Lassiter Siqi Guo Stephen Beebe

Nano-pulse stimulation (NPS), previously called nsPEFs, induced a vaccine-like effect after ablation of orthotopic N1-S1 hepatocellular carcinoma (HCC), protecting rats from subsequent challenges with N1-S1 cells. To determine immunity, immune cell phenotypes were analyzed in naïve, treated and protected rats. NPS provides a positive, post-ablation immuno-therapeutic outcome by alleviating immunosuppressive T regulatory cells (Treg) in the tumor microenvironment (TME), allowing dendritic cell influx and inducing dynamic changes in natural killer cells (NKs), NKT-cells and T-lymphocytes in blood, spleen and liver. NPS induced specific increases in NKs and NKT-cells expressing CD8 and activation receptors CD314-NKG2D and CD161 (NK1.1) in the TME after treatment, as well as some variable changes in CD4+ and CD8+ effector (Tem) and central memory (Tem) lymphocytes in blood and spleen. After orthotopic challenge, CD8+ T-cells were cytotoxic, inducing apoptosis in N1-S1 cells; additionally, in contrast to post-treatment immune responses, CD4+ and CD8+ memory precursor effector cells (MPECs) and short-lived effector cells (SLECs) were present, while still including CD8+ CD161 NK cells, but not involving CD8+ CD314-NKG2D+ NKs. This immunity was N1-S1-specific and was sustained for at least 8 months. NPS vaccinates rats in vivo against HCC by activating innate and adaptive immune memory mechanisms that prevent HCC recurrence.

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The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration

Abstract

Recently it has been observed in preclinical models that that radiation enhances the recruitment of circulating tumor cells to primary tumors, and results in tumor regrowth after treatment. This process may have implications for clinical radiotherapy, which improves control of a number of tumor types but which, despite continued dose escalation and aggressive fractionation, is unable to fully prevent local recurrences. By irradiating a single tumor within an animal bearing multiple lesions, we observed an increase in tumor cell migration to irradiated and unirradiated sites, suggesting a systemic component to this process. Previous work has identified the cytokine GM-CSF, produced by tumor cells following irradiation, as a key effector of this process. We evaluated the ability of systemic injections of a PEGylated form of GM-CSF to stimulate tumor cell migration. While increases in invasion and migration were observed for tumor cells in a transwell assay, we found that daily injections of PEG-GM-CSF to tumor-bearing animals did not increase migration of cells to tumors, despite the anticipated changes in circulating levels of granulocytes and monocytes produced by this treatment. Combination of PEG-GM-CSF treatment with radiation also did not increase tumor cell migration. These findings suggest that clinical use of GM-CSF to treat neutropenia in cancer patients will not have negative effects on the aggressiveness of residual cancer cells. However, further work is needed to characterize the mechanism by which GM-CSF facilitates systemic recruitment of trafficking tumor cells to tumors.

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The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration

Abstract

Recently it has been observed in preclinical models that that radiation enhances the recruitment of circulating tumor cells to primary tumors, and results in tumor regrowth after treatment. This process may have implications for clinical radiotherapy, which improves control of a number of tumor types but which, despite continued dose escalation and aggressive fractionation, is unable to fully prevent local recurrences. By irradiating a single tumor within an animal bearing multiple lesions, we observed an increase in tumor cell migration to irradiated and unirradiated sites, suggesting a systemic component to this process. Previous work has identified the cytokine GM-CSF, produced by tumor cells following irradiation, as a key effector of this process. We evaluated the ability of systemic injections of a PEGylated form of GM-CSF to stimulate tumor cell migration. While increases in invasion and migration were observed for tumor cells in a transwell assay, we found that daily injections of PEG-GM-CSF to tumor-bearing animals did not increase migration of cells to tumors, despite the anticipated changes in circulating levels of granulocytes and monocytes produced by this treatment. Combination of PEG-GM-CSF treatment with radiation also did not increase tumor cell migration. These findings suggest that clinical use of GM-CSF to treat neutropenia in cancer patients will not have negative effects on the aggressiveness of residual cancer cells. However, further work is needed to characterize the mechanism by which GM-CSF facilitates systemic recruitment of trafficking tumor cells to tumors.

http://ift.tt/2ImkUVi

Targeting mRNA Decapping in AML

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Akihide Yoshimi, Omar Abdel-Wahab
In this issue of Cancer Cell, Yamauchi et al. identify a dependency of acute myeloid leukemia (AML) on DCPS, which catalyzes the final step of 3′-to-5′ mRNA decay and is implicated in numerous aspects of RNA metabolism. DCPS is targetable with a clinical inhibitor, underscoring the translational importance of this discovery.

Teaser

In this issue of Cancer Cell, Yamauchi et al. identify a dependency of acute myeloid leukemia (AML) on DCPS, which catalyzes the final step of 3′-to-5′ mRNA decay and is implicated in numerous aspects of RNA metabolism. DCPS is targetable with a clinical inhibitor, underscoring the translational importance of this discovery.


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Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Tanya Schild, Vivien Low, John Blenis, Ana P. Gomes
Metastases arising from tumors have the proclivity to colonize specific organs, suggesting that they must rewire their biology to meet the demands of the organ colonized, thus altering their primary properties. Each metastatic site presents distinct metabolic challenges to a colonizing cancer cell, ranging from fuel and oxygen availability to oxidative stress. Here, we discuss the organ-specific metabolic adaptations that cancer cells must undergo, which provide the ability to overcome the unique barriers to colonization in foreign tissues and establish the metastatic tissue tropism phenotype.



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PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Mami Morita, Taku Sato, Miyuki Nomura, Yoshimi Sakamoto, Yui Inoue, Ryota Tanaka, Shigemi Ito, Koreyuki Kurosawa, Kazunori Yamaguchi, Yuki Sugiura, Hiroshi Takizaki, Yoji Yamashita, Ryuichi Katakura, Ikuro Sato, Masaaki Kawai, Yoshinori Okada, Hitomi Watanabe, Gen Kondoh, Shoko Matsumoto, Ayako Kishimoto, Miki Obata, Masaki Matsumoto, Tatsuro Fukuhara, Hozumi Motohashi, Makoto Suematsu, Masaaki Komatsu, Keiichi I. Nakayama, Toshio Watanabe, Tomoyoshi Soga, Hiroshi Shima, Makoto Maemondo, Nobuhiro Tanuma
Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways, is a hallmark of cancer. However, PKM2 function in tumorigenesis remains controversial. Here, we show that, when expressed rather than PKM2, the PKM isoform PKM1 exhibits a tumor-promoting function in KRAS^G12D-induced or carcinogen-initiated mouse models or in some human cancers. Analysis of Pkm mutant mouse lines expressing specific PKM isoforms established that PKM1 boosts tumor growth cell intrinsically. PKM1 activated glucose catabolism and stimulated autophagy/mitophagy, favoring malignancy. Importantly, we observed that pulmonary neuroendocrine tumors (NETs), including small-cell lung cancer (SCLC), express PKM1, and that PKM1 expression is required for SCLC cell proliferation. Our findings provide a rationale for targeting PKM1 therapeutically in certain cancer subtypes, including pulmonary NETs.

Graphical abstract

Teaser

The relative importance of PKM isoforms in tumor growth has been controversial. Morita et al. show that PKM1 promotes the growth of multiple tumor models using mouse lines expressing PKM1 or PKM2 from the endogenous Pkm locus. PKM1 is expressed in human SCLC, and it is important for SCLC cell proliferation.


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Glucose Metabolism in Cancer: The Saga of Pyruvate Kinase Continues

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Annamarie E. Allen, Jason W. Locasale
Altered glucose metabolism is common in cancer. In this issue of Cancer Cell, Morita et al. report new mouse models that express specific isoforms of pyruvate kinase to study glycolysis in tumors. They report several unanticipated findings that challenge current ideas in cancer metabolism.

Teaser

Altered glucose metabolism is common in cancer. In this issue of Cancer Cell, Morita et al. report new mouse models that express specific isoforms of pyruvate kinase to study glycolysis in tumors. They report several unanticipated findings that challenge current ideas in cancer metabolism.


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Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Tanmoy Mondal, Prasanna Kumar Juvvuna, Agnete Kirkeby, Sanhita Mitra, Subazini Thankaswamy Kosalai, Larissa Traxler, Falk Hertwig, Sara Wernig-Zorc, Caroline Miranda, Lily Deland, Ruth Volland, Christoph Bartenhagen, Deniz Bartsch, Sashidhar Bandaru, Anne Engesser, Santhilal Subhash, Tommy Martinsson, Helena Carén, Levent M. Akyürek, Leo Kurian, Meena Kanduri, Maite Huarte, Per Kogner, Matthias Fischer, Chandrasekhar Kanduri
Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.

Graphical abstract

Teaser

Mondal et al. show a sense/antisense lncRNA pair expressed from the neuroblastoma (NB) risk-associated 6p22.3 locus is important for retinoic acid-induced NB differentiation gene-regulatory network by controlling CHD7 stability via modulating the cellular localization of the ubiquitin specific protease USP36.


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NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Alexandra Garancher, Charles Y. Lin, Morgane Morabito, Wilfrid Richer, Nathalie Rocques, Magalie Larcher, Laure Bihannic, Kyle Smith, Catherine Miquel, Sophie Leboucher, Nirmitha I. Herath, Fanny Dupuy, Pascale Varlet, Christine Haberler, Christine Walczak, Nadine El Tayara, Andreas Volk, Stéphanie Puget, François Doz, Olivier Delattre, Sabine Druillennec, Olivier Ayrault, Robert J. Wechsler-Reya, Alain Eychène, Franck Bourdeaut, Paul A. Northcott, Celio Pouponnot
Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities.

Graphical abstract

Teaser

Garancher et al. show that NRL and CRX are master transcriptional regulators of a photoreceptor-specific differentiation program critical for group 3 medulloblastoma (MB) maintenance. They identify BCL-XL as a key NRL target and provide evidence supporting anti-BCL therapy as a strategy for some MB patients.


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Systematic Functional Annotation of Somatic Mutations in Cancer

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Patrick Kwok-Shing Ng, Jun Li, Kang Jin Jeong, Shan Shao, Hu Chen, Yiu Huen Tsang, Sohini Sengupta, Zixing Wang, Venkata Hemanjani Bhavana, Richard Tran, Stephanie Soewito, Darlan Conterno Minussi, Daniela Moreno, Kathleen Kong, Turgut Dogruluk, Hengyu Lu, Jianjiong Gao, Collin Tokheim, Daniel Cui Zhou, Amber M. Johnson, Jia Zeng, Carman Ka Man Ip, Zhenlin Ju, Matthew Wester, Shuangxing Yu, Yongsheng Li, Christopher P. Vellano, Nikolaus Schultz, Rachel Karchin, Li Ding, Yiling Lu, Lydia Wai Ting Cheung, Ken Chen, Kenna R. Shaw, Funda Meric-Bernstam, Kenneth L. Scott, Song Yi, Nidhi Sahni, Han Liang, Gordon B. Mills
The functional impact of the vast majority of cancer somatic mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of signaling effects for select aberrations. We apply the platform to annotate >1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes. Further, the platform is sufficiently sensitive to identify weak drivers. Our data are accessible through a user-friendly, public data portal. Our study will facilitate biomarker discovery, prediction algorithm improvement, and drug development.

Graphical abstract

Teaser

Ng et al. develop a moderate-throughput functional genomic platform and use it to annotate >1,000 cancer variants of unknown significance. The approach is sufficiently sensitive to identify weak drivers, potentially doubling the number of driver mutations characterized in clinically actionable genes.


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Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Yuying Liu, Xiaoyu Liang, Wenqian Dong, Yi Fang, Jiadi Lv, Tianzhen Zhang, Roland Fiskesund, Jing Xie, Jinyan Liu, Xiaonan Yin, Xun Jin, Degao Chen, Ke Tang, Jingwei Ma, Huafeng Zhang, Jing Yu, Jun Yan, Huaping Liang, Siqi Mo, Feiran Cheng, Yabo Zhou, Haizeng Zhang, Jing Wang, Jingnan Li, Yang Chen, Bing Cui, Zhuo-Wei Hu, Xuetao Cao, F. Xiao-Feng Qin, Bo Huang
Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8⁺ T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8⁺ T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8⁺ T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications.

Teaser

Liu et al. find that tumor-repopulating cells (TRCs) regulate PD-1 expression in CD8⁺ T cells. TRCs secrete kynurenine that is taken up by T cells and activates AhR, which directly regulates PD-1 expression. Blockade of this pathway enhances adoptive T cell therapy efficacy in a mouse melanoma model.


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Targeting mRNA Decapping in AML

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Akihide Yoshimi, Omar Abdel-Wahab
In this issue of Cancer Cell, Yamauchi et al. identify a dependency of acute myeloid leukemia (AML) on DCPS, which catalyzes the final step of 3′-to-5′ mRNA decay and is implicated in numerous aspects of RNA metabolism. DCPS is targetable with a clinical inhibitor, underscoring the translational importance of this discovery.

Teaser

In this issue of Cancer Cell, Yamauchi et al. identify a dependency of acute myeloid leukemia (AML) on DCPS, which catalyzes the final step of 3′-to-5′ mRNA decay and is implicated in numerous aspects of RNA metabolism. DCPS is targetable with a clinical inhibitor, underscoring the translational importance of this discovery.


http://ift.tt/2Ip4mfE

ORY-1001: Overcoming the Differentiation Block in AML

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Prithviraj Bose, Marina Y. Konopleva
In this issue of Cancer Cell, Maes and colleagues report in vitro and in vivo findings with ORY-1001—an oral, highly potent and selective covalent small-molecule inhibitor of lysine-specific demethylase 1 (LSD1)—in development for acute myeloid leukemia (AML), as well as correlative data from two AML patients receiving ORY-1001.

Teaser

In this issue of Cancer Cell, Maes and colleagues report in vitro and in vivo findings with ORY-1001—an oral, highly potent and selective covalent small-molecule inhibitor of lysine-specific demethylase 1 (LSD1)—in development for acute myeloid leukemia (AML), as well as correlative data from two AML patients receiving ORY-1001.


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A Non-canonical Polycomb Dependency in Synovial Sarcoma

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Joshua J. Waterfall, Paul S. Meltzer
Disruptions in the antagonistic balance between the chromatin-modifying Polycomb and Trithorax group proteins drive many malignancies. In this issue of Cancer Cell, Banito et al. describe how the SS18-SSX oncogenic fusion protein in synovial sarcoma directly co-opts these complexes to drive gene dysregulation and sustain the transformed state.

Teaser

Disruptions in the antagonistic balance between the chromatin-modifying Polycomb and Trithorax group proteins drive many malignancies. In this issue of Cancer Cell, Banito et al. describe how the SS18-SSX oncogenic fusion protein in synovial sarcoma directly co-opts these complexes to drive gene dysregulation and sustain the transformed state.


http://ift.tt/2IjLfDs

Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Tanya Schild, Vivien Low, John Blenis, Ana P. Gomes
Metastases arising from tumors have the proclivity to colonize specific organs, suggesting that they must rewire their biology to meet the demands of the organ colonized, thus altering their primary properties. Each metastatic site presents distinct metabolic challenges to a colonizing cancer cell, ranging from fuel and oxygen availability to oxidative stress. Here, we discuss the organ-specific metabolic adaptations that cancer cells must undergo, which provide the ability to overcome the unique barriers to colonization in foreign tissues and establish the metastatic tissue tropism phenotype.



http://ift.tt/2paUVaV

PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Mami Morita, Taku Sato, Miyuki Nomura, Yoshimi Sakamoto, Yui Inoue, Ryota Tanaka, Shigemi Ito, Koreyuki Kurosawa, Kazunori Yamaguchi, Yuki Sugiura, Hiroshi Takizaki, Yoji Yamashita, Ryuichi Katakura, Ikuro Sato, Masaaki Kawai, Yoshinori Okada, Hitomi Watanabe, Gen Kondoh, Shoko Matsumoto, Ayako Kishimoto, Miki Obata, Masaki Matsumoto, Tatsuro Fukuhara, Hozumi Motohashi, Makoto Suematsu, Masaaki Komatsu, Keiichi I. Nakayama, Toshio Watanabe, Tomoyoshi Soga, Hiroshi Shima, Makoto Maemondo, Nobuhiro Tanuma
Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways, is a hallmark of cancer. However, PKM2 function in tumorigenesis remains controversial. Here, we show that, when expressed rather than PKM2, the PKM isoform PKM1 exhibits a tumor-promoting function in KRAS^G12D-induced or carcinogen-initiated mouse models or in some human cancers. Analysis of Pkm mutant mouse lines expressing specific PKM isoforms established that PKM1 boosts tumor growth cell intrinsically. PKM1 activated glucose catabolism and stimulated autophagy/mitophagy, favoring malignancy. Importantly, we observed that pulmonary neuroendocrine tumors (NETs), including small-cell lung cancer (SCLC), express PKM1, and that PKM1 expression is required for SCLC cell proliferation. Our findings provide a rationale for targeting PKM1 therapeutically in certain cancer subtypes, including pulmonary NETs.

Graphical abstract

Teaser

The relative importance of PKM isoforms in tumor growth has been controversial. Morita et al. show that PKM1 promotes the growth of multiple tumor models using mouse lines expressing PKM1 or PKM2 from the endogenous Pkm locus. PKM1 is expressed in human SCLC, and it is important for SCLC cell proliferation.


http://ift.tt/2IjL5vQ

Glucose Metabolism in Cancer: The Saga of Pyruvate Kinase Continues

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Annamarie E. Allen, Jason W. Locasale
Altered glucose metabolism is common in cancer. In this issue of Cancer Cell, Morita et al. report new mouse models that express specific isoforms of pyruvate kinase to study glycolysis in tumors. They report several unanticipated findings that challenge current ideas in cancer metabolism.

Teaser

Altered glucose metabolism is common in cancer. In this issue of Cancer Cell, Morita et al. report new mouse models that express specific isoforms of pyruvate kinase to study glycolysis in tumors. They report several unanticipated findings that challenge current ideas in cancer metabolism.


http://ift.tt/2p9ZVwo

Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Tanmoy Mondal, Prasanna Kumar Juvvuna, Agnete Kirkeby, Sanhita Mitra, Subazini Thankaswamy Kosalai, Larissa Traxler, Falk Hertwig, Sara Wernig-Zorc, Caroline Miranda, Lily Deland, Ruth Volland, Christoph Bartenhagen, Deniz Bartsch, Sashidhar Bandaru, Anne Engesser, Santhilal Subhash, Tommy Martinsson, Helena Carén, Levent M. Akyürek, Leo Kurian, Meena Kanduri, Maite Huarte, Per Kogner, Matthias Fischer, Chandrasekhar Kanduri
Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.

Graphical abstract

Teaser

Mondal et al. show a sense/antisense lncRNA pair expressed from the neuroblastoma (NB) risk-associated 6p22.3 locus is important for retinoic acid-induced NB differentiation gene-regulatory network by controlling CHD7 stability via modulating the cellular localization of the ubiquitin specific protease USP36.


http://ift.tt/2pbCq5Z

NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Alexandra Garancher, Charles Y. Lin, Morgane Morabito, Wilfrid Richer, Nathalie Rocques, Magalie Larcher, Laure Bihannic, Kyle Smith, Catherine Miquel, Sophie Leboucher, Nirmitha I. Herath, Fanny Dupuy, Pascale Varlet, Christine Haberler, Christine Walczak, Nadine El Tayara, Andreas Volk, Stéphanie Puget, François Doz, Olivier Delattre, Sabine Druillennec, Olivier Ayrault, Robert J. Wechsler-Reya, Alain Eychène, Franck Bourdeaut, Paul A. Northcott, Celio Pouponnot
Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities.

Graphical abstract

Teaser

Garancher et al. show that NRL and CRX are master transcriptional regulators of a photoreceptor-specific differentiation program critical for group 3 medulloblastoma (MB) maintenance. They identify BCL-XL as a key NRL target and provide evidence supporting anti-BCL therapy as a strategy for some MB patients.


http://ift.tt/2Ine4PF

Systematic Functional Annotation of Somatic Mutations in Cancer

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Patrick Kwok-Shing Ng, Jun Li, Kang Jin Jeong, Shan Shao, Hu Chen, Yiu Huen Tsang, Sohini Sengupta, Zixing Wang, Venkata Hemanjani Bhavana, Richard Tran, Stephanie Soewito, Darlan Conterno Minussi, Daniela Moreno, Kathleen Kong, Turgut Dogruluk, Hengyu Lu, Jianjiong Gao, Collin Tokheim, Daniel Cui Zhou, Amber M. Johnson, Jia Zeng, Carman Ka Man Ip, Zhenlin Ju, Matthew Wester, Shuangxing Yu, Yongsheng Li, Christopher P. Vellano, Nikolaus Schultz, Rachel Karchin, Li Ding, Yiling Lu, Lydia Wai Ting Cheung, Ken Chen, Kenna R. Shaw, Funda Meric-Bernstam, Kenneth L. Scott, Song Yi, Nidhi Sahni, Han Liang, Gordon B. Mills
The functional impact of the vast majority of cancer somatic mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of signaling effects for select aberrations. We apply the platform to annotate >1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes. Further, the platform is sufficiently sensitive to identify weak drivers. Our data are accessible through a user-friendly, public data portal. Our study will facilitate biomarker discovery, prediction algorithm improvement, and drug development.

Graphical abstract

Teaser

Ng et al. develop a moderate-throughput functional genomic platform and use it to annotate >1,000 cancer variants of unknown significance. The approach is sufficiently sensitive to identify weak drivers, potentially doubling the number of driver mutations characterized in clinically actionable genes.


http://ift.tt/2p9ZVfS

Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Yuying Liu, Xiaoyu Liang, Wenqian Dong, Yi Fang, Jiadi Lv, Tianzhen Zhang, Roland Fiskesund, Jing Xie, Jinyan Liu, Xiaonan Yin, Xun Jin, Degao Chen, Ke Tang, Jingwei Ma, Huafeng Zhang, Jing Yu, Jun Yan, Huaping Liang, Siqi Mo, Feiran Cheng, Yabo Zhou, Haizeng Zhang, Jing Wang, Jingnan Li, Yang Chen, Bing Cui, Zhuo-Wei Hu, Xuetao Cao, F. Xiao-Feng Qin, Bo Huang
Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8⁺ T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8⁺ T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8⁺ T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications.

Teaser

Liu et al. find that tumor-repopulating cells (TRCs) regulate PD-1 expression in CD8⁺ T cells. TRCs secrete kynurenine that is taken up by T cells and activates AhR, which directly regulates PD-1 expression. Blockade of this pathway enhances adoptive T cell therapy efficacy in a mouse melanoma model.


http://ift.tt/2Ine4iD

Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Jaclyn Andricovich, Stephanie Perkail, Yan Kai, Nicole Casasanta, Weiqun Peng, Alexandros Tzatsos
KDM6A, an X chromosome-encoded histone demethylase and member of the COMPASS-like complex, is frequently mutated in a broad spectrum of malignancies and contributes to oncogenesis with poorly characterized mechanisms. We found that KDM6A loss induced squamous-like, metastatic pancreatic cancer selectively in females through deregulation of the COMPASS-like complex and aberrant activation of super-enhancers regulating ΔNp63, MYC, and RUNX3 oncogenes. This subtype of tumor developed in males had concomitant loss of UTY and KDM6A, suggesting overlapping roles, and points to largely demethylase independent tumor suppressor functions. We also demonstrate that KDM6A-deficient pancreatic cancer is selectively sensitive to BET inhibitors, which reversed squamous differentiation and restrained tumor growth in vivo, highlighting a therapeutic niche for patient tailored therapies.

Graphical abstract

Teaser

Andricovich et al. show that KDM6A loss, via aberrant activation of super-enhancers regulating several oncogenes, induces squamous-like, metastatic pancreatic cancer in females. In males, both KDM6A and UTY loss is required to induce squamous-like tumors. Importantly, KDM6A-deficient pancreatic cancer is sensitive to BET inhibitors.


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Targeting MDSCs and PD-L1 confers the therapeutic advantage of ablative hypofractionated radiotherapy over conventional fractionated radiotherapy

Publication date: Available online 12 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jie Lan, Rui Li, Li-Mei Yin, Lei Deng, Jun Gui, Bao-Qing Chen, Lin Zhou, Mao-Bing Men, Qiao-Rong Huang, Xian-Ming Mo, Yu-Quan Wei, Bo Lu, Adam Dicker, Jian-Xin Xue, You Lu
PurposeAblative hypofractionated radiotherapy (AHFRT) presents therapeutic advantage over conventional fractionated radiotherapy (CFRT) in primary and oligometastatic cancers, but the underlying mechanisms remain largely unknown. In this study, we compared the immune alterations in response to AHFRT vs. CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT.Experiment Design and ResultsWe established subcutaneous tumors using syngeneic lung cancer and melanoma cells in both immunocompetent and immunocompromised mice and treated them with AHFRT and CFRT under the same biological equivalent dose (BED). Compared to CFRT, AHFRT significantly inhibited tumor growth in immunocompetent, but not in immunocompromised mice. On the cellular level, AHFRT reduced the recruitment of myeloid-derived suppressor cells (MDSCs) into tumors, and decreased the expression of programmed death-ligand 1 (PD-L1) on those cells, which unlashed the cytotoxicity of CD8⁺ T cells. Through the down-regulation of vascular endothelial growth factor (VEGF), AHFRT inhibited VEGF/VEGFR signaling, which was essential for MDSC recruitment. When combined with anti-PD-L1 antibody, AHFRT presented a higher efficacy in controlling tumor growth and improving mouse survival. By altering immune regulation, AHFRT, but not CFRT, significantly delayed the growth of secondary tumors implanted outside the irradiation field.ConclusionTargeting MDSC recruitment and enhancing anti-tumor immunity are crucial for the therapeutic efficacy of AHFRT. When combined with anti-PD-L1 immunotherapy, AHFRT is more potent for cancer treatment.

Teaser

This study compared the immune alterations in response to ablative hypofractionated radiotherapy (AHFRT) and conventional fractionated radiotherapy (CFRT) under the same BED, and showed that AHFRT suppressed recruitment of MDSCs into tumors, releasing the inhibition on CD8⁺ T cells, and boosting not only local but also systemic anti-cancer immunity. Adding anti-PD-L1 immunotherapy further boosted the potency of AHFRT. This study extended the mechanisms underlying the efficacy of AHFRT and proposed strategy to combine radiotherapy with immunotherapy.


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Targeting MDSCs and PD-L1 confers the therapeutic advantage of ablative hypofractionated radiotherapy over conventional fractionated radiotherapy

Publication date: Available online 12 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jie Lan, Rui Li, Li-Mei Yin, Lei Deng, Jun Gui, Bao-Qing Chen, Lin Zhou, Mao-Bing Men, Qiao-Rong Huang, Xian-Ming Mo, Yu-Quan Wei, Bo Lu, Adam Dicker, Jian-Xin Xue, You Lu
PurposeAblative hypofractionated radiotherapy (AHFRT) presents therapeutic advantage over conventional fractionated radiotherapy (CFRT) in primary and oligometastatic cancers, but the underlying mechanisms remain largely unknown. In this study, we compared the immune alterations in response to AHFRT vs. CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT.Experiment Design and ResultsWe established subcutaneous tumors using syngeneic lung cancer and melanoma cells in both immunocompetent and immunocompromised mice and treated them with AHFRT and CFRT under the same biological equivalent dose (BED). Compared to CFRT, AHFRT significantly inhibited tumor growth in immunocompetent, but not in immunocompromised mice. On the cellular level, AHFRT reduced the recruitment of myeloid-derived suppressor cells (MDSCs) into tumors, and decreased the expression of programmed death-ligand 1 (PD-L1) on those cells, which unlashed the cytotoxicity of CD8⁺ T cells. Through the down-regulation of vascular endothelial growth factor (VEGF), AHFRT inhibited VEGF/VEGFR signaling, which was essential for MDSC recruitment. When combined with anti-PD-L1 antibody, AHFRT presented a higher efficacy in controlling tumor growth and improving mouse survival. By altering immune regulation, AHFRT, but not CFRT, significantly delayed the growth of secondary tumors implanted outside the irradiation field.ConclusionTargeting MDSC recruitment and enhancing anti-tumor immunity are crucial for the therapeutic efficacy of AHFRT. When combined with anti-PD-L1 immunotherapy, AHFRT is more potent for cancer treatment.

Teaser

This study compared the immune alterations in response to ablative hypofractionated radiotherapy (AHFRT) and conventional fractionated radiotherapy (CFRT) under the same BED, and showed that AHFRT suppressed recruitment of MDSCs into tumors, releasing the inhibition on CD8⁺ T cells, and boosting not only local but also systemic anti-cancer immunity. Adding anti-PD-L1 immunotherapy further boosted the potency of AHFRT. This study extended the mechanisms underlying the efficacy of AHFRT and proposed strategy to combine radiotherapy with immunotherapy.


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Liver Metastatic Melanoma: a Unique Case with Normal Alkaline Phosphatase and Melanuria

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Liver Metastatic Melanoma: a Unique Case with Normal Alkaline Phosphatase and Melanuria

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Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials, Published online: 13 March 2018; doi:10.1038/s41416-018-0015-z

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

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From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation, Published online: 13 March 2018; doi:10.1038/s41416-018-0017-x

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

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A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours, Published online: 13 March 2018; doi:10.1038/s41416-018-0006-0

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

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New Insights into Genomics of Pediatric Cancers [News in Brief]

Mutation type, number differ from those driving adult cancers, studies find.

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Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials, Published online: 13 March 2018; doi:10.1038/s41416-018-0015-z

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

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Influence of obesity-related risk factors in the aetiology of glioma

Influence of obesity-related risk factors in the aetiology of glioma

Influence of obesity-related risk factors in the aetiology of glioma, Published online: 13 March 2018; doi:10.1038/s41416-018-0009-x

Influence of obesity-related risk factors in the aetiology of glioma

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Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression

Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression

Pre-B acute lymphoblastic leukaemia recurrent fusion, <i>EP300-ZNF384</i>, is associated with a distinct gene expression, Published online: 13 March 2018; doi:10.1038/s41416-018-0022-0

Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression

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From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation, Published online: 13 March 2018; doi:10.1038/s41416-018-0017-x

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

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A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours, Published online: 13 March 2018; doi:10.1038/s41416-018-0006-0

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

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Editorial Board

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1





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A geographical and temporal analysis of melanoma awareness in an international population

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1
Author(s): Ryan Sugrue




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SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastases

Publication date: Available online 7 March 2018
Source:European Journal of Surgical Oncology
Author(s): Takashi Mizuno, Jordan M. Cloyd, Diego Vicente, Kiyohiko Omichi, Yun Shin Chun, Scott E. Kopetz, Dipen Maru, Claudius Conrad, Ching-Wei D. Tzeng, Steven H. Wei, Thomas A. Aloia, Jean-Nicolas Vauthey
IntroductionDorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is a key mediator in the transforming growth factor (TGF)-β signaling pathway and SMAD4 gene mutations are thought to play a critical role in colorectal cancer (CRC) progression. However, little is known about its influence on survival in patients undergoing resection for colorectal liver metastases (CLM).MethodsBetween 2005 and 2015, all patients with known SMAD4 mutation status who underwent resection of CLM were identified. Patients with SMAD4 mutation were compared to those with SMAD4 wild type. Next, the prognostic value of SMAD4 mutation was validated in a separate cohort of patients with synchronous stage IV CRC who underwent systemic therapy alone.ResultsOf 278 patients, 37 (13%) were SMAD4 mutant while 241 (87%) were wild type. Overall survival (OS) after hepatic resection was worse in SMAD4-mutant patients compared to SMAD4 wild type (OS rate at 3 years, 62% vs. 82%; P<0.0001). Independent predictors for worse OS were poor differentiation (hazard ratio [HR] 2.586; P=0.007), multiple tumors (HR 1.970; P=0.01), diameter greater than 3 cm (HR 1.752; P=0.017), R1 margin status (HR 2.452; P=0.014), RAS mutation (HR 2.044; P=0.002), and SMAD4 mutation (HR 2.773; P<0.0001). Among 237 patients in the validation cohort, SMAD4-mutations were significantly associated with worse 3-year OS rate (22% vs. 38%; P=0.012) and was an independent predictor for worse OS (HR, 1.647; P=0.032).ConclusionSMAD4 mutation is independently associated with worse outcomes among patients undergoing resection of CLM.



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Quality of life of elderly women with early breast cancer following surgery

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1
Author(s): Anne Shrestha, Charlene Martin, Karen Collins, Maria Burton, Riccardo Audisio, Tim Chater, Kirsty Pemberton, Kl Cheung, Sue Ward, Stephen Walters, Reed Malcolm, Tg Robinson, T. Green, Dierdre Revell, Jaqui Gath, Lynda Wyld




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Surgery with Curative intent is Associated with Prolonged Survival in Patients with Cutaneous Angiosarcoma of the Scalp and Face -A retrospective study of 38 untreated cases in the Japanese population

Publication date: Available online 6 March 2018
Source:European Journal of Surgical Oncology
Author(s): Kohei Oashi, Kenjiro Namikawa, Arata Tsutsumida, Akira Takahashi, Jun Itami, Hiroshi Igaki, Koji Inaba, Naoya Yamazaki
BackgroundIn patients with cutaneous angiosarcoma of the scalp and face, the validity of surgery remains controversial, because of the potentially diffuse nature of involvement and difficulty in obtaining negative margins.ObjectiveTo evaluate the survival benefit of surgery as primary treatment.Patients and methodsFifty-one patients with primary cutaneous angiosarcoma of the scalp and face presenting with locoregional involvement were referred to National Cancer Center Hospital, Tokyo, Japan, between May 1982 and March 2013. Data of those patients in whom the diagnosis had been confirmed histologically and the primary treatments had been initiated at our center were analysed retrospectively. Only untreated cases were selected with aim to evaluate actual survival benefit of surgery as primary treatment.ResultsOf the 51 patients, 38 were found to be eligible for inclusion in this analysis; of these 38 patients, 29 (29/38 = 76.3%) patients had tumour diameter ≥ 5 cm, and 29 underwent surgery with curative intent (curative-intent surgery) as the initial treatment. Histologically positive margins were found in 10 patients. Multivariate analysis identified curative-intent surgery as being significantly associated with improved overall survival (OS; HR = 0.26; 95% CI, 0.10-0.63). In the Surgery group, neither negative margins nor combined-modality treatment had any significant influence on the OS.ConclusionRemoval of primary tumour with curative-intent surgery may be a valid treatment option even for patients with primary cutaneous angiosarcoma of the scalp and face larger than 5cm in size, regardless of the histological surgical margin status.



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Assessment of the ERSPC and PCPT2.0 risk calculators in the prediction of prostate cancer in men attending a prostate assessment clinic

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1
Author(s): Sandesh Kc, Thomas King, David Mak, Rupesh Bhatt, Alan Doherty, Richard Viney, Prashant Patel, Brian Kelly




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ECCO essential requirements for quality cancer care – Melanoma

Publication date: Available online 2 March 2018
Source:European Journal of Surgical Oncology
Author(s): Michel W. Wouters




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Laparoscopic surgery in the treatment of stage I adult granulosa cells tumors of the ovary: results from the MITO-9 study

Publication date: Available online 10 March 2018
Source:European Journal of Surgical Oncology
Author(s): A. Bergamini, G. Ferrandina, M. Candiani, G. Cormio, G. Giorda, R. Lauria, A.M. Perrone, G. Scarfone, E. Breda, A. Savarese, L. Frigerio, A. Gadducci, F. Mascilini, F. Maneschi, C. Cassani, C. Marchetti, S.C. Cecere, N. Biglia, U. De Giorgi, F. Raspagliesi, D. Lorusso, G. Mangili
ObjectiveSurgery represents the mainstay of treatment of stage I adult type granulosa cell tumors of the ovary (AGCTs). Because of the rarity and indolent course of the disease, no prospective trials are available. Open surgery has long been considered the traditional approach; oncological safety of laparoscopy is only supported by small series or case reports. The aim of this study was to compare the oncological outcomes between laparoscopic and open surgery in stage I AGCTs treated within the MITO (Multicenter Italian Trials in Ovarian cancer) Group.Methodsdata from patients with stage I AGCTs were retrospectively collected. Clinicopathological features were evaluated for association with relapse and death. Survival curves were calculated using the Kaplan-Meier method and compared with the log-rank test. The role of clinicopathological variables as prognostic factors for survival was evaluated using Cox's regression model.Results223 patients were identified. Stage 1A, 1B and 1C were 61.5%, 1.3% and 29.6% respectively. 7.6% were apparently stage I. Surgical approach was laparoscopic for 93 patients (41.7%) and open for 130 (58.3%). 5-years DFS was 84% and 82%, 10-years DFS was 68% and 64% for the laparoscopic and open-group(p=0.6).5-years OS was 100% and 99%, 10 years OS was 98% and 97% for the laparoscopic and open-surgery group(p=0.8). At multivariate analyses stage IC, incomplete staging, site of primary surgery retained significant prognostic value.Conclusionthe present study suggests that surgical route does not affect the oncological safety of patients with stage I AGCTs, with comparable outcomes between laparoscopic and open approach.



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Calendar

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Issue 3





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University hospital status and surgeon volume and risk of reoperation following surgery for esophageal cancer

Publication date: Available online 2 March 2018
Source:European Journal of Surgical Oncology
Author(s): Joonas H. Kauppila, Karl Wahlin, Pernilla Lagergren, Jesper Lagergren
PurposeCentralization of surgery improves the survival following esophagectomy for cancer, but whether university hospital setting or surgeon volume influences the reoperation rates is unknown. We aimed to clarify whether hospital status or surgeon volume are associated with a risk of reoperation after esophagectomy.MethodsPatients who underwent esophagectomy for esophageal cancer in 1987-2010 were identified from a population-based, nationwide Swedish cohort study. University hospital status and cumulative surgeon volume were analyzed in relation to risk of reoperation or death (the latter included to avoid competing risk errors) within 30 days of surgery. Multivariable logistic regression provided odds ratios (OR) with 95% confidence intervals (CI), adjusted for calendar period, age, sex, comorbidity, tumor histology, stage, neoadjuvant therapy, resection margin, surgeon volume, and hospital status.ResultsAmong 1820 participants, 989 (54%) underwent esophagectomy in university hospitals and 271 (15%) died or were reoperated within 30 days of surgery. Non-university hospital status was associated with an increased risk of reoperation or death compared to university hospitals (adjusted OR 1.56, 95% CI 1.13-2.13). Regarding surgeon volume, the ORs were increased in the lower volume categories, but not statistically significant (OR 1.30, 95% CI 0.89-1.89 for surgeon volume <7 and OR 1.10, 95% CI 0.75-1.63 for surgeon volume 7-16, compared to surgeon volume >16).ConclusionThe risk of reoperation or death within 30 days of esophagectomy seems to be lower in university hospitals even after adjustment for surgeon volume and other potential confounders. These results support centralizing esophageal cancer patients to university hospitals.



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Theranostic CEA-Affimer functionalised silica nanoparticles allow specific in vitro fluorescent imaging of colorectal cancer cells

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1
Author(s): Yazan S. Khaled, Shazana Shamsuddin, Jim Tiernan, Mike McPherson, Thomas Hughes, Paul Millner, David G. Jayne




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Prognostic role of splenic vessel infiltration in distal pancreatic adenocarcinoma

Publication date: Available online 2 March 2018
Source:European Journal of Surgical Oncology
Author(s): Gaëtan-Romain Joliat, Nicolas Demartines, Markus Schäfer




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BRCA1 risk-reducing surgery appears to reduce risk of developing breast cancer

Publication date: March 2018
Source:European Journal of Surgical Oncology, Volume 44, Supplement 1
Author(s): Gareth Irwin, Gwyneth Hinds, Lesley McFaul, Patrick Morrison, Ian Harley, Stuart McIntosh




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B7-H3 negatively modulates CTL-mediated cancer immunity

Purpose: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting. Experimental Design: B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (n = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8⁺ tumor infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry. Results: B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8⁺ TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8⁺ TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8⁺ TILs and recovery of effector function. CD8⁺ T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8⁺ T-cells. Compared to a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the anti-tumor reaction. Conclusions:B7-H3 expressed on tumor cells potentially circumvents CD8⁺-T-cell-mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3-expressing NSCLCs.

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High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance)

Background: p95HER2 is a truncated form of human epidermal growth factor receptor 2 (HER2) that confers resistance to trastuzumab in vitro, but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials. Methods: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples. Results: In the multivariate model, increasing total HER2 level was significantly associated with longer overall survival (OS) (hazard ratio [HR]=0.33; P=.002) and decreasing p95HER2 level was significantly associated with longer OS (HR=4.2; P=.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR=0.57; P=.04) whereas p95HER2 level was not (HR= 1.7; P= .25). However, there was a positive association between p95HER2 and total HER2 expression levels (R2= 0.48; P<.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR= 1.7; P= .04) and OS (HR=2.8; P=.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR=1.8; P=.06) and OS (HR=2.3; P=.02). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies.

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Lipidomic profiling links the Fanconi anemia pathway to glycosphingolipid metabolism in head and neck cancer cells

Purpose:Mutations in Fanconi anemia (FA) genes are common in sporadic squamous cell carcinoma of the head and neck (HNSCC) and we have previously demonstrated that FA pathway depletion in HNSCC cell lines stimulates invasion. The goal of our studies was to use a systems approach in order to define FA pathway-dependent lipid metabolism, and to extract lipid-based signatures and effectors of invasion in FA-deficient cells. Experimental Design: We subjected FA-isogenic HNSCC keratinocyte cell lines to untargeted and targeted lipidomics analyses to discover novel biomarkers and candidate therapeutic targets in FA-deficient cells. Cellular invasion assays were carried out in the presence and absence of N-butyldeoxynojirimycin (NB-DNJ), a biosynthetic inhibitor of the newly identified class of gangliosides, to investigate the requirement of ganglioside upregulation in FA-deficient HNSCC cells. Results: The most notable element of the lipid profiling results was a consistent elevation of glycosphingolipids, and particularly the accumulation of gangliosides. Conversely, repression of this same class of lipids was observed upon genetic correction of FA patient derived HNSCC cells. Functional studies demonstrate that ganglioside upregulation is required for HNSCC cell invasion driven by FA pathway loss. The motility of non-transformed keratinocytes in response to FA loss displayed a similar dependence, thus supporting early and late roles for the FA pathway in controlling keratinocyte invasion through lipid regulation.   Conclusions: Elevation of glycosphingolipids including the ganglioside GM3 in response to FA loss stimulates invasive characteristics of immortalized and transformed keratinocytes. An inhibitor of glycosphingolipid biosynthesis NB-DNJ attenuates invasive characteristics of FA-deficient HNSCC cells.

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Association of p27 and cyclin D1 expression and benefit from adjuvant trastuzumab treatment in HER2-positive early breast cancer: a TransHERA study

Purpose: To assess the prognostic and predictive value of selected biomarkers involved in cell cycle regulation or proliferation in HER2-positive early breast cancer patients. Methods: Protein expression of TOP2A, Ki67, cyclin D1 and p27 was immunohistochemically determined in tissue microarrays of surgical specimens from 862 patients randomized to trastuzumab (1 or 2 year; N=561) and observation (N=301) arms of the HERA trial. The primary analysis endpoint was disease-free survival (DFS). Biomarkers were examined as continuous or categorical variables (pre-defined cutoffs). Interaction terms between biomarkers and treatment were assessed in multivariate Cox models adjusted for variables of clinical interest. Results: A significant interaction was detected between p27 and treatment (adjusted p=0.0049). Trastuzumab effect was significant in the p27 low subgroup (≤70% p27-positive tumor cells; N=318). HR _{CombTrast vs. Obs} 0.44, 95% CI: 0.29-0.65 (p<0.001). No trastuzumab effect was observed in the p27 high subgroup N=435; HR _{Comb Trast vs. Obs} 0.97, 95% CI: 0.66-1.44, p=0.89), indicating that these patients derived little or no benefit from trastuzumab treatment. A prognostic effect of p27 on DFS was observed, with p27 high patients experiencing half the hazard of a DFS event compared to low ones (HR _{p27 High vs. Low} 0.49, 95% CI: 0.32-0.75). TOP2A, Ki67 and cyclin D1, as categorical variables were not predictive, whereas cyclin D1 as continuous variable was predictive of trastuzumab benefit. Conclusions: In TransHERA, HER2-positive early breast cancer patients with low p27 expression in their tumors benefited from trastuzumab treatment, whereas patients with high p27 expression did not.

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Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance.

Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.      Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies. Results: In 200 EGFR-mutant pre-treatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1 and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1.  Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR=2.4, p=0.015) or MET (HR 3.7, p=0.019), or mutation in TP53 (HR 1.7, p=0.006). In the 136 post-treatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%) and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2914K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivo. Conclusions: EGFR-mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally.

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Activation of the receptor tyrosine kinase AXL regulates the immune microenvironment in glioblastoma

Glioblastoma (GBM) is a lethal disease with no effective therapies available. We previously observed upregulation of the TAM (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL in mesenchymal GBM and showed that knockdown of AXL induced apoptosis of mesenchymal, but not proneural, glioma sphere cultures (GSC). In this study, we report that BGB324, a novel small molecule inhibitor of AXL, prolongs the survival of immunocompromised mice bearing GSC-derived mesenchymal GBM-like tumors. We show that protein S (PROS1), a known ligand of other TAM receptors, was secreted by tumor-associated macrophages/microglia and subsequently physically associated with and activated AXL in mesenchymal GSC. PROS1-driven phosphorylation of AXL (pAXL) induced NF-κB activation in mesenchymal GSC, which was inhibited by BGB324 treatment. We also found that treatment of GSC-derived mouse GBM tumors with Nivolumab, a blocking antibody against the immune checkpoint protein PD-1, increased intratumoral macrophages/microglia and activation of AXL. Combinatorial therapy with Nivolumab plus BGB324 effectively prolonged the survival of mice bearing GBM tumors. Clinically, expression of AXL or PROS1 was associated with poor prognosis for GBM patients. Our results suggest that the PROS1-AXL pathway regulates intrinsic mesenchymal signaling as well as the extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors.

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RIPK1 binds MCU to mediate induction of mitochondrial Ca2+ uptake and promote colorectal oncogenesis

The receptor-interacting protein kinase 1 (RIPK1) is an essential signaling molecule in pathways for cell survival, apoptosis, and necroptosis. We report here that RIPK1 is upregulated in human colorectal cancer (CRC) and promotes cell proliferation when overexpressed in a colon cancer cell line. RIPK1 interacts with mitochondrial Ca2+ uniporter (MCU) to promote proliferation by increasing mitochondrial Ca2+ uptake and energy metabolism. The ubiquitination site of RIPK1 (RIPK1-K377) was critical for this interaction with MCU and function in promoting cell proliferation. These findings identify the RIPK1-MCU pathway as a promising target to treat CRC.

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Acetylation within the N- and C-terminal domains of Src regulate distinct roles of STAT3-mediated tumorigenesis

Post-translational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions: myristoylation of G2 controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylated an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylated the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activated transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocated into nuclei where it formed the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation.

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B7-H3 negatively modulates CTL-mediated cancer immunity

Purpose: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting. Experimental Design: B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (n = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8⁺ tumor infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry. Results: B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8⁺ TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8⁺ TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8⁺ TILs and recovery of effector function. CD8⁺ T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8⁺ T-cells. Compared to a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the anti-tumor reaction. Conclusions:B7-H3 expressed on tumor cells potentially circumvents CD8⁺-T-cell-mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3-expressing NSCLCs.

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High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance)

Background: p95HER2 is a truncated form of human epidermal growth factor receptor 2 (HER2) that confers resistance to trastuzumab in vitro, but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials. Methods: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples. Results: In the multivariate model, increasing total HER2 level was significantly associated with longer overall survival (OS) (hazard ratio [HR]=0.33; P=.002) and decreasing p95HER2 level was significantly associated with longer OS (HR=4.2; P=.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR=0.57; P=.04) whereas p95HER2 level was not (HR= 1.7; P= .25). However, there was a positive association between p95HER2 and total HER2 expression levels (R2= 0.48; P<.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR= 1.7; P= .04) and OS (HR=2.8; P=.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR=1.8; P=.06) and OS (HR=2.3; P=.02). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies.

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Lipidomic profiling links the Fanconi anemia pathway to glycosphingolipid metabolism in head and neck cancer cells

Purpose:Mutations in Fanconi anemia (FA) genes are common in sporadic squamous cell carcinoma of the head and neck (HNSCC) and we have previously demonstrated that FA pathway depletion in HNSCC cell lines stimulates invasion. The goal of our studies was to use a systems approach in order to define FA pathway-dependent lipid metabolism, and to extract lipid-based signatures and effectors of invasion in FA-deficient cells. Experimental Design: We subjected FA-isogenic HNSCC keratinocyte cell lines to untargeted and targeted lipidomics analyses to discover novel biomarkers and candidate therapeutic targets in FA-deficient cells. Cellular invasion assays were carried out in the presence and absence of N-butyldeoxynojirimycin (NB-DNJ), a biosynthetic inhibitor of the newly identified class of gangliosides, to investigate the requirement of ganglioside upregulation in FA-deficient HNSCC cells. Results: The most notable element of the lipid profiling results was a consistent elevation of glycosphingolipids, and particularly the accumulation of gangliosides. Conversely, repression of this same class of lipids was observed upon genetic correction of FA patient derived HNSCC cells. Functional studies demonstrate that ganglioside upregulation is required for HNSCC cell invasion driven by FA pathway loss. The motility of non-transformed keratinocytes in response to FA loss displayed a similar dependence, thus supporting early and late roles for the FA pathway in controlling keratinocyte invasion through lipid regulation.   Conclusions: Elevation of glycosphingolipids including the ganglioside GM3 in response to FA loss stimulates invasive characteristics of immortalized and transformed keratinocytes. An inhibitor of glycosphingolipid biosynthesis NB-DNJ attenuates invasive characteristics of FA-deficient HNSCC cells.

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Association of p27 and cyclin D1 expression and benefit from adjuvant trastuzumab treatment in HER2-positive early breast cancer: a TransHERA study

Purpose: To assess the prognostic and predictive value of selected biomarkers involved in cell cycle regulation or proliferation in HER2-positive early breast cancer patients. Methods: Protein expression of TOP2A, Ki67, cyclin D1 and p27 was immunohistochemically determined in tissue microarrays of surgical specimens from 862 patients randomized to trastuzumab (1 or 2 year; N=561) and observation (N=301) arms of the HERA trial. The primary analysis endpoint was disease-free survival (DFS). Biomarkers were examined as continuous or categorical variables (pre-defined cutoffs). Interaction terms between biomarkers and treatment were assessed in multivariate Cox models adjusted for variables of clinical interest. Results: A significant interaction was detected between p27 and treatment (adjusted p=0.0049). Trastuzumab effect was significant in the p27 low subgroup (≤70% p27-positive tumor cells; N=318). HR _{CombTrast vs. Obs} 0.44, 95% CI: 0.29-0.65 (p<0.001). No trastuzumab effect was observed in the p27 high subgroup N=435; HR _{Comb Trast vs. Obs} 0.97, 95% CI: 0.66-1.44, p=0.89), indicating that these patients derived little or no benefit from trastuzumab treatment. A prognostic effect of p27 on DFS was observed, with p27 high patients experiencing half the hazard of a DFS event compared to low ones (HR _{p27 High vs. Low} 0.49, 95% CI: 0.32-0.75). TOP2A, Ki67 and cyclin D1, as categorical variables were not predictive, whereas cyclin D1 as continuous variable was predictive of trastuzumab benefit. Conclusions: In TransHERA, HER2-positive early breast cancer patients with low p27 expression in their tumors benefited from trastuzumab treatment, whereas patients with high p27 expression did not.

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Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance.

Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.      Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies. Results: In 200 EGFR-mutant pre-treatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1 and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1.  Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR=2.4, p=0.015) or MET (HR 3.7, p=0.019), or mutation in TP53 (HR 1.7, p=0.006). In the 136 post-treatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%) and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2914K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivo. Conclusions: EGFR-mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally.

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Activation of the receptor tyrosine kinase AXL regulates the immune microenvironment in glioblastoma

Glioblastoma (GBM) is a lethal disease with no effective therapies available. We previously observed upregulation of the TAM (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL in mesenchymal GBM and showed that knockdown of AXL induced apoptosis of mesenchymal, but not proneural, glioma sphere cultures (GSC). In this study, we report that BGB324, a novel small molecule inhibitor of AXL, prolongs the survival of immunocompromised mice bearing GSC-derived mesenchymal GBM-like tumors. We show that protein S (PROS1), a known ligand of other TAM receptors, was secreted by tumor-associated macrophages/microglia and subsequently physically associated with and activated AXL in mesenchymal GSC. PROS1-driven phosphorylation of AXL (pAXL) induced NF-κB activation in mesenchymal GSC, which was inhibited by BGB324 treatment. We also found that treatment of GSC-derived mouse GBM tumors with Nivolumab, a blocking antibody against the immune checkpoint protein PD-1, increased intratumoral macrophages/microglia and activation of AXL. Combinatorial therapy with Nivolumab plus BGB324 effectively prolonged the survival of mice bearing GBM tumors. Clinically, expression of AXL or PROS1 was associated with poor prognosis for GBM patients. Our results suggest that the PROS1-AXL pathway regulates intrinsic mesenchymal signaling as well as the extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors.

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RIPK1 binds MCU to mediate induction of mitochondrial Ca2+ uptake and promote colorectal oncogenesis

The receptor-interacting protein kinase 1 (RIPK1) is an essential signaling molecule in pathways for cell survival, apoptosis, and necroptosis. We report here that RIPK1 is upregulated in human colorectal cancer (CRC) and promotes cell proliferation when overexpressed in a colon cancer cell line. RIPK1 interacts with mitochondrial Ca2+ uniporter (MCU) to promote proliferation by increasing mitochondrial Ca2+ uptake and energy metabolism. The ubiquitination site of RIPK1 (RIPK1-K377) was critical for this interaction with MCU and function in promoting cell proliferation. These findings identify the RIPK1-MCU pathway as a promising target to treat CRC.

http://ift.tt/2FCURHV

Acetylation within the N- and C-terminal domains of Src regulate distinct roles of STAT3-mediated tumorigenesis

Post-translational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions: myristoylation of G2 controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylated an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylated the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activated transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocated into nuclei where it formed the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation.

http://ift.tt/2FLFZtR

Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline

Publication date: Available online 12 March 2018
Source:Practical Radiation Oncology
Author(s): Benjamin D. Smith, Jennifer R. Bellon, Rachel Blitzblau, Gary Freedman, Bruce Haffty, Carol Hahn, Francine Halberg, Karen Hoffman, Kathleen Horst, Jean Moran, Caroline Patton, Jane Perlmutter, Laura Warren, Timothy Whelan, Jean L. Wright, Reshma Jagsi
IntroductionThe purpose of this guideline is to offer recommendations on fractionation for whole breast irradiation (WBI) with or without a tumor bed boost and guidance on treatment planning and delivery.Methods and materialsThe American Society for Radiation Oncology (ASTRO) convened a task force to address 5 key questions focused on dose-fractionation for WBI, indications and dose-fractionation for tumor bed boost, and treatment planning techniques for WBI and tumor bed boost. Guideline recommendations were based on a systematic literature review and created using a predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength.ResultsFor women with invasive breast cancer receiving WBI with or without inclusion of the low axilla, the preferred dose-fractionation scheme is hypofractionated WBI to a dose of 4000 cGy in 15 fractions or 4250 cGy in 16 fractions. The guideline discusses factors that might or should affect fractionation decisions. Use of boost should be based on shared decision-making that considers patient, tumor, and treatment factors, and the task force delineates specific subgroups in which it recommends or suggests use or omission of boost, along with dose recommendations. When planning, the volume of breast tissue receiving >105% of the prescription dose should be minimized and the tumor bed contoured with a goal of coverage with at least 95% of the prescription dose. Dose to the heart, contralateral breast, lung, and other normal tissues should be minimized.ConclusionsWBI represents a significant portion of radiation oncology practice, and these recommendations are intended to offer the groundwork for defining evidence-based practice for this common and important modality. This guideline also seeks to promote appropriately individualized, shared decision-making regarding WBI between physicians and patients.



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Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline

Publication date: Available online 12 March 2018
Source:Practical Radiation Oncology
Author(s): Benjamin D. Smith, Jennifer R. Bellon, Rachel Blitzblau, Gary Freedman, Bruce Haffty, Carol Hahn, Francine Halberg, Karen Hoffman, Kathleen Horst, Jean Moran, Caroline Patton, Jane Perlmutter, Laura Warren, Timothy Whelan, Jean L. Wright, Reshma Jagsi
IntroductionThe purpose of this guideline is to offer recommendations on fractionation for whole breast irradiation (WBI) with or without a tumor bed boost and guidance on treatment planning and delivery.Methods and materialsThe American Society for Radiation Oncology (ASTRO) convened a task force to address 5 key questions focused on dose-fractionation for WBI, indications and dose-fractionation for tumor bed boost, and treatment planning techniques for WBI and tumor bed boost. Guideline recommendations were based on a systematic literature review and created using a predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength.ResultsFor women with invasive breast cancer receiving WBI with or without inclusion of the low axilla, the preferred dose-fractionation scheme is hypofractionated WBI to a dose of 4000 cGy in 15 fractions or 4250 cGy in 16 fractions. The guideline discusses factors that might or should affect fractionation decisions. Use of boost should be based on shared decision-making that considers patient, tumor, and treatment factors, and the task force delineates specific subgroups in which it recommends or suggests use or omission of boost, along with dose recommendations. When planning, the volume of breast tissue receiving >105% of the prescription dose should be minimized and the tumor bed contoured with a goal of coverage with at least 95% of the prescription dose. Dose to the heart, contralateral breast, lung, and other normal tissues should be minimized.ConclusionsWBI represents a significant portion of radiation oncology practice, and these recommendations are intended to offer the groundwork for defining evidence-based practice for this common and important modality. This guideline also seeks to promote appropriately individualized, shared decision-making regarding WBI between physicians and patients.



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A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

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Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression

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From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

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Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

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A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

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Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression

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From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

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Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

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Influence of obesity-related risk factors in the aetiology of glioma

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Photons, protons or carbon ions for stage I non-small cell lung cancer – Results of the multicentric ROCOCO in silico study

To compare dose to organs at risk (OARs) and dose-escalation possibility for 24 stage I non-small cell lung cancer (NSCLC) patients in a ROCOCO (Radiation Oncology Collaborative Comparison) trial.

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Cancer patients’ wish for psychological support during outpatient radiation therapy

Abstract

Background

Cancer patients frequently suffer from physical and psychosocial impairments due to their disease and its treatment. Psychooncology (PO) can help to cope with stress resulting from outpatient radiotherapy (RT) treatment. There are currently few data regarding patients' wishes for PO support. The aim of this study was to investigate the number of patients with a wish for PO, treatment paths, and predictors of the wish for PO among cancer patients at the beginning of RT.

Methods

The results of routine psychological stress screening (Hornheide screening instrument; cut-off  ≥ 4) of 944 cancer patients between 2015 and 2017 were analyzed in a retrospective cross-sectional study. Predictors for a wish for PO support were identified by stepwise binary logistic regression, in which sociodemographic and treatment data were included in addition to the screening items.

Results

Around 20% of patients had above-average stress levels and 13% expressed a wish for PO support (participation rate was approximately 55%). Low emotional wellbeing (OR = 11.3) and lack of social support (OR = 9.4) were strong predictors for this treatment wish. Among patients with pancreatic cancer, head and neck tumors, and hematologic disease, there was a substantial difference between the degree of psychological stress and the wish for treatment. Patients with urological (23.5%) and lung tumors (20.9%) most frequently expressed a wish for PO support.

Conclusion

Patient-reported psychosocial problems were better predictors of a wish for PO support than sociodemographic or clinical data. Stress screening should thus be implemented in clinical routine.

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Overexpression of SLC7A11: a novel oncogene and an indicator of unfavorable prognosis for liver carcinoma

Future Oncology, Ahead of Print.


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Does sarcopenia affect outcome in patients with non-small-cell lung cancer harboring EGFR mutations?

Future Oncology, Ahead of Print.


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IFN-α in advanced well-differentiated neuroendocrine tumors: the neglected drug?

Future Oncology, Ahead of Print.


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Comparison of primary breast cancer and paired metastases: biomarkers discordance influence on outcome and therapy

Future Oncology, Ahead of Print.


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Utilization of radiotherapy and stereotactic body radiation therapy for renal cell cancer in the USA

Future Oncology, Ahead of Print.


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Triple negative breast cancer: are we scoring a home run?

Future Oncology, Ahead of Print.


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Overexpression of SLC7A11: a novel oncogene and an indicator of unfavorable prognosis for liver carcinoma

Future Oncology, Ahead of Print.


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Does sarcopenia affect outcome in patients with non-small-cell lung cancer harboring EGFR mutations?

Future Oncology, Ahead of Print.


http://ift.tt/2FwrFGB

IFN-α in advanced well-differentiated neuroendocrine tumors: the neglected drug?

Future Oncology, Ahead of Print.


http://ift.tt/2DmqumU

Comparison of primary breast cancer and paired metastases: biomarkers discordance influence on outcome and therapy

Future Oncology, Ahead of Print.


http://ift.tt/2Glj7Q1

Different inhibitors for the same target in metastatic luminal breast cancer: is there any difference?

Future Oncology, Ahead of Print.


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Utilization of radiotherapy and stereotactic body radiation therapy for renal cell cancer in the USA

Future Oncology, Ahead of Print.


http://ift.tt/2Fv7OHD

Triple negative breast cancer: are we scoring a home run?

Future Oncology, Ahead of Print.


http://ift.tt/2FzeAbn

Drug May Help Prevent Resistance to Toxin-Based Leukemia Therapy

A new study has identified a possible strategy for improving the efficacy of a toxin-based cancer treatment, moxetumomab pasudotox, in some patients with acute lymphoblastic leukemia (ALL).

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Drug May Help Prevent Resistance to Toxin-Based Leukemia Therapy

A new study has identified a possible strategy for improving the efficacy of a toxin-based cancer treatment, moxetumomab pasudotox, in some patients with acute lymphoblastic leukemia (ALL).

http://ift.tt/2FtC3yN

Could OX40 agonist antibody promote activation of the anti-tumor immune response in gastric cancer?

Background and Objectives

OX40, a membrane-bound molecule of the tumor-necrosis-factor-receptor superfamily, is a critical costimulatory receptor during the immune response, especially to T cells, but studies described their presence of OX-40 on neutrophils and monocytes, suggesting a potential role in the activation of immune response. Our aim was to characterize costimulatory receptors OX40 expression on circulating leukocytes in gastric cancer to identify novel targets for immunotherapy.

Methods

Peripheral blood mononuclear cells were isolated from 24 gastric cancer patients and 34 healthy controls and the expression of costimulatory (OX40) receptors were analyzed on T cells, neutrophil and monocyte using monoclonal antibodies by flow cytometry.

Results

We found that the higher levels of OX40 + T cells, monocytes/OX40+ and neutrophils/OX40+ from gastric cancer patients when compared to controls (P < 0.0001), and also higher levels of OX40+ T cells when compared to stages III and IV (P  = 0.02). Percentage levels of total T cells were similar between patients and controls.

Conclusions

OX40 as a therapeutic agent has been investigated in many preclinical tumor models. Our findings suggest that of levels of costimulatory in T cells in GC will direct future studies on the role that costimulatory receptors play in the failure of T cell-mediated immunity.

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DNA hydroxymethylation of colorectal primary carcinoma and its association with survival

Methods

A total of 71 cases of colorectal carcinoma with hepatic metastasis were enrolled from the Department of Pathology of SIR RUN RUN SHAW Hospital. Paired primary tumors, hepatic metastases, and normal mucosa samples were collected from formalin-fixed paraffin-embedded tissues by manual macrodissection. And global levels of DNA methylation and hydroxymethylation in these tissues, measured by an ELISA-like microplate-based colorimetric methods. The immunohistochemical expression of 5-methylcytosine and 5-hydroxymethylcytosine were analyzed also.

Results

The levels of DNA methylation in both primary and metastatic tumors were elevated when compared with normal mucosa, while DNA hydroxymethylation decreased slightly in those tissues. Similar results were observed in immunohistochemical staining. DNA methylation in hepatic metastases differed significantly in lymph node metastases (P = 0.037). And DNA hydroxymethylation in colorectal primary carcinoma was significantly different between tumor grade group (P = 0.018) and gender group (P = 0.048) respectively. And survival analyzes revealed that higher levels DNA hydroxymethylation were associated with better prognosis in colorectal primary carcinoma (P < 0.05).

Conclusion

DNA hydroxymethylation correlated with less aggressive tumor behavior in colorectal cancer and were identified as an independent prognostic factor in patients' overall survival, and downregulation of DNA hydroxymethylation may serve as a useful biomarker for colorectal cancer prognosis evaluation.

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Intralesional PV-10 for the treatment of in-transit melanoma metastases—Results of a prospective, non-randomized, single center study

Background

Patients with in-transit melanoma metastases frequently experience high rates of recurrence, limited overall survival and reduced quality of life. After promising results within a Phase II, multi-center study, PV-10 treatment was continued at our institution for patients with in-transit disease.

Methodology

An open-label, non-randomized, prospective study was performed at the Princess Alexandra Hospital, Queensland, Australia. Patients were treated with PV-10 in accordance with the treatment protocol established during a previous Phase II study. The primary outcome was the complete response of treated lesions.

Results

Forty-five patients were enrolled over a total of 82 treatment episodes from July 2008 to December 2015. With sequential PV-10 treatments the complete response rate was 42% and overall response rate 87% on an intention to treat analysis. The median follow-up duration was 22 months and the median overall survival was 25 months from first PV-10 treatment. Having fewer than 15 metastases at the time of treatment was associated with a complete response (P = 0.03).

Conclusions

Intralesional PV-10 provided rapid lesion-specific ablation of melanoma metastases with well-tolerated local effects and minimal systemic adverse events. This therapy should be considered for patients with multiple accessible deposits within the spectrum of low to moderate disease volume.

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RE: Magnitude of Clinical Benefit of Cancer Drugs Approved by the US Food and Drug Administration

We appreciate the important contribution of Tibau et al. (1) in evaluation of the magnitude of clinical benefit of US Food and Drug Administration (FDA)–approved anticancer agents. The authors report the proportion of FDA-approved indications meeting the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.0 threshold of scores for substantial clinical benefit (A and B for curative treatments or 4 or 5 for noncurative treatments, which the authors have used as a threshold for "meaningful clinical benefit").

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RE: The Rise of Radiomics and Implications for Oncologic Management

Radiomics is the high-throughput extraction of large amounts of image features from radiographic images, as previously defined in 2012 by Lambin and colleagues in the first publication in the field (1). In the July 2017 issue of Journal (2), Verma and colleagues highlighted the rise of radiomics, which may provide new insights into precision medicine in the next decades. Although the general process of radiomics has been well described (3), a major pitfall should be addressed before these methods can be used to personalize treatments: the lack of standardized procedures for radiomics features extraction (2,3). Lambin et al. recently proposed the radiomics quality score (RQS), assessing the quality of radiomics studies (4), to better address this issue of standardization between institutions (2), but the actual extraction methodologies currently available are clearly inconsistent (5).

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