Cuba Si. Cancer No.

Publication date: Available online 1 June 2018
Source:Seminars in Oncology
Author(s): Antonio Tito Fojo
The current double issue of Seminars in Oncology brings 11 contributions from the Center for Genetic Engineering and Biotechnology, the Center of Molecular Immunology, and the Center of Medical and Surgical Research in Cuba. Having left Cuba in 1960, my interest in these submissions admittedly could go beyond the merely scientific. But others, I guarantee, will find EVERY article remarkably interesting and informative. In an era where the overwhelming majority of therapies in development as well as clinical trials being conducted are following well-traveled paths that bring us limited new information, the investigators from Cuba present us with rational, novel approaches to drug development. This is truly out of the box thinking, crafted in a country where resource limitations have clearly incentivized novel approaches. Their basic science is solid and their clinical validation is either mature or a work very much in progress. Cancer, one realizes reading these contributions, is a scourge across the world. Enjoy the refreshing and exciting approach of these investigators!!!



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The role of niraparib for the treatment of ovarian cancer

Future Oncology, Ahead of Print.


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Talking to patients about biosimilars

Future Oncology, Ahead of Print.


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Targeting Rac and Cdc42 GTPases in Cancer

Rac and Cdc42 are small GTPases that have been linked to multiple human cancers and are implicated in epithelial to mesenchymal transition, cell-cycle progression, migration/invasion, tumor growth, angiogenesis, and oncogenic transformation. With the exception of the P29S driver mutation in melanoma, Rac and Cdc42 are not generally mutated in cancer, but are overexpressed (gene amplification and mRNA upregulation) or hyperactivated. Rac and Cdc42 are hyperactivated via signaling through oncogenic cell surface receptors, such as growth factor receptors, which converge on the guanine nucleotide exchange factors that regulate their GDP/GTP exchange. Hence, targeting Rac and Cdc42 represents a promising strategy for precise cancer therapy, as well as for inhibition of bypass signaling that promotes resistance to cell surface receptor-targeted therapies. Therefore, an understanding of the regulatory mechanisms of these pivotal signaling intermediates is key for the development of effective inhibitors. In this review, we focus on the role of Rac and Cdc42 in cancer and summarize the regulatory mechanisms, inhibitory efficacy, and the anticancer potential of Rac- and Cdc42-targeting agents. Cancer Res; 78(12); 1–11. ©2018 AACR.

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A functional homologous recombination assay predicts primary chemotherapy response and long-term survival in ovarian cancer patients

Purpose: Homologous recombination deficiency (HRD) correlates with platinum sensitivity in ovarian cancer patients, which clinically is the most useful predictor of sensitivity to PARPi. To date, there are no reliable diagnostic tools to anticipate response to platinum-based chemotherapy, thus we aimed to develop an ex vivo functional HRD detection test that could predict both platinum-sensitivity and patient eligibility to targeted drug treatments. Experimental Design: We obtained a functional HR score by quantifying homologous recombination (HR) repair after ionizing radiation-induced DNA damage in primary ovarian cancer samples (n=32). Samples clustered in 3 categories: HR-deficient, HR-low and HR-proficient. We analysed the HR score association with platinum sensitivity and treatment response, platinum-free interval (PFI) and overall survival (OS), and compared it with other clinical parameters. In parallel, we performed DNA-sequencing of HR genes to assess if functional HRD can be predicted by currently offered genetic screening. Results: Low HR scores predicted primary platinum sensitivity with high statistical significance (p=0.0103), associated with longer PFI (HR-deficient vs HR-proficient: 531 vs 53 days), and significantly correlated with improved OS (HR score <35 vs >=35, hazard ratio=0.08, p=0.0116). At the genomic level, we identified a few unclear mutations in HR genes and the mutational signature associated with HRD, but, overall, genetic screening failed to predict functional HRD. Conclusions: We developed an ex vivo assay that detects tumor functional HRD and an HR score able to predict platinum sensitivity, which holds the clinically relevant potential to become the routine companion diagnostic in the management of ovarian cancer patients.

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Antigen-Specific CD8 Lytic Phenotype Induced by Sipuleucel-T in Hormone-Sensitive or Castration-Resistant Prostate Cancer and Association With Overall Survival

Background: Sipuleucel-T is FDA-approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) based on the IMPACT trial showing a 4.1-month benefit in median overall survival (OS) for patients receiving sipuleucel-T vs control. Although efficacy of sipuleucel-T is well-established, its mechanism remains incompletely understood. Methods: Patient samples from three sipuleucel-T trials were assessed for peripheral cellular immune responses to the immunogen PA2024 and the target antigen prostatic acid phosphatase (PAP). PAP- and PA2024-specific proliferative and cytolytic responses were characterized to delineate sipuleucel-T-induced immune responses. To quantify potential cytotoxic T lymphocyte (CTL) activity, cell-surface CD107a expression on PAP- or PA2024-specific CD8+ T cells was measured in sipuleucel-T-treated patient and healthy volunteer samples. Results: Increased PA2024-specific CD4+ (p=0.030) and CD8+ (p=0.052) T-cell proliferation from baseline to week 6 was observed (N=14) post-sipuleucel-T, with greater magnitude of PA2024-specific responses compared to PAP. PAP- and PA2024-CTL activity (CD107a positivity) significantly increased at weeks 6 and 26 after sipuleucel-T treatment (p<0.0001; N=22). At 26 weeks post-sipuleucel-T, OS correlated with the magnitude of PAP (Pearson's R, 0.52; p=0.013) or PA2024 (Pearson's R, 0.67; p=0.0006) CTL activity. Higher PA2024-CTL activity at week 26 was significantly associated with longer OS using tertile analysis (p=0.0005; N=22), with PA2024 responses correlating with PAP responses at week 26 (R=0.90; p=1.53E^-08). Conclusions: This study is the first to report PAP-specific CD8+ T-cell responses elicited by sipuleucel-T treatment. Increased and persistent potential PA2024-specific CTL activity correlated with PAP-specific CTL activity and associated with improved OS following sipuleucel-T treatment.

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Go with the Flow: Cerebrospinal Fluid Flow Regulates Neural Stem Cell Proliferation

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Naoko Kaneko, Kazunobu Sawamoto
Adult neural stem cells in the wall of brain ventricles make direct contact with cerebrospinal fluid. In this issue of Cell Stem Cell, Petrik et al. (2018) demonstrate that these neural stem cells sense the flow of cerebrospinal fluid through a transmembrane sodium channel, ENaC, which regulates their proliferation.

Teaser

Adult neural stem cells in the wall of brain ventricles make direct contact with cerebrospinal fluid. In this issue of Cell Stem Cell, Petrik et al. (2018) demonstrate that these neural stem cells sense the flow of cerebrospinal fluid through a transmembrane sodium channel, ENaC, which regulates their proliferation.


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Intestinal Stem Cell Dynamics: A Story of Mice and Humans

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Michael C. Hodder, Dustin J. Flanagan, Owen J. Sansom
Stem cell dynamics define the probability of accumulating mutations within the intestinal epithelium. In this issue of Cell Stem Cell, Nicholson et al. (2018) report that human intestinal stem cell dynamics differ significantly from those of mice and establish that oncogenic mutations are more likely to expand; therefore, "normal" epithelium may carry multiple mutations.

Teaser

Stem cell dynamics define the probability of accumulating mutations within the intestinal epithelium. In this issue of Cell Stem Cell, Nicholson et al. (2018) report that human intestinal stem cell dynamics differ significantly from those of mice and establish that oncogenic mutations are more likely to expand; therefore, "normal" epithelium may carry multiple mutations.


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Lnc’ed in to Cardiogenesis

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Makoto Sahara, Elif Eroglu, Kenneth R. Chien
Despite the continuous discovery of long noncoding RNAs (lncRNAs) with critical developmental roles, our knowledge of lncRNAs that control cardiac lineage commitment is still limited. In this issue, Guo et al. (2018) report a novel lncRNA-mediated multiprotein complex assembly that directly regulates the key transcriptional programs of murine cardiogenesis.

Teaser

Despite the continuous discovery of long noncoding RNAs (lncRNAs) with critical developmental roles, our knowledge of lncRNAs that control cardiac lineage commitment is still limited. In this issue, Guo et al. (2018) report a novel lncRNA-mediated multiprotein complex assembly that directly regulates the key transcriptional programs of murine cardiogenesis.


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Stem-Cell-Derived Cardiomyocytes Grow Up: Start Young and Train Harder

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Joshua T. Maxwell, Chunhui Xu
Engineering cardiac tissue that accurately recapitulates adult myocardium is critical for advancing disease modeling, drug screening, and regenerative medicine. Ronaldson-Bouchard et al. report a new strategy for generating cardiac tissues from stem-cell-derived cardiomyocytes that reach a maturation level closer to human adult cardiac structure and function.

Teaser

Engineering cardiac tissue that accurately recapitulates adult myocardium is critical for advancing disease modeling, drug screening, and regenerative medicine. Ronaldson-Bouchard et al. report a new strategy for generating cardiac tissues from stem-cell-derived cardiomyocytes that reach a maturation level closer to human adult cardiac structure and function.


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Spotlight on Glycolysis: A New Target for Cord Blood Expansion

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Andrea M. Patterson, Louis M. Pelus
Umbilical cord blood (UCB) is a highly valuable but low-quantity source of hematopoietic stem cells (HSCs) for life-saving transplantations. Recently in Nature Medicine, Guo et al. (2018) found that antagonism of a glycolysis-blocking pathway enhances ex vivo expansion of long-term HSCs from human UCB.

Teaser

Umbilical cord blood (UCB) is a highly valuable but low-quantity source of hematopoietic stem cells (HSCs) for life-saving transplantations. Recently in Nature Medicine, Guo et al. (2018) found that antagonism of a glycolysis-blocking pathway enhances ex vivo expansion of long-term HSCs from human UCB.


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Mentoring the Next Generation: Janet Rossant

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6

Mentor-mentee relationships are essential for professional development, but developing these interpersonal skills is not often highlighted as a priority in scientific endeavors. In a yearlong series, Cell Stem Cell interviews prominent scientists who have prioritized mentorship over the years. Here, we chat with Dr. Janet Rossant about her views.



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Stem Cells in the Clinic

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Sheila Chari, Anh Nguyen, Jonathan Saxe




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Ask the Expert: Luigi Naldini

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6

New technologies are revolutionizing the potential of hematopoietic stem cell transplantation (HSCT) to effectively treat many hematologic disorders and malignancies. Here we chat with Dr. Luigi Naldini about the remaining challenges for successful transplantation, cutting-edge new technologies, and what exciting breakthroughs he looks forward to seeing on the horizon.



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CIRM Alpha Stem Cell Clinics: Collaboratively Addressing Regenerative Medicine Challenges

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Catriona H.M. Jamieson, Maria T. Millan, Abla A. Creasey, Geoff Lomax, Mary E. Donohoe, Mark C. Walters, Mehrdad Abedi, Daniela A. Bota, John A. Zaia, John S. Adams
The California Institute for Regenerative Medicine (CIRM) Alpha Stem Cell Clinic (ASCC) Network was launched in 2015 to address a compelling unmet medical need for rigorous, FDA-regulated, stem cell-related clinical trials for patients with challenging, incurable diseases. Here, we describe our multi-center experiences addressing current and future challenges.

Teaser

The California Institute for Regenerative Medicine (CIRM) Alpha Stem Cell Clinic (ASCC) Network was launched in 2015 to address a compelling unmet medical need for rigorous, FDA-regulated, stem cell-related clinical trials for patients with challenging, incurable diseases. Here, we describe our multi-center experiences addressing current and future challenges.


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Organoid Center Strategies for Accelerating Clinical Translation

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Takanori Takebe, James M. Wells, Michael A. Helmrath, Aaron M. Zorn
The meteoric rise in stem-cell-derived organoid technologies has ushered in a new era of "organoid medicine." Here we discuss how an organoid center can accelerate the translation of laboratory proof-of-principle experiments into clinical practice by developing and utilizing shared platforms for commercial and medical applications.

Teaser

The meteoric rise in stem-cell-derived organoid technologies has ushered in a new era of "organoid medicine." Here we discuss how an organoid center can accelerate the translation of laboratory proof-of-principle experiments into clinical practice by developing and utilizing shared platforms for commercial and medical applications.


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Stem Cell Therapies for Treating Diabetes: Progress and Remaining Challenges

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Julie B. Sneddon, Qizhi Tang, Peter Stock, Jeffrey A. Bluestone, Shuvo Roy, Tejal Desai, Matthias Hebrok
Restoration of insulin independence and normoglycemia has been the overarching goal in diabetes research and therapy. While whole-organ and islet transplantation have become gold-standard procedures in achieving glucose control in diabetic patients, the profound lack of suitable donor tissues severely hampers the broad application of these therapies. Here, we describe current efforts aimed at generating a sustainable source of functional human stem cell-derived insulin-producing islet cells for cell transplantation and present state-of-the-art efforts to protect such cells via immune modulation and encapsulation strategies.

Teaser

Sneddon et al. describe current efforts aimed at generating a sustainable source of functional human stem cell-derived insulin-producing islet cells for cell transplantation for the treatment of diabetes and present state-of-the-art efforts to protect such cells via immune modulation and encapsulation strategies.


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Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Jacques Galipeau, Luc Sensébé
Mesenchymal stromal cells (MSCs) have been the subject of clinical trials for more than a generation, and the outcomes of advanced clinical trials have fallen short of expectations raised by encouraging pre-clinical animal data in a wide array of disease models. In this Perspective, important biological and pharmacological disparities in pre-clinical research and human translational studies are highlighted, and analyses of clinical trial failures and recent successes provide a rational pathway to MSC regulatory approval and deployment for disorders with unmet medical needs.

Teaser

In this Perspective, Galipeau and Sensébé highlight important biological and pharmacological disparities in pre-clinical research and human translational studies. The authors also analyze clinical trial failures and recent successes to discuss a rational pathway toward MSC regulatory approval and deployment for disorders with unmet medical needs.


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Regenerating Eye Tissues to Preserve and Restore Vision

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Jeffrey H. Stern, Yangzi Tian, James Funderburgh, Graziella Pellegrini, Kang Zhang, Jeffrey L. Goldberg, Robin R. Ali, Michael Young, Yubing Xie, Sally Temple
Ocular regenerative therapies are on track to revolutionize treatment of numerous blinding disorders, including corneal disease, cataract, glaucoma, retinitis pigmentosa, and age-related macular degeneration. A variety of transplantable products, delivered as cell suspensions or as preformed 3D structures combining cells and natural or artificial substrates, are in the pipeline. Here we review the status of clinical and preclinical studies for stem cell-based repair, covering key eye tissues from front to back, from cornea to retina, and including bioengineering approaches that advance cell product manufacturing. While recognizing the challenges, we look forward to a deep portfolio of sight-restoring, stem cell-based medicine.Video Abstract

Teaser

Stern et al. review the status of clinical and preclinical studies for stem cell-based repair, covering key eye tissues from front to back, from cornea to retina, and including bioengineering approaches that advance cell product manufacturing.


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A First-in-Human, Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Erik Curtis, Joel R. Martin, Brandon Gabel, Nikki Sidhu, Teresa K. Rzesiewicz, Ross Mandeville, Sebastiaan Van Gorp, Marjolein Leerink, Takahiro Tadokoro, Silvia Marsala, Catriona Jamieson, Martin Marsala, Joseph D. Ciacci
We tested the feasibility and safety of human-spinal-cord-derived neural stem cell (NSI-566) transplantation for the treatment of chronic spinal cord injury (SCI). In this clinical trial, four subjects with T2–T12 SCI received treatment consisting of removal of spinal instrumentation, laminectomy, and durotomy, followed by six midline bilateral stereotactic injections of NSI-566 cells. All subjects tolerated the procedure well and there have been no serious adverse events to date (18–27 months post-grafting). In two subjects, one to two levels of neurological improvement were detected using ISNCSCI motor and sensory scores. Our results support the safety of NSI-566 transplantation into the SCI site and early signs of potential efficacy in three of the subjects warrant further exploration of NSI-566 cells in dose escalation studies. Despite these encouraging secondary data, we emphasize that this safety trial lacks statistical power or a control group needed to evaluate functional changes resulting from cell grafting.

Graphical abstract

Teaser

After promising results were seen in a pre-clinical human-spinal-cord-derived neural stem cell NSI-566 transplantation study for spinal cord injury in rats, a phase I clinical trial for NSI-566 transplantation was initiated in patients with complete thoracic SCI.


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Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia

Publication date: 1 June 2018
Source:Cell Stem Cell, Volume 22, Issue 6
Author(s): Michael Y. Choi, George F. Widhopf, Emanuela M. Ghia, Reilly L. Kidwell, Md Kamrul Hasan, Jian Yu, Laura Z. Rassenti, Liguang Chen, Yun Chen, Emily Pittman, Minya Pu, Karen Messer, Charles E. Prussak, Januario E. Castro, Catriona Jamieson, Thomas J. Kipps
Cirmtuzumab is a humanized monoclonal antibody (mAb) that targets ROR1, an oncoembryonic orphan receptor for Wnt5a found on cancer stem cells (CSCs). Aberrant expression of ROR1 is seen in many malignancies and has been linked to Rho-GTPase activation and cancer stem cell self-renewal. For patients with chronic lymphocytic leukemia (CLL), self-renewing, neoplastic B cells express ROR1 in 95% of cases. High-level leukemia cell expression of ROR1 is associated with an unfavorable prognosis. We conducted a phase 1 study involving 26 patients with progressive, relapsed, or refractory CLL. Patients received four biweekly infusions, with doses ranging from 0.015 to 20 mg/kg. Cirmtuzumab had a long plasma half-life and did not have dose-limiting toxicity. Inhibition of ROR1 signaling was observed, including decreased activation of RhoA and HS1. Transcriptome analyses showed that therapy inhibited CLL stemness gene expression signatures in vivo. Cirmtuzumab is safe and effective at inhibiting tumor cell ROR1 signaling in patients with CLL.

Graphical abstract

Teaser

Choi et al. find that cirmtuzumab, a humanized mAb specific for the cancer stem cell antigen ROR1, was well tolerated and stable in clinical testing in patients with relapsed chronic lymphocytic leukemia. Treatment inhibited activation of Rho-GTPase and HS1 in vivo and reversed the stemness gene expression signatures in leukemia cells.


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Gender and cancer immunotherapy efficacy

Fabio Conforti talks to The Lancet Oncology about a meta-analysis showing that a patient's sex can affect the efficacy of cancer immunotherapy.

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Post-Partum Thrombotic Thrombocytopenic Purpura (TTP) in a Patient with known Idiopathic (Immune) Thrombocytopenic Purpura: a case report and review of the literature

Incidences of immune thrombocytopenic purpura occur in 1 in every 1000–10,000 pregnancies accounting for 3% of all thrombocytopenic pregnancies. A pre-existing immune thrombocytopenic purpura is known to be a ...

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Postpartum acute fatty liver of pregnancy: a case report

Acute fatty liver of pregnancy can be a very dramatic clinical event with significant risk of mortality to healthy women. The pathogenesis is still unknown. It usually occurs in the third trimester or in the i...

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Half brain irradiation in a murine model of breast cancer brain metastasis: magnetic resonance imaging and histological assessments of dose-response

Brain metastasis is becoming increasingly prevalent in breast cancer due to improved extra-cranial disease control. With emerging availability of modern image-guided radiation platforms, mouse models of brain ...

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Easing Concerns about Giving Research Study Participants Their Genetic Test Results

Do cancer study participants want to receive their genetic test results? A recent study involving women with a history of breast cancer tested an approach for returning genetic research results and evaluated the impact those results had on the women.

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Survival analysis and pathological features of advanced non-small cell lung cancer with miliary pulmonary metastases in patients harboring epidermal growth factor receptor mutations

Abstract

Purpose

Metastasis of non-small cell lung cancer (NSCLC), indicating hematogenous dissemination, is more frequent in patients harboring epidermal growth factor receptor (EGFR) mutations, who respond dramatically to EGFR–tyrosine kinase inhibitors (TKIs).

Methods

Based on the proposed association of miliary pulmonary metastasis and EGFR mutations in the previous studies, we conducted a retrospective study to assess survival of NSCLC with miliary pulmonary metastases in 223 patients harboring EGFR mutations who were treated with single agent EGFR–TKIs.

Results

Progression-free survival (PFS) and overall survival (OS) with single agent EGFR–TKIs were 11.7 months [95% confidence interval (CI) 9.6–13.7] and 23.7 months (95% CI 20.3–26.9), respectively. Patients with and without miliary pulmonary metastases were matched using propensity scores (n = 29 per group) based on clinical characteristics. After matching, the PFS were 8.2 months (95% CI 5.2–15.0) and 14.3 months (95% CI 9.6–30.0) (p = 0.02) in patients with and without miliary pulmonary metastases, respectively. Conversely, the OS were 15.3 months (95% CI 10.6–19.4) and 27.9 months (95% CI 22.0–33.0) (p = 0.003) in patients with and without miliary pulmonary metastases, respectively. By multivariate analysis, miliary pulmonary metastasis was associated with poor prognosis (p = 0.0035).

Conclusion

The prognosis of patients with advanced NSCLC harboring EGFR mutations with miliary pulmonary metastasis demonstrated significantly worse outcomes compared to those without miliary pulmonary metastasis.

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Development and internal validation of PI-RADs v2-based model for clinically significant prostate cancer

Abstract

Background

Our objective is to build a model based on Prostate Imaging Reporting and Data System version 2 (PI-RADs v2) and assess its accuracy by internal validation.

Methods

Patients who took prostate biopsy from 2014 to 2015 were retrospectively collected to compose training cohort according to the inclusion criteria and patients in 2016 composing validation cohort. Diagnostic performance was evaluated by analyzing the area under the curve (AUC), calibration curves, and decision curves.

Results

Of the 441 patients involved, the clinically significant prostate cancer (csPCa) detection rate were 40.6% (114/281) and 43.8% (70/160) in the training and validation cohort, respectively. Meanwhile, PCa detection rate were 50.2% (141/281) and 53.8% (86/160). Age, prostate-specific antigen density (PSAD)*10 and PI-RADs v2 score composed the model for PCa (model 1) and csPCa (model 2). The area under the curve of models 1 and 2 was 0.870 (95% CI 0.827–0.912) and 0.753 (95% CI 0.717–0.828) in the training cohort, while 0.845 (95% CI 0.786–0.904) and 0.834 (95% CI 0.787–0.882) in the validation cohort. Both models illustrated good calibration, and decision curve analyses showed good performance in predicting PCa or csPCa when the threshold was 0.35 or above.

Conclusions

The model based on age, PSAD*10 and PI-RADs v2 score showed internally validated high predictive value for both PCa and csPCa. It could be used to improve the diagnostic performance of suspicious PCa.

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Keine Überlegenheit der Protonentherapie gegenüber der IMRT beim lokal fortgeschrittenen NSCLC

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Treating metastatic prostate cancer with microRNA-145

Abstract

Prostate cancer (PCa) is an incurable disease at the metastatic stage. Although there are different options for treatment, the results are limited. MicroRNAs (miRNAs) are a group of small, noncoding, regulatory RNAs with important roles in regulating gene expression. miR-145 is reported to be a key tumor suppressor miRNA (tsmiR) that controls important oncogenes, such as MYC and RAS. In this study, in vitro studies were performed to show the control of MYC and RAS by miR-145. Flow cytometry was used to analyze cell proliferation and apoptosis. The efficacy of miR-145 in treating metastatic PCa was tested in nude mice using a model of bone metastasis promoted by intraventricular injection of PC-3MLuc-C6 cells. Tumor growth was evaluated by an in vivo bioluminescence system. After the full establishment of metastases on day 21, six animals were treated with three intravenous doses of miR-145 (on days 21, 24 and 27), and six were injected with scramble miRNA as controls. Compared to the controls, tumor growth was significantly reduced in animals receiving miR-145, most importantly on day 7 after the third and last dose of miRNA. After discontinuing the treatment, tumor growth resumed, becoming similar to the group of non-treated animals. A decrease in MYC and RAS expression was observed in all cell lines after treatment with miR-145, although statistical significance was achieved only in experiments with LNCaP and PC3 cell lines, with a decrease in 56% (p = 0.012) and 31% (p = 0.013) of RAS expression, respectively. Our results suggest that miR-145 is a potential molecule to be tested for treatment of metastatic, castration-resistant PCa.

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Apoptosis on the move

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Downregulation of Raf-1 kinase inhibitory protein as a sorafenib resistance mechanism in hepatocellular carcinoma cell lines

Abstract

Purpose

Although sorafenib enhances overall survival, sorafenib resistance has been reported to be a significant limiting factor for improved prognosis in patients with hepatocellular carcinoma (HCC). Therefore, it is important to identify the mechanism of sorafenib resistance. This study aimed to identify the causative factor of sorafenib resistance and suggest methods for overcoming it.

Methods

The sensitivity to sorafenib was compared in human HCC cell lines and patient-derived HCC primary cells. Based on its cytotoxicity, signaling pathways altered by sorafenib and the causative factors were examined through assays. The mechanism by which sorafenib modified the sorafenib-resistance inducer through gene or protein expression or stability was also investigated. We also designed a treatment option to overcome sorafenib resistance.

Results

Sorafenib activated the Raf/MEK/ERK pathway and caused sorafenib resistance in HCC cell lines and patient-derived HCC primary cells. Sorafenib reactivated the MAPK pathway by down-regulating RKIP at the post-translational level. Knockdown of RKIP increased phosphorylated ERK and thus suppressed sorafenib-mediated cell death. We also found that sorafenib-reactivated ERK maybe an attractive target for second-line therapy for patients with sorafenib resistance. Sequential combination treatment with sorafenib and PD98059 significantly reduced the viability and proliferation of sorafenib-resistant cells, while their increasing apoptosis efficacy.

Conclusion

Reactivation of the Raf/MEK/ERK pathway through aberrant expression of RKIP is one of the mechanisms behind sorafenib resistance in HCC. Sequential combination treatment with sorafenib and PD98059 could provide a new strategy to overcome sorafenib resistance in future clinical studies.

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Erratum to “Plasma magnesium is inversely associated with Epstein-Barr virus load in peripheral blood and Burkitt lymphoma in Uganda” [Cancer Epidemiol. 52 (2018) 70–74]

Publication date: Available online 1 June 2018
Source:Cancer Epidemiology
Author(s): Juan Ravell, Isaac Otim, Hadijah Nabalende, Ismail D. Legason, Steven J. Reynolds, Martin D. Ogwang, Christopher M. Ndugwa, Vickie Marshall, Denise Whitby, James J. Goedert, Eric A. Engels, Kishor Bhatia, Michael J. Lenardo, Sam M. Mbulaiteye




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Cancers, Vol. 10, Pages 176: Emerging and Established Models of Bone Metastasis

Cancers, Vol. 10, Pages 176: Emerging and Established Models of Bone Metastasis

Cancers doi: 10.3390/cancers10060176

Authors: Alexander H. Jinnah Benjamin C. Zacks Chukwuweike U. Gwam Bethany A. Kerr

Metastasis is the leading cause of cancer-related death and drives patient morbidity as well as healthcare costs. Bone is the primary site of metastasis for several cancers&mdash;breast and prostate cancers in particular. Efforts to treat bone metastases have been stymied by a lack of models to study the progression, cellular players, and signaling pathways driving bone metastasis. In this review, we examine newly described and classic models of bone metastasis. Through the use of current in vivo, microfluidic, and in silico computational bone metastasis models we may eventually understand how cells escape the primary tumor and how these circulating tumor cells then home to and colonize the bone marrow. Further, future models may uncover how cells enter and then escape dormancy to develop into overt metastases. Recreating the metastatic process will lead to the discovery of therapeutic targets for disrupting and treating bone metastasis.

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Hemodynamic Management of Patients During Endovascular Treatment of Acute Ischemic Stroke Under Conscious Sedation: A Retrospective Cohort Study

Background: Anesthetic modality and hemodynamic management during mechanical thrombectomy (MT) for acute ischemic stroke (AIS) are potential contributors to the success of revascularization. The aims of our study were to review the hemodynamic management by anesthesiologists and clinical outcomes in patients undergoing MT under conscious sedation. Methods: Retrospective cohort study of patients with anterior circulation AIS from January 2012 to March 2016. Primary outcome was hemodynamic intervention, defined as administration of vasoactive drugs to maintain systolic blood pressure (BP) between 140 and 180 mm Hg. The secondary outcome was poor hemodynamic control, defined as BP outside target for >15 minutes despite hemodynamic intervention. We performed regression analysis to determine the predictors of hemodynamic intervention and poor hemodynamic control. Results: A total of 126 patients were included in this study; 92% (116) receiving conscious sedation and 8% (10) no sedation. Upon arrival to the neuroradiology suite, systolic BP was 180 mm Hg in 14.3%. Hemodynamic intervention was required in 38.9% of patients; 15.1% for hypotension and 19.8% for hypertension. In the multivariate analysis, systolic BP on hospital admission (odds ratio, 1.02; 95% confidence interval, 1.00-1.04; P=0.019) constituted a predictor for hemodynamic intervention. Poor hemodynamic control occurred in 12.7% of patients, with lower baseline systolic BP being associated with higher risk of intraprocedural hypotension (odds ratio, 0.92; 95% confidence interval, 0.89-0.96; P

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Effects of sequentially applied single and combined temozolomide, hydroxychloroquine and AT101 treatment in a long-term stimulation glioblastoma in vitro model

Abstract

Purpose

Glioblastoma multiforme (GBM) is a poorly curable disease due to its heterogeneity that enables single cells to survive treatment regimen and initiate tumor regrowth. Although some progress in therapy has been achieved in the last years, the efficient treatment of GBMs is still a clinical challenge. Besides the standard therapeutic drug temozolomide (TMZ), quinoline-based antimalarial drugs such as hydroxychloroquine (HCQ) and BH3 mimetics such as AT101 were considered as possible drugs for GBM therapy.

Methods

We investigated the effects of sequentially applied single and combined TMZ, HCQ and AT101 treatments in a long-term stimulation GBM in vitro model. We performed all investigations in parallel in human astrocytes and two differentially TMZ-responsive human GBM cell lines and adjusted used drug concentrations to known liquor/plasma concentrations in patients. We determined amounts of dead cells and still remaining growth rates and depicted our results in a heatmap-like summary to visualize which sequential long-term treatment schedule seemed to be most promising.

Results

We showed that sequential stimulations yielded higher cytotoxicity and better tumor growth control in comparison to single TMZ treatment. This was especially the case for the sequences TMZ/HCQ and TMZ + AT101/AT101 which was as effective as the non-sequential combination TMZ + AT101. Importantly, those affected both less and more TMZ-responsive glioma cell lines, whilst being less harmful for astrocytes in comparison to single TMZ treatment.

Conclusions

Sequential treatment with mechanistically different acting drugs might be an option to reduce side effects in long-term treatment, for example in local administration approaches.

https://ift.tt/2HcHgGZ

Major vessel sealing in laparoscopic surgery for colorectal cancer: a single-center experience with 759 patients

Abstract

Background

Efficient hemostatic techniques are essential in laparoscopic surgery for ideal intraoperative and postoperative results. A variety of advanced devices are available for the sealing of major vascular structures. The aim of this study is to assess effectiveness and safety of major vessel sealing with a radiofrequency device during laparoscopic colorectal resections for cancer based on the experience of a single hospital.

Methods

Early outcomes of a consecutive series of patients who received elective laparoscopic colorectal resections for cancer over a 10-year period (January 2008–September 2017) are analyzed.

In all procedures, the Ligasure® electrothermal bipolar device was used for the closure of the major colonic vessels and the dissection of all the structures. No other products such clips, staplers, hemostatic products, or other devices were used.

Results

Seven-hundred fifty-nine procedures were performed in laparoscopy: 179 rectal resections, 247 sigmoidectomies and left hemicolectomies, 240 right hemicolectomies, 33 resections of the splenic flexure, 35 transverse colonic resections, and 25 other procedures.

In 39 cases, the laparoscopic procedure was converted to open surgery, and in these cases, vessel sealing was also achieved with the radiofrequency device alone.

Vessel dissection and sealing was realized in all cases without any intraoperative or postoperative bleeding. No reoperations for bleeding from major vessels were performed in any patients. One case of reoperation was recorded postoperatively, at 3 h after right hemicolectomy, due to a small bleeding from the fat of the transverse colon stump.

Conclusions

The use of Ligasure® radiofrequency device for sealing and dividing the major colonic vessels is safe, fast, and effective during laparoscopic colorectal resections.

https://ift.tt/2H8e9EZ

Pre-operative stromal stiffness measured by shear wave elastography is independently associated with breast cancer-specific survival

Abstract

Introduction

With the increased use of neoadjuvant therapy for breast cancer, there is a need for pre-operative prediction of prognosis. We aimed to assess the prognostic value of tumour stiffness measured by ultrasound shear wave elastography (SWE).

Methods

A consecutive cohort of patients with invasive breast cancer underwent breast ultrasound (US) including SWE. The following were recorded prospectively: US diameter, stiffness at SWE, presentation source, core biopsy grade, oestrogen receptor (ER) status and pre-operative nodal status. Breast cancer-specific survival (BCSS) was analysed with regard to US size and stiffness, tumour grade on core biopsy, ER status, presentation mode and pre-operative nodal status. Analysis used Cox proportional hazards regression.

Results

Of the 520 patients, 42 breast cancer and 53 non-breast cancer deaths were recorded at mean follow-up of 5.4 years. Hazard ratios (HR) for tertiles of stiffness were 1, 4.8 and 8.1 (P = 0.0001). HR for 2 groups based on US size < or ≥ 20 mm were 1 and 5.1 (P < 0.0001). HR for each unit increase in tumour grade on core biopsy was 3.9 (P < 0.0001). The HR for ER positivity compared to ER negativity was 0.21 (P < 0.001). BCSS was also associated with presentation mode and pre-operative nodal status. In a multivariable model, stiffness, US size and ER status were independently associated with BCSS.

Conclusion

Multiple pre-operative factors including stromal stiffness at SWE have independent prognostic significance. A larger dataset with longer follow-up could be used in the future to construct a pre-operative prognostic model to guide treatment decisions.

https://ift.tt/2szfgZ7

Hyaluronic acid-modified polyamidoamine dendrimer G5-entrapped gold nanoparticles delivering METase gene inhibits gastric tumor growth via targeting CD44+ gastric cancer cells

Abstract

Background

Gastric cancer (GC) is the second most common leading cause of cancer-related death. Cancer stem cell (CSC) with the mark of CD44 played an important role in GC. rMETase was wildly exploited as chemotherapeutic option for GC. Polymers synthetic nanoparticle drug delivery systems have been commonly used for cancer therapy. With the decorating of Hyaluronic acid (HA), a receptor of CD44, nanoparticles exhibit with good biocompatibility and aqueous solubility.

Methods

The characteristic of nanoparticles (NPs) was analyzed by TEM and DLS. The viability and proliferation of GC cells were examined by MTT assays. The levels of CD44, Cyt C, and c-caspase 3 were examined by Western blot. The level of ROS was measured by DCFH-DA assays. The morphology of tissues was detected using hematoxylin–eosin (H&E) stain. Nude mice xenograft models were used to evaluate the effect of HA-PAMAM-Au-METase on GC.

Results

The transfection of rMETase carried by HA-G5 PAMAM-Au visibly inhibited the proliferation and tumorsphere formation of GC cells through obviously enhancing METase activity. Elevation of METase activity suppressed the proliferation of CD44(+) GC cells through down-regulating MET in cellular supernatant that resulted in the increase of Cyc C and ROS levels. The number of CD44(+) GC cells in nude mice injected with G5 PAMAM-Au-METase decorated by HA was markly declined resulting in the inhibition of tumor growth.

Conclusion

HA-G5 PAMAM-Au-METase significantly suppressed tumor growth of GC by targeted damaging the mitochondrial function of CD44(+) gastric CSCs.

https://ift.tt/2kEM2V5

Correction to: SEOM clinical guidelines for anaplastic gliomas (2017)

The SEOM/GEINO clinical guidelines provide recommendations for radiological, and molecular diagnosis, treatment and follow-up of adult patients with anaplastic gliomas (AG). We followed the 2016 WHO classification which specifies the major diagnostic/prognostic and predictive value of IDH1/IDH2 missense mutations and 1p/19q codeletions in AG. The diagnosis of anaplastic oligoastrocytoma is discouraged. Surgery, radiotherapy and chemotherapy with PCV or TMZ are the first-line standard of care for AG with slight modifications according to molecular variables. A multidisciplinary team is highly recommended in the management of these tumors.

https://ift.tt/2kFe2I1

Tissue preservation with mass spectroscopic analysis: Implications for cancer diagnostics

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https://ift.tt/2JpEunj

Breast cancer in an 18-year-old female: A fatal case report and literature review

Volume 19, Issue 7, July 2018, Page 543-548
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https://ift.tt/2L9eDgv

Cancers, Vol. 10, Pages 175: Factors Influencing the Clinical Presentation of Breakthrough Pain in Cancer Patients

Cancers, Vol. 10, Pages 175: Factors Influencing the Clinical Presentation of Breakthrough Pain in Cancer Patients

Cancers doi: 10.3390/cancers10060175

Authors: Mercadante Sebastiano Marchetti Paolo Cuomo Arturo Caraceni Augusto Masedu Francesco Aielli Federica on behalf of the IOPS-MS Study Group

Background: The aim of this study was to identify potential variables influencing the clinical presentation of breakthrough cancer pain (BTP). Methods: Cancer patients with a diagnosis of BTP were enrolled. Demographic and clinical characteristics, as well as background pain and BTP characteristics were collected. Multivariate analyses were conducted to assess the correlation between BTP characteristics and the variables examined. Results: Data of 4016 patients were analysed. Average daily number of BTP episodes was 2.4, mean intensity was 7.5, and a mean duration was 43.3 min. A short onset BTP was observed in 68.9% of patients. In 30.5% of patients BTP was predictable. There were 86.0% of participants who reported a marked interference of BTP with their daily activities. Furthermore, 86.8% of patients were receiving opioids for the management of BTP. The average time to meaningful pain relief was 16.5 min and 70.9% of patients were satisfied with their BTP medications. Age, head and neck cancer, Karnofsky, background pain intensity, predictable and fast onset BTP were independently associated with the number of BTP episodes. BTP pain intensity was independently associated with background pain intensity, fast onset BTP, and Karnofsky. Neuropathic pain mechanism was independently associated with unpredictable BTP. Variables independently associated with a longer duration of BTP were age, place of visit, cancer diagnosis, disease-oriented therapy, background pain intensity and mechanism, and unpredictable BTP. Age, Karnofsky, background pain intensity, fast onset, and long duration of BTP were independently associated with interference with daily activity. Conclusions: BTP has a variable presentation depending on interdependent relationships among its different characteristics.

https://ift.tt/2sq8XaQ

Prognostic role of plasma mammaglobin A expression in breast carcinoma patients: a meta-analysis

https://ift.tt/2J7PcLN

Postoperative Care Handbook of the Massachusetts General Hospital

No abstract available

https://ift.tt/2kGWF9G

Starving Patients Before Cataract Surgery Under Regional Anesthesia: Needed or Not?

No abstract available

https://ift.tt/2swuJZL

Race/Ethnicity and Sex Both Affect Opioid Administration in the Emergency Room

BACKGROUND: Although racial/ethnic and sex disparities have been examined in health care generally and pain management more specifically, the combined influence of these sociodemographic factors together has not been well documented. The aim of this study was to examine the association between administration of opioid analgesics in the emergency department (ED) and interaction of race/ethnicity and sex. METHODS: We conducted a retrospective cohort study using 2010–2014 Center for Disease Control-National Hospital Ambulatory Medical Care Survey data for patients 12–55 years of age presenting to EDs with a primary diagnosis of appendicitis or gallbladder disease as defined by International Classification of Diseases, Ninth Revision codes. The primary outcome was the receipt of opioid analgesic medications. Secondary outcomes included: receipt of nonopioids, receipt of antiemetic medications, wait time to see a provider, and length of visit in the ED. The association between sex and analgesic receipt within Caucasian non-Hispanic and non-Caucasian groups was evaluated adjusting for pain score on presentation, patient age, emergent status, city/noncity location, number of comorbidities, time of visit (month, day of the week, standard versus nonstandard working hours, year), and US region. RESULTS: After exclusions, a weighted sample of 553 ED visits was identified, representing 2,622,926 unique visits. The sample population was comprised of 1,858,035 (70.8%) females and 1,535,794 (58.6%) Caucasian non-Hispanics. In adjusted models, Caucasian non-Hispanic males 317,427/525,435 (60.4%) were slightly less likely to receive opioids than Caucasian non-Hispanic females 621,638/1,010,360 (61.5), odds ratio = 0.962, 95% CI, 0.955–0.970; P

https://ift.tt/2J0U09A

Fibrinogen Concentrate in Cardiovascular Surgery: A Meta-analysis of Randomized Controlled Trials

BACKGROUND: Postoperative bleeding remains a frequent complication after cardiovascular surgery and may contribute to serious morbidity and mortality. Observational studies have suggested a relationship between low endogenous plasma fibrinogen concentration and increased risk of postoperative blood loss in cardiac surgery. Although the transfusion of fibrinogen concentrate has been increasing, potential benefits and risks associated with perioperative fibrinogen supplementation in cardiovascular surgery are not fully understood. METHODS: PubMed, Cochrane Library, Ovid MEDLINE, Embase, Web of Science, and China National Knowledge Infrastructure were searched on January 15, 2017, with automated updates searched until February 15, 2018, to identify all randomized controlled trials (RCTs) of fibrinogen concentrate, whether for prophylaxis or treatment of bleeding, in adults undergoing cardiovascular surgery. All RCTs comparing fibrinogen infusion versus any other comparator (placebo/standard of care or another active comparator) in adult cardiovascular surgery and reporting at least 1 predefined clinical outcome were included. The random-effects model was used to calculate risk ratios and weighted mean differences (95% confidence interval [CI]) for dichotomous and continuous variables, respectively. Subgroup analyses by fibrinogen dose and by baseline risk for bleeding were preplanned. RESULTS: A total of 8 RCTs of fibrinogen concentrate in adults (n = 597) of mixed risk or high risk undergoing cardiovascular surgery were included. Compared to placebo or inactive control, perioperative fibrinogen concentrate did not significantly impact risk of all-cause mortality (risk ratio, 0.41; 95% CI, 0.12–1.38; I2 = 10%; P = .15). Fibrinogen significantly reduced incidence of allogeneic red blood cell transfusion (risk ratio, 0.64; 95% CI, 0.49–0.83; I2 = 0%; P = .001). No significant differences were found for other clinical outcomes. Subgroup analyses were unremarkable when analyzed according to fibrinogen dose, time of infusion initiation, mean cardiopulmonary bypass time, and rotational thromboelastometry/fibrinogen temogram use (all P values for subgroup interaction were nonsignificant). CONCLUSIONS: Current evidence remains insufficient to support or refute routine perioperative administration of fibrinogen concentrate in patients undergoing cardiovascular surgery. Fibrinogen concentrate may reduce the need for additional allogeneic blood product transfusion in cardiovascular surgery patients at high risk or with evidence of bleeding. However, no definitive advantage was found for reduction in risk of mortality or other clinically relevant outcomes. The small number of clinical events within existing randomized trials suggests that further well-designed studies of adequate power and duration to measure all-cause mortality, stroke, myocardial infarction, reoperation, and thromboembolic events should be conducted. Future studies should also address cost-effectiveness relative to standard of care. Accepted for publication April 30, 2018. Funding: This work was supported by the Department of Anesthesia and Perioperative Medicine, Western University. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Janet Martin, PharmD, MSc(HTA&M), Department of Anesthesia and Perioperative Medicine, Schulich School of Medicine & Dentistry, Western University, University Hospital, Room C3-412, 339 Windermere Rd, London, ON N6A 5A5, Canada. Address e-mail to jmarti83@uwo.ca. © 2018 International Anesthesia Research Society

https://ift.tt/2Hai2sQ

Inhibition of Fatty Acid Amide Hydrolase Improves Depressive-Like Behaviors Independent of Its Peripheral Antinociceptive Effects in a Rat Model of Neuropathic Pain

BACKGROUND: Neuropathic pain is often associated with depression. Enhancing endocannabinoids by fatty acid amide hydrolase (FAAH) inhibitors relieves neuropathic pain and stress-induced depressive-like behaviors in animal models. However, it is unclear whether FAAH inhibitor can relieve neuropathic pain–induced depression by or not by its antinociceptive effects. METHODS: Adult male Wistar rats with chronic constriction injury (CCI) to the sciatic nerve were treated with the systemic FAAH inhibitor URB597 (5.8 mg·kg−1·day−1, intraperitoneally) or peripherally acting FAAH inhibitor URB937 (1.6 mg·kg−1·d−1, intraperitoneally; n = 11–12). The treatment was applied from the 15th day after surgery and continued for 15 days. Mechanical withdrawal threshold was examined by Von Frey test before surgery and on the 28th day after CCI. Depressive-like behaviors were evaluated by forced swimming test (FST) and novelty-suppressed feeding (NSF) after 15-day treatment. The levels of anandamide and 2-arachidonoylglycerol in hippocampus were examined by liquid chromatography and mass spectrometry. Hippocampal neurogenesis including proliferation, differentiation, and survival of newborn cells was assessed by immunohistochemistry. RESULTS: After CCI injury, the rats developed significantly nociceptive and depressive-like behaviors, indicated by persistent mechanical hypersensitivity in Von Frey test, significantly prolonged immobility time in FST (sham: 84.2 ± 13.4 seconds versus CCI: 137.9 ± 18.8 seconds; P

https://ift.tt/2J0TTea

Resuscitation of Endotheliopathy and Bleeding in Thoracic Aortic Dissections: The VIPER-OCTA Randomized Clinical Pilot Trial

BACKGROUND: Thoracic aorta dissection is an acute critical condition associated with shock-induced endotheliopathy, coagulopathy, massive bleeding, and significant morbidity and mortality. Our aim was to compare the effect of coagulation support with solvent/detergent-treated pooled plasma (OctaplasLG) versus standard fresh frozen plasma (FFP) on glycocalyx and endothelial injury, bleeding, and transfusion requirements. METHODS: Investigator-initiated, single-center, blinded, randomized clinical pilot trial of adult patients undergoing emergency surgery for thoracic aorta dissection. Patients were randomized to receive OctaplasLG or standard FFP as coagulation factor replacement related to bleeding. The primary outcome was glycocalyx and endothelial injury. Other outcomes included bleeding, transfusions and prohemostatics at 24 hours, organ failure, length of stay in the intensive care unit and in the hospital, safety, and mortality at 30 and 90 days. RESULTS: Fifty-seven patients were included to obtain 44 evaluable on the primary outcome. The OctaplasLG group displayed significantly reduced damage to the endothelial glycocalyx (syndecan-1) and reduced endothelial tight junction injury (sVE-cadherin) compared to standard FFP. In the OctaplasLG group compared to the standard FFP, days on ventilator (1 day [interquartile range, 0–1] vs 2 days [1–3]; P = .013), bleeding during surgery (2150 [1600–3087] vs 2750 [2130–6875]; P = .046), 24-hour total transfusion and platelet transfusion volume (3975 mL [2640–6828 mL] vs 6220 mL [4210–10,245 mL]; P = .040, and 1400 mL [1050–2625 mL] vs 2450 mL [1400–3500 mL]; P = .027), and goal-directed use of prohemostatics (7/23 [30.4%] vs 13/21 [61.9%]; P = .036) were all significantly lower. Among the 57 patients randomized, 30-day mortality was 20.7% (6/29) in the OctaplasLG group and 25% (7/28) in the standard FFP group (P = .760). No safety concern was raised. CONCLUSIONS: In this randomized, clinical pilot trial of patients undergoing emergency surgery for thoracic aorta dissections, we found that OctaplasLG reduced glycocalyx and endothelial injury, reduced bleeding, transfusions, use of prohemostatics, and time on ventilator after surgery compared to standard FFP. An adequately powered multicenter trial is warranted to confirm the clinical importance of the findings. Accepted for publication May 8, 2018. Funding: This investigator-initiated trial was funded by internal department funds and an unrestricted research grant from Octapharma AG, the manufacturer of OctaplasLG, paid to and administered by Copenhagen University Hospital, Rigshospitalet, to support the execution of the trial covering expenses to assisting staff, on-call research assistants, blood samples, laboratory analyses, etc. Octapharma AG also supplied the investigational product of the trial free of charge. None of the authors involved have received ­personal income from Octapharma AG, have shares or financial interests in Octapharma AG, and Octapharma AG had no role in the design of this study, its execution, analysis, interpretation of the data, writing of the article, or decision to submit results. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). The trial was registered before patient enrollment at clinicaltrials.gov (NCT02253082, principal investigator: J.S.; date of registration: October 1, 2014). Reprints will not be available from the authors. Address correspondence to Jakob Stensballe, PhD, Section for Transfusion Medicine, Capital Region Blood Bank and Department of Anesthesia, Centre of Head and Orthopedics, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen DK-2100, Denmark. Address e-mail to jakob.stensballe@regionh.dk. © 2018 International Anesthesia Research Society

https://ift.tt/2syuPQy

Chemotherapy and Cognition: International Cognition and Cancer Task Force Recommendations for Harmonising Preclinical Research

Publication date: Available online 1 June 2018
Source:Cancer Treatment Reviews
Author(s): Gordon Winocur, Ian Johnston, Hélène Castel
Cancer survivors who undergo chemotherapy for non-CNS tumours often report substantial cognitive disturbances that adversely affect quality of life, during and after treatment. The neurotoxic effects of anti-cancer drugs have been confirmed in clinical and pre-clinical research. Work with animals has also identified a range of factors and underlying mechanisms that contribute to chemotherapy-induced cognitive impairment. However, there is a continuing need to develop standard cognitive testing procedures for validation and comparison purposes, broaden the search for biological and neurochemical mechanisms, and develop improved animal models for investigating the combined effects of treatment, the disease, and other potential factors (e.g., age, stress). In this paper, a working group, formed under the auspices of the International Cognition and Cancer Task Force, reviews the state of pre-clinical research, formulates strategic priorities, and provides recommendations to guide animal research that meaningfully informs clinical investigations.



https://ift.tt/2J1BuxU

Vitamin d in melanoma: controversies and potential role in combination with immune check-point inhibitors

Publication date: Available online 31 May 2018
Source:Cancer Treatment Reviews
Author(s): Luigia Stefania Stucci, Stella D'Oronzo, Marco Tucci, Antonella Macerollo, Simone Ribero, Francesco Spagnolo, Elena Marra, Virginia Picasso, Laura Orgiano, Riccardo Marconcini, Francesco De Rosa, Lorenza di Guardo, Giulia Galli, Sara Gandini, Raffaele Palmirotta, Giuseppe Palmieri, Paola Queirolo, Francesco Silvestris
The role of vitamin D in melanoma is still controversial. Although several Authors described a correlation between vitamin D deficiency and poor survival in metastatic melanoma patients, clinical trials exploring the effects of vitamin D supplementation in this clinical setting were mostly inconclusive.However, recent evidence suggests that vitamin D exerts both anti-proliferative effects on tumor cells and immune-modulating activities, that have been widely explored in auto-immune disorders. On the one hand, vitamin D has been shown to inhibit T-helper17 lymphocytes, notoriously involved in the pathogenesis of immune-related adverse events (iAEs) which complicate immune-checkpoint inhibitor (ICI) treatment. On the other hand, vitamin D up-regulates PDL-1 expression on both epithelial and immune cells, suggesting a synergic effect in combination with ICIs, for which further investigation is needed.



https://ift.tt/2H9BF4y

Non-small cell lung cancer brain metastases and the immune system: from brain metastases development to treatment

Publication date: Available online 31 May 2018
Source:Cancer Treatment Reviews
Author(s): Elie El Rassy, Angela Botticella, Joseph Kattan, Cecile Le Péchoux, Benjamin Besse, Lizza Hendriks
Brain metastases (BM) are diagnosed frequently in non-small cell lung cancer (NSCLC) patients. Despite the high incidence of BM (up to 40% in unselected patients), patients with untreated and/or unstable BM were excluded from pivotal immune checkpoint inhibitors (ICI) NSCLC trials. Percentage of patients with stable and treated BM in these trials ranged from 9.1 to 14.7% and ICI benefit over chemotherapy was not always demonstrated. Only small trials have been completed that demonstrated ICI efficacy in locally untreated, selected BM patients. With 33%, cranial objective response rate (ORR) was comparable to extracranial ORR and responses were often durable. With the promising survival benefits of ICI, in daily practice also unstable and/or untreated BM patients will often receive treatment with ICI and extrapolating clinical trial data to these patients can be challenging. In this review, we will summarize the preclinical rationale and potential concerns for the use of ICI in BM patients. Furthermore, we will summarize BM subgroup data from the pivotal NSCLC trials, retrospective series, the NSCLC BM specific ICI trials and the use of cranial radiation and ICI. Last, we provide an overview of response measurement criteria and future directions.



https://ift.tt/2J0zd5T

Cancers, Vol. 10, Pages 174: Signal-Targeted Therapies and Resistance Mechanisms in Pancreatic Cancer: Future Developments Reside in Proteomics

Cancers, Vol. 10, Pages 174: Signal-Targeted Therapies and Resistance Mechanisms in Pancreatic Cancer: Future Developments Reside in Proteomics

Cancers doi: 10.3390/cancers10060174

Authors: Célia Cintas Thibaut Douché Nicole Therville Silvia Arcucci Fernanda Ramos-Delgado Céline Basset Benoît Thibault Julie Guillermet-Guibert

For patients with metastatic pancreatic cancer that are not eligible for surgery, signal-targeted therapies have so far failed to significantly improve survival. These therapeutic options have been tested in phase II/III clinical trials mostly in combination with the reference treatment gemcitabine. Innovative therapies aim to annihilate oncogenic dependency, or to normalize the tumoural stroma to allow immune cells to function and/or re-vascularisation to occur. Large scale transcriptomic and genomic analysis revealed that pancreatic cancers display great heterogeneity but failed to clearly delineate specific oncogene dependency, besides oncogenic Kras. Beyond these approaches, proteomics appears to be an appropriate approach to classify signal dependency and to identify specific alterations at the targetable level. However, due to difficulties in sampling, proteomic data for this pathology are scarce. In this review, we will discuss the current state of clinical trials for targeted therapies against pancreatic cancer. We will then highlight the most recent proteomic data for pancreatic tumours and their metastasis, which could help to identify major oncogenic signalling dependencies, as well as provide future leads to explain why pancreatic tumours are intrinsically resistant to signal-targeted therapies. We will finally discuss how studies on phosphatidylinositol-3-kinase (PI3K) signalling, as the paradigmatic pro-tumoural signal downstream of oncogenic Kras in pancreatic cancer, would benefit from exploratory proteomics to increase the efficiency of targeted therapies.

https://ift.tt/2JibZHR