Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CSPOR-HN02)

Abstract

Background

The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN.

Patients and methods

Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100mg/m² on days 1, 8; carboplatin AUC 2.5 on days 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400mg/m², followed by 250mg/m² weekly until disease progression or unacceptable toxicities. Primary endpoint was overall response rate (ORR). Secondary endpoints were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients.

Results

Forty-seven subjects were accrued from July 2013 to Oct 2014. Of 45 evaluable, 40 were male; median age was 63 years; ECOG PS was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/non-smokers, respectively. ORR, the primary end point, was 40%. Median overall survival was 14.7 months and progression-free survival was 5.2 months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia.

Conclusions

The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population.

Registered clinical trial numbers

UMIN000010507

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Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2-positive gastric cancer patients

Abstract

Background

To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics.

Patients and Methods

We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer (AGC). A parallel biomarker study was conducted by simultaneously performing immunohistochemistry (IHC) and next-generation sequencing with tumor and blood samples.

Results

Complete response (CR) was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed CR. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. Next-generation sequencing (NGS) of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2-positive tumors. The relationship between CCNE1 amplification and lack of response to HER2 targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; p = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared to patients with low level ERBB2 amplification (p = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications.

Conclusions

The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.

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Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CSPOR-HN02)

Abstract

Background

The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN.

Patients and methods

Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100mg/m² on days 1, 8; carboplatin AUC 2.5 on days 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400mg/m², followed by 250mg/m² weekly until disease progression or unacceptable toxicities. Primary endpoint was overall response rate (ORR). Secondary endpoints were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients.

Results

Forty-seven subjects were accrued from July 2013 to Oct 2014. Of 45 evaluable, 40 were male; median age was 63 years; ECOG PS was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/non-smokers, respectively. ORR, the primary end point, was 40%. Median overall survival was 14.7 months and progression-free survival was 5.2 months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia.

Conclusions

The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population.

Registered clinical trial numbers

UMIN000010507

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Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2-positive gastric cancer patients

Abstract

Background

To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics.

Patients and Methods

We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer (AGC). A parallel biomarker study was conducted by simultaneously performing immunohistochemistry (IHC) and next-generation sequencing with tumor and blood samples.

Results

Complete response (CR) was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed CR. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. Next-generation sequencing (NGS) of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2-positive tumors. The relationship between CCNE1 amplification and lack of response to HER2 targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; p = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared to patients with low level ERBB2 amplification (p = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications.

Conclusions

The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.

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FAOund the Link: Phospholipid Remodeling and Intestinal Stem Cell Growth and Tumorigenesis

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Chia-Wei Cheng, Ömer H. Yilmaz
In this issue of Cell Stem Cell, Wang et al. (2018) identify a novel link between Lpcat3-mediated phospholipid remodeling (the Lands cycle) and cholesterol biosynthesis that modulates intestinal stem cell proliferation and tumorigenesis. Notably, inhibition of cholesterol biosynthesis dampens many of the Lpcat3-deficiency-mediated effects in the intestine.

Teaser

In this issue of Cell Stem Cell, Wang et al. (2018) identify a novel link between Lpcat3-mediated phospholipid remodeling (the Lands cycle) and cholesterol biosynthesis that modulates intestinal stem cell proliferation and tumorigenesis. Notably, inhibition of cholesterol biosynthesis dampens many of the Lpcat3-deficiency-mediated effects in the intestine.


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Tracing Stem Cell Division in Adult Neurogenesis

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Nina S. Corsini, Juergen A. Knoblich
Neural stem cells in the ventricular-subventricular zone of the adult brain continuously generate differentiated neurons without depleting the stem cell pool. In this issue of Cell Stem Cell, Obernier et al. (2018) present the surprising finding that this occurs through mostly symmetric divisions that either generate two differentiating or two self-renewing daughter cells.

Teaser

Neural stem cells in the ventricular-subventricular zone of the adult brain continuously generate differentiated neurons without depleting the stem cell pool. In this issue of Cell Stem Cell, Obernier et al. (2018) present the surprising finding that this occurs through mostly symmetric divisions that either generate two differentiating or two self-renewing daughter cells.


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Slow Your Roll: Inhibiting SETD7 Activity Permits Ex Vivo Expansion of Muscle Stem Cells

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Ryo Fujita, Colin Crist
Muscle stem cell regenerative capacity is rapidly lost during ex vivo culture. In this issue of Cell Stem Cell, Judson et al. (2018) show that inhibition of cytoplasmic SETD7, a lysine methyltransferase, potently expands naive, undifferentiated mouse and human muscle stem cells by restricting their progression through the myogenic program.

Teaser

Muscle stem cell regenerative capacity is rapidly lost during ex vivo culture. In this issue of Cell Stem Cell, Judson et al. (2018) show that inhibition of cytoplasmic SETD7, a lysine methyltransferase, potently expands naive, undifferentiated mouse and human muscle stem cells by restricting their progression through the myogenic program.


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Shaping the Pluripotent Genome: Switches, Borders, and Loops

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Effie Apostolou
Three-dimensional genome organization is largely cell type specific and requires reorganization during cell fate transitions. A recent study in Nature Genetics (Stadhouders et al., 2018) offers important insights into the principles and drivers of such reorganization during reprogramming of somatic cells into pluripotent stem cells.

Teaser

Three-dimensional genome organization is largely cell type specific and requires reorganization during cell fate transitions. A recent study in Nature Genetics (Stadhouders et al., 2018) offers important insights into the principles and drivers of such reorganization during reprogramming of somatic cells into pluripotent stem cells.


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Meddling with METTLs in Normal and Leukemia Stem Cells

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Gaëlle H. Martin, Christopher Y. Park
Three recent studies independently identified the m⁶A RNA modifying enzymes METTL3 and METTL14 as critical regulators of differentiation in both normal hematopoiesis and AML pathogenesis. These studies expand the described roles of the epitranscriptome in maintaining the undifferentiated state in somatic stem cells and human cancer.

Teaser

Three recent studies independently identified the m⁶A RNA modifying enzymes METTL3 and METTL14 as critical regulators of differentiation in both normal hematopoiesis and AML pathogenesis. These studies expand the described roles of the epitranscriptome in maintaining the undifferentiated state in somatic stem cells and human cancer.


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Japan Strengthens Regenerative Medicine Oversight

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Douglas Sipp, Hideyuki Okano
The Japanese government initiated sweeping reforms targeting regenerative medicine in 2014, accompanied by substantial investment into stem cell research and development. We survey the impact of these developments and discuss how the government is working to accelerate regenerative medicine while ensuring safety and efficacy.

Teaser

The Japanese government initiated sweeping reforms targeting regenerative medicine in 2014, accompanied by substantial investment into stem cell research and development. We survey the impact of these developments and discuss how the government is working to accelerate regenerative medicine while ensuring safety and efficacy.


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Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Robert L. Bowman, Lambert Busque, Ross L. Levine
Clonal hematopoiesis (CH) broadly describes the expansion of a clonal population of blood cells with one or more somatic mutations. Individuals with CH are at greater risk for hematological malignancies, cardiovascular disease, and increased mortality from non-hematological cancers. Understanding the causes of CH and how these mutant cells interact with cells of other tissues will provide critical insights into preleukemic development, stem cell biology, host-immune interactions, and cancer evolution. Here we discuss the clinical manifestations of CH, mechanisms contributing to its development, the role of CH in clonal evolution toward leukemia, and the contribution of CH to non-hematological disease states.

Teaser

Bowman et al. discuss the clinical manifestations of clonal hematopoiesis (CH), mechanisms contributing to its development, the role of CH in clonal evolution towards leukemia, and the contribution of CH to non-hematological disease states.


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Phospholipid Remodeling and Cholesterol Availability Regulate Intestinal Stemness and Tumorigenesis

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Bo Wang, Xin Rong, Elisa N.D. Palladino, Jiafang Wang, Alan M. Fogelman, Martín G. Martín, Waddah A. Alrefai, David A. Ford, Peter Tontonoz
Adequate availability of cellular building blocks, including lipids, is a prerequisite for cellular proliferation, but excess dietary lipids are linked to increased cancer risk. Despite these connections, specific regulatory relationships between membrane composition, intestinal stem cell (ISC) proliferation, and tumorigenesis are unclear. We reveal an unexpected link between membrane phospholipid remodeling and cholesterol biosynthesis and demonstrate that cholesterol itself acts as a mitogen for ISCs. Inhibition of the phospholipid-remodeling enzyme Lpcat3 increases membrane saturation and stimulates cholesterol biosynthesis, thereby driving ISC proliferation. Pharmacologic inhibition of cholesterol synthesis normalizes crypt hyperproliferation in Lpcat3-deficient organoids and mice. Conversely, increasing cellular cholesterol content stimulates crypt organoid growth, and providing excess dietary cholesterol or driving endogenous cholesterol synthesis through SREBP-2 expression promotes ISC proliferation in vivo. Finally, disruption of Lpcat3-dependent phospholipid and cholesterol homeostasis dramatically enhances tumor formation in Apc^min mice. These findings identify a critical dietary-responsive phospholipid-cholesterol axis regulating ISC proliferation and tumorigenesis.

Graphical abstract

Teaser

Tontonoz and colleagues show that the phospholipid remodeling enzyme Lpcat3 regulates intestinal stem cells and progenitor cells by stimulating cholesterol biosynthesis. Furthermore, enhancing cholesterol availability, either by providing it in the diet or through genetic manipulation, promotes tumorigenesis in Apc^min/+ mice.


http://ift.tt/2DTeOcs

Adult Neurogenesis Is Sustained by Symmetric Self-Renewal and Differentiation

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Kirsten Obernier, Arantxa Cebrian-Silla, Matthew Thomson, José Ignacio Parraguez, Rio Anderson, Cristina Guinto, José Rodas Rodriguez, José-Manuel Garcia-Verdugo, Arturo Alvarez-Buylla
Somatic stem cells have been identified in multiple adult tissues. Whether self-renewal occurs symmetrically or asymmetrically is key to understanding long-term stem cell maintenance and generation of progeny for cell replacement. In the adult mouse brain, neural stem cells (NSCs) (B1 cells) are retained in the walls of the lateral ventricles (ventricular-subventricular zone [V-SVZ]). The mechanism of B1 cell retention into adulthood for lifelong neurogenesis is unknown. Using multiple clonal labeling techniques, we show that the vast majority of B1 cells divide symmetrically. Whereas 20%–30% symmetrically self-renew and can remain in the niche for several months before generating neurons, 70%–80% undergo consuming divisions generating progeny, resulting in the depletion of B1 cells over time. This cellular mechanism decouples self-renewal from the generation of progeny. Limited rounds of symmetric self-renewal and consuming symmetric differentiation divisions can explain the levels of neurogenesis observed throughout life.

Graphical abstract

Teaser

Obernier et al. show that juvenile/adult neural stem cells (NSCs) generate progeny or self-renew through symmetric divisions. The prevailing consuming symmetric divisions progressively deplete NSCs, yet this mechanism enables lifelong generation of large numbers of neurons for the olfactory bulb while decoupling proliferation from differentiation.


http://ift.tt/2Ewwufd

In Vivo Labeling by CD73 Marks Multipotent Stromal Cells and Highlights Endothelial Heterogeneity in the Bone Marrow Niche

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Martin Breitbach, Kenichi Kimura, Tiago C. Luis, Christopher J. Fuegemann, Petter S. Woll, Michael Hesse, Raffaella Facchini, Sarah Rieck, Katarzyna Jobin, Julia Reinhardt, Osamu Ohneda, Daniela Wenzel, Caroline Geisen, Christian Kurts, Wolfgang Kastenmüller, Michael Hölzel, Sten E.W. Jacobsen, Bernd K. Fleischmann
Despite much work studying ex vivo multipotent stromal cells (MSCs), the identity and characteristics of MSCs in vivo are not well defined. Here, we generated a CD73-EGFP reporter mouse to address these questions and found EGFP⁺ MSCs in various organs. In vivo, EGFP⁺ mesenchymal cells were observed in fetal and adult bones at proliferative ossification sites, while in solid organs EGFP⁺ cells exhibited a perivascular distribution pattern. EGFP⁺ cells from the bone compartment could be clonally expanded ex vivo from single cells and displayed trilineage differentiation potential. Moreover, in the central bone marrow CD73-EGFP⁺ specifically labeled sinusoidal endothelial cells, thought to be a critical component of the hematopoietic stem cell niche. Purification and molecular characterization of this CD73-EGFP⁺ population revealed an endothelial subtype that also displays a mesenchymal signature, highlighting endothelial cell heterogeneity in the marrow. Thus, the CD73-EGFP mouse is a powerful tool for studying MSCs and sinusoidal endothelium.

Graphical abstract

Teaser

Breitbach et al. generated a CD73-EGFP reporter mouse that enabled identification and tracking of multipotent stromal cells in vivo. CD73-EGFP also labeled sinusoidal endothelial cells within the bone marrow, enabling the molecular characterization of this important endothelial component of the hematopoietic stem cell niche.


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Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Maria Kleppe, Matthew H. Spitzer, Sheng Li, Corinne E. Hill, Lauren Dong, Efthymia Papalexi, Sofie De Groote, Robert L. Bowman, Matthew Keller, Priya Koppikar, Franck T. Rapaport, Julie Teruya-Feldstein, Jorge Gandara, Christopher E. Mason, Garry P. Nolan, Ross L. Levine




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Development of a 99mTc-Labeled CXCR4 Antagonist Derivative as a New Tumor Radiotracer

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Schottenfeld and Fraumeni Cancer Epidemiology and Prevention, Fourth Edition Oxford University Press, (2018).

Publication date: Available online 1 February 2018
Source:Cancer Epidemiology
Author(s): Freddy Sitas




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Schottenfeld and Fraumeni Cancer Epidemiology and Prevention, Fourth Edition Oxford University Press, (2018).

Publication date: Available online 1 February 2018
Source:Cancer Epidemiology
Author(s): Freddy Sitas




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MicroRNA-1246 is an exosomal biomarker for aggressive prostate cancer

Due to high heterogeneity, molecular characterization of prostate cancer (PCa) based on biopsy sampling is often challenging. Hence, a minimally invasive method to determine the molecular imprints of a patient's tumor for risk stratification would be advantageous. In this study, we employ a novel, digital amplification-free quantification method using the nCounter technology (Nanostring Technologies) to profile exosomal serum miRNAs (ex-miRNA) from aggressive PCa cases, benign prostatic hyperplasia (BPH), and disease-free controls. We identified several dysregulated miRNAs, one of which was the tumor suppressor miR-1246. miR-1246 was downregulated in PCa clinical tissues and cell lines and was selectively released into exosomes. Overexpression of miR-1246 in a PCa cell line significantly inhibited xenograft tumor growth in vivo and increased apoptosis and decreased proliferation, invasiveness, and migration in vitro. miR-1246 inhibited N-cadherin and vimentin activities, thereby inhibiting epithelial-mesenchymal transition. Ex-miR-1246 expression correlated with increasing pathological grade, positive metastasis, and poor prognosis. Our analyses suggest ex-miR-1246 as a promising PCa biomarker with diagnostic potential that can predict disease aggressiveness.

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MicroRNA-1246 is an exosomal biomarker for aggressive prostate cancer

Due to high heterogeneity, molecular characterization of prostate cancer (PCa) based on biopsy sampling is often challenging. Hence, a minimally invasive method to determine the molecular imprints of a patient's tumor for risk stratification would be advantageous. In this study, we employ a novel, digital amplification-free quantification method using the nCounter technology (Nanostring Technologies) to profile exosomal serum miRNAs (ex-miRNA) from aggressive PCa cases, benign prostatic hyperplasia (BPH), and disease-free controls. We identified several dysregulated miRNAs, one of which was the tumor suppressor miR-1246. miR-1246 was downregulated in PCa clinical tissues and cell lines and was selectively released into exosomes. Overexpression of miR-1246 in a PCa cell line significantly inhibited xenograft tumor growth in vivo and increased apoptosis and decreased proliferation, invasiveness, and migration in vitro. miR-1246 inhibited N-cadherin and vimentin activities, thereby inhibiting epithelial-mesenchymal transition. Ex-miR-1246 expression correlated with increasing pathological grade, positive metastasis, and poor prognosis. Our analyses suggest ex-miR-1246 as a promising PCa biomarker with diagnostic potential that can predict disease aggressiveness.

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Radiomic Biomarkers to Refine Risk Models for Distant Metastasis in HPV-related Oropharyngeal Carcinoma

Publication date: Available online 1 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jennifer Yin Yee Kwan, Jie Su, Shao Hui Huang, Laleh S. Ghoraie, Wei Xu, Biu Chan, Kenneth W. Yip, Meredith Giuliani, Andrew Bayley, John Kim, Andrew J. Hope, Jolie Ringash, John Cho, Andrea McNiven, Aaron Hansen, David Goldstein, John de Almeida, Hugo J. Aerts, John N. Waldron, Benjamin Haibe-Kains, Brian O'Sullivan, Scott V. Bratman, Fei-Fei Liu
PurposeDistant metastasis (DM) is the main cause of death for patients with human papillomavirus (HPV)-related oropharyngeal cancers (OPC); yet there are few reliable predictors of DM in this disease. The role of quantitative imaging (i.e. radiomic) analysis was examined to determine whether there are primary tumor features discernible on imaging studies that associate with a higher risk of developing DM.MethodsRadiotherapy planning CT scans were retrieved for all non-metastatic p16-positive OPC patients treated with radiotherapy or chemoradiotherapy at a single institution between 2005 and 2010. Radiomic biomarkers were derived from each gross tumor volume (GTV). Biomarkers included four representative radiomic features from tumor first order statistics, shape, texture, and wavelet groups as well as a combined four-feature signature. Univariable Cox proportional hazards models for DM risk were identified. Discriminative performance of prognostic univariable and multivariable models was compared using the concordance index (C-index). Subgroup analyses were performed.ResultsThere were 300 HPV-related OPC patients who were eligible for the analysis. A total of 36 DM events occurred within a median follow-up of five years. On univariable analysis, top results included the four representative radiomic features (C-index=0.670-0.686; p<0.001), the radiomic signature (C-index=0.670; p<0.001), tumor stage (C-index=0.633; p<0.001), tumor diameter (C-index=0.653; p<0.001), and tumor volume (C-index=0.674; p<0.001); which demonstrated moderate discrimination of DM risk. Combined clinical-radiomic models yielded significantly improved performance (C-index=0.701-0.714; p<0.05). In subgroup analyses, the radiomic biomarkers consistently stratified patients for DM risk, particularly for those cohorts with greater risks (C-index=0.663-0.796), such as patients with stage III disease.ConclusionsRadiomic biomarkers appear to classify DM risk for patients with non-metastatic HPV-related OPC. Radiomic biomarkers could be used either alone or with other clinical characteristics in assignment of DM risk in future HPV-related OPC clinical trials.



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The impact of HIV infection on survival and acute toxicities from chemoradiation therapy for cervical cancer patients in a limited resource setting

Publication date: Available online 1 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Surbhi Grover, Memory Bvochora-Nsingo, Alyssa Yeager, Sebathu Chiyapo, Rohini Bhatia, Emily MacDuffie, Priya Puri, Dawn Balang, Sarah Ratcliffe, Mohan Narasimhamurthy, Elliphine Gwangwava, Sylvia Tsietso, Mukendi K.A. Kayembe, Doreen Ramogola-Masire, Scott Dryden-Peterson, Umesh Mahantshetty, Akila N. Viswanathan, Nicola M. Zetola, Lilie L. Lin
PurposeCervical cancer is the leading cause of cancer death for women in sub-Saharan Africa. Human immunodeficiency virus (HIV) infection increases the risk of cervical cancer. However, prospective data on the outcomes of cervical cancer patients with HIV infection treated with curative intent are limited.MethodsWomen with locally advanced cervical cancer with or without HIV infection initiating radical chemoradiation therapy (CRT) in Botswana were enrolled in a prospective observational cohort study from July 2013 through January 2015.ResultsOf 182 women treated for cervical cancer during the study period, 143 women initiating curative CRT were included in the study. Eighty-five percent of the participants (122/143) had stage II/III cervical cancer, and 67% (96/143) were HIV-infected. All HIV-infected patients were on anti-retroviral treatment (ART) at the time of curative cervical cancer treatment initiation. We found no difference in toxicities between HIV-infected and HIV-uninfected women. The two-year overall survival (OS) rates were 65% for HIV-infected women (95% confidence interval [CI] 54-74%) and 66% for HIV-uninfected women (95% CI 49-79%) (p=0.70). Factors associated with better two-year OS on multivariate analyses included baseline hemoglobin >10 g/dL (hazard ratio [HR] 0.37, 95% CI 0.19-0.72, p=0.003), total radiation dose ≥75 Gy (HR 0.52, 95% CI 0.27-0.97, p=0.04), and age <40 years vs. 40-59 years (HR 2.17, 95% CI 1.05-4.47, p=0.03).ConclusionsHIV status had no effect on two-year OS or on acute toxicities in women with well-managed HIV infection who initiated curative CRT in Botswana. In our cohort, we found that baseline hemoglobin levels, total radiation dose, and age were associated with survival, regardless of HIV status.



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Effect of Radiation Treatment Volume Reduction on Lymphopenia in Patients Receiving Chemoradiotherapy for Glioblastoma

Publication date: Available online 1 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Soumon Rudra, Caressa Hui, Yuan Rao, Pamela Samson, Alexander Lin, Xiao Chang, Christina Tsien, Sandra Fergus, Dan Mullen, Deshan Yang, Dinesh Thotala, Dennis Hallahan, Jian Li Campian, Jiayi Huang
ObjectiveAcute severe lymphopenia (ASL) in glioblastoma (GBM) patients after radiation therapy (RT) and concurrent temozolomide (TMZ) predicts for poorer overall survival (OS). This study aims to evaluate whether reduction in radiation treatment volume can reduce risk of ASL.MethodsA total of 210 patients with supratentorial/non-metastatic GBM were treated with RT+TMZ from 2007-2016 and had laboratory data on total lymphocyte counts (TLC). Before 2015, 164 patients were treated with standard-field RT (SFRT), and limited-field RT (LFRT) was implemented thereafter for 46 patients to reduce treatment volume. TLCs were evaluated at baseline, during RT, and at approximately week 12 from initiating RT. ASL was defined as any TLC<500 cells/μL within 3 months (by week 12) of initiating RT. Multivariate analysis (MVA) for OS was performed with Cox regression and with logistic regression for ASL. Propensity-score matching was performed to adjust for variability between cohorts. ASL, progression-free survival (PFS), and OS were compared using Kaplan-Meier method.ResultsLFRT patients had higher gross tumor volume (GTV) than SFRT patients yet lower brain dose-volume parameters including volume receiving 25Gy (V25Gy: 41% vs 53%, respectively, P<0.01). TLC at week 12 was significantly higher for LFRT than SFRT (median: 1100 cells/μL vs. 900 cells/μL, respectively, P=0.02). On MVA, ASL was an independent predictor of OS, and brain V25Gy was an independent predictor of ASL. ASL rate at 3 months was 15.5% for LFRT and 33.8% for SFRT (P=0.12). In a propensity-matched comparison of 45 pairs of LFRT and SFRT patients, PFS (median: 5.9 vs 6.2 months, respectively, P=0.58) and OS (median: 16.2 vs 13.9 months, respectively, P=0.69) were not significantly different.ConclusionLFRT is associated with less lymphopenia after RT+TMZ and does not adversely affect PFS or OS. Brain V25Gy is confirmed as an important dosimetric predictor for ASL.



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Radiomic Biomarkers to Refine Risk Models for Distant Metastasis in HPV-related Oropharyngeal Carcinoma

Publication date: Available online 1 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jennifer Yin Yee Kwan, Jie Su, Shao Hui Huang, Laleh S. Ghoraie, Wei Xu, Biu Chan, Kenneth W. Yip, Meredith Giuliani, Andrew Bayley, John Kim, Andrew J. Hope, Jolie Ringash, John Cho, Andrea McNiven, Aaron Hansen, David Goldstein, John de Almeida, Hugo J. Aerts, John N. Waldron, Benjamin Haibe-Kains, Brian O'Sullivan, Scott V. Bratman, Fei-Fei Liu
PurposeDistant metastasis (DM) is the main cause of death for patients with human papillomavirus (HPV)-related oropharyngeal cancers (OPC); yet there are few reliable predictors of DM in this disease. The role of quantitative imaging (i.e. radiomic) analysis was examined to determine whether there are primary tumor features discernible on imaging studies that associate with a higher risk of developing DM.MethodsRadiotherapy planning CT scans were retrieved for all non-metastatic p16-positive OPC patients treated with radiotherapy or chemoradiotherapy at a single institution between 2005 and 2010. Radiomic biomarkers were derived from each gross tumor volume (GTV). Biomarkers included four representative radiomic features from tumor first order statistics, shape, texture, and wavelet groups as well as a combined four-feature signature. Univariable Cox proportional hazards models for DM risk were identified. Discriminative performance of prognostic univariable and multivariable models was compared using the concordance index (C-index). Subgroup analyses were performed.ResultsThere were 300 HPV-related OPC patients who were eligible for the analysis. A total of 36 DM events occurred within a median follow-up of five years. On univariable analysis, top results included the four representative radiomic features (C-index=0.670-0.686; p<0.001), the radiomic signature (C-index=0.670; p<0.001), tumor stage (C-index=0.633; p<0.001), tumor diameter (C-index=0.653; p<0.001), and tumor volume (C-index=0.674; p<0.001); which demonstrated moderate discrimination of DM risk. Combined clinical-radiomic models yielded significantly improved performance (C-index=0.701-0.714; p<0.05). In subgroup analyses, the radiomic biomarkers consistently stratified patients for DM risk, particularly for those cohorts with greater risks (C-index=0.663-0.796), such as patients with stage III disease.ConclusionsRadiomic biomarkers appear to classify DM risk for patients with non-metastatic HPV-related OPC. Radiomic biomarkers could be used either alone or with other clinical characteristics in assignment of DM risk in future HPV-related OPC clinical trials.



http://ift.tt/2nz4wXX

The impact of HIV infection on survival and acute toxicities from chemoradiation therapy for cervical cancer patients in a limited resource setting

Publication date: Available online 1 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Surbhi Grover, Memory Bvochora-Nsingo, Alyssa Yeager, Sebathu Chiyapo, Rohini Bhatia, Emily MacDuffie, Priya Puri, Dawn Balang, Sarah Ratcliffe, Mohan Narasimhamurthy, Elliphine Gwangwava, Sylvia Tsietso, Mukendi K.A. Kayembe, Doreen Ramogola-Masire, Scott Dryden-Peterson, Umesh Mahantshetty, Akila N. Viswanathan, Nicola M. Zetola, Lilie L. Lin
PurposeCervical cancer is the leading cause of cancer death for women in sub-Saharan Africa. Human immunodeficiency virus (HIV) infection increases the risk of cervical cancer. However, prospective data on the outcomes of cervical cancer patients with HIV infection treated with curative intent are limited.MethodsWomen with locally advanced cervical cancer with or without HIV infection initiating radical chemoradiation therapy (CRT) in Botswana were enrolled in a prospective observational cohort study from July 2013 through January 2015.ResultsOf 182 women treated for cervical cancer during the study period, 143 women initiating curative CRT were included in the study. Eighty-five percent of the participants (122/143) had stage II/III cervical cancer, and 67% (96/143) were HIV-infected. All HIV-infected patients were on anti-retroviral treatment (ART) at the time of curative cervical cancer treatment initiation. We found no difference in toxicities between HIV-infected and HIV-uninfected women. The two-year overall survival (OS) rates were 65% for HIV-infected women (95% confidence interval [CI] 54-74%) and 66% for HIV-uninfected women (95% CI 49-79%) (p=0.70). Factors associated with better two-year OS on multivariate analyses included baseline hemoglobin >10 g/dL (hazard ratio [HR] 0.37, 95% CI 0.19-0.72, p=0.003), total radiation dose ≥75 Gy (HR 0.52, 95% CI 0.27-0.97, p=0.04), and age <40 years vs. 40-59 years (HR 2.17, 95% CI 1.05-4.47, p=0.03).ConclusionsHIV status had no effect on two-year OS or on acute toxicities in women with well-managed HIV infection who initiated curative CRT in Botswana. In our cohort, we found that baseline hemoglobin levels, total radiation dose, and age were associated with survival, regardless of HIV status.



http://ift.tt/2DTfFhi

Effect of Radiation Treatment Volume Reduction on Lymphopenia in Patients Receiving Chemoradiotherapy for Glioblastoma

Publication date: Available online 1 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Soumon Rudra, Caressa Hui, Yuan Rao, Pamela Samson, Alexander Lin, Xiao Chang, Christina Tsien, Sandra Fergus, Dan Mullen, Deshan Yang, Dinesh Thotala, Dennis Hallahan, Jian Li Campian, Jiayi Huang
ObjectiveAcute severe lymphopenia (ASL) in glioblastoma (GBM) patients after radiation therapy (RT) and concurrent temozolomide (TMZ) predicts for poorer overall survival (OS). This study aims to evaluate whether reduction in radiation treatment volume can reduce risk of ASL.MethodsA total of 210 patients with supratentorial/non-metastatic GBM were treated with RT+TMZ from 2007-2016 and had laboratory data on total lymphocyte counts (TLC). Before 2015, 164 patients were treated with standard-field RT (SFRT), and limited-field RT (LFRT) was implemented thereafter for 46 patients to reduce treatment volume. TLCs were evaluated at baseline, during RT, and at approximately week 12 from initiating RT. ASL was defined as any TLC<500 cells/μL within 3 months (by week 12) of initiating RT. Multivariate analysis (MVA) for OS was performed with Cox regression and with logistic regression for ASL. Propensity-score matching was performed to adjust for variability between cohorts. ASL, progression-free survival (PFS), and OS were compared using Kaplan-Meier method.ResultsLFRT patients had higher gross tumor volume (GTV) than SFRT patients yet lower brain dose-volume parameters including volume receiving 25Gy (V25Gy: 41% vs 53%, respectively, P<0.01). TLC at week 12 was significantly higher for LFRT than SFRT (median: 1100 cells/μL vs. 900 cells/μL, respectively, P=0.02). On MVA, ASL was an independent predictor of OS, and brain V25Gy was an independent predictor of ASL. ASL rate at 3 months was 15.5% for LFRT and 33.8% for SFRT (P=0.12). In a propensity-matched comparison of 45 pairs of LFRT and SFRT patients, PFS (median: 5.9 vs 6.2 months, respectively, P=0.58) and OS (median: 16.2 vs 13.9 months, respectively, P=0.69) were not significantly different.ConclusionLFRT is associated with less lymphopenia after RT+TMZ and does not adversely affect PFS or OS. Brain V25Gy is confirmed as an important dosimetric predictor for ASL.



http://ift.tt/2nAMd4L

Radiomics as a Quantitative Imaging Biomarker: Practical Considerations and the Current Standpoint in Neuro-oncologic Studies

Abstract

Radiomics utilizes high-dimensional imaging data to discover the association with diagnostic, prognostic, predictive endpoint or radiogenomics. It is an emerging field of study that potentially depicts the intratumoral heterogeneity from quantitative and classified high-throughput data. The radiomics approach has an analytic pipeline where the imaging features are extracted, processed and analyzed. At this point, special data handling is essential because it faces issues of a high-dimensional biomarker compared to a single biomarker approach. This article describes the potential role of radiomics in oncologic studies, the basic analytic pipeline and special data handling with high-dimensional data to facilitate the radiomics approach as a tool for personalized medicine in oncology.

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Radiomics as a Quantitative Imaging Biomarker: Practical Considerations and the Current Standpoint in Neuro-oncologic Studies

Abstract

Radiomics utilizes high-dimensional imaging data to discover the association with diagnostic, prognostic, predictive endpoint or radiogenomics. It is an emerging field of study that potentially depicts the intratumoral heterogeneity from quantitative and classified high-throughput data. The radiomics approach has an analytic pipeline where the imaging features are extracted, processed and analyzed. At this point, special data handling is essential because it faces issues of a high-dimensional biomarker compared to a single biomarker approach. This article describes the potential role of radiomics in oncologic studies, the basic analytic pipeline and special data handling with high-dimensional data to facilitate the radiomics approach as a tool for personalized medicine in oncology.

http://ift.tt/2DWJ6uM

Allogeneic Stem-Cell Transplantation — A T-Cell Balancing ACT

Success in the bone marrow transplantation clinic has always depended on scientific discovery. Before the discovery of histocompatibility antigens, for example, allogeneic hematopoietic stem-cell transplantation (HSCT) was uniformly fatal as a result of overwhelming immunologic catastrophe and…

http://ift.tt/2GF06I4

Differentiation between radiation-induced brain injury and glioma recurrence using 3D pCASL and dynamic susceptibility contrast-enhanced perfusion-weighted imaging

This study was performed to validate the efficacy of three-dimensional pseudocontinuous arterial spin labeling (pCASL) compared with dynamic susceptibility contrast-enhanced perfusion-weighted imaging (DSC-PWI) in distinguishing radiation-induced brain injury from glioma recurrence in patients with glioma.

http://ift.tt/2BNK7n8

Allogeneic Stem-Cell Transplantation — A T-Cell Balancing ACT

Success in the bone marrow transplantation clinic has always depended on scientific discovery. Before the discovery of histocompatibility antigens, for example, allogeneic hematopoietic stem-cell transplantation (HSCT) was uniformly fatal as a result of overwhelming immunologic catastrophe and…

http://ift.tt/2GF06I4

Allogeneic Stem-Cell Transplantation — A T-Cell Balancing ACT

Success in the bone marrow transplantation clinic has always depended on scientific discovery. Before the discovery of histocompatibility antigens, for example, allogeneic hematopoietic stem-cell transplantation (HSCT) was uniformly fatal as a result of overwhelming immunologic catastrophe and…

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Reply to: professionalisation rather than monopolisation is the future of emergency medicine in Europe

No abstract available

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Reply to: emergency medicine is about collaboration, not monopolisation

No abstract available

http://ift.tt/2DTGiyP

Does the β-receptor antagonist esmolol have analgesic effects?: A randomised placebo-controlled cross-over study on healthy volunteers undergoing the cold pressor test

BACKGROUND Esmolol may attenuate the sympathetic response to pain and reduce postoperative opioid consumption. It is not clear whether esmolol has an analgesic effect per se. OBJECTIVES The aim of this study was to evaluate the analgesic effect of esmolol in the absence of anaesthetics and opioids. We tested the hypothesis that esmolol would reduce the maximum pain intensity perceived during the cold pressor test (CPT) by 2 points on a 0 to 10 numeric pain rating scale (NRS) compared to placebo. DESIGN Randomised, placebo-controlled cross-over study. SETTING Postoperative recovery area, Örebro University Hospital. Study period, November 2013 to February 2014. PARTICIPANTS Fourteen healthy volunteers. Exclusion criteria included ongoing medication, pregnancy and breastfeeding and participation in other medical trials. INTERVENTIONS At separate study sessions, participants received interventions: esmolol (0.7 mg kg−1 bolus over 1 min followed by infusion at 10 μg kg−1 min−1); 0.9% normal saline bolus then remifentanil infusion at 0.2 μg kg−1 min−1 and 0.9% normal saline bolus and infusion according to a random sequence. All infusions were administered over 30 min. MAIN OUTCOME MEASURES Perceived maximum pain intensity score, pain tolerance and haemodynamic changes during CPT, and occurrence of side-effects to interventions compared to placebo, respectively. RESULTS Esmolol did not reduce perceived pain intensity or pain tolerance during the CPT. The NRS-max score was similar for esmolol, 8.5 (±1.4) and placebo, 8.4 (±1.3). The mean difference was 0.1 [95% confidence interval (−1.2 to 1.4)], P value equal to 0.83. Remifentanil significantly reduced NRS-max scores, 5.4 (±2.1) compared to placebo, [mean difference −3.1 (95% confidence interval (−4.4 to −1.8)), P 

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Reply to: who takes the lead in critical illness?

No abstract available

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Neostigmine-based reversal of intermediate acting neuromuscular blocking agents to prevent postoperative residual paralysis: A systematic review

BACKGROUND Neostigmine is widely used to antagonise residual paralysis. Over the last decades, the benchmark of acceptable neuromuscular recovery has increased progressively to a train-of-four (TOF) ratio of at least 0.9. Raising this benchmark may impact on the efficacy of neostigmine. OBJECTIVE(S) The systematic review evaluates the efficacy of neostigmine to antagonise neuromuscular block to attain a TOF ratio of at least 0.9. DESIGN We performed a systematic search of the literature from January 1992 to December 2015. DATA SOURCES OR SETTING PubMed, EMBASE and the Cochrane Controlled Clinical Trials database were searched for randomised controlled human studies. Search was performed without language restrictions, using the following free text terms: 'neostigmine', 'sugammadex', 'edrophonium' or 'pyridostigmine' AND 'neuromuscular block', 'reversal' or 'reverse'. ELIGIBILITY CRITERIA Studies were accepted for inclusion if they used quantitative neuromuscular monitoring and neostigmine as the reversal agent. Selected trials were checked by two of the authors for data integrity. Trials relevant for inclusion had to report the number of patients included, the type of anaesthetic maintenance, the type of neuromuscular blocking agent used, the reversal agent and dose used, the depth of neuromuscular block when neostigmine was administered and the reversal time (time from injection of neostigmine until a TOF ratio ≥0.9 was attained). RESULTS 19 trials were eligible for quantitative analysis. In patients with deep residual block [T1 (first twitch height) 25% of baseline), or that a recovery time longer than 15 min be accepted.

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Reply to: collaboration in emergency medical care in Europe the ten principles of CRitical Emergency Medicine (CREM)

No abstract available

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Emergency medicine is about collaboration, not monopolisation

No abstract available

http://ift.tt/2EvGBAL

Effects of propofol on wound closure and barrier function of cultured endothelial cells: An in vitro experimental study

BACKGROUND Propofol is widely used in routine clinical practice for the induction and maintenance of anaesthesia. Although propofol is regarded as a well tolerated anaesthetic, its effect on intact or damaged endothelial cells has not yet been elucidated. OBJECTIVE The aim of this study was to investigate the effects of different concentrations of propofol on cell damage, metabolic activity, barrier function and wound healing capacity of human endothelial cells. DESIGN An in vitro investigation. SETTING Research Laboratory of the Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Kiel, Germany. MATERIALS In vitro cultures of primary human umbilical vein endothelial cells (HUVECs). INTERVENTIONS Intact HUVEC or wounded HUVEC monolayers were incubated with or without different concentrations of propofol (10, 30 and 100 μmol l-1). MAIN OUTCOME MEASURES Cell damage, metabolic activity, monolayer permeability, wound healing capacity, protein phosphorylation. RESULTS Propofol did not alter the morphology, induce cell damage or influence metabolic activity of intact HUVEC cells. Permeability of a HUVEC monolayer was increased by propofol 100 μmol l-1 (P 

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Who takes the lead in critically ill patients?

No abstract available

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Evaluation of recombinant factor VIIa, tranexamic acid and desmopressin to reduce prasugrel-related bleeding: A randomised, placebo-controlled study in a rabbit model

BACKGROUND Prasugrel is a thienopyridine that inhibits platelet aggregation more rapidly and effectively than clopidogrel, with an increased bleeding risk. OBJECTIVE The current study aimed to evaluate the efficacy of three nonspecific haemostatic drugs – recombinant activated factor VII (rFVIIa), tranexamic acid and desmopressin (DDAVP) – to limit blood loss after administration of prasugrel in a rabbit model of bleeding while also evaluating any prothrombotic effects. DESIGN Randomised, placebo-controlled study. SETTING Faculty of Medicine, University of Geneva, Switzerland, in 2013. ANIMALS Anaesthetised and artificially ventilated rabbits (n=56). INTERVENTIONS Animals were randomly allocated to one of five groups: control (placebo–placebo), prasugrel–placebo, rFVIIa (prasugrel–rFVIIa 150 μg kg−1), tranexamic acid (prasugrel–tranexamic acid 20 mg kg−1) or DDAVP (prasugrel–DDAVP 1 μg kg−1). Two hours after an oral prasugrel loading dose (4 mg kg−1), a stenosis and an injury were inflicted on the carotid artery to induce cyclic flow reductions (CFRs) due to thrombosis. Haemostatic drugs were administered during the ensuing observation period. MAIN OUTCOME MEASURES Standardised hepatosplenic sections were performed to evaluate the primary endpoint of blood loss, monitored for 15 min. Ear-immersion bleeding time and incidence of CFRs were secondary endpoints. RESULTS Prasugrel decreased ADP-induced platelet aggregation (light transmission method) from 66 ± 4% (mean ± SD) to 41 ± 7% (P 

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Professionalisation rather than monopolisation is the future of emergency medicine in Europe

No abstract available

http://ift.tt/2ExkMkn

Impact of pectoral nerve block on postoperative pain and quality of recovery in patients undergoing breast cancer surgery: A randomised controlled trial

BACKGROUND In recent years, thoracic wall nerve blocks, such as the pectoral nerve (PECS) block and the serratus plane block have become popular for peri-operative pain control in patients undergoing breast cancer surgery. The effect of PECS block on quality of recovery (QoR) after breast cancer surgery has not been evaluated. OBJECTIVES To evaluate the ability of PECS block to decrease postoperative pain and anaesthesia and analgesia requirements and to improve postoperative QoR in patients undergoing breast cancer surgery. DESIGN Randomised controlled study. SETTING A tertiary hospital. PATIENTS Sixty women undergoing breast cancer surgery between April 2014 and February 2015. INTERVENTIONS The patients were randomised to receive a PECS block consisting of 30 ml of levobupivacaine 0.25% after induction of anaesthesia (PECS group) or a saline mock block (control group). The patients answered a 40-item QoR questionnaire (QoR-40) before and 1 day after breast cancer surgery. MAIN OUTCOME MEASURES Numeric Rating Scale score for postoperative pain, requirement for intra-operative propofol and remifentanil, and QoR-40 score on postoperative day 1. RESULTS PECS block combined with propofol–remifentanil anaesthesia significantly improved the median [interquartile range] pain score at 6 h postoperatively (PECS group 1 [0 to 2] vs. Control group 1 [0.25 to 2.75]; P = 0.018]. PECS block also reduced propofol mean (± SD) estimated target blood concentration to maintain bispectral index (BIS) between 40 and 50 (PECS group 2.65 (± 0.52) vs. Control group 3.08 (± 0.41) μg ml−1; P 

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Collaboration in emergency medical care in Europe: the patient is the winner

No abstract available

http://ift.tt/2EwAhcv

Ultrasound in Anesthesia, Critical Care, and Pain Management

No abstract available

http://ift.tt/2Ey4fgi

Antileukemic effects of neurokinin-1 receptor inhibition on hematologic malignant cells: a novel therapeutic potential for aprepitant

Genetic and laboratory studies have remodeled the conventional understanding of cancer pathogenesis by identifying different molecular alterations. Intrigued by the contribution of neurokinin-1 receptor (NK1R) network in cancer pathogenesis, we investigated the antileukemic effects of aprepitant, a nonpeptide antagonist of NK1R, in a panel of hematological cell lines. In this study, we found that aprepitant decreased the survival of all the tested cells; however, as compared with NB4, viability of the other cell lines was inhibited at higher concentrations. By increasing both p21 and p73 along with suppressing c-Myc and hTERT, aprepitant probably disordered cell distribution in the cell cycle, decreased DNA replication rate, and, thereby, impeded the proliferative capability of NB4 cells. Moreover, exposing cells to this agent led to activation of the caspase-3-dependent apoptotic pathway through altering the expression of apoptosis-related genes. Noteworthy, aprepitant also sensitized NB4 cells to the cytotoxic effects of arsenic trioxide and vincristine. Overall, it seems that pharmaceutical targeting of NK1R using aprepitant, either as a single agent or in combination, possesses novel promising potential for leukemia treatment strategies. Correspondence to Davood Bashash, PhD, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1971653312, Iran Tel: +98 212 271 7504; fax: +98 212 272 1150; e-mail: d.bashash@sbmu.ac.ir Received July 18, 2017 Accepted December 12, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Norleual, a hepatocyte growth factor and macrophage stimulating protein dual antagonist, increases pancreatic cancer sensitivity to gemcitabine

Pancreatic cancer is a leading cause of cancer deaths in the USA and is characterized by an exceptionally poor long-term survival rate compared with other major cancers. The hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) growth factor systems are frequently over-activated in pancreatic cancer and significantly contribute to cancer progression, metastasis, and chemotherapeutic resistance. Small molecules homologous to the 'hinge' region of HGF, which participates in its dimerization and activation, had been developed and shown to bind HGF with high affinity, antagonize HGF's actions, and possess anticancer activity. Encouraged by sequence homology between HGF's hinge region and a similar sequence in MSP, our laboratory previously investigated and determined that these same antagonists could also block MSP-dependent cellular responses. Thus, the purpose of this study was to establish that the dual HGF/MSP antagonist Norleual could inhibit the prosurvival activity imparted by both HGF and MSP to pancreatic cancer cells in vitro, and to determine whether this effect translated into an improved chemotherapeutic impact for gemcitabine when delivered in combination in a human pancreatic cancer xenograft model. Our results demonstrate that Norleual does indeed suppress HGF's and MSP's prosurvival effects as well as sensitizing pancreatic cancer cells to gemcitabine in vitro. Most importantly, treatment with Norleual in combination with gemcitabine markedly inhibited in-vivo tumor growth beyond the suppression observed with gemcitabine alone. These results suggest that dual functional HGF/MSP antagonists like Norleual warrant further development and may offer an improved therapeutic outcome for pancreatic cancer patients. Correspondence to Joseph W. Harding, PhD, Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99164-6520, USA Tel: +1 509 335 7927; fax: +1 509 335 4650; e-mail: hardingj@vetmed.wsu.edu Received April 28, 2017 Accepted January 7, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Dioscin inhibits colon cancer cells’ growth by reactive oxygen species-mediated mitochondrial dysfunction and p38 and JNK pathways

Dioscin is a natural steroid saponin derived from several plants that shows potent anticancer effects against a variety of cancer cells. Here, we investigated the antitumor effect of dioscin against human colon cancer cells and evaluated the molecular mechanism involved in this process. The cell cytotoxicity was studied by the MTT assay and BrdU incorporation. The proapoptotic mechanism of dioscin was characterized by flow cytometry analysis. A western blot and an immunofluorescence staining were used to investigate how dioscin induces apoptosis in vitro. In our study, dioscin could significantly inhibit the growth of colon cancer cells in a time-dependent and dose-dependent manner. Dioscin induces apoptosis and reactive oxygen species (ROS) generation, promoting the disruption of mitochondrial membrane potential, Bax translocation to the mitochondria, cytochrome C release to cytosol, activations of caspase-9/3, PARP cleavage, and subsequent apoptosis. Dioscin-induced apoptosis was accompanied by sustained phosphorylation of JNK, p38-MAPK. N-acetyl-L-cysteine, a scavenger of ROS, significantly reversed dioscin-induced cell death and activation of JNK and p38. Collectively, the data indicate that the induction of apoptosis by dioscin is mediated through ROS proteins, which are critical upstream signals for JNK/p38-MAPK activation. *Shu Li and Binbin Cheng contributed equally to the writing of this article. Correspondence to Shuang Li, MSc, Department of Gastroenterology, Baoshan Branch, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201900, China Tel:+86 215 660 1100 x317 fax: +86 218 187 1559; e-mail: lishuangbs@126.com Received August 28, 2017 Accepted December 9, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Antileukemic effects of neurokinin-1 receptor inhibition on hematologic malignant cells: a novel therapeutic potential for aprepitant

Genetic and laboratory studies have remodeled the conventional understanding of cancer pathogenesis by identifying different molecular alterations. Intrigued by the contribution of neurokinin-1 receptor (NK1R) network in cancer pathogenesis, we investigated the antileukemic effects of aprepitant, a nonpeptide antagonist of NK1R, in a panel of hematological cell lines. In this study, we found that aprepitant decreased the survival of all the tested cells; however, as compared with NB4, viability of the other cell lines was inhibited at higher concentrations. By increasing both p21 and p73 along with suppressing c-Myc and hTERT, aprepitant probably disordered cell distribution in the cell cycle, decreased DNA replication rate, and, thereby, impeded the proliferative capability of NB4 cells. Moreover, exposing cells to this agent led to activation of the caspase-3-dependent apoptotic pathway through altering the expression of apoptosis-related genes. Noteworthy, aprepitant also sensitized NB4 cells to the cytotoxic effects of arsenic trioxide and vincristine. Overall, it seems that pharmaceutical targeting of NK1R using aprepitant, either as a single agent or in combination, possesses novel promising potential for leukemia treatment strategies. Correspondence to Davood Bashash, PhD, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1971653312, Iran Tel: +98 212 271 7504; fax: +98 212 272 1150; e-mail: d.bashash@sbmu.ac.ir Received July 18, 2017 Accepted December 12, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2Fyi5hR

Norleual, a hepatocyte growth factor and macrophage stimulating protein dual antagonist, increases pancreatic cancer sensitivity to gemcitabine

Pancreatic cancer is a leading cause of cancer deaths in the USA and is characterized by an exceptionally poor long-term survival rate compared with other major cancers. The hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) growth factor systems are frequently over-activated in pancreatic cancer and significantly contribute to cancer progression, metastasis, and chemotherapeutic resistance. Small molecules homologous to the 'hinge' region of HGF, which participates in its dimerization and activation, had been developed and shown to bind HGF with high affinity, antagonize HGF's actions, and possess anticancer activity. Encouraged by sequence homology between HGF's hinge region and a similar sequence in MSP, our laboratory previously investigated and determined that these same antagonists could also block MSP-dependent cellular responses. Thus, the purpose of this study was to establish that the dual HGF/MSP antagonist Norleual could inhibit the prosurvival activity imparted by both HGF and MSP to pancreatic cancer cells in vitro, and to determine whether this effect translated into an improved chemotherapeutic impact for gemcitabine when delivered in combination in a human pancreatic cancer xenograft model. Our results demonstrate that Norleual does indeed suppress HGF's and MSP's prosurvival effects as well as sensitizing pancreatic cancer cells to gemcitabine in vitro. Most importantly, treatment with Norleual in combination with gemcitabine markedly inhibited in-vivo tumor growth beyond the suppression observed with gemcitabine alone. These results suggest that dual functional HGF/MSP antagonists like Norleual warrant further development and may offer an improved therapeutic outcome for pancreatic cancer patients. Correspondence to Joseph W. Harding, PhD, Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99164-6520, USA Tel: +1 509 335 7927; fax: +1 509 335 4650; e-mail: hardingj@vetmed.wsu.edu Received April 28, 2017 Accepted January 7, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2FDHh6r

Dioscin inhibits colon cancer cells’ growth by reactive oxygen species-mediated mitochondrial dysfunction and p38 and JNK pathways

Dioscin is a natural steroid saponin derived from several plants that shows potent anticancer effects against a variety of cancer cells. Here, we investigated the antitumor effect of dioscin against human colon cancer cells and evaluated the molecular mechanism involved in this process. The cell cytotoxicity was studied by the MTT assay and BrdU incorporation. The proapoptotic mechanism of dioscin was characterized by flow cytometry analysis. A western blot and an immunofluorescence staining were used to investigate how dioscin induces apoptosis in vitro. In our study, dioscin could significantly inhibit the growth of colon cancer cells in a time-dependent and dose-dependent manner. Dioscin induces apoptosis and reactive oxygen species (ROS) generation, promoting the disruption of mitochondrial membrane potential, Bax translocation to the mitochondria, cytochrome C release to cytosol, activations of caspase-9/3, PARP cleavage, and subsequent apoptosis. Dioscin-induced apoptosis was accompanied by sustained phosphorylation of JNK, p38-MAPK. N-acetyl-L-cysteine, a scavenger of ROS, significantly reversed dioscin-induced cell death and activation of JNK and p38. Collectively, the data indicate that the induction of apoptosis by dioscin is mediated through ROS proteins, which are critical upstream signals for JNK/p38-MAPK activation. *Shu Li and Binbin Cheng contributed equally to the writing of this article. Correspondence to Shuang Li, MSc, Department of Gastroenterology, Baoshan Branch, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201900, China Tel:+86 215 660 1100 x317 fax: +86 218 187 1559; e-mail: lishuangbs@126.com Received August 28, 2017 Accepted December 9, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2E4rOzr

miR-302a-5p/367-3p-HMGA2 axis regulates malignant processes during endometrial cancer development

Metastasis is one of the main reasons for treatment failure in endometrial cancer. Notably, high mobility group AT-hook 2 (HMGA2) has been recognized as a driving factor of tumour metastasis. microRNAs (miRNAs...

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Integrin-β5, a miR-185-targeted gene, promotes hepatocellular carcinoma tumorigenesis by regulating β-catenin stability

The tumour microenvironment is essential for cancer progress and metastasis. Integrin-β5 (ITGB5), a member of the integrin family, has been implicated to mediate the interactions of cells with the extracellula...

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Adapting the Elixhauser comorbidity index for cancer patients

BACKGROUND

This study was designed to adapt the Elixhauser comorbidity index for 4 cancer-specific populations (breast, prostate, lung, and colorectal) and compare 3 versions of the Elixhauser comorbidity score (individual comorbidities, summary comorbidity score, and cancer-specific summary comorbidity score) with 3 versions of the Charlson comorbidity score for predicting 2-year survival with 4 types of cancer.

METHODS

This cohort study used Texas Cancer Registry–linked Medicare data from 2005 to 2011 for older patients diagnosed with breast (n = 19,082), prostate (n = 23,044), lung (n = 26,047), or colorectal cancer (n = 16,693). For each cancer cohort, the data were split into training and validation cohorts. In the training cohort, competing risk regression was used to model the association of Elixhauser comorbidities with 2-year noncancer mortality, and cancer-specific weights were derived for each comorbidity. In the validation cohort, competing risk regression was used to compare 3 versions of the Elixhauser comorbidity score with 3 versions of the Charlson comorbidity score. Model performance was evaluated with c statistics.

RESULTS

The 2-year noncancer mortality rates were 14.5% (lung cancer), 11.5% (colorectal cancer), 5.7% (breast cancer), and 4.1% (prostate cancer). Cancer-specific Elixhauser comorbidity scores (c = 0.773 for breast cancer, c = 0.772 for prostate cancer, c = 0.579 for lung cancer, and c = 0.680 for colorectal cancer) performed slightly better than cancer-specific Charlson comorbidity scores (ie, the National Cancer Institute combined index; c = 0.762 for breast cancer, c = 0.767 for prostate cancer, c = 0.578 for lung cancer, and c = 0.674 for colorectal cancer). Individual Elixhauser comorbidities performed best (c = 0.779 for breast cancer, c = 0.783 for prostate cancer, c = 0.587 for lung cancer, and c = 0.687 for colorectal cancer).

CONCLUSIONS

The cancer-specific Elixhauser comorbidity score performed as well as or slightly better than the cancer-specific Charlson comorbidity score in predicting 2-year survival. If the sample size permits, using individual Elixhauser comorbidities may be the best way to control for confounding in cancer outcomes research. Cancer 2018. © 2018 American Cancer Society.

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Satisfaction with cancer care, self-efficacy, and health-related quality of life in Latino cancer survivors

BACKGROUND

The objective of the current study was to examine how modifiable factors such as satisfaction with cancer care and self-efficacy impact health-related quality of life (HRQOL) among Latino cancer survivors.

METHODS

Latinos previously diagnosed with breast, prostate, or colorectal cancer (N = 288) completed questionnaires (Patient Satisfaction with Cancer Care Scale, Stanford Chronic Disease Self-Management Measures, Functional Assessment of Cancer Therapy-General, and Short Acculturation Scale for Hispanics) within 2 years after receiving primary cancer treatment.

RESULTS

Path model analyses demonstrated that satisfaction with cancer care was associated with greater HRQOL and that this relationship was explained by several facets of self-efficacy (ie, confidence in managing psychological distress [z = 3.81; P<.001], social support from close others [z = 2.46; P = .014], social/recreational activities [z = 3.30; P = .001], and patient-provider communication [z = −3.72; P<.001]). Importantly, foreign-born, less acculturated, and monolingual Spanish-speaking survivors reported lower self-efficacy in patient-provider communication; however, adjusting for acculturation, language, nativity, and other covariates did not alter these results.

CONCLUSIONS

Factors that contribute to disparities in HRQOL among Latino cancer survivors compared with non-Latino whites, such as low income, less education, and a lack of health insurance, can be difficult to address. The findings of the current study emphasize the importance of self-efficacy within the context of patient-centered cancer care practices (eg, patient inclusion in care decisions, sufficient time with provider, ready access to medical advice) and suggest that improving satisfaction with care may increase patients' confidence in managing important aspects of their cancer experience and, in turn, improve HRQOL among Latino cancer survivors. Cancer 2018. © 2018 American Cancer Society.

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Adapting the Elixhauser comorbidity index for cancer patients

BACKGROUND

This study was designed to adapt the Elixhauser comorbidity index for 4 cancer-specific populations (breast, prostate, lung, and colorectal) and compare 3 versions of the Elixhauser comorbidity score (individual comorbidities, summary comorbidity score, and cancer-specific summary comorbidity score) with 3 versions of the Charlson comorbidity score for predicting 2-year survival with 4 types of cancer.

METHODS

This cohort study used Texas Cancer Registry–linked Medicare data from 2005 to 2011 for older patients diagnosed with breast (n = 19,082), prostate (n = 23,044), lung (n = 26,047), or colorectal cancer (n = 16,693). For each cancer cohort, the data were split into training and validation cohorts. In the training cohort, competing risk regression was used to model the association of Elixhauser comorbidities with 2-year noncancer mortality, and cancer-specific weights were derived for each comorbidity. In the validation cohort, competing risk regression was used to compare 3 versions of the Elixhauser comorbidity score with 3 versions of the Charlson comorbidity score. Model performance was evaluated with c statistics.

RESULTS

The 2-year noncancer mortality rates were 14.5% (lung cancer), 11.5% (colorectal cancer), 5.7% (breast cancer), and 4.1% (prostate cancer). Cancer-specific Elixhauser comorbidity scores (c = 0.773 for breast cancer, c = 0.772 for prostate cancer, c = 0.579 for lung cancer, and c = 0.680 for colorectal cancer) performed slightly better than cancer-specific Charlson comorbidity scores (ie, the National Cancer Institute combined index; c = 0.762 for breast cancer, c = 0.767 for prostate cancer, c = 0.578 for lung cancer, and c = 0.674 for colorectal cancer). Individual Elixhauser comorbidities performed best (c = 0.779 for breast cancer, c = 0.783 for prostate cancer, c = 0.587 for lung cancer, and c = 0.687 for colorectal cancer).

CONCLUSIONS

The cancer-specific Elixhauser comorbidity score performed as well as or slightly better than the cancer-specific Charlson comorbidity score in predicting 2-year survival. If the sample size permits, using individual Elixhauser comorbidities may be the best way to control for confounding in cancer outcomes research. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2BLIVRq

Satisfaction with cancer care, self-efficacy, and health-related quality of life in Latino cancer survivors

BACKGROUND

The objective of the current study was to examine how modifiable factors such as satisfaction with cancer care and self-efficacy impact health-related quality of life (HRQOL) among Latino cancer survivors.

METHODS

Latinos previously diagnosed with breast, prostate, or colorectal cancer (N = 288) completed questionnaires (Patient Satisfaction with Cancer Care Scale, Stanford Chronic Disease Self-Management Measures, Functional Assessment of Cancer Therapy-General, and Short Acculturation Scale for Hispanics) within 2 years after receiving primary cancer treatment.

RESULTS

Path model analyses demonstrated that satisfaction with cancer care was associated with greater HRQOL and that this relationship was explained by several facets of self-efficacy (ie, confidence in managing psychological distress [z = 3.81; P<.001], social support from close others [z = 2.46; P = .014], social/recreational activities [z = 3.30; P = .001], and patient-provider communication [z = −3.72; P<.001]). Importantly, foreign-born, less acculturated, and monolingual Spanish-speaking survivors reported lower self-efficacy in patient-provider communication; however, adjusting for acculturation, language, nativity, and other covariates did not alter these results.

CONCLUSIONS

Factors that contribute to disparities in HRQOL among Latino cancer survivors compared with non-Latino whites, such as low income, less education, and a lack of health insurance, can be difficult to address. The findings of the current study emphasize the importance of self-efficacy within the context of patient-centered cancer care practices (eg, patient inclusion in care decisions, sufficient time with provider, ready access to medical advice) and suggest that improving satisfaction with care may increase patients' confidence in managing important aspects of their cancer experience and, in turn, improve HRQOL among Latino cancer survivors. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2nt9Xsj

Association of urinary and plasma DNA in early breast cancer patients and its links to disease relapse

Abstract

Purpose

Identifying patients who are at risk of relapse is a key challenge of primary breast cancer. The current study investigates the utility of urinary DNA in breast cancer management and as a predictor of relapse. This work also compares the sensitivity of plasma DNA with urinary DNA.

Methods

Blood plasma and urine specimens were collected concurrently from 200 breast cancer patients receiving neoadjuvant chemotherapy. Comparison of both plasma and urinary DNA was performed at baseline to determine assay significance. Serial measurements of urinary DNA were conducted to gauge DNA variations after surgery. Correlations to disease relapse were performed to affirm the clinical utility of urinary DNA.

Results

Molecular analysis showed patients were successfully identified with mutant PIK3CA using urinary DNA. A strong correlation was affirmed from urinary and plasma DNA at baseline with the correlation coefficient r = 0.859. We analyzed post-surgery measurements of urinary DNA for disease-relapse predictions. In subsequent serial followup of urinary DNA samples, we confirmed increased sensitivity in predicting relapse of these patients. The hazard ratio determined at the 9-month was 1.51 that identified patients at greater risk of disease relapse.

Conclusion

Urinary DNA offers a unique opportunity to glimpse upon dynamic changes in early breast cancer. Our results demonstrated good correlation to plasma DNA and post monitoring of cancer patients to identify individuals susceptible to a high risk of relapse. This potentially allows for early intervention such as adjuvant chemotherapy to be administered to better manage these patients.

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Association of urinary and plasma DNA in early breast cancer patients and its links to disease relapse

Abstract

Purpose

Identifying patients who are at risk of relapse is a key challenge of primary breast cancer. The current study investigates the utility of urinary DNA in breast cancer management and as a predictor of relapse. This work also compares the sensitivity of plasma DNA with urinary DNA.

Methods

Blood plasma and urine specimens were collected concurrently from 200 breast cancer patients receiving neoadjuvant chemotherapy. Comparison of both plasma and urinary DNA was performed at baseline to determine assay significance. Serial measurements of urinary DNA were conducted to gauge DNA variations after surgery. Correlations to disease relapse were performed to affirm the clinical utility of urinary DNA.

Results

Molecular analysis showed patients were successfully identified with mutant PIK3CA using urinary DNA. A strong correlation was affirmed from urinary and plasma DNA at baseline with the correlation coefficient r = 0.859. We analyzed post-surgery measurements of urinary DNA for disease-relapse predictions. In subsequent serial followup of urinary DNA samples, we confirmed increased sensitivity in predicting relapse of these patients. The hazard ratio determined at the 9-month was 1.51 that identified patients at greater risk of disease relapse.

Conclusion

Urinary DNA offers a unique opportunity to glimpse upon dynamic changes in early breast cancer. Our results demonstrated good correlation to plasma DNA and post monitoring of cancer patients to identify individuals susceptible to a high risk of relapse. This potentially allows for early intervention such as adjuvant chemotherapy to be administered to better manage these patients.

http://ift.tt/2GEm9yu

Home Sweet Home

In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows. A 25-year-old woman presented to the emergency…

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Exploratory analyses assessing the impact of early tumour shrinkage and depth of response on survival outcomes in patients with RAS wild-type metastatic colorectal cancer receiving treatment in three randomised panitumumab trials

Abstract

Purpose

To report exploratory analyses of early tumour shrinkage (ETS) and depth of response (DpR) in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), receiving the first-line treatment in three randomised panitumumab trials.

Methods

Data from the PRIME (NCT00364013), PEAK (NCT00819780) and PLANET (NCT00885885) studies were included. Median DpR, the proportion of patients achieving ETS ≥ 20% or ≥ 30% at week 8, and the impact of ETS and DpR (including by category) on outcome were analysed. Factors associated with ETS and DpR and the optimal ETS/DpR cut-off values for predicting improved overall survival (OS) were assessed.

Results

Overall, 505, 170 and 53 patients had RAS WT mCRC in PRIME, PEAK and PLANET, respectively. Patients receiving panitumumab had higher ETS rates (≥ 30%: PRIME 59% vs. 38%; PEAK 64% vs. 45%) and greater DpR (PRIME: 54% vs. 46%; PEAK: 65% vs. 46%) than those receiving treatment without panitumumab. In multiple regression analyses, panitumumab treatment, liver-only metastases and WT BRAF status were consistently associated with improved ETS and DpR outcomes. Irrespective of treatment, ETS and DpR were associated with improved progression-free survival, overall survival and resection rates; most resections occurred in patients in the two highest DpR categories. In PRIME and PEAK, respectively, the optimal cut-offs for predicting improved OS were 32 and 34% for ETS, and 59 and 70% for DpR.

Conclusions

These exploratory analyses suggest that panitumumab is associated ETS and DpR benefits in patients with RAS WT mCRC and that achieving these endpoints during first-line treatment is linked with favourable outcomes.

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Expression profile of microRNA-146a along HPV-induced multistep carcinogenesis: a study in HPV16 transgenic mice

Abstract

Purpose

Persistent human papillomavirus (HPV) infection is associated with the development of certain types of cancer and the dysregulation of microRNAs has been implicated in HPV-associated carcinogenesis. This is the case of microRNA-146a (miR-146a), which is thought to regulate tumor-associated inflammation. We sought to investigate the expression levels of miR-146a during HPV16-mediated carcinogenesis using skin samples from K14-HPV16 transgenic mice which develop the consecutive phases of the carcinogenesis process.

Methods

Female transgenic (HPV^+/−) and wild-type (HPV^−/−) mice were sacrificed at 24–26 weeks-old or 28–30 weeks-old. Chest and ear skin samples from HPV^+/− and HPV^−/− mice were histologically classified and used for microRNA extraction and quantification by qPCR.

Results

Chest skin samples from 24 to 26 weeks-old HPV^+/− mice presented diffuse epidermal hyperplasia and only 22.5% showed multifocal dysplasia, while at 28–30 weeks-old all (100.0%) HPV^+/− animals showed epidermal dysplasia. All HPV^+/− ear skin samples showed carcinoma in situ (CIS). MiR-146a expression levels were higher in HPV^+/− compared to HPV^−/− mice (p = 0.006). There was also an increase in miR-146a expression in dysplastic skin lesions compared with hyperplasic lesions (p = 0.011). Samples showing CIS had a significant decrease in miR-146a expression when compared to samples showing epidermal hyperplasia (p = 0.018) and epidermal dysplasia (p = 0.009).

Conclusions

These results suggest that HPV16 induces the overexpression of miR-146a in the initial stages of carcinogenesis (hyperplasia and dysplasia), whereas decreases its expression at later stages (CIS). Taken together, these data implicate and suggest different roles of miR-146a in HPV-mediated carcinogenesis.

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Analysis of TSC1 mutation spectrum in mucosal melanoma

Abstract

Purpose

Mucosal melanoma is a relatively rare subtype of melanoma for which no clearly established therapeutic strategy exists. The genes of the mTOR signalling pathway have drawn great attention as key targets for cancer treatment, including melanoma. In this study, we aimed to investigate the mutation status of the upstream mTOR regulator TSC1 and evaluated its correlation with the clinicopathological features of mucosal melanoma.

Methods

We collected 91 mucosal melanoma samples for detecting TSC1 mutations. All the coding exons of TSC1 were amplified by PCR and subjected to Sanger sequencing. Expression level of TSC1 encoding protein (hamartin) was detected by immunohistochemistry. The activation of mTOR pathway was determined by evaluating the phosphorylation status of S6RP and 4E-BP1.

Results

The overall mutation frequency of TSC1 was found to be 17.6% (16/91 patients). TSC1 mutations were more inclined to occur in advanced mucosal melanoma (stages III and IV). In the 16 patients with TSC1 mutations, 14 different mutations were detected, affecting 11 different exons. TSC1 mutations were correlated with upregulation of S6RP phosphorylation but were unrelated to 4E-BP1 phosphorylation or hamartin expression. Mucosal melanoma patients with TSC1 mutations had a worse outcome than patients without TSC1 mutations (24.0 versus 34.0 months, P = 0.007).

Conclusions

Our findings suggest that TSC1 mutations are frequent in mucosal melanoma. TSC1 mutations can activate the mTOR pathway through phospho-S6RP and might be a poor prognostic predictor of mucosal melanoma. Our data implicate the potential significance of TSC1 mutations for effective and specific drug therapy for mucosal melanoma.

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The risk of lung cancer among cooking adults: a meta-analysis of 23 observational studies

Abstract

Purpose

Cooking has been regarded as a potential risk factor for lung cancer. We aim to investigate the evidence of cooking oil fume and risk of lung cancer.

Methods

Medline and Embase were searched for eligible studies. We conducted a meta-analysis to summarize the evidences of case–control or cohort studies, with subgroup analysis for the potential discrepancy. Sensitivity analysis was employed to test the robustness.

Results

We included 23 observational studies, involving 9411 lung cancer cases. Our meta-analysis found that, for cooking female, the pooled OR of cooking oil fume exposure was 1.98 (95% CI 1.54, 2.54, I ² = 79%, n = 15) among non-smoking population and 2.00 (95% CI 1.46, 2.74, I ² = 75%, n = 10) among partly smoking population. For cooking males, the pooled OR of lung cancer was 1.15 (95% CI 0.71, 1.87; I ² = 80%, n = 4). When sub grouped by ventilation condition, the pooled OR for poor ventilation was 1.20 (95% CI 1.10, 1.31, I ² = 2%) compared to good ventilation. For different cooking methods, our results suggested that stir frying (OR = 1.89, 95% CI 1.23, 2.90; I ² = 66%) was associated with increased risk of lung cancer while not for deep frying (OR = 1.41, 95% CI 0.87, 2.29; I ² = 5%). Sensitivity analysis suggested our results were stable.

Conclusion

Cooking oil fume is likely to be a risk factor for lung cancer for female, regardless of smoking status. Poor ventilation may increase the risk of lung cancer. Cooking methods may have different effect on lung cancer that deep frying may be healthier than stir frying.

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Induction of apoptosis in breast cancer cells in vitro by Fas ligand reverse signaling

Abstract

Purpose

The Fas-antigen is a cell surface receptor that transduces apoptotic signals into cells. The purpose of this study was to evaluate FasL expression in breast cancer and to elucidate the role of its signaling in different breast cancer cell lines.

Methods

T47D and MCF7 cells were used and cultured in Dulbecco's modified Eagle's medium. FasL translocation to the membrane was achieved by culturing the cells in the presence of human interferon-γ (IFNγ). Translocation was detected by immunofluorescence. The ability of a Fas:Fc fusion protein to trigger apoptosis in these cells was investigated by cell death detection ELISA. After incubation with IFNγ for 4 h and 18 h, apoptosis was assessed in response to treatment with Fas:Fc.

Results

Immunofluorescence revealed that the used cell lines were positive for FasL which was increased and changed to more membrane-bound FasL expression after IFNγ stimulation. After stimulation with 50 IU/ml IFNγ, Fas:Fc significantly increased MCF7 apoptosis (1.39 ± 0.06-fold, p = 0.0004) after 18 h. After stimulation with 100 IU/ml, Fas:Fc significantly increased apoptosis both after 4 h (1.49 ± 0.15-fold, p = 0.018) and 18 h (1.30 ± 0.06-fold, p = 0.013). In T47D cells this effect was seen after 4 h of stimulation with 50 IU/ml and addition of Fas:Fc (1.6 ± 0.08-fold, p = 0.03).

Conclusion

Membrane-bound FasL expression could be induced by IFNγ in a breast cancer cell model. More importantly, in the presence of IFNγ the Fas:Fc fusion protein was able to transmit pro-apoptotic signals to T47D and MCF7 cells, significantly inducing apoptosis. The current findings support further in vivo studies regarding FasL activation as a potential target for therapeutic intervention in breast cancer.

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Exploratory analyses assessing the impact of early tumour shrinkage and depth of response on survival outcomes in patients with RAS wild-type metastatic colorectal cancer receiving treatment in three randomised panitumumab trials

Abstract

Purpose

To report exploratory analyses of early tumour shrinkage (ETS) and depth of response (DpR) in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), receiving the first-line treatment in three randomised panitumumab trials.

Methods

Data from the PRIME (NCT00364013), PEAK (NCT00819780) and PLANET (NCT00885885) studies were included. Median DpR, the proportion of patients achieving ETS ≥ 20% or ≥ 30% at week 8, and the impact of ETS and DpR (including by category) on outcome were analysed. Factors associated with ETS and DpR and the optimal ETS/DpR cut-off values for predicting improved overall survival (OS) were assessed.

Results

Overall, 505, 170 and 53 patients had RAS WT mCRC in PRIME, PEAK and PLANET, respectively. Patients receiving panitumumab had higher ETS rates (≥ 30%: PRIME 59% vs. 38%; PEAK 64% vs. 45%) and greater DpR (PRIME: 54% vs. 46%; PEAK: 65% vs. 46%) than those receiving treatment without panitumumab. In multiple regression analyses, panitumumab treatment, liver-only metastases and WT BRAF status were consistently associated with improved ETS and DpR outcomes. Irrespective of treatment, ETS and DpR were associated with improved progression-free survival, overall survival and resection rates; most resections occurred in patients in the two highest DpR categories. In PRIME and PEAK, respectively, the optimal cut-offs for predicting improved OS were 32 and 34% for ETS, and 59 and 70% for DpR.

Conclusions

These exploratory analyses suggest that panitumumab is associated ETS and DpR benefits in patients with RAS WT mCRC and that achieving these endpoints during first-line treatment is linked with favourable outcomes.

http://ift.tt/2DUHRAs

Expression profile of microRNA-146a along HPV-induced multistep carcinogenesis: a study in HPV16 transgenic mice

Abstract

Purpose

Persistent human papillomavirus (HPV) infection is associated with the development of certain types of cancer and the dysregulation of microRNAs has been implicated in HPV-associated carcinogenesis. This is the case of microRNA-146a (miR-146a), which is thought to regulate tumor-associated inflammation. We sought to investigate the expression levels of miR-146a during HPV16-mediated carcinogenesis using skin samples from K14-HPV16 transgenic mice which develop the consecutive phases of the carcinogenesis process.

Methods

Female transgenic (HPV^+/−) and wild-type (HPV^−/−) mice were sacrificed at 24–26 weeks-old or 28–30 weeks-old. Chest and ear skin samples from HPV^+/− and HPV^−/− mice were histologically classified and used for microRNA extraction and quantification by qPCR.

Results

Chest skin samples from 24 to 26 weeks-old HPV^+/− mice presented diffuse epidermal hyperplasia and only 22.5% showed multifocal dysplasia, while at 28–30 weeks-old all (100.0%) HPV^+/− animals showed epidermal dysplasia. All HPV^+/− ear skin samples showed carcinoma in situ (CIS). MiR-146a expression levels were higher in HPV^+/− compared to HPV^−/− mice (p = 0.006). There was also an increase in miR-146a expression in dysplastic skin lesions compared with hyperplasic lesions (p = 0.011). Samples showing CIS had a significant decrease in miR-146a expression when compared to samples showing epidermal hyperplasia (p = 0.018) and epidermal dysplasia (p = 0.009).

Conclusions

These results suggest that HPV16 induces the overexpression of miR-146a in the initial stages of carcinogenesis (hyperplasia and dysplasia), whereas decreases its expression at later stages (CIS). Taken together, these data implicate and suggest different roles of miR-146a in HPV-mediated carcinogenesis.

http://ift.tt/2nwT27q

Analysis of TSC1 mutation spectrum in mucosal melanoma

Abstract

Purpose

Mucosal melanoma is a relatively rare subtype of melanoma for which no clearly established therapeutic strategy exists. The genes of the mTOR signalling pathway have drawn great attention as key targets for cancer treatment, including melanoma. In this study, we aimed to investigate the mutation status of the upstream mTOR regulator TSC1 and evaluated its correlation with the clinicopathological features of mucosal melanoma.

Methods

We collected 91 mucosal melanoma samples for detecting TSC1 mutations. All the coding exons of TSC1 were amplified by PCR and subjected to Sanger sequencing. Expression level of TSC1 encoding protein (hamartin) was detected by immunohistochemistry. The activation of mTOR pathway was determined by evaluating the phosphorylation status of S6RP and 4E-BP1.

Results

The overall mutation frequency of TSC1 was found to be 17.6% (16/91 patients). TSC1 mutations were more inclined to occur in advanced mucosal melanoma (stages III and IV). In the 16 patients with TSC1 mutations, 14 different mutations were detected, affecting 11 different exons. TSC1 mutations were correlated with upregulation of S6RP phosphorylation but were unrelated to 4E-BP1 phosphorylation or hamartin expression. Mucosal melanoma patients with TSC1 mutations had a worse outcome than patients without TSC1 mutations (24.0 versus 34.0 months, P = 0.007).

Conclusions

Our findings suggest that TSC1 mutations are frequent in mucosal melanoma. TSC1 mutations can activate the mTOR pathway through phospho-S6RP and might be a poor prognostic predictor of mucosal melanoma. Our data implicate the potential significance of TSC1 mutations for effective and specific drug therapy for mucosal melanoma.

http://ift.tt/2DU5R6R

The NF-κB signalling pathway in colorectal cancer: associations between dysregulated gene and miRNA expression

Abstract

Background

The nuclear factor-kappa B (NF-κB) signalling pathway is a regulator of immune response and inflammation that has been implicated in the carcinogenic process. We examined differentially expressed genes in this pathway and miRNAs to determine associations with colorectal cancer (CRC).

Methods

We used data from 217 CRC cases to evaluate differences in NF-κB signalling pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analysed. We evaluated genes most strongly associated and differentially expressed (fold change (FC) of > 1.5 or < 0.67) that were statistically significant after adjustment for multiple comparisons.

Results

Of the 92 genes evaluated, 22 were significantly downregulated and nine genes were significantly upregulated in all tumours. Two additional genes (CD14 and CSNK2A1) were dysregulated in MSS tumours and two genes (CARD11 and VCAM1) were downregulated and six genes were upregulated (LYN, TICAM2, ICAM1, IL1B, CCL4 and PTGS2) in MSI tumours. Sixteen of the 21 dysregulated genes were associated with 40 miRNAs. There were 76 miRNA:mRNA associations of which 38 had seed-region matches. Genes were associated with multiple miRNAs, with TNFSRF11A (RANK) being associated with 15 miRNAs. Likewise several miRNAs were associated with multiple genes (miR-150-5p with eight genes, miR-195-5p with four genes, miR-203a with five genes, miR-20b-5p with four genes, miR-650 with six genes and miR-92a-3p with five genes).

Conclusions

Focusing on the genes and their associated miRNAs within the entire signalling pathway provides a comprehensive understanding of this complex pathway as it relates to CRC and offers insight into potential therapeutic agents.

http://ift.tt/2nAfpc3