MicroRNAs function as key regulators in various human cancers, including breast cancer (BC). MiR-361-5p has been proved to be a tumor suppressor in colorectal cancer and gastric cancer in our previous study. I...
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 13 Νοεμβρίου 2017
MiR-361-5p inhibits glycolytic metabolism, proliferation and invasion of breast cancer by targeting FGFR1 and MMP-1
Delayed recovery of serum immunoglobulin G is a poor prognostic marker in patients with follicular lymphoma treated with rituximab maintenance
Abstract
Clinical trials involving various treatment schedules for rituximab maintenance have been conducted for patients with follicular lymphoma (FL) and have not confirmed their impact on serum immunoglobulin (sIg) levels until the completion of maintenance. However, the long-term use of rituximab is a concern because of circulating plasma cell-depletion risk, suggesting that the mechanism of change in sIg levels after RM has not been determined. Additionally, the relationship between host humoral immunity and the prognosis of patients with B cell malignancies has not been determined. We retrospectively investigated data from 213 patients with FL from a single institute who achieved at least a partial response with rituximab, cyclophosphamide, vincristine, and prednisolone with or without doxorubicin. Of these, 166 patients underwent RM with a median period of 1.6 years. A significantly delayed recovery of sIgG levels was observed in the maintenance group until 3 years after RM in comparison to the observation group. A multivariate analysis showed that a sIgG level of < 718 mg/dl 1 year after RM was an independent predictor for poor progression-free survival (PFS) (hazard ratio, 2.3; P = 0.04). Therefore, the sIgG levels scarcely recovered and were significantly delayed after RM, leading to shorter PFS in patients with FL.
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Elevated mitochondrial DNA copy numbers in pediatric acute lymphoblastic leukemia: A potential biomarker for predicting inferior survival
Abstract
Background
Studies on mitochondrial DNA copy number reveal an increase or decrease in copy number that appears to be cancer specific, but data on acute lymphoblastic leukemia have been inconsistent regarding the significance of changes in mitochondrial DNA copies. The purpose of this pilot study was to analyze mitochondrial DNA copy number and mitochondrial DNA integrity.
Procedure
Copy number and mitochondrial deletion ratios were estimated in the bone marrow of 51 patients and peripheral blood of 30 healthy controls using quantitative real-time PCR. The copy number values were correlated with prognostic markers in patients.
Results
Significantly increased mitochondrial DNA copy number (P-value < 0.0001) and increased mitochondrial deletion ratios (P-value = 0.0018) were observed in patients compared with controls. The copy numbers were significantly decreased in patients after chemotherapy (P-value = 0.0232). Patients with higher copy numbers exhibited significantly inferior survival than patients with lower copy numbers (for event-free survival, P-value = 0.04 and overall survival, P-value = 0.1175).
Conclusions
Significant decreases in mitochondrial DNA copy number with therapy indicates that copy number could be evaluated as a potential marker for therapeutic efficacy and a higher mitochondrial DNA copy number could be a poor prognostic marker.
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Acute chest syndrome among children hospitalized with vaso-occlusive crisis: A nationwide study in the United States
Abstract
Purpose
Acute chest syndrome (ACS) is a common complication among pediatric inpatients with sickle cell disease and vaso-occlusive crisis (VOC). However, little is known about the factors associated with ACS complication. The present study assessed the epidemiological features of children hospitalized with VOC and ascertained factors associated with ACS complication.
Methods
Hospital discharge records of patients with VOC aged <20 years were obtained for the years 2003, 2006, 2009, and 2012 from the Kids' Inpatient Database. Data were weighted to estimate the annual hospitalization rates with respect to gender and race/ethnicity in the United States. Multivariable logistic regression was conducted to ascertain factors associated with ACS complication after adjusting for patient and hospital characteristics.
Results
The total annual hospitalizations for VOC increased from 22,511 in 2003 to 24,292 in 2012. Multivariable logistic regression analysis showed that children aged 5–9 years had 2.59 times higher odds of ACS than children aged 15–19 years (95% confidence interval [CI], 2.32–2.88). Comorbidity of asthma (odds ratio [OR], 1.42; 95% CI, 1.31–1.54) and obstructive sleep apnea (OR, 1.70; 95% CI, 1.31–2.20) were associated with ACS development. ACS was also associated with male gender and the summer and fall seasons.
Conclusion
We reported nationwide estimates of the annual hospitalization rate for childhood VOC in the United States and demonstrated the major risk factors associated with ACS complication. Vigilance is needed for ACS complications in high-risk VOC admissions.
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A Two-Faced mSWI/SNF Subunit: Dual Roles for ARID1A in Tumor Suppression and Oncogenicity in the Liver
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Jordan E. Otto, Cigall Kadoch
In this issue of Cancer Cell, Sun et al. describe context-dependent oncogenic and tumor-suppressive functions for the mammalian SWI/SNF (BAF) complex subunit ARID1A in the development and progression of hepatocellular carcinoma (HCC).
Teaser
In this issue of Cancer Cell, Sun et al. describe context-dependent oncogenic and tumor-suppressive functions for the mammalian SWI/SNF (BAF) complex subunit, ARID1A, in the development and progression of hepatocellular carcinoma (HCC).from Cancer via ola Kala on Inoreader http://ift.tt/2AIrD8y
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Early GalNAc O-Glycosylation: Pushing the Tumor Boundaries
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Joana Gomes, Stefan Mereiter, Ana Magalhães, Celso A. Reis
Glycosylation alterations are frequently observed in cancer cells and shape tumor progression. In this issue of Cancer Cell, Nguyen et al. show that GALNT1 relocation from Golgi to endoplasmic reticulum drives liver tumor growth and invasion, due to enhanced glycosylation and consequential activation of the extracellular matrix-degrading metalloproteinase MMP14.
Teaser
Glycosylation alterations are frequently observed in cancer cells and shape tumor progression. In this issue of Cancer Cell, Nguyen et al. show that GALNT1 relocation from Golgi to endoplasmic reticulum drives liver tumor growth and invasion, due to enhanced glycosylation and consequential activation of the extracellular matrix-degrading metalloproteinase MMP14.from Cancer via ola Kala on Inoreader http://ift.tt/2yAjFfU
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Does CSF1R Blockade Turn into Friendly Fire?
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Tim F. Greten
In this issue of Cancer Cell, Kumar et al. describe how CSF1R blockade induces not only an expected deprivation of tumor-associated macrophages, but also an accumulation of tumor-infiltrating polymorphonuclear mononuclear cells caused by Cxcl-1 released from cancer-associated fibroblasts.
Teaser
In this issue of Cancer Cell, Kumar et al. describe how CSF1R blockade induces not only an expected deprivation of tumor-associated macrophages, but also an accumulation of tumor-infiltrating polymorphonuclear mononuclear cells caused by Cxcl-1 released from cancer-associated fibroblasts.from Cancer via ola Kala on Inoreader http://ift.tt/2AHEbgf
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Pontine Infantile Glioma Simplified
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Vijay Ramaswamy, Michael D. Taylor
In this issue of Cancer Cell, Pathania et al. report sporadic childhood histone K27M mutant malignant glioma mouse models that faithfully recapitulate the human tumor phenotypes. Beyond emphasizing the importance of correct timing in mouse modeling of cancer, these models will facilitate research to effectively treat this lethal childhood cancer.
Teaser
In this issue of Cancer Cell, Pathania et al. report sporadic childhood histone K27M mutant malignant glioma mouse models that faithfully recapitulate the human tumor phenotypes. Beyond emphasizing the importance of correct timing in mouse modeling of cancer, these models will facilitate research to effectively treat this lethal childhood cancer.from Cancer via ola Kala on Inoreader http://ift.tt/2yBIOap
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Molecular Landscape of Non-Muscle Invasive Bladder Cancer
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Joshua J. Meeks, Seth P. Lerner
In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling. Tumors from female patients have a higher frequency of KDM6A mutations.
Teaser
In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling and increased risk of recurrence. Tumors from female patients have a higher frequency of KDM6A mutations.from Cancer via ola Kala on Inoreader http://ift.tt/2AI22wk
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Oncogene-Stimulated Congestion at the KEAP1 Stress Signaling Hub Allows Bypass of NRF2 and Induction of NRF2-Target Genes that Promote Tumor Survival
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): John D. Hayes, Albena T. Dinkova-Kostova
In this issue of Cancer Cell, Ge et al. show that overexpression of the oncoprotein iASPP in cancer cells provokes NRF2-mediated induction of cytoprotective genes, because it logjams the ubiquitin ligase substrate adaptor function of KEAP1 by virtue of the fact that it possesses a novel DLT-containing KEAP1-interaction motif.
Teaser
In this issue of Cancer Cell, Ge et al. show that overexpression of the oncoprotein iASPP in cancer cells provokes NRF2-mediated induction of cytoprotective genes, because it logjams the ubiquitin ligase substrate adaptor function of KEAP1 by virtue of the fact that it possesses a novel DLT-containing KEAP1-interaction motif.from Cancer via ola Kala on Inoreader http://ift.tt/2yBIoAR
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Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Hugues de Thé, Pier Paolo Pandolfi, Zhu Chen
Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.
Teaser
Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.from Cancer via ola Kala on Inoreader http://ift.tt/2AJptFG
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Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Xuxu Sun, Sam C. Wang, Yonglong Wei, Xin Luo, Yuemeng Jia, Lin Li, Purva Gopal, Min Zhu, Ibrahim Nassour, Jen-Chieh Chuang, Thomas Maples, Cemre Celen, Liem H. Nguyen, Linwei Wu, Shunjun Fu, Weiping Li, Lijian Hui, Feng Tian, Yuan Ji, Shuyuan Zhang, Mahsa Sorouri, Tae Hyun Hwang, Lynda Letzig, Laura James, Zixi Wang, Adam C. Yopp, Amit G. Singal, Hao Zhu
ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer.
Graphical abstract
Teaser
Sun el al. uncover context-specific roles for the SWI/SNF component Arid1a in liver cancer, where elevated Arid1a promotes tumor initiation through CYP450-mediated oxidative stress, whereas reduced Arid1a in established tumors increases metastasis due to reduced expression of inhibitory factors.from Cancer via ola Kala on Inoreader http://ift.tt/2yz2fk6
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Inhibition of TRF1 Telomere Protein Impairs Tumor Initiation and Progression in Glioblastoma Mouse Models and Patient-Derived Xenografts
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Leire Bejarano, Alberto J. Schuhmacher, Marinela Méndez, Diego Megías, Carmen Blanco-Aparicio, Sonia Martínez, Joaquín Pastor, Massimo Squatrito, Maria A. Blasco
Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. The telomere binding protein TRF1 is essential for telomere protection, and for adult and pluripotent stem cells. Here, we find TRF1 upregulation in mouse and human GBM. Brain-specific Trf1 genetic deletion in GBM mouse models inhibited GBM initiation and progression, increasing survival. Trf1 deletion increased telomeric DNA damage and reduced proliferation and stemness. TRF1 chemical inhibitors mimicked these effects in human GBM cells and also blocked tumor sphere formation and tumor growth in xenografts from patient-derived primary GSCs. Thus, targeting telomeres throughout TRF1 inhibition is an effective therapeutic strategy for GBM.
Graphical abstract
Teaser
Bejarano et al. show that genetic or chemical inhibition of TRF1 increases telomeric DNA damage and reduces proliferation and stemness independent of telomere length. TRF1 inhibition also inhibits glioblastoma initiation and progression and prolongs survival in genetic and xenograft glioblastoma models.from Cancer via ola Kala on Inoreader http://ift.tt/2yBI6df
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A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Javier Robles-Valero, L. Francisco Lorenzo-Martín, Mauricio Menacho-Márquez, Isabel Fernández-Pisonero, Antonio Abad, Mireia Camós, María L. Toribio, Lluis Espinosa, Anna Bigas, Xosé R. Bustelo
Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX+ clinical subtype, further underscoring the suppressor role of this pathway.
Graphical abstract
Teaser
Robles-Valero et al. find that Vav1 facilitates binding of Cbl-b to the intracellular domain of Notch1 (ICN1) and promotes ICN1 degradation. Loss of Vav1 induces T cell acute lymphoblastic leukemia (T-ALL) by increasing ICN1 signaling, and TLX inhibits Vav1 expression to stimulate ICN1 signaling in TLX+ T-ALL.from Cancer via ola Kala on Inoreader http://ift.tt/2yAjEZo
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Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Anh Tuan Nguyen, Joanne Chia, Manon Ros, Kam Man Hui, Frederic Saltel, Frederic Bard
Cancers grow within tissues through molecular mechanisms still unclear. Invasiveness correlates with perturbed O-glycosylation, a covalent modification of cell-surface proteins. Here, we show that, in human and mouse liver cancers, initiation of O-glycosylation by the GALNT glycosyl-transferases increases and shifts from the Golgi to the endoplasmic reticulum (ER). In a mouse liver cancer model, expressing an ER-targeted GALNT1 (ER-G1) massively increased tumor expansion, with median survival reduced from 23 to 10 weeks. In vitro cell growth was unaffected, but ER-G1 strongly enabled matrix degradation and tissue invasion. Unlike its Golgi-localized counterpart, ER-G1 glycosylates the matrix metalloproteinase MMP14, a process required for tumor expansion. Together, our results indicate that GALNTs strongly promote liver tumor growth after relocating to the ER.
Graphical abstract
Teaser
Nguyen et al. find that O-glycosylation increases during liver tumor progression, with increased expression of GALNT1 and glycosylation of ER-associated proteins. In mouse models, expression of GALNT1 in the ER, but not the Golgi, accelerates tumorigenesis and increases invasion through glycosylation of MMP14.from Cancer via ola Kala on Inoreader http://ift.tt/2yzhcCB
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Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Vinit Kumar, Laxminarasimha Donthireddy, Douglas Marvel, Thomas Condamine, Fang Wang, Sergio Lavilla-Alonso, Ayumi Hashimoto, Prashanthi Vonteddu, Reeti Behera, Marlee A. Goins, Charles Mulligan, Brian Nam, Neil Hockstein, Fred Denstman, Shanti Shakamuri, David W. Speicher, Ashani T. Weeraratna, Timothy Chao, Robert H. Vonderheide, Lucia R. Languino, Peter Ordentlich, Qin Liu, Xiaowei Xu, Albert Lo, Ellen Puré, Chunsheng Zhang, Andrey Loboda, Manuel A. Sepulveda, Linda A. Snyder, Dmitry I. Gabrilovich
Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.
Graphical abstract
Teaser
Kumar et al. show that CSF1R inhibition alters chemokine secretion by cancer-associated fibroblasts, which attracts pro-tumor PMN-MDSCs and results in poor efficacy. Combined inhibition of CSF1R and CXCR2 blocks MDSC recruitment and reduces tumor growth, which is further improved by the addition of anti-PD-1.from Cancer via ola Kala on Inoreader http://ift.tt/2yz28oG
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An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Asis Palazon, Petros A. Tyrakis, David Macias, Pedro Veliça, Helene Rundqvist, Susan Fitzpatrick, Nikola Vojnovic, Anthony T. Phan, Niklas Loman, Ingrid Hedenfalk, Thomas Hatschek, John Lövrot, Theodoros Foukakis, Ananda W. Goldrath, Jonas Bergh, Randall S. Johnson
Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8+ T cells. Furthermore, loss of HIF-1α in CD8+ T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8+ T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8+ T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1α/VEGF-A axis is an essential aspect of tumor immunity.
Teaser
Palazon et al. demonstrate the importance of the HIF-1α/VEGF-A axis in tumor immunity. HIF-1α, but not HIF-2α, drives CD8+ T cell glycolytic metabolism, migration, and effector function, while the HIF-1α transcriptional target VEGF-A contributes to tumor vascularization.from Cancer via ola Kala on Inoreader http://ift.tt/2yCxL0g
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Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Carolyn D. Hurst, Olivia Alder, Fiona M. Platt, Alastair Droop, Lucy F. Stead, Julie E. Burns, George J. Burghel, Sunjay Jain, Leszek J. Klimczak, Helen Lindsay, Jo-An Roulson, Claire F. Taylor, Helene Thygesen, Angus J. Cameron, Anne J. Ridley, Helen R. Mott, Dmitry A. Gordenin, Margaret A. Knowles
Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. One of these was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response, and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone lysine demethylase KDM6A were present in non-invasive tumors from females than males.
Graphical abstract
Teaser
By analyzing 140 primary patient samples, Hurst et al. identify two genomic subtypes of stage Ta non-invasive bladder cancer. The more genomically unstable subtype is distinguished by loss of chromosome 9q sequences, upregulated mTORC1 signaling, and altered metabolic profile. They also find that females have a higher frequency of KDM6A mutations than males.from Cancer via ola Kala on Inoreader http://ift.tt/2AI13vW
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SnapShot: Chronic Lymphocytic Leukemia
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Elisa ten Hacken, Romain Guièze, Catherine J. Wu
Despite the recent advances in the therapeutic management of Chronic Lymphocytic Leukemia (CLL) patients, this common B cell malignancy still remains incurable. This SnapShot provides an overview of CLL biology and therapy, with a focus on genetics and microenvironmental interactions, which contribute to disease progression and therapy resistance. To view this SnapShot, open or download the PDF.
Teaser
Despite the recent advances in the therapeutic management of Chronic Lymphocytic Leukemia (CLL) patients, this common B cell malignancy still remains incurable. This SnapShot provides an overview of CLL biology and therapy, with a focus on genetics and microenvironmental interactions, which contribute to disease progression and therapy resistance. To view this SnapShot, open or download the PDF.from Cancer via ola Kala on Inoreader http://ift.tt/2AIS4uP
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Elevated mitochondrial DNA copy numbers in pediatric acute lymphoblastic leukemia: A potential biomarker for predicting inferior survival
Abstract
Background
Studies on mitochondrial DNA copy number reveal an increase or decrease in copy number that appears to be cancer specific, but data on acute lymphoblastic leukemia have been inconsistent regarding the significance of changes in mitochondrial DNA copies. The purpose of this pilot study was to analyze mitochondrial DNA copy number and mitochondrial DNA integrity.
Procedure
Copy number and mitochondrial deletion ratios were estimated in the bone marrow of 51 patients and peripheral blood of 30 healthy controls using quantitative real-time PCR. The copy number values were correlated with prognostic markers in patients.
Results
Significantly increased mitochondrial DNA copy number (P-value < 0.0001) and increased mitochondrial deletion ratios (P-value = 0.0018) were observed in patients compared with controls. The copy numbers were significantly decreased in patients after chemotherapy (P-value = 0.0232). Patients with higher copy numbers exhibited significantly inferior survival than patients with lower copy numbers (for event-free survival, P-value = 0.04 and overall survival, P-value = 0.1175).
Conclusions
Significant decreases in mitochondrial DNA copy number with therapy indicates that copy number could be evaluated as a potential marker for therapeutic efficacy and a higher mitochondrial DNA copy number could be a poor prognostic marker.
http://ift.tt/2zGoQwr
Acute chest syndrome among children hospitalized with vaso-occlusive crisis: A nationwide study in the United States
Abstract
Purpose
Acute chest syndrome (ACS) is a common complication among pediatric inpatients with sickle cell disease and vaso-occlusive crisis (VOC). However, little is known about the factors associated with ACS complication. The present study assessed the epidemiological features of children hospitalized with VOC and ascertained factors associated with ACS complication.
Methods
Hospital discharge records of patients with VOC aged <20 years were obtained for the years 2003, 2006, 2009, and 2012 from the Kids' Inpatient Database. Data were weighted to estimate the annual hospitalization rates with respect to gender and race/ethnicity in the United States. Multivariable logistic regression was conducted to ascertain factors associated with ACS complication after adjusting for patient and hospital characteristics.
Results
The total annual hospitalizations for VOC increased from 22,511 in 2003 to 24,292 in 2012. Multivariable logistic regression analysis showed that children aged 5–9 years had 2.59 times higher odds of ACS than children aged 15–19 years (95% confidence interval [CI], 2.32–2.88). Comorbidity of asthma (odds ratio [OR], 1.42; 95% CI, 1.31–1.54) and obstructive sleep apnea (OR, 1.70; 95% CI, 1.31–2.20) were associated with ACS development. ACS was also associated with male gender and the summer and fall seasons.
Conclusion
We reported nationwide estimates of the annual hospitalization rate for childhood VOC in the United States and demonstrated the major risk factors associated with ACS complication. Vigilance is needed for ACS complications in high-risk VOC admissions.
http://ift.tt/2iTTGcK
A Two-Faced mSWI/SNF Subunit: Dual Roles for ARID1A in Tumor Suppression and Oncogenicity in the Liver
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Jordan E. Otto, Cigall Kadoch
In this issue of Cancer Cell, Sun et al. describe context-dependent oncogenic and tumor-suppressive functions for the mammalian SWI/SNF (BAF) complex subunit ARID1A in the development and progression of hepatocellular carcinoma (HCC).
Teaser
In this issue of Cancer Cell, Sun et al. describe context-dependent oncogenic and tumor-suppressive functions for the mammalian SWI/SNF (BAF) complex subunit, ARID1A, in the development and progression of hepatocellular carcinoma (HCC).http://ift.tt/2AIrD8y
Early GalNAc O-Glycosylation: Pushing the Tumor Boundaries
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Joana Gomes, Stefan Mereiter, Ana Magalhães, Celso A. Reis
Glycosylation alterations are frequently observed in cancer cells and shape tumor progression. In this issue of Cancer Cell, Nguyen et al. show that GALNT1 relocation from Golgi to endoplasmic reticulum drives liver tumor growth and invasion, due to enhanced glycosylation and consequential activation of the extracellular matrix-degrading metalloproteinase MMP14.
Teaser
Glycosylation alterations are frequently observed in cancer cells and shape tumor progression. In this issue of Cancer Cell, Nguyen et al. show that GALNT1 relocation from Golgi to endoplasmic reticulum drives liver tumor growth and invasion, due to enhanced glycosylation and consequential activation of the extracellular matrix-degrading metalloproteinase MMP14.http://ift.tt/2yAjFfU
Does CSF1R Blockade Turn into Friendly Fire?
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Tim F. Greten
In this issue of Cancer Cell, Kumar et al. describe how CSF1R blockade induces not only an expected deprivation of tumor-associated macrophages, but also an accumulation of tumor-infiltrating polymorphonuclear mononuclear cells caused by Cxcl-1 released from cancer-associated fibroblasts.
Teaser
In this issue of Cancer Cell, Kumar et al. describe how CSF1R blockade induces not only an expected deprivation of tumor-associated macrophages, but also an accumulation of tumor-infiltrating polymorphonuclear mononuclear cells caused by Cxcl-1 released from cancer-associated fibroblasts.http://ift.tt/2AHEbgf
Pontine Infantile Glioma Simplified
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Vijay Ramaswamy, Michael D. Taylor
In this issue of Cancer Cell, Pathania et al. report sporadic childhood histone K27M mutant malignant glioma mouse models that faithfully recapitulate the human tumor phenotypes. Beyond emphasizing the importance of correct timing in mouse modeling of cancer, these models will facilitate research to effectively treat this lethal childhood cancer.
Teaser
In this issue of Cancer Cell, Pathania et al. report sporadic childhood histone K27M mutant malignant glioma mouse models that faithfully recapitulate the human tumor phenotypes. Beyond emphasizing the importance of correct timing in mouse modeling of cancer, these models will facilitate research to effectively treat this lethal childhood cancer.http://ift.tt/2yBIOap
Molecular Landscape of Non-Muscle Invasive Bladder Cancer
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Joshua J. Meeks, Seth P. Lerner
In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling. Tumors from female patients have a higher frequency of KDM6A mutations.
Teaser
In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling and increased risk of recurrence. Tumors from female patients have a higher frequency of KDM6A mutations.http://ift.tt/2AI22wk
Oncogene-Stimulated Congestion at the KEAP1 Stress Signaling Hub Allows Bypass of NRF2 and Induction of NRF2-Target Genes that Promote Tumor Survival
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): John D. Hayes, Albena T. Dinkova-Kostova
In this issue of Cancer Cell, Ge et al. show that overexpression of the oncoprotein iASPP in cancer cells provokes NRF2-mediated induction of cytoprotective genes, because it logjams the ubiquitin ligase substrate adaptor function of KEAP1 by virtue of the fact that it possesses a novel DLT-containing KEAP1-interaction motif.
Teaser
In this issue of Cancer Cell, Ge et al. show that overexpression of the oncoprotein iASPP in cancer cells provokes NRF2-mediated induction of cytoprotective genes, because it logjams the ubiquitin ligase substrate adaptor function of KEAP1 by virtue of the fact that it possesses a novel DLT-containing KEAP1-interaction motif.http://ift.tt/2yBIoAR
Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Hugues de Thé, Pier Paolo Pandolfi, Zhu Chen
Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.
Teaser
Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.http://ift.tt/2AJptFG
Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Xuxu Sun, Sam C. Wang, Yonglong Wei, Xin Luo, Yuemeng Jia, Lin Li, Purva Gopal, Min Zhu, Ibrahim Nassour, Jen-Chieh Chuang, Thomas Maples, Cemre Celen, Liem H. Nguyen, Linwei Wu, Shunjun Fu, Weiping Li, Lijian Hui, Feng Tian, Yuan Ji, Shuyuan Zhang, Mahsa Sorouri, Tae Hyun Hwang, Lynda Letzig, Laura James, Zixi Wang, Adam C. Yopp, Amit G. Singal, Hao Zhu
ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer.
Graphical abstract
Teaser
Sun el al. uncover context-specific roles for the SWI/SNF component Arid1a in liver cancer, where elevated Arid1a promotes tumor initiation through CYP450-mediated oxidative stress, whereas reduced Arid1a in established tumors increases metastasis due to reduced expression of inhibitory factors.http://ift.tt/2yz2fk6
Inhibition of TRF1 Telomere Protein Impairs Tumor Initiation and Progression in Glioblastoma Mouse Models and Patient-Derived Xenografts
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Leire Bejarano, Alberto J. Schuhmacher, Marinela Méndez, Diego Megías, Carmen Blanco-Aparicio, Sonia Martínez, Joaquín Pastor, Massimo Squatrito, Maria A. Blasco
Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. The telomere binding protein TRF1 is essential for telomere protection, and for adult and pluripotent stem cells. Here, we find TRF1 upregulation in mouse and human GBM. Brain-specific Trf1 genetic deletion in GBM mouse models inhibited GBM initiation and progression, increasing survival. Trf1 deletion increased telomeric DNA damage and reduced proliferation and stemness. TRF1 chemical inhibitors mimicked these effects in human GBM cells and also blocked tumor sphere formation and tumor growth in xenografts from patient-derived primary GSCs. Thus, targeting telomeres throughout TRF1 inhibition is an effective therapeutic strategy for GBM.
Graphical abstract
Teaser
Bejarano et al. show that genetic or chemical inhibition of TRF1 increases telomeric DNA damage and reduces proliferation and stemness independent of telomere length. TRF1 inhibition also inhibits glioblastoma initiation and progression and prolongs survival in genetic and xenograft glioblastoma models.http://ift.tt/2yBI6df
A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Javier Robles-Valero, L. Francisco Lorenzo-Martín, Mauricio Menacho-Márquez, Isabel Fernández-Pisonero, Antonio Abad, Mireia Camós, María L. Toribio, Lluis Espinosa, Anna Bigas, Xosé R. Bustelo
Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX+ clinical subtype, further underscoring the suppressor role of this pathway.
Graphical abstract
Teaser
Robles-Valero et al. find that Vav1 facilitates binding of Cbl-b to the intracellular domain of Notch1 (ICN1) and promotes ICN1 degradation. Loss of Vav1 induces T cell acute lymphoblastic leukemia (T-ALL) by increasing ICN1 signaling, and TLX inhibits Vav1 expression to stimulate ICN1 signaling in TLX+ T-ALL.http://ift.tt/2yAjEZo
Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Anh Tuan Nguyen, Joanne Chia, Manon Ros, Kam Man Hui, Frederic Saltel, Frederic Bard
Cancers grow within tissues through molecular mechanisms still unclear. Invasiveness correlates with perturbed O-glycosylation, a covalent modification of cell-surface proteins. Here, we show that, in human and mouse liver cancers, initiation of O-glycosylation by the GALNT glycosyl-transferases increases and shifts from the Golgi to the endoplasmic reticulum (ER). In a mouse liver cancer model, expressing an ER-targeted GALNT1 (ER-G1) massively increased tumor expansion, with median survival reduced from 23 to 10 weeks. In vitro cell growth was unaffected, but ER-G1 strongly enabled matrix degradation and tissue invasion. Unlike its Golgi-localized counterpart, ER-G1 glycosylates the matrix metalloproteinase MMP14, a process required for tumor expansion. Together, our results indicate that GALNTs strongly promote liver tumor growth after relocating to the ER.
Graphical abstract
Teaser
Nguyen et al. find that O-glycosylation increases during liver tumor progression, with increased expression of GALNT1 and glycosylation of ER-associated proteins. In mouse models, expression of GALNT1 in the ER, but not the Golgi, accelerates tumorigenesis and increases invasion through glycosylation of MMP14.http://ift.tt/2yzhcCB
Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Vinit Kumar, Laxminarasimha Donthireddy, Douglas Marvel, Thomas Condamine, Fang Wang, Sergio Lavilla-Alonso, Ayumi Hashimoto, Prashanthi Vonteddu, Reeti Behera, Marlee A. Goins, Charles Mulligan, Brian Nam, Neil Hockstein, Fred Denstman, Shanti Shakamuri, David W. Speicher, Ashani T. Weeraratna, Timothy Chao, Robert H. Vonderheide, Lucia R. Languino, Peter Ordentlich, Qin Liu, Xiaowei Xu, Albert Lo, Ellen Puré, Chunsheng Zhang, Andrey Loboda, Manuel A. Sepulveda, Linda A. Snyder, Dmitry I. Gabrilovich
Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.
Graphical abstract
Teaser
Kumar et al. show that CSF1R inhibition alters chemokine secretion by cancer-associated fibroblasts, which attracts pro-tumor PMN-MDSCs and results in poor efficacy. Combined inhibition of CSF1R and CXCR2 blocks MDSC recruitment and reduces tumor growth, which is further improved by the addition of anti-PD-1.http://ift.tt/2yz28oG
An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Asis Palazon, Petros A. Tyrakis, David Macias, Pedro Veliça, Helene Rundqvist, Susan Fitzpatrick, Nikola Vojnovic, Anthony T. Phan, Niklas Loman, Ingrid Hedenfalk, Thomas Hatschek, John Lövrot, Theodoros Foukakis, Ananda W. Goldrath, Jonas Bergh, Randall S. Johnson
Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8+ T cells. Furthermore, loss of HIF-1α in CD8+ T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8+ T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8+ T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1α/VEGF-A axis is an essential aspect of tumor immunity.
Teaser
Palazon et al. demonstrate the importance of the HIF-1α/VEGF-A axis in tumor immunity. HIF-1α, but not HIF-2α, drives CD8+ T cell glycolytic metabolism, migration, and effector function, while the HIF-1α transcriptional target VEGF-A contributes to tumor vascularization.http://ift.tt/2yCxL0g
Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Carolyn D. Hurst, Olivia Alder, Fiona M. Platt, Alastair Droop, Lucy F. Stead, Julie E. Burns, George J. Burghel, Sunjay Jain, Leszek J. Klimczak, Helen Lindsay, Jo-An Roulson, Claire F. Taylor, Helene Thygesen, Angus J. Cameron, Anne J. Ridley, Helen R. Mott, Dmitry A. Gordenin, Margaret A. Knowles
Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. One of these was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response, and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone lysine demethylase KDM6A were present in non-invasive tumors from females than males.
Graphical abstract
Teaser
By analyzing 140 primary patient samples, Hurst et al. identify two genomic subtypes of stage Ta non-invasive bladder cancer. The more genomically unstable subtype is distinguished by loss of chromosome 9q sequences, upregulated mTORC1 signaling, and altered metabolic profile. They also find that females have a higher frequency of KDM6A mutations than males.http://ift.tt/2AI13vW
SnapShot: Chronic Lymphocytic Leukemia
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Elisa ten Hacken, Romain Guièze, Catherine J. Wu
Despite the recent advances in the therapeutic management of Chronic Lymphocytic Leukemia (CLL) patients, this common B cell malignancy still remains incurable. This SnapShot provides an overview of CLL biology and therapy, with a focus on genetics and microenvironmental interactions, which contribute to disease progression and therapy resistance. To view this SnapShot, open or download the PDF.
Teaser
Despite the recent advances in the therapeutic management of Chronic Lymphocytic Leukemia (CLL) patients, this common B cell malignancy still remains incurable. This SnapShot provides an overview of CLL biology and therapy, with a focus on genetics and microenvironmental interactions, which contribute to disease progression and therapy resistance. To view this SnapShot, open or download the PDF.http://ift.tt/2AIS4uP
Controversies and recommendations regarding sentinel lymph node biopsy in primary breast cancer: a comprehensive review of current data
Source:European Journal of Surgical Oncology
Author(s): Petros Charalampoudis, Christos Markopoulos, Tibor Kovacs
In primary breast cancer, sentinel lymph node biopsy has been established as the gold standard for regional axillary staging. A robust body of randomized data support its accuracy and safety in patients with early, clinically node negative disease. However, the role of SLNB remains debatable in various patient subgroups, and recent advances in histopathology, dedicated axillary ultrasound imaging and chemotherapy regimens, put its role under a new perspective. Herein, we review the current literature data on the indications for SLNB and discuss the challenges in management germane to special patient subgroups and patterns of disease. We also present emerging data on the optimal management of the SLN+ patient, in light of recent trials challenging the dogma of completion axillary dissection after a positive sentinel node biopsy.
http://ift.tt/2hxp4kI
Management of benign papilloma without atypia diagnosed at ultrasound-guided core needle biopsy: Scoring system for predicting malignancy
Source:European Journal of Surgical Oncology
Author(s): Soo kyung Ahn, Wonshik Han, Hyeong-Gon Moon, Min Kyoon Kim, Dong-Young Noh, Bong-wha Jung, Sung-Won Kim, M.D. Eunyoung ko
BackgroundThe management of benign intraductal papilloma diagnosed on core needle biopsy (CNB) remains unclear. This study was designed to evaluate factors predicting malignancy in patients diagnosed with benign papilloma without atypia at ultrasound-guided CNB and to develop a scoring system predicting malignancy based on clinical, radiological and pathological factors on further excisional biopsy.MethodsThe study enrolled patients diagnosed with benign papillomas (including benign and atypical papillary lesions) at CNB. Multivariate analysis was used to identify relevant clinical, radiological and pathological factors that may predict malignancy.ResultsA total of 520 CNBs were diagnosed with benign or atypical papilloma. Of these, 452 were benign papilloma without atypia. Of the 250 lesions subsequently excised surgically from 234 women, 17 (6.8%) were diagnosed with malignancy. Multivariate analysis revealed that bloody nipple discharge, size on imaging ≥15 mm, BI-RADS≥4b, peripheral location and palpability were independent predictors of malignancy. A scoring system was developed based on logistic regression models and beta coefficients for each variable. The area under the ROC curve was 0.947 (95% CI: 0.913–0.981, p<0.001) and a negative predictive value was100%. In a validation set of 62 patients, an area under the ROC curve was 0.926 (95% CI: 0.857–0.995, p<0.001).ConclusionsA scoring system predicting malignancy in patients diagnosed by CNB with benign papilloma without atypia was developed.This system was able to identify a subset of patients with lesions likely to be benign, indicating that imaging follow-up rather than surgical excision may be appropriate.
http://ift.tt/2hx6OYO
Exome sequencing of synchronously resected primary colorectal tumours and colorectal liver metastases to inform oncosurgical management
Source:European Journal of Surgical Oncology
Author(s): P.A. Sutton, P.V. Jithesh, R.P. Jones, J.P. Evans, D. Vimalachandran, H.Z. Malik, B.K. Park, C.E. Goldring, D.H. Palmer, N.R. Kitteringham
BackgroundNext generation sequencing technology has facilitated mapping of the colorectal cancer genotype and furthered our understanding of metastogenesis. The aim of this study was to investigate for conserved and different mutations in the exomes of synchronously resected primary colorectal tumour and liver metastases. This information could potentially be utilised to guide the treatment of advanced disease with the help of biological information from the primary tumour.MethodsWe performed exome sequencing of synchronously resected primary colorectal cancer and colorectal liver metastases as well as normal colonic mucosa and liver parenchyma, from four patients who had received neo-adjuvant chemotherapy, at a depth of 50X using the Ion Proton platform. Raw data was mapped to the reference genome prior to variant calling, annotation and downstream analysis.ResultsExome sequencing identified 585 non-synonymous missense single nucleotide variants (SNVs), of which 215 (36.8%) were unique to the primary tumour, 226 (38.6%) unique to the metastasis and 81 (13.8%) present in patient matched pairs. SNVs identified in the ErbB pathway appear to be concordant between primary and metastatic tumours.ConclusionOnly 13.8% of the metastatic exome can be predicted by the genotype of the primary tumour. We have demonstrated concordance of a number of SNVs in the ErbB pathway, which may inform selection of therapeutic agents in advanced colorectal cancer.
http://ift.tt/2jpAo38
Early Education and Employment Outcomes After Cancer in Adolescents and Young Adults
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Early Education and Employment Outcomes After Cancer in Adolescents and Young Adults
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
http://ift.tt/2zHd593
Neurokinin 1 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant
Future Oncology, Ahead of Print.
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Nivolumab in recurrent/metastatic head and neck cancers
Future Oncology, Ahead of Print.
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Image-guided surgery and therapy for lung cancer: a critical review
Future Oncology, Ahead of Print.
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Proteasome-associated deubiquitinases and cancer
Abstract
Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS.
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Proteasome-associated deubiquitinases and cancer
Abstract
Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS.
http://ift.tt/2zzZfYh
Neurokinin 1 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant
Future Oncology, Ahead of Print.
http://ift.tt/2zC9Th6
Nivolumab in recurrent/metastatic head and neck cancers
Future Oncology, Ahead of Print.
http://ift.tt/2zURMDP
Image-guided surgery and therapy for lung cancer: a critical review
Future Oncology, Ahead of Print.
http://ift.tt/2zC9NWM
Neurokinin 1 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant
Future Oncology, Ahead of Print.
from Cancer via ola Kala on Inoreader http://ift.tt/2zC9Th6
via IFTTT
Nivolumab in recurrent/metastatic head and neck cancers
Future Oncology, Ahead of Print.
from Cancer via ola Kala on Inoreader http://ift.tt/2zURMDP
via IFTTT
Image-guided surgery and therapy for lung cancer: a critical review
Future Oncology, Ahead of Print.
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Therapeutic Impact of Nanoparticle Therapy Targeting Tumor Associate Macrophages
Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest anti-angiogenic therapy induced hypoxia can induce tumor "stemness' as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor associated macrophages (TAMs). As such TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin. G5-methotrexate (G5-MTX) Nps deplete tumor associated macrophages in both solid tumor and ascites models of ovarian cancer. As a therapeutic these nanoparticles are more effective than cisplatin. Importantly, these nanoparticles could (i) overcome resistance to anti-angiogenic therapy, (ii) prevent antiangiogenic therapy induced increases in cancer stem-like cells in both murine and human tumor cell models, and (iii) prevent anti-angiogenic therapy induced increases in VEGF-C (iv) prevent anti-angiogenic therapy induce BRCA1 gene expression. Combine this work strongly supports the development of TAM targeted nanoparticle therapy.
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Response and resistance to paradox breaking BRAF inhibitor in melanomas in vivo and ex vivo
FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox breaking RAF inhibitor (PLX8394) has been designed. Here we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenib-resistant BRAF splice-variant expressing tumors and reduced splice-variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test efficacy of therapeutic agents.
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Clinical application of circulating tumor DNA in the genetic analysis of patients with advanced GIST
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of digestive tract. In the past, tissue biopsy was the main method for the diagnosis of GISTs. While circulating tumor DNA (ctDNA) detection by next-generation sequencing (NGS) may be a feasible and replaceable method for diagnosis of GISTs. We retrospectively analyzed the data for ctDNA and tissue DNA detection from 32 advanced GIST patients. We found that NGS obviously increased the positive rate of ctDNA detection. ctDNA detection identified rare mutations that were not detected in tissue DNA detection. Tumor size and Ki-67 were significant influencing factors of the positive rate of ctDNA detection and concordance between ctDNA and tissue DNA detection. In all patients, the concordance rate between ctDNA and tissue DNA detection was 71.9%, with moderate concordance. But the concordance was strong for patients with tumor size>10cm or Ki-67>5%. Tumor size, mitotic figure, Ki-67 and ctDNA mutation type were the significant influencing factors of prognosis, but only tumor size and ctDNA mutation type were the independent prognostic factors for advanced GIST patients. We confirmed that ctDNA detection by NGS is a feasible and promising method for the diagnosis and prognosis of advanced GIST patients.
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IMMU-140, a novel SN-38-antibody-drug conjugate targeting HLA-DR, mediates dual cytotoxic effects in hematological cancers and malignant melanoma
HLA-DR is a member of the MHC class II antigen family expressed on hematological and solid tumors. Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development. IMMU-140 is an anti-HLA-DR antibody-drug conjugate comprised of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti-HLA-DR IgG4 antibody (IMMU-114); the IgG4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR-expressing tumors. In vitro, IMMU-140 had dual-therapeutic mechanisms, as evidenced by its retention of non-overlapping anti-HLA-DR non-classical apoptotic signaling and classical apoptosis mediated by its SN-38 payload. In seven human disease models (acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], multiple myeloma [MM], acute myeloid leukemia [AML], diffuse large B-cell lymphoma [DLBCL], Hodgkin lymphoma [HL], and melanoma), IMMU-140 provided significant therapeutic efficacy compared to controls, in vivo and in 3D spheroid models. Except for MM and HL, IMMU-140 imparted significantly improved antitumor effects compared to parental IMMU-114. Even in intractable AML and ALL, where IMMU-114 only had modest antitumor effects, IMMU-140 therapy mediated >80% improvement in survival. Therapy was well-tolerated, as demonstrated by no marked loss in body weight. Combined with doxorubicin, IMMU-140 produced significantly greater antitumor effects in HL than with monotherapy and without any added toxicity. The dual-therapeutic action of IMMU-140 resulted in promising therapeutic activity in a range of hematopoietic tumors and melanoma, and therefore warrants clinical development.
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Ceritinib enhances the efficacy of trametinib in BRAF/NRAS-wild type melanoma cell lines
Targeted therapy options are currently lacking for the heterogeneous population of patients whose melanomas lack BRAF or NRAS mutations (~35% of cases). We undertook a chemical biology screen to identify potential novel drug targets for this understudied group of tumors. Screening a panel of 8 BRAF/NRAS-WT melanoma cell lines against 240 targeted drugs identified ceritinib and trametinib as potential hits with single agent activity. Ceritinib enhanced the efficacy of trametinib across the majority of the BRAF/NRAS-WT cell lines, and the combination showed increased cytotoxicity in both 3D spheroid culture and long-term colony formation experiments. Co-administration of ceritinib and trametinib led to robust inhibition of tumor growth in an in vivo xenograft BRAF/NRAS-WT melanoma model; this was not due to ALK inhibition by ceritinib. Mechanistic studies showed the ceritinib-trametinib combination to increase suppression of MAPK and TORC1 signaling. Similar results were seen when BRAF/NRAS-WT melanoma cells were treated with a combination of trametinib and the TORC1/2 inhibitor INK128. We next used mass spectrometry-based chemical proteomics and identified known and new ceritinib targets, such as IGF1R and ACK1, respectively. Validation studies suggested that ceritinib could suppress mTORC1 signaling in the presence of trametinib through inhibition of IGF1R and/or ACK1 in a cell line-dependent manner. Together our studies demonstrated that combining a specific inhibitor (trametinib) with a more broadly targeted agent (ceritinib) has efficacy against tumors with heterogeneous mutational profiles.
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Evaluation of CDK12 Protein Expression as a Potential Novel Biomarker for DNA Damage Response Targeted Therapies in Breast Cancer
Disruption of Cyclin Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and poly(ADP-ribose) polymerase 1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by immunohistochemistry (IHC) in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10.5% were absent, by IHC. CDK12 positivity correlated with HER2 positivity but was not an independent predictor of breast cancer specific survival taking HER2 status into account, however absent CDK12 protein expression significantly correlated with a triple negative phenotype. Interestingly, CDK12 protein absence was associated with reduced expression of a number of DDR proteins including ATR, Ku70/Ku80, PARP1, DNA-PK and gamma-H2AX, suggesting a novel mechanism of CDK12 associated DDR dysregulation in breast cancer. Our data suggest that diagnostic IHC quantification of CDK12 in BC is feasible, with CDK12 absence possibly signifying defective DDR function. This may have important therapeutic implications, particularly for triple negative breast cancers.
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Therapeutic Impact of Nanoparticle Therapy Targeting Tumor Associate Macrophages
Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest anti-angiogenic therapy induced hypoxia can induce tumor "stemness' as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor associated macrophages (TAMs). As such TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin. G5-methotrexate (G5-MTX) Nps deplete tumor associated macrophages in both solid tumor and ascites models of ovarian cancer. As a therapeutic these nanoparticles are more effective than cisplatin. Importantly, these nanoparticles could (i) overcome resistance to anti-angiogenic therapy, (ii) prevent antiangiogenic therapy induced increases in cancer stem-like cells in both murine and human tumor cell models, and (iii) prevent anti-angiogenic therapy induced increases in VEGF-C (iv) prevent anti-angiogenic therapy induce BRCA1 gene expression. Combine this work strongly supports the development of TAM targeted nanoparticle therapy.
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Response and resistance to paradox breaking BRAF inhibitor in melanomas in vivo and ex vivo
FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox breaking RAF inhibitor (PLX8394) has been designed. Here we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenib-resistant BRAF splice-variant expressing tumors and reduced splice-variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test efficacy of therapeutic agents.
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Clinical application of circulating tumor DNA in the genetic analysis of patients with advanced GIST
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of digestive tract. In the past, tissue biopsy was the main method for the diagnosis of GISTs. While circulating tumor DNA (ctDNA) detection by next-generation sequencing (NGS) may be a feasible and replaceable method for diagnosis of GISTs. We retrospectively analyzed the data for ctDNA and tissue DNA detection from 32 advanced GIST patients. We found that NGS obviously increased the positive rate of ctDNA detection. ctDNA detection identified rare mutations that were not detected in tissue DNA detection. Tumor size and Ki-67 were significant influencing factors of the positive rate of ctDNA detection and concordance between ctDNA and tissue DNA detection. In all patients, the concordance rate between ctDNA and tissue DNA detection was 71.9%, with moderate concordance. But the concordance was strong for patients with tumor size>10cm or Ki-67>5%. Tumor size, mitotic figure, Ki-67 and ctDNA mutation type were the significant influencing factors of prognosis, but only tumor size and ctDNA mutation type were the independent prognostic factors for advanced GIST patients. We confirmed that ctDNA detection by NGS is a feasible and promising method for the diagnosis and prognosis of advanced GIST patients.
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IMMU-140, a novel SN-38-antibody-drug conjugate targeting HLA-DR, mediates dual cytotoxic effects in hematological cancers and malignant melanoma
HLA-DR is a member of the MHC class II antigen family expressed on hematological and solid tumors. Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development. IMMU-140 is an anti-HLA-DR antibody-drug conjugate comprised of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti-HLA-DR IgG4 antibody (IMMU-114); the IgG4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR-expressing tumors. In vitro, IMMU-140 had dual-therapeutic mechanisms, as evidenced by its retention of non-overlapping anti-HLA-DR non-classical apoptotic signaling and classical apoptosis mediated by its SN-38 payload. In seven human disease models (acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], multiple myeloma [MM], acute myeloid leukemia [AML], diffuse large B-cell lymphoma [DLBCL], Hodgkin lymphoma [HL], and melanoma), IMMU-140 provided significant therapeutic efficacy compared to controls, in vivo and in 3D spheroid models. Except for MM and HL, IMMU-140 imparted significantly improved antitumor effects compared to parental IMMU-114. Even in intractable AML and ALL, where IMMU-114 only had modest antitumor effects, IMMU-140 therapy mediated >80% improvement in survival. Therapy was well-tolerated, as demonstrated by no marked loss in body weight. Combined with doxorubicin, IMMU-140 produced significantly greater antitumor effects in HL than with monotherapy and without any added toxicity. The dual-therapeutic action of IMMU-140 resulted in promising therapeutic activity in a range of hematopoietic tumors and melanoma, and therefore warrants clinical development.
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Ceritinib enhances the efficacy of trametinib in BRAF/NRAS-wild type melanoma cell lines
Targeted therapy options are currently lacking for the heterogeneous population of patients whose melanomas lack BRAF or NRAS mutations (~35% of cases). We undertook a chemical biology screen to identify potential novel drug targets for this understudied group of tumors. Screening a panel of 8 BRAF/NRAS-WT melanoma cell lines against 240 targeted drugs identified ceritinib and trametinib as potential hits with single agent activity. Ceritinib enhanced the efficacy of trametinib across the majority of the BRAF/NRAS-WT cell lines, and the combination showed increased cytotoxicity in both 3D spheroid culture and long-term colony formation experiments. Co-administration of ceritinib and trametinib led to robust inhibition of tumor growth in an in vivo xenograft BRAF/NRAS-WT melanoma model; this was not due to ALK inhibition by ceritinib. Mechanistic studies showed the ceritinib-trametinib combination to increase suppression of MAPK and TORC1 signaling. Similar results were seen when BRAF/NRAS-WT melanoma cells were treated with a combination of trametinib and the TORC1/2 inhibitor INK128. We next used mass spectrometry-based chemical proteomics and identified known and new ceritinib targets, such as IGF1R and ACK1, respectively. Validation studies suggested that ceritinib could suppress mTORC1 signaling in the presence of trametinib through inhibition of IGF1R and/or ACK1 in a cell line-dependent manner. Together our studies demonstrated that combining a specific inhibitor (trametinib) with a more broadly targeted agent (ceritinib) has efficacy against tumors with heterogeneous mutational profiles.
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Evaluation of CDK12 Protein Expression as a Potential Novel Biomarker for DNA Damage Response Targeted Therapies in Breast Cancer
Disruption of Cyclin Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and poly(ADP-ribose) polymerase 1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by immunohistochemistry (IHC) in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10.5% were absent, by IHC. CDK12 positivity correlated with HER2 positivity but was not an independent predictor of breast cancer specific survival taking HER2 status into account, however absent CDK12 protein expression significantly correlated with a triple negative phenotype. Interestingly, CDK12 protein absence was associated with reduced expression of a number of DDR proteins including ATR, Ku70/Ku80, PARP1, DNA-PK and gamma-H2AX, suggesting a novel mechanism of CDK12 associated DDR dysregulation in breast cancer. Our data suggest that diagnostic IHC quantification of CDK12 in BC is feasible, with CDK12 absence possibly signifying defective DDR function. This may have important therapeutic implications, particularly for triple negative breast cancers.
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The Anti-inflammatory Effect of Personalized Omega-3 Fatty Acid Dosing for Reducing Prostaglandin E2 in the Colonic Mucosa Is Attenuated in Obesity
This clinical trial developed a personalized dosing model for reducing prostaglandin E2 (PGE2) in colonic mucosa using -3 fatty acid supplementation. The model utilized serum eicosapentaenoic acid (EPA, -3):arachidonic acid (AA, -6) ratios as biomarkers of colonic mucosal PGE2 concentration. Normal human volunteers were given low and high -3 fatty acid test doses for 2 weeks. This established a slope and intercept of the line for dose versus serum EPA:AA ratio in each individual. The slope and intercept was utilized to calculate a personalized target dose that was given for 12 weeks. This target dose was calculated on the basis of a model, initially derived from lean rodents, showing a log-linear relationship between serum EPA:AA ratios and colonic mucosal PGE2 reduction. Bayesian methods allowed addition of human data to the rodent model as the trial progressed. The dosing model aimed to achieve a serum EPA:AA ratio that is associated with a 50% reduction in colonic PGE2. Mean colonic mucosal PGE2 concentrations were 6.55 ng/mg protein (SD, 5.78) before any supplementation and 3.59 ng/mg protein (SD, 3.29) after 12 weeks of target dosing. In secondary analyses, the decreases in PGE2 were significantly attenuated in overweight and obese participants. This occurred despite a higher target dose for the obese versus normal weight participants, as generated by the pharmacodynamic predictive model. Large decreases also were observed in 12-hydroxyicosatetraenoic acids, and PGE3 increased substantially. Future biomarker-driven dosing models for cancer prevention therefore should consider energy balance as well as overall eicosanoid homeostasis in normal tissue. Cancer Prev Res; 1–9. ©2017 AACR.
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Basket Study Yields Approval for Rare Blood Cancer [News in Brief]
Histology-independent trial leads to label expansion for vemurafenib.
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Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer
Summary
Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 μg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p < 0.0001). ORR was 46.78% in the dulanermin arm versus 30.00% in the placebo arm (p = 0.0019). Median OS was 14.6 months in the dulanermin arm versus 13.9 months in the placebo arm (HR, 0.94; 95% CI, 0.74 to 1.21, p = 0.64). The most common grade ≥ 3 adverse events (AEs) were oligochromemia, leukopenia, neutropenia, and oligocythemia. Overall incidence of AEs, grade ≥ 3 AEs, and serious AEs were similar across the two arms. Conclusion Addition of dulanermin to the NP regimen significantly improved PFS and ORR. However, our results showed that the combination of dulanermin with chemotherapy had a synergic activity and favorable toxic profile in the treatment of patients with advanced NSCLC.
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Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer
Summary
Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 μg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p < 0.0001). ORR was 46.78% in the dulanermin arm versus 30.00% in the placebo arm (p = 0.0019). Median OS was 14.6 months in the dulanermin arm versus 13.9 months in the placebo arm (HR, 0.94; 95% CI, 0.74 to 1.21, p = 0.64). The most common grade ≥ 3 adverse events (AEs) were oligochromemia, leukopenia, neutropenia, and oligocythemia. Overall incidence of AEs, grade ≥ 3 AEs, and serious AEs were similar across the two arms. Conclusion Addition of dulanermin to the NP regimen significantly improved PFS and ORR. However, our results showed that the combination of dulanermin with chemotherapy had a synergic activity and favorable toxic profile in the treatment of patients with advanced NSCLC.
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Relative Performance of HPV and Cytology Components of Cotesting in Cervical Screening
Abstract
Background
The main goal of cervical screening programs is to detect and treat precancer before cancer develops. Human papillomavirus (HPV) testing is more sensitive than cytology for detecting precancer. However, reports of rare HPV-negative, cytology-positive cancers are motivating continued use of both tests (cotesting) despite increased testing costs. Methods
We quantified the detection of cervical precancer and cancer by cotesting compared with HPV testing alone at Kaiser Permanente Northern California (KPNC), where 1 208 710 women age 30 years and older have undergone triennial cervical cotesting since 2003. Screening histories preceding cervical cancers (n = 623) and precancers (n = 5369) were examined to assess the relative contribution of the cytology and HPV test components in identifying cases. The performances of HPV testing and cytology were compared using contingency table methods, general estimating equation models, and nonparametric statistics; all statistical tests were two-sided. Results
HPV testing identified more women subsequently diagnosed with cancer (P < .001) and precancer (P < .001) than cytology. HPV testing was statistically significantly more likely to be positive for cancer at any time point (P < .001), except within 12 months (P = .10). HPV-negative/cytology-positive results preceded only small fractions of cases of precancer (3.5%) and cancer (5.9%); these cancers were more likely to be regional or distant stage with squamous histopathology than other cases. Given the rarity of cancers among screened women, the contribution of cytology to screening translated to earlier detection of at most five cases per million women per year. Two-thirds (67.9%) of women found to have cancer during 10 years of follow-up at KPNC were detected by the first cotest performed. Conclusions
The added sensitivity of cotesting vs HPV alone for detection of treatable cancer affected extremely few women.http://ift.tt/2yXrYXz
Roles of Fibroblast Activation Protein and Hepatocyte Growth Factor Expressions in Angiogenesis and Metastasis of Gastric Cancer
Abstract
This study aims to explore the roles of fibroblast activation protein (FAP) and hepatocyte growth factor (HGF) expressions in the angiogenesis and metastasis of gastric cancer (GC). From May 2012 to December 2015, 110 GC patients who received surgical treatment in the First Hospital of Qinhuangdao were selected. The HGF and FAP expressions in 110 cases of GC, 130 cases of normal gastric mucosa and 115 cases of gastric ulcer were detected by streptavidin-perosidase (SP) method. Venous blood HGF level of GC patients was tested by enzyme-linked immunosorbent assay (ELISA). The micro-vessel number of the patients in the three groups were calculated and analyzed. In GC group, positive expression rates of FAP and HGF protein were 61.8% and 67.3% respectively, which were both higher than those in normal gastric mucosa and gastric ulcer groups. The micro-vessel numbers in patients of the normal gastric mucosa and gastric ulcer groups are far less than that in GC group. FAP, HGF and micro-vessel density (MVD) were significantly correlated with infiltration depth, tumor-node-metastasis (TNM) staging, lymph node metastasis (LNM) and distant metastasis. The results of ELISA showed that serum HGF level was related to tumor size, infiltration degree, TNM staging, LNM and distant metastasis. FAP and HGF expressions in GC were positively correlated with MVD, and the expressions of FAP and HGF in GC were in positive correlation. Our study provided evidence that high FAP and HGF expressions may be positively correlated with the angiogenesis and metastasis of GC.
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Roles of Fibroblast Activation Protein and Hepatocyte Growth Factor Expressions in Angiogenesis and Metastasis of Gastric Cancer
Abstract
This study aims to explore the roles of fibroblast activation protein (FAP) and hepatocyte growth factor (HGF) expressions in the angiogenesis and metastasis of gastric cancer (GC). From May 2012 to December 2015, 110 GC patients who received surgical treatment in the First Hospital of Qinhuangdao were selected. The HGF and FAP expressions in 110 cases of GC, 130 cases of normal gastric mucosa and 115 cases of gastric ulcer were detected by streptavidin-perosidase (SP) method. Venous blood HGF level of GC patients was tested by enzyme-linked immunosorbent assay (ELISA). The micro-vessel number of the patients in the three groups were calculated and analyzed. In GC group, positive expression rates of FAP and HGF protein were 61.8% and 67.3% respectively, which were both higher than those in normal gastric mucosa and gastric ulcer groups. The micro-vessel numbers in patients of the normal gastric mucosa and gastric ulcer groups are far less than that in GC group. FAP, HGF and micro-vessel density (MVD) were significantly correlated with infiltration depth, tumor-node-metastasis (TNM) staging, lymph node metastasis (LNM) and distant metastasis. The results of ELISA showed that serum HGF level was related to tumor size, infiltration degree, TNM staging, LNM and distant metastasis. FAP and HGF expressions in GC were positively correlated with MVD, and the expressions of FAP and HGF in GC were in positive correlation. Our study provided evidence that high FAP and HGF expressions may be positively correlated with the angiogenesis and metastasis of GC.
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Combined use of high doses of vasopressin and corticosteroids in a patient with Crohn’s disease with refractory septic shock after intestinal perforation: a case report
In this article, we present a clinical case of refractory septic shock resulting from intestinal perforation treated with high doses of vasopressin and hydrocortisone during emergency surgery.
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Editorial Board
Source:Practical Radiation Oncology, Volume 7, Issue 6
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Table of Contents
Source:Practical Radiation Oncology, Volume 7, Issue 6
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Masthead
Source:Practical Radiation Oncology, Volume 7, Issue 6
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Editorial Board
Source:Practical Radiation Oncology, Volume 7, Issue 6
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Table of Contents
Source:Practical Radiation Oncology, Volume 7, Issue 6
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Early motor function after local treatment of brain metastases in the motor cortex region with stereotactic radiotherapy/radiosurgery or microsurgical resection: a retrospective study of two consecutive cohorts
We compared the functional outcome and influential factors of two standard treatment modalities for central cerebral metastases: electrophysiological-controlled microsurgical resection (MSR) and stereotactic r...
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Early motor function after local treatment of brain metastases in the motor cortex region with stereotactic radiotherapy/radiosurgery or microsurgical resection: a retrospective study of two consecutive cohorts
We compared the functional outcome and influential factors of two standard treatment modalities for central cerebral metastases: electrophysiological-controlled microsurgical resection (MSR) and stereotactic r...
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Low-Grade Central Osteosarcoma: Report of Two Unusual Morphologic Variants
Abstract
Low-grade central osteosarcoma (LGCO) is a rare subtype of osteosarcoma, constituting < 2% of all osteosarcomas. If not treated appropriately, the tumor can recur with higher-grade disease. We report two cases of low-grade central osteosarcoma with unusual morphologic features and belonging to different age groups. Both presented with pain and swelling in the lower end of femur. Radiologically, both the lesions revealed a large mass with irregular borders and soft tissue invasion.
One patient underwent above-knee amputation and wide local excision of tumor was done in the other patient. Histologically, both the tumors showed spindle cell proliferation displaying mild atypia. In synopsis with radiology, diagnosis of low-grade central osteosarcoma was made in both cases. These cases highlight the varied morphological spectrum of low-grade central osteosarcoma and underscore the diagnostic difficulties faced. Recognition of the variants of low-grade central osteosarcoma is based on aggressive radiological appearance and on adequate tumor sampling for histologic examination.
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Low-Grade Central Osteosarcoma: Report of Two Unusual Morphologic Variants
Abstract
Low-grade central osteosarcoma (LGCO) is a rare subtype of osteosarcoma, constituting < 2% of all osteosarcomas. If not treated appropriately, the tumor can recur with higher-grade disease. We report two cases of low-grade central osteosarcoma with unusual morphologic features and belonging to different age groups. Both presented with pain and swelling in the lower end of femur. Radiologically, both the lesions revealed a large mass with irregular borders and soft tissue invasion.
One patient underwent above-knee amputation and wide local excision of tumor was done in the other patient. Histologically, both the tumors showed spindle cell proliferation displaying mild atypia. In synopsis with radiology, diagnosis of low-grade central osteosarcoma was made in both cases. These cases highlight the varied morphological spectrum of low-grade central osteosarcoma and underscore the diagnostic difficulties faced. Recognition of the variants of low-grade central osteosarcoma is based on aggressive radiological appearance and on adequate tumor sampling for histologic examination.
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Targeting the Wnt/beta-catenin Pathway in Cancer: Update on Effectors and Inhibitors
Publication date: Available online 13 November 2017
Source:Cancer Treatment Reviews
Author(s): Nithya Krishnamurthy, Razelle Kurzrock
The Wnt/beta -catenin pathway is a family of proteins that is implicated in manyvital cellular functions like stem cell regeneration and organogenesis. Several intra-cellular signal transduction pathways are induced by Wnt, notably the Wnt/beta-catenin dependent pathway or canonical pathway and the non-canonical or beta-catenin-independent pathway, the latter includes the Wnt/Ca2+ and Planar Cell Polarity pathway (PCP). Wnt activation occurs at the intestinal crypt floor, and is critical to optimal maintenance of stem cells. Colorectal cancers show evidence of Wnt signaling pathway activation and this is associated with loss of function of the tumor regulator APC. Wnt activation has been observed in breast, lung, and hematopoietic malignancies and contributes to tumor recurrence. The Wnt pathway cross talks with the Notch and Sonic Hedgehog pathways, which has implications for therapeutic interventions in cancers. There are significant challenges in targeting the Wnt pathway, including finding agents that are efficacious without damaging the system of normal somatic stem cell function in cellular repair and tissue homeostasis. Here, we comprehensively review the Wnt pathway and its interactions with the Notch and Sonic Hedgehog pathways. We present the state of the field in effectors and inhibitors of Wnt signaling, including updates on clinical trials in various cancers with inhibitors of Wnt, Notch, and Sonic Hedgehog.
Graphical abstract
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Triple negative breast cancer: emerging therapeutic modalities and novel combination therapies
Source:Cancer Treatment Reviews
Author(s): Alice Lee, Mustafa B.A. Djamgoz
Triple negative breast cancer (TNBC) is a complex and aggressive subtype of breast cancer which lacks oestrogen receptors, progesterone receptors and HER2 amplification, thereby making it difficult to target therapeutically. In addition, TNBC has the highest rates of metastatic disease and the poorest overall survival of all breast cancer subtypes. Resultantly, development of targeted therapies for TNBC is urgently needed. Recent efforts aimed at molecular characterisation of TNBCs have revealed various emerging therapeutic targets including PARP1, receptor and non-receptor tyrosine kinases, immune-checkpoint proteins, the androgen receptor and epigenetic proteins. Key successes include that of the PARP inhibitor, olaparib, which prolonged progression-free survival in a trial of BRCA-mutated breast cancer and for which clinical approval (in this setting) appears imminent. Nevertheless, the heterogeneity of TNBC has limited the clinical benefits of many trialled therapies in 'unselected' patients. Further, drug resistance develops following use of many targeted monotherapies due to upregulation of compensatory signalling pathways. In this review, we evaluate the current status of investigational targeted treatments and present evidence for the role of novel biomarkers and combination therapies in increasing response rates and circumventing drug-induced resistance. Additionally, we discuss promising novel targets in metastatic TNBC identified through preclinical and/or epidemiological studies.
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SEOM clinical guideline for treatment of kidney cancer (2017)
Abstract
The goal of this article is to provide recommendations about the management of kidney cancer. Based on pathologic and molecular features, several kidney cancer variants were described. Nephron-sparing techniques are the gold standard of localized disease. After a randomized trial, sunitinib could be considered in adjuvant treatment in high-risk patients. Patients with advanced disease constitute a heterogeneous population. Prognostic classification should be considered. Both sunitinib and pazopanib are the standard options for first-line systemic therapy in advanced renal cell carcinoma. Based on the results of two randomized trials, both nivolumab and cabozantinib should be considered the standard for second and further lines of therapy. Response evaluation for present therapies is a challenge.
http://ift.tt/2hptOoZ
SEOM clinical guideline for treatment of kidney cancer (2017)
Abstract
The goal of this article is to provide recommendations about the management of kidney cancer. Based on pathologic and molecular features, several kidney cancer variants were described. Nephron-sparing techniques are the gold standard of localized disease. After a randomized trial, sunitinib could be considered in adjuvant treatment in high-risk patients. Patients with advanced disease constitute a heterogeneous population. Prognostic classification should be considered. Both sunitinib and pazopanib are the standard options for first-line systemic therapy in advanced renal cell carcinoma. Based on the results of two randomized trials, both nivolumab and cabozantinib should be considered the standard for second and further lines of therapy. Response evaluation for present therapies is a challenge.
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