Galactosylated iodine-based small molecule I.V. CT contrast agent for bile duct imaging Biomaterials (IF 8.402) Pub Date : 2018-01-12 Yeonjin Jung, Hee Sook Hwang, Kun Na
Computed tomography (CT) with contrast plays an important role as a clinical diagnostic tool but still has a limited diagnostic range. In this work, we developed a novel injectable iodine-based small molecule CT contrast agent, even can be used for bile duct diagnostics. The bile duct diagnosable CT contrast agent (BDICA) is synthesized with 5-amino-2,4,6-triiodoisophthaloyl dichloride (ATIPC), tromethamine and lactobionic acid (LBA) for asialoglycoprotein receptor (ASGPR) targeted delivery via receptor-mediated endocytosis and transport to the bile canaliculi. Specific binding to the ASGPRs was confirmed by in vitro cellular uptake in HepG2 cells (ASGPR positive) and HCT 116 cells (ASGPR negative). Compared to iohexol, BDICA has equal in vivo distribution and a 13-fold iodine increase in content was observed in bile juice after BDICA injection. The radiopaque contrast effect in the bile duct has been clearly shown in in vivo CT scans. Furthermore, within 36 h, 91.3% of the BDICA was eliminated without organ damage, which verified the overall safety of the contrast agent. BDICA not only provides sufficient contrast images similar to iohexol, but also provides superior images of the bile duct. Based on recent studies, it has been shown that BDICA is a promising, safe and effective contrast agent for CT imaging of the organs and soft tissues, including the bile duct.
Therapeutic effects of gefitinib-encapsulated thermosensitive injectable hydrogel in intervertebral disc degeneration Biomaterials (IF 8.402) Pub Date : 2018-01-11 Zongyou Pan, Heng Sun, Binbin Xie, Dongdong Xia, Xiaoan Zhang, Dongsheng Yu, Jun Li, Yuzi Xu, Zuhua Wang, Yan Wu, Xiaolei Zhang, Yafei Wang, Qianbao Fu, Wei Hu, Yang Yang, Varitsara Bunpetch, Weiliang Shen, Boon Chin Heng, Shufang Zhang, Hongwei Ouyang
Intervertebral disc (IVD) degeneration is one of the most widespread musculoskeletal diseases worldwide, which remains an intractable clinical challenge. The aim of this study is to investigate the therapeutic potential of the small molecule gefitinib (an epidermal growth factor receptor (EGFR) inhibitor) in ameliorating IVD degeneration. Aberrant EGFR activation levels were detected in both human and rat degenerative IVDs, which prompted us to investigate the functional roles of EGFR by utilizing inducible cartilage-specific EGFR-deficient mice. We demonstrated that conditional EGFR deletion in mice increased nucleus pulposus (NP) extracellular matrix (ECM) production and autophagy marker activation while MMP13 expression decreased. These outcomes are comparable to the use of a controlled-release injectable thermosensitive hydrogel of gefitinib to block EGFR activity in a puncture-induced rat model. We also conducted a case series study involving patients with non-small cell lung cancer and IVD degeneration who received gefitinib treatment from 2010 to 2015. Gefitinib-treated patients displayed a relative slower disc degenerating progression, in contrast to control subjects. These findings thus provide evidence that suppression of EGFR by the FDA-approved drug gefitinib can protect IVD degeneration in rats, implying the potential application of gefitinib as a small molecule drug for treating IVD degeneration.
Evaluation of sulfane sulfur bioeffects via a mitochondria-targeting selenium-containing near-infrared fluorescent probe Biomaterials (IF 8.402) Pub Date : 2018-01-11 Min Gao, Rui Wang, Fabiao Yu, Lingxin Chen
As a crucial member in antioxidant regulatory systems, sulfane sulfur plays essential roles in cytoprotective mechanisms by directly eliminating ROS and altering ROS-mediated redox signaling. Despite the rising interests in sulfane sulfur, there only a few bio-compatible methods are available for its direct detection. Moreover, most of the existing methods cannot meet the requirements of real-time detection due to the reactive and labile chemical properties of sulfane sulfur. Therefore, we strive to clarify the mutual relationship between mitochondria sulfane sulfur and ROS under hypoxia stress. Herein, we report a near-infrared fluorescent probe Mito-SeH for the selective imaging of mitochondrial sulfane sulfur in cells and in vivo under hypoxia stress. Mito-SeH includes three moieties: a selenol group (<img border="0" alt="single bond" src="https://cdn.els-cdn.com/sd/entities/sbnd">SeH) as the stronger sulfur-acceptor; a near-infrared azo-BODIPY fluorophore as the fluorescent modulator; a lipophilic alkyltriphenylphosphonium cation as the mitochondrial delivery. Mito-SeH exhibits excellent selectivity and sensitivity towards the detection of mitochondria sulfane sulfur. The hypoxia response behavior of Mito-SeH is evaluated in monolayer cell and three-dimensional multicellular spheroid to clarify the relationship between sulfane sulfur and hypoxia. We confirm that sulfane sulfur protection mechanism against hypoxia is to inhibition of caspase-dependent apoptosis through directly scavenging ROS pathway. The probe is also applied to measurement of sulfane sulfur in ex vivo-dissected organs of hypoxic mouse model, as well as the probe is successfully used for real-time monitoring the changes of sulfane sulfur and ROS in acute ischemia mice model. We suggest that sulfane sulfur may be a novel therapeutic agent for hypoxia-induced injury.
Perineurium-like sheath derived from long-term surviving mesenchymal stem cells confers nerve protection to the injured spinal cord Biomaterials (IF 8.402) Pub Date : 2018-01-11 Yuan-Huan Ma, Xiang Zeng, Xue-Cheng Qiu, Qing-Shuai Wei, Ming-Tian Che, Ying Ding, Zhou Liu, Guo-Hui Wu, Jia-Hui Sun, Mao Pang, Li-Min Rong, Bin Liu, Zaid Aljuboori, Inbo Han, Eng-Ang Ling, Yuan-Shan Zeng
The functional multipotency enables mesenchymal stem cells (MSCs) promising translational potentials in treating spinal cord injury (SCI). Yet the fate of MSCs grafted into the injured spinal cord has not been fully elucidated even in preclinical studies, rendering concerns of their safety and genuine efficacy. Here we used a rat spinal cord transection model to evaluate the cell fate of allograft bone marrow derived MSCs. With the application of immunosuppressant, donor cells, delivered by biocompatible scaffold, survived up to 8 weeks post-grafting. Discernible tubes formed by MSCs were observed beginning 2 weeks after transplantation and they dominated the morphological features of implanted MSCs at 8 weeks post-grafting. The results of immunocytochemistry and transmission electron microscopy displayed the formation of perineurium-like sheath by donor cells, which, in a manner comparable to the perineurium in peripheral nerve, enwrapped host myelins and axons. The MSC-derived perineurium-like sheath secreted a group of trophic factors and permissive extracellular matrix, and served as a physical and chemical barrier to insulate the inner nerve fibers from ambient oxidative insults by the secretion of soluble antioxidant, superoxide dismutase-3 (SOD3). As a result, many intact regenerating axons were preserved in the injury/graft site following the forming of perineurium-like sheath. A parallel study utilizing a good manufacturing practice (GMP) grade human umbilical cord-derived MSCs or allogenic MSCs in an acute contusive/compressive SCI model exhibited a similar perineurium-like sheath formed by surviving donor cells in rat spinal cord at 3 weeks post-grafting. The present study for the first time provides an unambiguous morphological evidence of perineurium-like sheath formed by transplanted MSCs and a novel therapeutic mechanism of MSCs in treating SCI.
Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy Biomaterials (IF 8.402) Pub Date : 2018-01-09 Jun Zhao, Huamin Wang, Cheng-Hui Hsiao, Diana S-L. Chow, Eugene J. Koay, Yaan Kang, Xiaoxia Wen, Qian Huang, Ying Ma, James A. Bankson, Stephen E. Ullrich, Willem Overwijk, Anirban Maitra, David Piwnica-Worms, Jason B. Fleming, Chun Li
Non-genetic engineering of cytotoxic T cells to target IL-4 receptor enhances tumor homing and therapeutic efficacy against melanoma Biomaterials (IF 8.402) Pub Date : 2018-01-08 Gowri Rangaswamy Gunassekaran, Chae-Moon Hong, Sri Murugan Poongkavithai Vadevoo, Lianhua Chi, Padmanaban Guruprasath, Byung-Cheol Ahn, Ha-Jeong Kim, Tae Heung Kang, Byungheon Lee
Biomimetic and enzyme-responsive dynamic hydrogels for studying cell-matrix interactions in pancreatic ductal adenocarcinoma Biomaterials (IF 8.402) Pub Date : 2018-01-08 Hung-Yi Liu, Murray Korc, Chien-Chi Lin
The tumor microenvironment (TME) governs all aspects of cancer progression and in vitro 3D cell culture platforms are increasingly developed to emulate the interactions between components of the stromal tissues and cancer cells. However, conventional cell culture platforms are inadequate in recapitulating the TME, which has complex compositions and dynamically changing matrix mechanics. In this study, we developed a dynamic gelatin-hyaluronic acid hybrid hydrogel system through integrating modular thiol-norbornene photopolymerization and enzyme-triggered on-demand matrix stiffening. In particular, gelatin was dually modified with norbornene and 4-hydroxyphenylacetic acid to render this bioactive protein photo-crosslinkable (through thiol-norbornene gelation) and responsive to tyrosinase-triggered on-demand stiffening (through HPA dimerization). In addition to the modified gelatin that provides basic cell adhesive motifs and protease cleavable sequences, hyaluronic acid (HA), an essential tumor matrix, was modularly and covalently incorporated into the cell-laden gel network. We systematically characterized macromer modification, gel crosslinking, as well as enzyme-triggered stiffening and degradation. We also evaluated the influence of matrix composition and dynamic stiffening on pancreatic ductal adenocarcinoma (PDAC) cell fate in 3D. We found that either HA-containing matrix or a dynamically stiffened microenvironment inhibited PDAC cell growth. Interestingly, these two factors synergistically induced cell phenotypic changes that resembled cell migration and/or invasion in 3D. Additional mRNA expression array analyses revealed changes unique to the presence of HA, to a stiffened microenvironment, or to the combination of both. Finally, we presented immunostaining and mRNA expression data to demonstrate that these irregular PDAC cell phenotypes were a result of matrix-induced epithelial-mesenchymal transition (EMT).
Unifying in vitro and in vivo IVT mRNA expression discrepancies in skeletal muscle via mechanotransduction Biomaterials (IF 8.402) Pub Date : 2018-01-06 Sushma M. Bhosle, Kristin H. Loomis, Jonathan L. Kirschman, Emmeline L. Blanchard, Daryll A. Vanover, Chiara Zurla, Damien Habrant, Darin Edwards, Patrick Baumhof, Bruno Pitard, Philip J. Santangelo
Mechanically resilient injectable scaffolds for intramuscular stem cell delivery and cytokine release Biomaterials (IF 8.402) Pub Date : 2018-01-04 Stuart A. Young, Stephen E. Sherman, Tyler T. Cooper, Cody Brown, Fraz Anjum, David A. Hess, Lauren E. Flynn, Brian G. Amsden
A promising strategy for treating peripheral ischemia involves the delivery of stem cells to promote angiogenesis through paracrine signaling. Treatment success depends on cell localization, retention, and survival within the mechanically dynamic intramuscular (IM) environment. Herein we describe an injectable, in situ-gelling hydrogel for the IM delivery of adipose-derived stem/stromal cells (ASCs), specifically designed to withstand the dynamic loading conditions of the lower limb and facilitate cytokine release from encapsulated cells. Copolymers of poly(trimethylene carbonate)-b-poly(ethylene glycol)-b-poly(trimethylene carbonate) diacrylate were used to modulate the properties of methacrylated glycol chitosan hydrogels crosslinked by thermally-initiated polymerization using ammonium persulfate and N,N,N′,N′-tetramethylethylenediamine. The scaffolds had an ultimate compressive strain over 75% and maintained mechanical properties during compressive fatigue testing at physiological levels. Rapid crosslinking (<3 min) was achieved at low initiator concentration (5 mM). Following injection and crosslinking within the scaffolds, human ASCs demonstrated high viability (>90%) over two weeks in culture under both normoxia and hypoxia. Release of angiogenic and chemotactic cytokines was enhanced from encapsulated cells under sustained hypoxia, in comparison to normoxic and tissue culture polystyrene controls. When delivered by IM injection in a mouse model of hindlimb ischemia, human ASCs were well retained in the scaffold over 28 days and significantly increased the IM vascular density compared to untreated controls.
Realizing highly chemoselective detection of H2S in vitro and in vivo with fluorescent probes inside core-shell silica nanoparticles Biomaterials (IF 8.402) Pub Date : 2018-01-04 Feiyi Wang, Ge Xu, Xianfeng Gu, Zhijun Wang, Zhiqiang Wang, Ben Shi, Cuifen Lu, Xueqing Gong, Chunchang Zhao
Generation of Matched Patient-Derived Xenograft In Vitro-In Vivo Models Using 3D Macroporous Hydrogels for the Study of Liver Cancer Biomaterials (IF 8.402) Pub Date : 2018-01-04 Eliza Li Shan Fong, Tan Boon Toh, Xiaoxuan Lin, Zheng Liu, Lissa Hooi, Masturah Bte Mohd Abdul Rashid, Touati Benoukraf, Edward Kai-Hua Chow, The Hung Huynh, Hanry Yu
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, often manifesting at the advanced stage when cure is no longer possible. The discrepancy between preclinical findings and clinical outcome in HCC is well-recognized. So far, sorafenib is the only targeted therapy approved as first-line therapy for patients with advanced HCC. There is an urgent need for improved preclinical models for the development of HCC-targeted therapies. Patient-derived xenograft (PDX) tumor models have been shown to closely recapitulate human tumor biology and predict patient drug response. However, the use of PDX models is currently limited by high costs and low throughput. In this study, we engineered in vitro conditions conducive for the culture of HCC-PDX organoids derived from a panel of 14 different HCC-PDX lines through the use of a three-dimensional macroporous cellulosic sponge system. To validate the in vitro HCC-PDX models, both in vivo and in vitro HCC-PDX models were subjected to whole exome sequencing and RNA-sequencing. Correlative studies indicate strong concordance in genomic and transcriptomic profiles as well as intra-tumoral heterogeneity between each matched in vitro-in vivo HCC-PDX pairs. Furthermore, we demonstrate the feasibility of using these in vitro HCC-PDX models for drug testing, paving the way for more efficient preclinical studies in HCC drug development.
NIR-responsive cancer cytomembrane-cloaked carrier-free nanosystems for highly efficient and self-targeted tumor drug delivery Biomaterials (IF 8.402) Pub Date : 2018-01-04 Ning Zhang, Minghui Li, Xuetan Sun, Huizhen Jia, Wenguang Liu
Cell membrane-camouflaged nanoparticles for cancer therapy have received a burgeoning interest over the past years. However, the low drug loading and intratumoral release efficiency, and lack of precise targeting remains a big challenge; in addition, foreign carriers used may pose an expected burden in the course of metabolism. In this study, we designed and fabricated a novel NIR-responsive highly targeted carrier-free nanosystem by coating the exactly identical source of cracked cancer cell membranes (CCCMs) specifically derived from the homologous tumors onto the surface of the co-assembly nanoparticles of doxorubicin (DOX) and FDA-approved photothermal agent, indocyanine green (ICG). The nanosystems exhibited a high drug loading capacity (89.8%), cancer cell self-recognized ability and immune escape function. Further, the nanodrugs could be efficiently released for the membrane disturbance triggered by photothermal effect of ICG under NIR irradiation. The tumor-bearing mice model demonstrated that the self-carried DOX NPs@ICG@CCCM nanoparticles possessed a strong synergistic chemo-/photothermal therapeutic efficacy against tumors in vivo. The present strategy could be developed as a universal approach for designing and constructing carrier-free theranostic nanovehicles by intentionally selecting specific cancer cell membrane and the inner loading cargoes.
Clay nanoparticles for regenerative medicine and biomaterial design: a review of clay bioactivity Biomaterials (IF 8.402) Pub Date : 2018-01-03 Mohamed Mousa, Nicholas D. Evans, Richard O.C. Oreffo, Jonathan I. Dawson
Clay nanoparticles, composites and hydrogels are emerging as a new class of biomaterial with exciting potential for tissue engineering and regenerative medicine applications. Clay particles have been extensively explored in polymeric nanocomposites for self-assembly and enhanced mechanical properties as well as for their potential as drug delivery modifiers. In recent years, a cluster of studies have explored cellular interactions with clay nanoparticles alone or in combination with polymeric matrices. These pioneering studies have suggested new and unforeseen utility for certain clays as bioactive additives able to enhance cellular functions including adhesion, proliferation and differentiation, most notably for osteogenesis. This review examines the recent literature describing the potential effects of clay-based nanomaterials on cell function and examines the potential role of key clay physicochemical properties in influencing such interactions and their exciting possibilities for regenerative medicine.
Dual non-viral gene delivery from microparticles within 3D high-density stem cell constructs for enhanced bone tissue engineering Biomaterials (IF 8.402) Pub Date : 2018-01-03 Alexandra McMillan, Minh Khanh Nguyen, Tomas Gonzalez-Fernandez, Peilin Ge, Xiaohua Yu, William Murphy, Daniel J. Kelly, Eben Alsberg
High-density mesenchymal stem cell (MSC) aggregates can be guided to form bone-like tissue via endochondral ossification in vitro when culture media is supplemented with proteins, such as growth factors (GFs), to first guide the formation of a cartilage template, followed by culture with hypertrophic factors. Recent reports have recapitulated these results through the controlled spatiotemporal delivery of chondrogenic transforming growth factor-β1 (TGF-β1) and chondrogenic and osteogenic bone morphogenetic protein-2 (BMP-2) from microparticles embedded within human MSC aggregates to avoid diffusion limitations and the lengthy, costly in vitro culture necessary with repeat exogenous supplementation. However, since GFs have limited stability, localized gene delivery is a promising alternative to the use of proteins. Here, mineral-coated hydroxyapatite microparticles (MCM) capable of localized delivery of Lipofectamine-plasmid DNA (pDNA) nanocomplexes encoding for TGF-β1 (pTGF-β1) and BMP-2 (pBMP-2) were incorporated, alone or in combination, within MSC aggregates from three healthy porcine donors to induce sustained production of these transgenes. Three donor populations were investigated in this work due to the noted MSC donor-to-donor variability in differentiation capacity documented in the literature. Delivery of pBMP-2 within Donor 1 aggregates promoted chondrogenesis at week 2, followed by an enhanced osteogenic phenotype at week 4. Donor 2 and 3 aggregates did not promote robust glycosaminoglycan (GAG) production at week 2, but by week 4, Donor 2 aggregates with pTGF-β1/pBMP-2 and Donor 3 aggregates with both unloaded MCM and pBMP-2 enhanced osteogenesis compared to controls. These results demonstrate the ability to promote osteogenesis in stem cell aggregates through controlled, non-viral gene delivery within the cell masses. These findings also indicate the need to screen donor MSC regenerative potential in response to gene transfer prior to clinical application. Taken together, this work demonstrates a promising gene therapy approach to control stem cell fate in biomimetic 3D condensations for treatment of bone defects.
Engineered cardiac tissue patch maintains structural and electrical properties after epicardial implantation Biomaterials (IF 8.402) Pub Date : 2018-01-03 Christopher P. Jackman, Asvin M. Ganapathi, Huda Asfour, Ying Qian, Brian W. Allen, Yanzhen Li, Nenad Bursac
Functional cardiac tissue engineering holds promise as a candidate therapy for myocardial infarction and heart failure. Generation of “strong-contracting and fast-conducting” cardiac tissue patches capable of electromechanical coupling with host myocardium could allow efficient improvement of heart function without increased arrhythmogenic risks. Towards that goal, we engineered highly functional 1 cm × 1 cm cardiac tissue patches made of neonatal rat ventricular cells which after 2 weeks of culture exhibited force of contraction of 18.0 ± 1.4 mN, conduction velocity (CV) of 32.3 ± 1.8 cm/s, and sustained chronic activation when paced at rates as high as 8.7 ± 0.8 Hz. Patches transduced with genetically-encoded calcium indicator (GCaMP6) were implanted onto adult rat ventricles and after 4–6 weeks assessed for action potential conduction and electrical integration by two-camera optical mapping of GCaMP6-reported Ca2+ transients in the patch and RH237-reported action potentials in the recipient heart. Of the 13 implanted patches, 11 (85%) engrafted, maintained structural integrity, and conducted action potentials with average CVs and Ca2+ transient durations comparable to those before implantation. Despite preserved graft electrical properties, no anterograde or retrograde conduction could be induced between the patch and host cardiomyocytes indicating lack of electrical integration. Electrical properties of the underlying myocardium were not changed by the engrafted patch. From immunostaining analyses, implanted patches were highly vascularized and expressed abundant electromechanical junctions, but remained separated from the epicardium by a non-myocyte layer. In summary, our studies demonstrate generation of highly functional cardiac tissue patches that can robustly engraft on the epicardial surface, vascularize, and maintain electrical function, but do not couple with host tissue. The lack of graft-host electrical integration is therefore a critical obstacle to development of efficient tissue engineering therapies for heart repair.
Injectable polypeptide hydrogel for dual-delivery of antigen and TLR3 agonist to modulate dendritic cells in vivo and enhance potent cytotoxic T-lymphocyte response against melanoma Biomaterials (IF 8.402) Pub Date : 2018-01-03 Huijuan Song, Pingsheng Huang, Jinfeng Niu, Gaona Shi, Chuangnian Zhang, Deling Kong, Weiwei Wang
Transplantation of immune cells manipulated in vitro to dictate immune responses in the body is promising in cancer immunotherapy. However, this approach suffers from low cell survival after administration, insufficient cell homing to lymph nodes, and off-target. Here we demonstrate an injectable and self-assembled poly(l-valine) hydrogel as the delivery carrier of cargoes including antigen and immunopotentiator for DCs modulation. Our results indicate the vaccine formulation composed of tumor cell lysates (TCL), TLR3 agonist, poly(I:C) and polypeptide hydrogel can robustly recruit, activate and mature DCs in vitro and in vivo by sustained release of TCL and poly(I:C). Hydrogel as the delivery system significantly improves antigen persistence at the injection site and antigen drainage to lymph nodes. Strikingly, subcutaneous injection of hydrogel-based vaccine formulations in melanoma-bearing mice elicits good antitumor efficiency by evoking strong cytotoxic T-lymphocyte immune response. Hydrogel vaccine significantly promotes the production of CD8+ T cells in draining lymph nodes and tumor infiltrating T-lymphocytes. These findings suggest that in vivo program of DCs by injectable polypeptide hydrogel encapsulated with antigen and immunopentiator is able to direct immune responses against cancer. Our study also implies that such a hydrogel may serve as a multifunctional delivery platform of vaccines.
Renal-clearable quaternary chalcogenide nanocrystal for photoacoustic/magnetic resonance imaging guided tumor photothermal therapy Biomaterials (IF 8.402) Pub Date : 2018-01-02 Longfei Tan, Jing Wan, Weisheng Guo, Caizhang Ou, Tianlong Liu, Changhui Fu, Qiang Zhang, Xiangling Ren, Xing-Jie Liang, Jun Ren, Laifeng Li, Xianwei Meng
Ultrasmall Cu2ZnSnS4 (CZTS) nanocrystals with high near infrared (NIR) photothermal conversion abilities and peroxidase-mimic properties were synthesized and functionalized with bovine serum albumin (BSA) for rapid clearance multifunctional theranostic platform. Due to the presence of Cu (I) of CZTS@BSA, H2O2 could be decomposed to produce highly reactive oxygen species (ROS), catalyzed by intrinsic peroxidase like activity of CZTS. The CZTS@BSA possesses high NIR absorption and excellent photoacoustic (PA) imaging abilities. The as-prepared CZTS@BSA is also reported as an efficient T1 contrast agent for in vivo MR imaging. Therefore, in vivo distribution and rapid renal clearance of CZTS@BSA are successfully tracked by PA/MR dual-modal-imaging and further proved by ICP-MS analysis. Systemic acute toxicity evaluation indicates CZTS@BSA have good biocompatibility to normal tissues and blood. All results reveal that CZTS@BSA could act as a rapid clearance theranostic nanoplatform for dual-modal-imaging guided tumor PTT.
Bio-inspired redox-cycling antimicrobial film for sustained generation of reactive oxygen species Biomaterials (IF 8.402) Pub Date : 2018-01-02 Huan Liu, Xue Qu, Eunkyoung Kim, Miao Lei, Kai Dai, Xiaoli Tan, Miao Xu, Jinyang Li, Yangping Liu, Xiaowen Shi, Peng Li, Gregory F. Payne, Changsheng Liu
Efficient and cost-effective generation of hepatocyte-like cells through microparticle-mediated delivery of growth factors in a 3D culture of human pluripotent stem cells Biomaterials (IF 8.402) Pub Date : 2018-01-02 Zeinab Heidariyan, Mohammad Hossein Ghanian, Mohsen Ashjari, Zahra Farzaneh, Mostafa Najarasl, Mehran Rezaei Larijani, Abbas Piryaei, Massoud Vosough, Hossein Baharvand
Biomedical application of human pluripotent stem cell-derived hepatocyte-like cells (hPSC-HLCs) relies on efficient large-scale differentiation, which is commonly performed by a suspension culture of three-dimensional (3D) multicellular spheroids in bioreactors. However, this approach requires large amounts of growth factors (GFs) and the need to overcome limited diffusional transport posed by the inherent 3D structure of hPSC spheroids. Here, we have hypothesized that localized delivery of GFs by incorporation of GF-laden degradable polymeric microparticles (MPs) within the hPSC spheroids would circumvent such limitations. In this study, GFs for hepatocytic differentiation were encapsulated in gelatin-coated poly (l-lactic acid)/poly (DL-lactic-co-glycolic acid) (PLLA/PLGA) MPs which were subsequently incorporated into the hPSC spheroids. Gene expression analyses demonstrated that MP delivery of the GFs resulted in similar expression levels of hepatocytic markers despite the use of 10-fold less total GFs. The differentiated HLCs in the MP group exhibited ultrastructure and functional characteristics comparable with the conventional soluble GF group. The generated HLCs in the MP group were successfully engrafted in an acute liver injury mouse model and maintained hepatocytic function after implantation. These results suggested that sustained and localized delivery of GFs using MPs might offer a novel approach towards scalable technologies for hepatocytic differentiation and engineer a better 3D microenvironment for cells.
Mesenchymal Stem Cell-Macrophage Crosstalk and Bone Healing Biomaterials (IF 8.402) Pub Date : 2018-01-02 Jukka Pajarinen, Tzuhua Lin, Emmanuel Gibon, Yusuke Kohno, Masahiro Maruyama, Karthik Nathan, Laura Lu, Zhenyu Yao, Stuart B. Goodman
Recent research has brought about a clear understanding that successful fracture healing is based on carefully coordinated cross-talk between inflammatory and bone forming cells. In particular, the key role that macrophages play in the recruitment and regulation of the differentiation of mesenchymal stem cells (MSCs) during bone regeneration has been brought to focus. Indeed, animal studies have comprehensively demonstrated that fractures do not heal without the direct involvement of macrophages. Yet the exact mechanisms by which macrophages contribute to bone regeneration remain to be elucidated. Macrophage–derived paracrine signaling molecules such as Oncostatin M, Prostaglandin E2 (PGE2), and Bone Morphogenetic Protein-2 (BMP2) have been shown to play critical roles; however the relative importance of inflammatory (M1) and tissue regenerative (M2) macrophages in guiding MSC differentiation along the osteogenic pathway remains poorly understood. In this review, we summarize the current understanding of the interaction of macrophages and MSCs during bone regeneration, with the emphasis on the role of macrophages in regulating bone formation. The potential implications of aging to this cellular cross-talk are reviewed. Emerging treatment options to improve facture healing by utilizing or targeting MSC-macrophage crosstalk are also discussed.
Platelet membrane coating coupled with solar irradiation endows a photodynamic nanosystem with both improved antitumor efficacy and undetectable skin damage Biomaterials (IF 8.402) Pub Date : 2018-01-02 Lulu Xu, Feng Gao, Feng Fan, Lihua Yang
The therapeutic efficacy of tumor photodynamic therapy (PDT) is hindered by the following three challenges. The extremely short lifetime of reactive oxygen species (ROS, the cytotoxic factor of PDT) limits the radius of their action to tens-of-nanometer scale; functionalizing a photodynamic nanosystem with active targeting moieties helps bring the target cells into reach of ROS but requires extra research efforts. Current photodynamic systems are in general excited by light on the short end of near-infrared (NIR) region; deep tissue penetration necessitates the development of those excitable by longer NIR light. Reducing irradiation dose is necessary for avoiding skin damages but impacts the therapeutic outcome; how to resolve this delimma remains a challenge. We herein show that platelet membrane-coating over a photodynamic nanoparticle coupled with solar irradiation may simultaneously resolve all challenges above. Platelet membrane-coating provides both long circulation and active targeting, leading to preferential internalization by tumor over fibroblast cells in vitro and higher tumor uptake than the red blood cell (RBC) membrane-coated counterpart. Preloading a photodynamic sensitizer into a synthetic nanocarrier shifts its absorption peak to longer wavelength, which favors deep tissue penetration. Upon irradiation with NIR light from a solar simulator at extremely low output power density, the platelet membrane-coated photodynamic-nanoparticle outperforms its RBC membrane-coated counterpart and effectively ablates tumor without causing skin damages, which underscores the importance of active targeting in tumor PDT. We anticipate that platelet membrane coating may facilitate the in vivo applications of antitumor photodynamic therapy.
Stable gadolinium based nanoscale lyophilized injection for enhanced MR angiography with efficient renal clearance Biomaterials (IF 8.402) Pub Date : 2017-12-28 Kun Liu, Liang Dong, Yunjun Xu, Xu Yan, Fei Li, Yang Lu, Wei Tao, Huangyong Peng, Yadong Wu, Yang Su, Daishun Ling, Tao He, Haisheng Qian, Shuhong Yu
There is a great demand to develop high-relaxivity nanoscale contrast agents for magnetic resonance (MR) angiography with high resolution. However, there should be more focus on stability, ion leakage and excretion pathway of the intravenously injected nanoparticles, which are closely related to their clinic potentials. Herein, uniform ultrasmall-sized NaGdF4 nanocrystal (sub-10 nm) was synthesized using a facile high temperature organic solution method, and the nanocrystals were modified by a ligand-exchange approach using PEG-PAA di-block copolymer. The PEG-PAA modified NaGdF4 nanocrystal (denoted as ppNaGdF4 nanocrystal) exhibited a high r1 relaxivity which was twice of commercially used gadopentetate dimeglumine (Gd-DTPA) injection. MR angiography on rabbit using ppNaGdF4 nanocrystal at a low dose showed enhanced vascular details and long circulation time. Lyophilized powder of ppNaGdF4 nanocrystals have been successfully prepared without aggregation or reduction of MR performance, indicating the stability and an effective way to store this nanoscale contrast agent. No haemolysis was induced by ppNaGdF4 nanocrystal, and an extremely low leakage of gadolinium ions was confirmed. Furthermore, efficient renal excretion was one of the clearance pathways of ppNaGdF4 nanocrystal according to both the time dependent distribution data in blood and tissues and MR images. The in vivo toxicity evaluation further validated the great potential as a clinical agent for blood pool imaging.
Gadolinium-chelate functionalized Bismuth Nanotheranostic Agent for in Vivo MRI/CT/PAI Imaging-Guided Photothermal Cancer Therapy Biomaterials (IF 8.402) Pub Date : 2017-12-28 Bo Wu, Shu-Ting Lu, Hui Yu, Ru-Fang Liao, Huan Li, B.V. Lucie Zafitatsimo, Yu-Shuang Li, Ying Zhang, Xiao-Lei Zhu, Hong-Guang Liu, Hai-Bo Xu, Shi-Wen Huang, Zhen Cheng
Ex-vivo generation of drug-eluting islets improves transplant outcomes by inhibiting TLR4-Mediated NFkB upregulation Biomaterials (IF 8.402) Pub Date : 2017-12-28 Charles A. Chang, Babatope Akinbobuyi, Jeremy M. Quintana, Gumpei Yoshimatsu, Bashoo Naziruddin, Robert R. Kane
The systemic administration of immunosuppressive and anti-inflammatory drugs is routinely employed in organ transplantation to minimize graft rejection and improve graft survival. Localized drug delivery has the potential to improve transplant outcomes by providing sustained exposure to efficacious drug concentrations while avoiding systemic immunosuppression and off-target effects. Here, we describe the synthesis of a novel prodrug and its direct covalent conjugation to pancreatic islets via a cleavable linker. Post-transplant, linker hydrolysis results in the release of a potent anti-inflammatory antagonist of TLR4, localized to the site of implantation. This covalent islet modification significantly reduces the time and the minimal effective dose of islets necessary to achieve normoglycemia in a murine transplantation model. In streptozotocin-induced diabetic C57BL/6 mice a syngeneic transplant of ∼100 modified islets achieved a 100% cure rate by the end of a 4-week monitoring period, compared to a 0% cure rate for untreated control islets. Overall, this direct prodrug conjugation to islets is well tolerated and preserves their functionality while affording significantly superior transplant outcomes. The development of drug-eluting tissues that deliver sustained and localized doses of small-molecule therapeutics represents a novel pathway for enhancing success in transplantation.
Degradable rhenium trioxide nanocubes with high localized surface plasmon resonance absorbance like gold for photothermal theranostics Biomaterials (IF 8.402) Pub Date : 2017-12-27 Wenlong Zhang, Guoying Deng, Bo Li, Xinxin Zhao, Tao Ji, Guosheng Song, Zhiyin Xiao, Qing Cao, Jingbo Xiao, Xiaojuan Huang, Guoqiang Guan, Rujia Zou, Xinwu Lu, Junqing Hu
The applications of inorganic theranostic agents in clinical trials are generally limited to their innate non-biodegradability and potential long-term biotoxicity. To address this problem, herein via a straightforward and tailored space-confined on-substrate route, we obtained rhenium trioxide (ReO3) nanocubes (NCs) that display a good biocompatibility and biosafety. Importantly, their aqueous dispersion has high localized surface plasmon resonance (LSPR) absorbance in near-infrared (NIR) region different from previous report, which possibly associates with the charge transfer and structural distortion in hydrogen rhenium bronze (HxReO3), as well as ReO3's cubic shape. Such a high LSPR absorbance in the NIR region endows them with photoacoustic (PA)/infrared (IR) thermal imaging, and high photothermal conversion efficiency (∼57.0%) for efficient ablation of cancer cells. Also, ReO3 NCs show X-ray computed tomography (CT) imaging derived from the high-Z element Re. More attractively, those ReO3 NCs, with pH-dependent oxidized degradation behaviors, are revealed to be relatively stable in hypoxic and weakly acidic microenvironment of tumor for imaging and treatment whilst degradable in normal physiological environments of organs to enable effective clearance. In spite of their degradability, ReO3 NCs still possess tumor targeting capabilities. We thus develop a simple but powerful, safe and biodegradable inorganic theranostic platform to achieve PA/CT/IR imaging-guided cancer photothermal therapy (PTT) for improved therapeutic efficacy and decreased toxic side effects.
Caveolin-mediated endocytosis of the Chlamydia M278 outer membrane peptide encapsulated in poly(lactic acid)-Poly(ethylene glycol) nanoparticles by mouse primary dendritic cells enhances specific immune effectors mediated by MHC class II and CD4+ T cells Biomaterials (IF 8.402) Pub Date : 2017-12-26 Saurabh Dixit, Rajnish Sahu, Richa Verma, Skyla Duncan, Guillermo H. Giambartolomei, Shree R. Singh, Vida A. Dennis
We previously developed a Chlamydia trachomatis nanovaccine (PPM) by encapsulating a chlamydial M278 peptide within poly(lactic acid)-poly(ethylene glycol) biodegradable nanoparticles that immunopotentiated Chlamydia-specific immune effector responses in mice. Herein, we investigated the mechanistic interactions of PPM with mouse bone marrow-derived dendritic cells (DCs) for its uptake, trafficking, and T-cell activation. Our results reveal that PPM triggered enhanced expression of effector cytokines and chemokines, surface activation markers (Cd1d2, Fcgr1), pathogen-sensing receptors (TLR2, Nod1), co-stimulatory (CD40, CD80, CD86) and MHC class I and II molecules. Co-culturing of PPM-primed DCs with T cells from C. muridarium vaccinated mice yielded an increase in Chlamydia-specific immune effector responses including CD3+ lymphoproliferation, CD3+CD4+ IFN-γ-secreting cells along with CD3+CD4+ memory (CD44highand CD62high) and effector (CD44high and CD62low) phenotypes. Intracellular trafficking analyses revealed an intense expression and colocalization of PPM predominantly in endosomes. PPM also upregulated the transcriptional and protein expression of the endocytic mediator, caveolin-1 in DCs. More importantly, the specific inhibition of caveolin-1 led to decreased expression of PPM-induced cytokines and co-stimulatory molecules. Our investigation shows that PPM provided enhancement of uptake, probably by exploiting the caveolin-mediated endocytosis pathway, endosomal processing, and MHC II presentation to immunopotentiate Chlamydia-specific immune effector responses mediated by CD4+ T cells.
Heterocellular 3D scaffolds as biomimetic to recapitulate the tumor microenvironment of peritoneal metastases in vitro and in vivo Biomaterials (IF 8.402) Pub Date : 2017-12-23 Emiel De Jaeghere, Elly De Vlieghere, Jasper Van Hoorick, Sandra Van Vlierberghe, Glenn Wagemans, Leen Pieters, Elodie Melsens, Marleen Praet, Jo Van Dorpe, Mathieu Boone, Rouba Ghobeira, Nathalie De Geyter, Marc Bracke, Christian Vanhove, Sara Neyt, Geert Berx, Bruno G. De Geest, Peter Dubruel, Heidi Declercq, Wim Ceelen, Olivier De Wever
Peritoneal metastases cause cancer mortality and preclinical models are urgently needed to boost therapeutic progress. This study reports on a hybrid hydrogel-polylactic acid (PLA) scaffold that mimics the architecture of peritoneal metastases at the qualitative, quantitative and spatial level. Porous PLA scaffolds with controllable pore size, geometry, and surface properties are functionalized by type I collagen hydrogel. Co-seeding of cancer-associated fibroblast (CAF) increases cancer cell adhesion, recovery, and exponential growth by in situ heterocellular spheroid formation. Scaffold implantation into the peritoneum allows long-term follow-up (>14 weeks) and results in a time-dependent increase in vascularization, which correlates with cancer cell colonization in vivo. CAF, endothelial cells, macrophages and cancer cells show spatial and quantitative aspects as similarly observed in patient-derived peritoneal metastases. CAF provide long-term secretion of complementary paracrine factors implicated in spheroid formation in vitro as well as in recruitment and organization of host cells in vivo. In conclusion, the multifaceted heterocellular interactions that occur within peritoneal metastases are reproduced in this tissue-engineered implantable scaffold model.
Targeting death receptors for drug-resistant cancer therapy: Codelivery of pTRAIL and monensin using dual-targeting and stimuli-responsive self-assembling nanocomposites Biomaterials (IF 8.402) Pub Date : 2017-12-22 Fan Xu, Huihai Zhong, Ya Chang, Dongdong Li, Hongyue Jin, Meng Zhang, Huiyuan Wang, Chen Jiang, Youqing Shen, Yongzhuo Huang
Simultaneous three-dimensional visualization of mineralized and soft skeletal tissues by a novel microCT contrast agent with polyoxometalate structure Biomaterials (IF 8.402) Pub Date : 2017-12-22 Greet Kerckhofs, Steve Stegen, Nick van Gastel, Annelies Sap, Guillaume Falgayrac, Guillaume Penel, Marjorie Durand, Frank P. Luyten, Liesbet Geris, Katleen Vandamme, Tatjana Parac-Vogt, Geert Carmeliet
Precision design of nanomedicines to restore gemcitabine chemosensitivity for personalized pancreatic ductal adenocarcinoma treatment Biomaterials (IF 8.402) Pub Date : 2017-12-20 Xiao Zhao, Xiuchao Wang, Wei Sun, Keman Cheng, Hao Qin, Xuexiang Han, Yu Lin, Yongwei Wang, Jiayan Lang, Ruifang Zhao, Xiaowei Zheng, Ying Zhao, Jian shi, Jihui Hao, Qing Robert Miao, Guangjun Nie, He Ren
Amino-Si-rhodamines: A new class of two-photon fluorescent dyes with intrinsic targeting ability for lysosomes Biomaterials (IF 8.402) Pub Date : 2017-12-16 Hongxing Zhang, Jing Liu, Linfang Wang, Minjia Sun, Xiaohan Yan, Juanjuan Wang, Jian-Ping Guo, Wei Guo
VE-Cadherin regulates the self-renewal of mouse embryonic stem cells via LIF/Stat3 signaling pathway Biomaterials (IF 8.402) Pub Date : 2017-12-16 Ningning He, Xiaoniao Chen, Dan Wang, Ke Xu, Lingling Wu, Yuanyuan Liu, Hongyan Tao, Qinjun Zhao, Xiaocang Cao, Yuhao Li, Na Liu, Xin Qi, Zhongchao Han, Deling Kong, Jun Yang, Zongjin Li
With the abilities of self-renewal and differentiation, embryonic stem (ES) cells provide an unlimited source for stem cell-based therapeutics. However, the maintenance of ES cells with mouse embryonic fibroblasts (MEFs) can limit the clinical translation of ES cells. In the present study, we synthesized a fusion protein of the immunoglobulin G (IgG) fragment crystallizable region and vascular endothelial cadherin (VE-cadherin) extracellular domain (VE-cad-Fc) as a substrate for mouse ES cell culture, and we hypothesized that VE-cadherin could enhance the pluripotency and self-renewal of ES cells. Furthermore, we introduced a Stat3 reporter imaging system into ES cells and investigated the mechanism of the pluripotency enhancement mediated by VE-cadherin through cultured ES cells on VE-cad-Fc-coated plates using molecular imaging techniques. The resulting data revealed that VE-cad-Fc could activate the Stat3 signaling pathway, leading to the upregulation of stemness-related markers SSEA-1 and alkaline phosphatase (ALP). Moreover, VE-cad-Fc recovered the expression of Oct4, c-Myc, Nanog, Sox2, Tbx3 and Klf4 in differentiated ES cells, as well as enhanced the pluripotency of ES cells. In conclusion, VE-cadherin fusion protein coating methods provide an alternative towards feeder free culture of ES cells, and the strategy developed in the present study may benefit the clinical translation of ES cell-based therapeutics.
Noninvasive small-animal imaging of galectin-1 upregulation for predicting tumor resistance to radiotherapy Biomaterials (IF 8.402) Pub Date : 2017-12-15 Jianhao Lai, Dehua Lu, Chenran Zhang, Hua Zhu, Liquan Gao, Yanpu Wang, Rui Bao, Yang Zhao, Bing Jia, Fan Wang, Zhi Yang, Zhaofei Liu
Cancer chemoprevention revisited: Cytochrome P450 family 1B1 as a target in the tumor and the microenvironment Biomaterials (IF 8.402) Pub Date : 2017-11-11 Gabriele D'Uva, Denisa Baci, Adriana Albini, Douglas M. Noonan
Cancer chemoprevention is the use of synthetic, natural or biological agents to prevent or delay the development or progression of malignancies. Intriguingly, many phytochemicals with anti-inflammatory and anti-angiogenic effects, recently proposed as chemoprevention strategies, are inhibitors of Cytochrome P450 family 1B1 (CYP1B1), an enzyme overexpressed in a wide variety of tumors and associated with angiogenesis. In turn, pro-inflammatory cytokines were reported to boost CYP1B1 expression, suggesting a key role of CYP1B1 in a positive loop of inflammatory angiogenesis. Other well-known pro-tumorigenic activities of CYP1B1 rely on metabolic bioactivation of xenobiotics and steroid hormones into their carcinogenic derivatives. In contrast to initial in vitro observations, in vivo studies demonstrated a protecting role against cancer for the other CYP1 family members (CYP1A1 and CYP1A2), suggesting that the specificity of CYP1 family inhibitors should be carefully taken into account for developing potential chemoprevention strategies. Recent studies also proposed a role of CYP1B1 in multiple cell types found within the tumor microenvironment, including fibroblasts, endothelial and immune cells. Overall, our review of the current literature suggests a positive loop between inflammatory cytokines and CYP1B1, which in turn may play a key role in cancer angiogenesis, acting on both cancer cells and the tumor microenvironment. Strategies aiming at specific CYP1B1 inhibition in multiple cell types may translate into clinical chemoprevention and angioprevention approaches.
Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation Biomaterials (IF 8.402) Pub Date : 2017-12-02 Robert L. Ferris, Heinz-Josef Lenz, Anna Maria Trotta, Jesús García-Foncillas, Jeltje Schulten, François Audhuy, Marco Merlano, Gerard Milano
Immunoglobulin (Ig) G1 antibodies stimulate antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab, an IgG1 isotype monoclonal antibody, is a standard-of-care treatment for locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and metastatic colorectal cancer (CRC). Here we review evidence regarding the clinical relevance of cetuximab-mediated ADCC and other immune functions and provide a biological rationale concerning why this property positions cetuximab as an ideal partner for immune checkpoint inhibitors (ICIs) and other emerging immunotherapies. We performed a nonsystematic review of available preclinical and clinical data involving cetuximab-mediated immune activity and combination approaches of cetuximab with other immunotherapies, including ICIs, in SCCHN and CRC. Indeed, cetuximab mediates ADCC activity in the intratumoral space and primes adaptive and innate cellular immunity. However, counterregulatory mechanisms may lead to immunosuppressive feedback loops. Accordingly, there is a strong rationale for combining ICIs with cetuximab for the treatment of advanced tumors, as targeting CTLA-4, PD-1, and PD-L1 can ostensibly overcome these immunosuppressive counter-mechanisms in the tumor microenvironment. Moreover, combining ICIs (or other immunotherapies) with cetuximab is a promising strategy for boosting immune response and enhancing response rates and durability of response. Cetuximab immune activity—including, but not limited to, ADCC—provides a strong rationale for its combination with ICIs or other immunotherapies to synergistically and fully mobilize the adaptive and innate immunity against tumor cells. Ongoing prospective studies will evaluate the clinical effect of these combination regimens and their immune effect in CRC and SCCHN and in other indications.
Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium Biomaterials (IF 8.402) Pub Date : S.C. Clement, L.C.M. Kremer, F.A. Verburg, J.H. Simmons, M. Goldfarb, R.P. Peeters, E.K. Alexander, E. Bardi, E. Brignardello, L.S. Constine, C.A. Dinauer, V.M. Drozd, F. Felicetti, E. Frey, A. Heinzel, M.M. van den Heuvel-Eibrink, S.A. Huang, T.P. Links, H.M. van Santen
Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.
CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy Biomaterials (IF 8.402) Pub Date : 2017-11-26 Ryuma Tokunaga, Wu Zhang, Madiha Naseem, Alberto Puccini, Martin D Berger, Shivani Soni, Michelle McSkane, Hideo Baba, Heinz-Josef Lenz
Chemokines are proteins which induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation. Given these properties, their role in anti-tumor immune response in the cancer environment is of great interest. Although immunotherapy has shown clinical benefit for some cancer patients, other patients do not respond. One of the mechanisms of resistance to checkpoint inhibitors may be chemokine signaling. The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation, leading to tumor suppression (paracrine axis). However, there are some reports that show involvements of this axis in tumor growth and metastasis (autocrine axis). Thus, a better understanding of CXCL9, -10, -11/CXCR3 axis is necessary to develop effective cancer control. In this article, we summarize recent evidence regarding CXCL9, CXCL10, CXCL11/CXCR3 axis in the immune system and discuss their potential role in cancer treatment.
Advances in chromosomal translocations and fusion genes in sarcomas and potential therapeutic applications Biomaterials (IF 8.402) Pub Date : 2017-12-06 Xin Xiao, Cassandra C. Garbutt, Francis Hornicek, Zheng Guo, Zhenfeng Duan
Chromosomal translocations and fusion genes are very common in human cancer especially in subtypes of sarcomas, such as rhabdomyosarcoma, Ewing's sarcoma, synovial sarcoma and liposarcoma. The discovery of novel chromosomal translocations and fusion genes in different tumors are due to the advancement of next-generation sequencing (NGS) technologies such as whole genome sequencing. Recently, many novel chromosomal translocations and gene fusions have been identified in different types of sarcoma through NGS approaches. In addition to previously known sarcoma fusion genes, these novel specific fusion genes and associated molecular events represent important targets for novel therapeutic approaches in the treatment of sarcomas. This review focuses on recent advances in chromosomal translocations and fusion genes in sarcomas and their potential therapeutic applications in the treatment of sarcomas.
Triple negative breast cancer in Asia: An insider’s view Biomaterials (IF 8.402) Pub Date : 2017-11-10 Chao Wang, Shreya Kar, Xianning Lai, Wanpei Cai, Frank Arfuso, Gautam Sethi, Peter E. Lobie, Boon C. Goh, Lina H.K. Lim, Mikael Hartman, Ching W. Chan, Soo C. Lee, Sing H. Tan, Alan P. Kumar
While tremendous improvement has been made for the treatment of breast cancers, the treatment of triple negative breast cancer (TNBC) still remains a challenge due to its aggressive characteristics and limited treatment options. Most of the studies on TNBC were conducted in Western population and TNBC is reported to be more frequent in the African women. This review encapsulates the studies conducted on TNBC patients in Asian population and elucidates the similarities and differences between these two regions. The current treatment of TNBC includes surgery, radiotherapy and chemotherapy. In addition to the current chemotherapies, which mainly include cytotoxic agents, such as taxanes and anthracyclines, many clinical trials are investigating the potential use of other chemotherapy drugs, targeted therapeutics and combinational therapies to treat TNBC. Moreover, this review also integrates the studies involving novel markers, which will help us to dissect the pathologic process of TNBC and in turn facilitate the development of better treatment strategies to combat TNBC.
PD-1 blockade in advanced NSCLC: A focus on pembrolizumab Biomaterials (IF 8.402) Pub Date : 2017-10-23 Solange Peters, Keith M Kerr, Rolf Stahel
Non–small cell lung cancer (NSCLC) is one of the most prevalent cancers and is responsible for a large proportion of all cancer-related deaths. Current treatment options are inadequate, reflecting a substantial unmet clinical need. Increasing knowledge regarding the mechanisms and genetic aberrations underlying tumor development and growth has heralded a new era of therapy in oncology, moving away from indiscriminate cytotoxic chemotherapy toward more finely focused, targeted medicine. The development of small-molecule drugs and monoclonal antibodies directed toward specific components of dysfunctional molecular or immune pathways, and mutated genes specific to particular cancer types, is leading the field to more personalized and less toxic treatment options, many of which have demonstrated greater efficacy and survival benefits than their chemotherapeutic counterparts. Particularly successful examples are agents that interfere with the programmed death 1 (PD-1) pathway, which many tumors can hijack to avoid immune surveillance and editing. Pembrolizumab, a monoclonal antibody directed at PD-1 that blocks the engagement between PD-1 and its ligands, has been explored as a treatment for solid tumors, and demonstrated survival benefits in several studies. The use of PD-1 inhibitors such as nivolumab and pembrolizumab in advanced cancers is widespread, and pembrolizumab is available in more than 60 countries for at least one of the following: advanced melanoma, PD-L1–expressing NSCLC, head and neck squamous cell carcinoma, and adult and pediatric patients with refractory classical Hodgkin’s lymphoma. This work provides a brief overview of the role of pembrolizumab in the treatment of advanced (recurrent/metastatic) NSCLC.
Hypofractionated radiotherapy for prostate cancer in the postoperative setting: What is the evidence so far? Biomaterials (IF 8.402) Pub Date : 2017-11-14 Cristina Picardi, Ioan Perret, Raymond Miralbell, Thomas Zilli
Postoperative external beam radiation therapy (EBRT) is a validated treatment option in the adjuvant setting for prostate cancer patients with aggressive pathological features following radical prostatectomy (RP) or as salvage modality in patients with biochemical recurrence after RP. Contemporary randomized phase III trials have provided evidence for using hypofractionation in the definitive treatment setting as an alternative to standard fractionated regimens. Biomathematical modeling for prostate cancer fractionated EBRT associated with widely available refined treatment delivery techniques such as volumetric modulated-arc therapy with image-guided RT may improve the therapeutic ratio. Nevertheless, the role of hypofractionation in the postoperative setting still remains investigational. In this systematic review of the literature we reviewed the role of hypofractionation for postoperative EBRT in the adjuvant or salvage setting in prostate cancer patients previously treated by RP. A favorable acute toxicity profile with, at least, as good biochemical control rates with hypofractionation has been suggested. And yet conflicting results have been reported concerning long-term genitourinary late toxicity. Prospective studies are eagerly awaited to assess the role of hypofractionation in the postoperative setting.
Efficacy and safety of regorafenib in the treatment of metastatic colorectal cancer: A systematic review Biomaterials (IF 8.402) Pub Date : 2017-11-10 Maria Røed Skårderud, Anne Polk, Kirsten Kjeldgaard Vistisen, Finn Ole Larsen, Dorte Lisbet Nielsen
Purpose Despite advances in the treatment of colorectal cancer, third-line treatment options are still limited. Regorafenib was approved in 2012 for the treatment of patients with metastatic colorectal cancer previously treated with approved standard therapy. The purpose of this review is to present existing clinical data on regorafenib. Method We systematically searched the PubMed and Embase databases, as well as ASCO and ESMO conference abstracts, for studies in English including ≥30 patients, evaluating the efficacy and safety of regorafenib in patients with metastatic colorectal cancer. A meta-analysis was conducted on the published, randomized phase III trials. Results 24 eligible studies were included. In two phase III trials, regorafenib significantly increased overall survival (OS), progression free survival (PFS), and disease control rate when compared to placebo. Survival benefits of 1.4 and 2.5 months were presented. The meta-analysis indicated a significant greater treatment effect on OS (hazard ratio 0.67) and PFS (hazard ratio 0.40), compared to placebo. The non-randomized studies mostly supported these results. The most frequently reported adverse events were hand-foot-skin reaction (25%–86%), hypertension (11%–47%) and fatigue (2%–73%). Conclusion Large phase III randomized trials indicate that regorafenib provides a benefit in OS and PFS when compared to placebo. Adverse events were common, but manageable and typical of multi-target tyrosine kinase inhibitors. Further research is needed to investigate alternative approaches to the dosing of regorafenib and to explore clinical and molecular biomarkers that can guide patient selection.
Epidermal growth factor receptor overexpression and outcomes in early breast cancer: A systematic review and a meta-analysis Biomaterials (IF 8.402) Pub Date : 2017-10-31 Galileo A. Gonzalez-Conchas, Laura Rodriguez-Romo, David Hernandez-Barajas, Juan F. Gonzalez-Guerrero, Ivan A. Rodriguez-Fernandez, Adrian Verdines-Perez, Arnoud J. Templeton, Alberto Ocana, Bostjan Seruga, Ian F. Tannock, Eitan Amir, Francisco E. Vera-Badillo
Background The epidermal growth factor receptor (EGFR) is a member of the ErbB family of membrane tyrosine-kinase receptors. Studies exploring the prognostic role of EGFR-overexpression in early breast cancer have shown variable results, and the true prognostic value of EGFR is unknown. Methods A systematic review of identified publications exploring the association between EGFR-overexpression (as defined from different techniques and cut-offs) and outcomes [disease-free (DFS) and, overall survival (OS)] in women with early breast cancer. The hazard ratios (HR) for DFS and OS were weighted and pooled in a meta-analysis using generic inverse variance and random effects modeling. Results Fifty-three studies comprising 21,418 women were included. EGFR-overexpression was found in 27% of the patients. Primary analysis included studies reporting HRs from multivariable analyses (10 studies including 4857 patients with HRs for OS and 17 studies comprising 8747 patients with HRs for DFS), EGFR-overexpression was associated with worse OS (HR 1.98, 95% CI: 1.59–2.47, p < .001) and DFS (HR 1.59, 95% CI 1.30–1.95, p < .001). The influence of EGFR overexpression on DFS was greater in women with triple negative tumors compared to women with non-triple negative tumors (HR 2.35 versus HR 1.45, respectively; p = .01). Analysis looking at odd ratios for both 5-year and 10-year for DFS and OS showed similar results. Conclusion EGFR-overexpression appears to be associated with reduced OS and DFS in women with early breast cancer. Patients with triple negative and EGFR-overexpression have poorer OS and DFS than those with triple negative tumors and normal EGFR expression.
The anti-tumor effect of RANKL inhibition in malignant solid tumors – A systematic review Biomaterials (IF 8.402) Pub Date : 2017-11-01 A.F. de Groot, N.M. Appelman-Dijkstra, S.H. van der Burg, J.R. Kroep
At present, accumulating evidence suggests that inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) does not only induce an increase in bone mass and strength, but also has anti-tumor effects. Denosumab, an antibody targeting RANKL, is used to treat osteoporosis and to prevent skeletal related events (SREs) in patients with bone metastases originating from solid tumors. However, expression of RANKL and its receptor activator of nuclear factor kappa-B (RANK) is not solely restricted to cells involved in homeostasis of the bone and RANKL-RANK signalling appears to play a substantial role in many other processes in the body like mammary physiology, mammary tumorigenesis and the immune system. In pre-clinical models, RANKL inhibition has been shown to reduce skeletal tumor burden and distant metastases as well as to decrease mammary carcinogenesis. Clinically, RANKL inhibition improves bone-metastasis free survival in patients with prostate cancer and disease-free survival in patients with breast cancer. In addition, RANKL treatment may form a preventative strategy in patients at high risk for malignancies of the breast. Current clinical studies are evaluating the effect of denosumab on survival, the immune system and other biomarkers into a greater extent. To that purpose, a systematic review of the literature was performed and a narrative review synthesized, describing the present pre-clinical and clinical evidence of an anti-tumor effect of RANKL inhibition and the potential role of the immune system as one of the underlying mechanisms.
The updated network meta-analysis of neoadjuvant therapy for HER2-positive breast cancer Biomaterials (IF 8.402) Pub Date : 2017-10-31 Ayako Nakashoji, Tetsu Hayashida, Takamichi Yokoe, Hinako Maeda, Tomoka Toyota, Masayuki Kikuchi, Rurina Watanuki, Aiko Nagayama, Tomoko Seki, Maiko Takahashi, Takayuki Abe, Yuko Kitagawa
Background We previously described a systematic assessment of the neoadjuvant therapies for human epidermal growth factor receptor-2 (HER2) positive breast cancer, using network meta-analysis. Accumulation of new clinical data has compelled us to update the analysis. Methods Randomized trials comparing different anti-HER2 regimens in the neoadjuvant setting were included, and odds ratio for pathologic complete response (pCR) in seven treatment arms were assessed by pooling effect sizes. Direct and indirect comparisons using a Bayesian statistical model were performed. All statistical tests were two-sided. Results A database search identified 993 articles with 13 studies meeting the eligibility criteria, including three new studies with lapatinib (lpnb). In an indirect comparison, dual anti-HER2 agents with CT achieved a better pCR rate than other arms. The credibility intervals of CT + tzmb + lpnb arm were largely reduced compared to our former report, which we added sufficient clinical evidence by this update. Values of surface under the cumulative ranking (SUCRA) suggested that CT + tzmb + pzmb had the highest probability of being the best treatment arm for pCR, widening the difference between the top two dual-HER2 blockade arms compared to our former report. The overall consistency with our first report enhanced the credibility of the results. Conclusion Network meta-analysis using new clinical data firmly establish that combining two anti-HER2 agents with CT is most effective against HER2-positive breast cancer in the neoadjuvant setting. New pzmb related trials are required to fully determine the best neoadjuvant dual-HER2 blockade regimen.
Advances in sarcoma gene mutations and therapeutic targets Biomaterials (IF 8.402) Pub Date : 2017-11-11 Peng Gao, Nicole A. Seebacher, Francis Hornicek, Zheng Guo, Zhenfeng Duan
Sarcomas are rare and complex malignancies that have been associated with a poor prognostic outcome. Over the last few decades, traditional treatment with surgery and/or chemotherapy has not significantly improved outcomes for most types of sarcomas. In recent years, there have been significant advances in the understanding of specific gene mutations that are important in driving the pathogenesis and progression of sarcomas. Identification of these new gene mutations, using next-generation sequencing and advanced molecular techniques, has revealed a range of potential therapeutic targets. This, in turn, may lead to the development of novel agents targeted to different sarcoma subtypes. In this review, we highlight the advances made in identifying sarcoma gene mutations, including those of p53, RB, PI3K and IDH genes, as well as novel therapeutic strategies aimed at utilizing these mutant genes. In addition, we discuss a number of preclinical studies and ongoing early clinical trials in sarcoma targeting therapies, as well as gene editing technology, which may provide a better choice for sarcoma patient management.
Systematic review of the clinical and economic value of gene expression profiles for invasive early breast cancer available in Europe Biomaterials (IF 8.402) Pub Date : 2017-11-06 E.J. Blok, E. Bastiaannet, W.B. van den Hout, G.J. Liefers, V.T.H.B.M. Smit, J.R. Kroep, C.J.H. van de Velde
Gene expression profiles with prognostic capacities have shown good performance in multiple clinical trials. However, with multiple assays available and numerous types of validation studies performed, the added value for daily clinical practice is still unclear. In Europe, the MammaPrint, OncotypeDX, PAM50/Prosigna and Endopredict assays are commercially available. In this systematic review, we aim to assess these assays on four important criteria: Assay development and methodology, clinical validation, clinical utility and economic value. We performed a literature search covering PubMed, Embase, Web of Science and Cochrane, for studies related to one or more of the four selected assays. We identified 147 papers for inclusion in this review. MammaPrint and OncotypeDX both have evidence available, including level IA clinical trial results for both assays. Both assays provide prognostic information. Predictive value has only been shown for OncotypeDX. In the clinical utility studies, a higher reduction in chemotherapy was achieved by OncotypeDX, although the number of available studies differ considerably between tests. On average, economic evaluations estimate that genomic testing results in a moderate increase in total costs, but that these costs are acceptable in relation to the expected improved patient outcome. PAM50/prosigna and EndoPredict showed comparable prognostic capacities, but with less economical and clinical utility studies. Furthermore, for these assays no level IA trial data are available yet. In summary, all assays have shown excellent prognostic capacities. The differences in the quantity and quality of evidence are discussed. Future studies shall focus on the selection of appropriate subgroups for testing and long-term outcome of validation trials, in order to determine the place of these assays in daily clinical practice.
Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors Biomaterials (IF 8.402) Pub Date : 2017-11-13 Nithya Krishnamurthy, Razelle Kurzrock
Triple negative breast cancer: Emerging therapeutic modalities and novel combination therapies Biomaterials (IF 8.402) Pub Date : 2017-11-13 Alice Lee, Mustafa B.A. Djamgoz
Triple negative breast cancer (TNBC) is a complex and aggressive subtype of breast cancer which lacks oestrogen receptors, progesterone receptors and HER2 amplification, thereby making it difficult to target therapeutically. In addition, TNBC has the highest rates of metastatic disease and the poorest overall survival of all breast cancer subtypes. Resultantly, development of targeted therapies for TNBC is urgently needed. Recent efforts aimed at molecular characterisation of TNBCs have revealed various emerging therapeutic targets including PARP1, receptor and non-receptor tyrosine kinases, immune-checkpoints, androgen receptor and epigenetic proteins. Key successes include that of the PARP inhibitor, olaparib, which prolonged progression-free survival in a trial of BRCA-mutated breast cancer and for which clinical approval (in this setting) appears imminent. Nevertheless, the heterogeneity of TNBC has limited the clinical benefits of many trialled therapies in ‘unselected’ patients. Further, drug resistance develops following use of many targeted monotherapies due to upregulation of compensatory signalling pathways. In this review, we evaluate the current status of investigational targeted treatments and present evidence for the role of novel biomarkers and combination therapies in increasing response rates and circumventing drug-induced resistance. Additionally, we discuss promising novel targets in metastatic TNBC identified through preclinical and/or epidemiological studies.
Staging and Surgical Approaches in Gastric Cancer: A Systematic Review Biomaterials (IF 8.402) Pub Date : 2017-12-13 Natalie Coburn, Roxanne Cosby, Laz Klein, Gregory Knight, Richard Malthaner, Joseph Mamazza, C. Dale Mercer, Jolie Ringash
Background Gastric adenocarcinoma accounted for 6.8% of new cancer cases and 8.8% of cancer deaths worldwide in 2012. Although resection is the cornerstone for cure, several aspects of surgical intervention remain controversial or sub-optimally applied at the population level. These include staging, extent of lymph node dissection (LND), optimal requirements of LN assessment, minimum resection margins, surgical technique (laparoscopic vs. open), relationship between surgical volumes and patient outcomes, and resection of stage IV gastric cancer. Methods A systematic review was conducted to inform surgical care. Results The evidence included in this systematic review consists of one guideline, seven systematic reviews and 48 primary studies. Conclusions All patients should be discussed at a multidisciplinary team meeting and a staging CT of the chest and abdomen should always be performed. Diagnostic laparoscopy should be performed in patients at risk for stage IV disease. A D2 LND is preferred for curative-intent resection in advanced non-metastatic gastric cancer. At least 16 LNs should be assessed for adequate staging of curative-resected gastric cancer. Gastric cancer surgery should aim to achieve an RO resection margin. In the metastatic setting, surgery should only be considered for palliation of symptoms. Patients should be referred to higher volume centres, and those with adequate support to manage potential complications. Laparoscopic resections should be performed to the same standards as open resections.
A systematic review of the effectiveness of patient-based educational interventions to improve cancer-related pain Biomaterials (IF 8.402) Pub Date : 2017-12-13 Wendy H. Oldenmenger, Jenske I. Geerling, Irina Mostovaya, Kris C.P. Vissers, Alexander de Graeff, Anna K.L. Reyners, Yvette M. van der Linden
Background Despite existing guidelines to assess and manage pain, the management of cancer-related pain is often suboptimal with patients often being undertreated. Inadequate pain management may be due to patient-related barriers. Educating patients may decrease these barriers. However, the effect of pain education on patient-related outcomes is still unclear. This review aimed to study the effect of educational interventions on cancer-related pain. Design We performed a systematic review of randomized controlled trials (RCTs) identified from Medline and Cinahl, from 1995 to May 2017.Two reviewers independently selected trials comparing educational intervention to usual care or an active control intervention. The methodological quality was assessed and data extraction was done independently. Primary outcome measures were pain intensity and interference. Secondary outcome measures were knowledge/barriers, medication adherence and self-efficacy. Results Twenty-six RCTs totaling 4735 patients met our inclusion criteria. Compared to the control group, 31% of the studies (including 19% of all patients) reported a significant difference in pain intensity in favor of the intervention group. Twelve studies measured pain interference and four (30%) found a significant improvement. With regard to secondary endpoints, significant differences in favor of the experimental arms were found for pain knowledge or barriers (15/22 studies; 68%), medication adherence (3/6 studies; 50%) and self-efficacy (1/2 studies). Conclusions Patient-based pain educational programs may result in improvements of relevant patient-reported outcomes. However, the interventions are heterogeneous and improvement of pain was only seen in less than one third of the studies and in less than 20% of all included patients.
Cancer Immunotherapy in a Neglected Population: The Current Use and Future of T-cell-Mediated Checkpoint Inhibitors in Organ Transplant Patients Biomaterials (IF 8.402) Pub Date : 2017-12-08 Young Kwang Chae, Carlos Galvez, Jonathan F. Anker, Wade T. Iams, Manali Bhave
Although the indications for immune checkpoint inhibitors continue to grow, organ transplant recipients with advanced malignancies have been largely excluded from clinical trials testing the safety and efficacy of these therapies given their need for chronic immunosuppression and the risk of allograft rejection. With the rapid growth of transplant medicine and the increased risk of malignancy associated with chronic immunosuppression, it is critical that we systematically analyze the available data describing immune checkpoint blockade in the organ transplant population. Herein we provide a current and comprehensive review of cases in which immune checkpoint blockade was used on organ transplant recipients. Furthermore, we discuss the differences in efficacy and risk of allograft rejection between CTLA-4 and PD-1 inhibitors and make recommendations based on the limited available clinical data. We also discuss the future of immune checkpoint blockade in this subpopulation and explore the emerging data of promising combination therapies with mTOR, BRAF/MEK, and BTK/ITK inhibitors. Further clinical experience and larger clinical trials involving immune checkpoint inhibitors, whether as monotherapies or combinatorial therapies, will help develop regimens that optimize anti-tumor response and minimize the risk of allograft rejection in organ transplant patients.
Aiming for the Insulin-like Growth Factor-1 system in breast cancer therapeutics Biomaterials (IF 8.402) Pub Date : 2017-12-06 Panagiotis F. Christopoulos, Alexandre Corthay, Michael Koutsilieris
Despite the major discoveries occurred in oncology the recent years, breast malignancies remain one of the most common causes of cancer-related deaths for women in developed countries. Development of HER2-targeting drugs has been considered a breakthrough in anti-cancer approaches and alluded to the potential of targeting growth factors in breast cancer (BrCa) therapeutics. More than twenty five years have passed since the Insulin-like Growth Factor-1 (IGF-1) system was initially recognized as a potential target candidate in BrCa therapy. To date, a growing body of studies have implicated the IGF-1 signaling with the BrCa biology. Despite the promising experimental evidence, the impression from clinical trials is rather disappointing. Several reasons may account for this and the last word regarding the efficacy of this system as a target candidate in BrCa therapeutics is probably not written yet. Herein, we provide the theoretical basis, as well as, a comprehensive overview of the current literature, regarding the different strategies targeting the various components of the IGF-1/IGF-1R axis in several pathophysiological aspects of BrCa, including the tumor micro-environment and cancer stemness. In addition, we review the rationale for targeting the IGF-1 system in the different BrCa molecular subtypes and in treatment resistant breast tumors with a focus on both the molecular mechanisms and on the clinical perspectives of such approaches in specific population subgroups. We also discuss the future challenges, as well as, the development of novel molecules and strategies targeting the system and suggest potential improvements in the field.
Ongoing Unmet Needs in Treating Estrogen Receptor-Positive/HER2-Negative Metastatic Breast Cancer Biomaterials (IF 8.402) Pub Date : 2017-12-06 Gül A. Başaran, Chris Twelves, Véronique Diéras, Javier Cortés, Ahmad Awada
Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 (HER2)−negative advanced or metastatic breast cancer (MBC) is the most common MBC subtype and currently remains incurable, with a median overall survival of 24.8 months (95% confidence interval, 21.3–30.3). Common sites of metastases are bone, viscera, and brain, causing significant symptoms that negatively affect patient functioning, quality of life (QoL), and work productivity. Guidelines state that endocrine therapy (ET) is preferable to chemotherapy as first-line treatment for patients with ER+ MBC, regardless of limited visceral metastases, unless rapid tumor response is required or ET resistance is suspected. Although response rates up to 40% have been reported for first-line MBC treatment, the majority of initial responders eventually develop ET resistance. Notwithstanding the steep decline in efficacy between first and later lines of ET, some patients may receive chemotherapy earlier than necessary. Although new treatments have been approved for patients with ER+/HER2− advanced or MBC in the past decade, neither survival nor QoL appear to have improved significantly. Thus, there remain significant unmet needs for this patient population, including improved survival, maintaining or improving patient QoL, and emphasizing the importance of treatment selection to assist healthcare practitioners managing patient care. In this review, we identify current challenges and unmet needs in this patient population, review cutting-edge treatments, and provide clinically relevant suggestions for treatment selection that can optimize outcomes and patients’ health-related QoL.
Management of QT prolongation induced by anti-cancer drugs: target therapy and old agents. Different algorithms for different drugs. Biomaterials (IF 8.402) Pub Date : 2017-12-06 Carmela Coppola, Anna Rienzo, Giovanna Piscopo, Antonio Barbieri, Claudio Arra, Nicola Maurea
Multi-agent chemotherapy in advanced soft tissue sarcoma (STS) – A systematic review and meta-analysis Biomaterials (IF 8.402) Pub Date : 2017-12-06 Alona Zer, Rebecca M. Prince, Eitan Amir, Albiruni R Abdul Razak
Background Despite a lack of improvement in overall survival (OS) with doxorubicin-based combinations over doxorubicin alone in advanced STS, the role of multi-agent chemotherapy remains poorly defined. Methods We conducted a systematic review and meta-analysis to evaluate benefits and harms of multi-agent chemotherapy in advanced STS. Eligible studies were randomized trials of chemotherapy in advanced STS comparing single agent to multi-agent therapy. Data from studies reporting a hazard ratio (HR) and 95% confidence intervals (CI) for OS and progression-free survival (PFS) were pooled in a meta-analysis. Meta-regression was utilized to explore the association between efficacy (OS and PFS) and both toxicity and dose intensity. Results We identified 22 trials published between 1974 and April 2016 and comprising 5044 patients. Overall, multi-agent chemotherapy was associated with improved OS (HR:0.79, p=0.02), and borderline improvement in PFS (HR:0.86, p=0.05). While the effect on OS was similar in trials with non-anthracycline controls compared to those with anthracycline controls (HR for OS 0.73 vs. 0.82, p for difference=0.63) there was a non-significantly greater effect for multi-agent chemotherapy on PFS in non-anthracycline RCT (HR for PFS 0.73 vs. 0.91, p for difference=0.13). Compared to studies with cytotoxic therapy-based multi-agent therapy, a non-significantly greater magnitude of effect among studies with biological/cytostatic experimental groups was seen (HR for OS 0.64 vs. 0.86, p for difference=0.37). There was a borderline significant association between dose reductions (which were more common in combination arms) and worse PFS (beta=0.70, p=0.053). Conclusion Multi-agent chemotherapy is associated with a modest, but statistically significant improvement in outcomes in STS. Combining chemotherapy with non-cytotoxic agents might represent a promising strategy.
Risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutated patients: An evidence-based approach on what women should know Biomaterials (IF 8.402) Pub Date : 2017-09-28 F. De Felice, C. Marchetti, S.M. Boccia, A. Romito, C.M. Sassu, M.G. Porpora, L. Muzii, V. Tombolini, P. Benedetti Panici
This review is focused on the ovarian cancer risk reduction management in BRCA mutation carriers and is intended to assist with clinical decision-making. Obviously, treatment decisions must be based on the available evidence. Despite risk-reducing salpingo-oophorectomy is firmly recommended, several separate questions can be raised to address the variety of intense controversy of this approach. A special emphasis lies in the effective preventive surgical measure against ovarian cancer risk, in an attempt to detect the optimal timing and mitigate the impact on patients. The long term implications of risk-reducing salpingo-oophorectomy as well as hormone replacement therapy are also actively debated. This is expected to represent an opportunity for improved management modelling of BRCA mutated patients.
Androgen receptor in estrogen receptor positive breast cancer: Beyond expression Biomaterials (IF 8.402) Pub Date : 2017-10-06 Debora Basile, Marika Cinausero, Donatella Iacono, Giacomo Pelizzari, Marta Bonotto, Maria Grazia Vitale, Lorenzo Gerratana, Fabio Puglisi
In recent years, new therapeutic approaches have reshaped the overall strategy of breast cancer (BC) treatment and have markedly improved patient survival. This is, in part, due to novel therapies for estrogen receptor (ER)-positive BC. Unfortunately, many patients present de novo resistance to these therapies or develop an acquired resistance over time. Therefore, research is now focused on discovering new molecular targets to overcome these resistances. Interestingly, preclinical and clinical studies have shown a critical role for the cross-talk between androgen receptor (AR) and ER in luminal-like BC. AR is expressed in >60% of BC and in up to 90% of ERα-positive tumors. Multiple studies suggest that AR is associated with a favorable prognosis. However, AR overexpression and, in particular, the high AR:ER ratio, seem to be involved in resistance to hormonal treatment. In this setting, a group of BCs could benefit from AR-inhibitors; nevertheless, some ER-positive BC patients do not seem to benefit from this strategy. Therefore, it is crucial to identify biomarkers that would enable the selection of patients who might benefit from combination treatment with ER and AR inhibitors.
The next era of treatment for hormone receptor-positive, HER2-negative advanced breast cancer: Triplet combination-based endocrine therapies Biomaterials (IF 8.402) Pub Date : 2017-10-12 Javier Cortés, Seock-Ah Im, Esther Holgado, Jose M. Perez-Garcia, Peter Schmid, Mariana Chavez-MacGregor
Until recently, the standard of care for hormone receptor-positive (HR+) breast cancer was single-agent endocrine therapy, which aims to prevent estrogen receptor signaling. This therapeutic strategy has extended survival without the toxicity associated with chemotherapy, but primary endocrine therapy resistance is common, and secondary resistance develops over time. Adjunct downstream inhibition of the cyclin-dependent kinase (CDK)4/6 pathway, intended to delay and prevent endocrine therapy resistance, has further extended progression-free survival in patients receiving endocrine therapy; however, resistance still eventually develops in these patients. Addition of phosphatidylinositol-3 kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitors to combined CDK4/6 and endocrine inhibitor regimens may help prolong CDK4/6 inhibitor sensitivity. Early trials combining CDK4/6 inhibitors, PI3K or mTOR inhibitors, and endocrine therapy have shown encouraging signs of clinical activity. However, further research is needed to help understand the extent of treatment benefit from triplet therapy and where this strategy will fit in the treatment sequence for patients with HR+ breast cancer.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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