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Cancers, Volume 7, Issue 2 (June 2015) – 33 articles

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18 pages, 720 KiB  
Review
Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets
by Meena Jhanwar-Uniyal *, Michael Labagnara, Marissa Friedman, Amanda Kwasnicki and Raj Murali
Department of Neurosurgery, New York Medical College, Valhalla, NY 10595, USA
Cancers 2015, 7(2), 538-555; https://doi.org/10.3390/cancers7020538 - 25 Mar 2015
Cited by 102 | Viewed by 12160
Abstract
Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to [...] Read more.
Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM. Full article
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18 pages, 662 KiB  
Review
cMET in NSCLC: Can We Cut off the Head of the Hydra? From the Pathway to the Resistance
by Nele Van Der Steen 1, Patrick Pauwels 1,2, Ignacio Gil-Bazo 3, Eduardo Castañon 3,6, Luis Raez 4, Federico Cappuzzo 5 and Christian Rolfo 1,6,*
1 Center for Oncological Research Antwerp, University of Antwerp, Universiteitsplein 1, Wilrijk 2610, Belgium
2 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Wilrijkstraat 10, Edegem 2650, Belgium
3 Department of Oncology, Clínica Universidad de Navarra, Pamplona 31008, Spain
4 Thoracic Oncology Program, Memorial Cancer Institute, Memorial Health Care System, Pembroke Pines, FL 33024, USA
5 Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy viale Alfieri 36, Livorno 57100, Italy
6 Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Wilrijkstraat 10, Edegem 2650, Belgium
Cancers 2015, 7(2), 556-573; https://doi.org/10.3390/cancers7020556 - 25 Mar 2015
Cited by 37 | Viewed by 8389
Abstract
In the last decade, the tyrosine kinase receptor cMET, together with its ligand hepatocyte growth factor (HGF), has become a target in non-small cell lung cancer (NSCLC). Signalization via cMET stimulates several oncological processes amongst which are cell motility, invasion and metastasis. It [...] Read more.
In the last decade, the tyrosine kinase receptor cMET, together with its ligand hepatocyte growth factor (HGF), has become a target in non-small cell lung cancer (NSCLC). Signalization via cMET stimulates several oncological processes amongst which are cell motility, invasion and metastasis. It also confers resistance against several currently used targeted therapies, e.g., epidermal growth factor receptor (EGFR) inhibitors. In this review, we will discuss the basic structure of cMET and the most important signaling pathways. We will also look into aberrations in the signaling and the effects thereof in cancer growth, with the focus on NSCLC. Finally, we will discuss the role of cMET as resistance mechanism. Full article
(This article belongs to the Special Issue Non-Small Cell Lung Cancer Therapies)
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11 pages, 1451 KiB  
Communication
Improved Beam Angle Arrangement in Intensity Modulated Proton Therapy Treatment Planning for Localized Prostate Cancer
by Wenhua Cao 1, Gino J. Lim 1, Yupeng Li 2, X. Ronald Zhu 3 and Xiaodong Zhang 3,*
1 Department of Industrial Engineering, University of Houston, Houston, TX 77204, USA
2 Applied Research, Varian Medical Systems, Palo Alto, CA 94304, USA
3 Department of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Cancers 2015, 7(2), 574-584; https://doi.org/10.3390/cancers7020574 - 30 Mar 2015
Cited by 20 | Viewed by 9670
Abstract
Purpose: This study investigates potential gains of an improved beam angle arrangement compared to a conventional fixed gantry setup in intensity modulated proton therapy (IMPT) treatment for localized prostate cancer patients based on a proof of principle study. Materials and Methods: [...] Read more.
Purpose: This study investigates potential gains of an improved beam angle arrangement compared to a conventional fixed gantry setup in intensity modulated proton therapy (IMPT) treatment for localized prostate cancer patients based on a proof of principle study. Materials and Methods: Three patients with localized prostate cancer retrospectively selected from our institution were studied. For each patient, IMPT plans were designed using two, three and four beam angles, respectively, obtained from a beam angle optimization algorithm. Those plans were then compared with ones using two lateral parallel-opposed beams according to the conventional planning protocol for localized prostate cancer adopted at our institution. Results: IMPT plans with two optimized angles achieved significant improvements in rectum sparing and moderate improvements in bladder sparing against those with two lateral angles. Plans with three optimized angles further improved rectum sparing significantly over those two-angle plans, whereas four-angle plans found no advantage over three-angle plans. A possible three-beam class solution for localized prostate patients was suggested and demonstrated with preserved dosimetric benefits because individually optimized three-angle solutions were found sharing a very similar pattern. Conclusions: This study has demonstrated the potential of using an improved beam angle arrangement to better exploit the theoretical dosimetric benefits of proton therapy and provided insights of selecting quality beam angles for localized prostate cancer treatment. Full article
(This article belongs to the Special Issue Proton Therapy for Cancer)
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13 pages, 1030 KiB  
Review
Profiling Invasiveness in Head and Neck Cancer: Recent Contributions of Genomic and Transcriptomic Approaches
by Lluís Nisa 1,2,3,*, Daniel Matthias Aebersold 1,2, Roland Giger 3, Marco Domenico Caversaccio 3, Urs Borner 3, Michaela Medová 1,2 and Yitzhak Zimmer 1,2,*
1 Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern 3010, Switzerland
2 Department of Clinical Research, Inselspital, Bern University Hospital, and University of Bern, MEM-E807, Murtenstrasse 35, Bern 3010, Switzerland
3 Department of Otorhinolaryngology—Head and Neck Surgery, Inselspital, Bern University Hospital, and University of Bern, Bern 3010, Switzerland
Cancers 2015, 7(2), 585-597; https://doi.org/10.3390/cancers7020585 - 31 Mar 2015
Cited by 8 | Viewed by 6590
Abstract
High-throughput molecular profiling approaches have emerged as precious research tools in the field of head and neck translational oncology. Such approaches have identified and/or confirmed the role of several genes or pathways in the acquisition/maintenance of an invasive phenotype and the execution of [...] Read more.
High-throughput molecular profiling approaches have emerged as precious research tools in the field of head and neck translational oncology. Such approaches have identified and/or confirmed the role of several genes or pathways in the acquisition/maintenance of an invasive phenotype and the execution of cellular programs related to cell invasion. Recently published new-generation sequencing studies in head and neck squamous cell carcinoma (HNSCC) have unveiled prominent roles in carcinogenesis and cell invasion of mutations involving NOTCH1 and PI3K-patwhay components. Gene-expression profiling studies combined with systems biology approaches have allowed identifying and gaining further mechanistic understanding into pathways commonly enriched in invasive HNSCC. These pathways include antigen-presenting and leucocyte adhesion molecules, as well as genes involved in cell-extracellular matrix interactions. Here we review the major insights into invasiveness in head and neck cancer provided by high-throughput molecular profiling approaches. Full article
(This article belongs to the Special Issue Cancer Cell Invasion)
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19 pages, 522 KiB  
Review
The Roles of MicroRNAs in Breast Cancer
by Ryou-u Takahashi 1, Hiroaki Miyazaki 1,2 and Takahiro Ochiya 1,*
1 Division of Molecular and Cellular Medicine, National Cancer Center Research Institute 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
2 Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, 1-5-8 Hatanodai Shinagawa-ku, Tokyo 142-8555, Japan
Cancers 2015, 7(2), 598-616; https://doi.org/10.3390/cancers7020598 - 9 Apr 2015
Cited by 126 | Viewed by 13220
Abstract
MicroRNAs (miRNAs) constitute a large family of small, approximately 20–22 nucleotide, non-coding RNAs that regulate the expression of target genes, mainly at the post-transcriptional level. Accumulating lines of evidence have indicated that miRNAs play important roles in the maintenance of biological homeostasis and [...] Read more.
MicroRNAs (miRNAs) constitute a large family of small, approximately 20–22 nucleotide, non-coding RNAs that regulate the expression of target genes, mainly at the post-transcriptional level. Accumulating lines of evidence have indicated that miRNAs play important roles in the maintenance of biological homeostasis and that aberrant expression levels of miRNAs are associated with the onset of many diseases, including cancer. In various cancers, miRNAs play important roles in tumor initiation, drug resistance and metastasis. Recent studies reported that miRNAs could also be secreted via small endosome-derived vesicles called exosomes, which are derived from multiple cell types, including dendritic cells, lymphocytes, and tumor cells. Exosomal miRNAs play an important role in cell-to-cell communication and have been investigated as prognostic and diagnostic biomarkers. In this review, we summarize the major findings related to the functions of miRNAs in breast cancer, which is the most frequent cancer in women, and discuss the potential clinical uses of miRNAs, including their roles as therapeutic targets and diagnostic markers. Full article
(This article belongs to the Special Issue Breast Cancer Biology and Treatment)
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14 pages, 906 KiB  
Article
Predictive Risk of Radiation Induced Cerebral Necrosis in Pediatric Brain Cancer Patients after VMAT Versus Proton Therapy
by Derek Freund 1,2,†, Rui Zhang 1,2,*, Mary Sanders 1 and Wayne Newhauser 1,2
1 Department of Radiation Oncology, Mary Bird Perkins Cancer Center, 4950 Essen Ln., Baton Rouge, LA 70809, USA
2 Department of Physics and Astronomy, Louisiana State University, Nicholson Hall, Tower Dr., Baton Rouge, LA 70810, USA
Current address: Department of Radiation Oncology, Willis Knighton Cancer Center, 2600 Kings Hwy, Shreveport, LA 71103, USA.
Cancers 2015, 7(2), 617-630; https://doi.org/10.3390/cancers7020617 - 10 Apr 2015
Cited by 23 | Viewed by 8566
Abstract
Cancer of the brain and central nervous system (CNS) is the second most common of all pediatric cancers. Treatment of many of these cancers includes radiation therapy of which radiation induced cerebral necrosis (RICN) can be a severe and potentially devastating side effect. [...] Read more.
Cancer of the brain and central nervous system (CNS) is the second most common of all pediatric cancers. Treatment of many of these cancers includes radiation therapy of which radiation induced cerebral necrosis (RICN) can be a severe and potentially devastating side effect. Risk factors for RICN include brain volume irradiated, the dose given per fraction and total dose. Thirteen pediatric patients were selected for this study to determine the difference in predicted risk of RICN when treating with volumetric modulated arc therapy (VMAT) compared to passively scattered proton therapy (PSPT) and intensity modulated proton therapy (IMPT). Plans were compared on the basis of dosimetric endpoints in the planned treatment volume (PTV) and brain and a radiobiological endpoint of RICN calculated using the Lyman-Kutcher-Burman probit model. Uncertainty tests were performed to determine if the predicted risk of necrosis was sensitive to positional errors, proton range errors and selection of risk models. Both PSPT and IMPT plans resulted in a significant increase in the maximum dose to the brain, a significant reduction in the total brain volume irradiated to low doses, and a significant lower predicted risk of necrosis compared with the VMAT plans. The findings of this study were upheld by the uncertainty analysis. Full article
(This article belongs to the Special Issue Proton Therapy for Cancer)
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17 pages, 1114 KiB  
Review
Towards Effective and Efficient Patient-Specific Quality Assurance for Spot Scanning Proton Therapy
by X. Ronald. Zhu 1,*, Yupeng Li 1, Dennis Mackin 1, Heng Li 1, Falk Poenisch 1, Andrew K. Lee 2, Anita Mahajan 2, Steven J. Frank 2, Michael T. Gillin 1, Narayan Sahoo 1 and Xiaodong Zhang 1
1 Department of Radiation Physics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
2 Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
Cancers 2015, 7(2), 631-647; https://doi.org/10.3390/cancers7020631 - 10 Apr 2015
Cited by 64 | Viewed by 10751
Abstract
An intensity-modulated proton therapy (IMPT) patient-specific quality assurance (PSQA) program based on measurement alone can be very time consuming due to the highly modulated dose distributions of IMPT fields. Incorporating independent dose calculation and treatment log file analysis could reduce the time required [...] Read more.
An intensity-modulated proton therapy (IMPT) patient-specific quality assurance (PSQA) program based on measurement alone can be very time consuming due to the highly modulated dose distributions of IMPT fields. Incorporating independent dose calculation and treatment log file analysis could reduce the time required for measurements. In this article, we summarize our effort to develop an efficient and effective PSQA program that consists of three components: measurements, independent dose calculation, and analysis of patient-specific treatment delivery log files. Measurements included two-dimensional (2D) measurements using an ionization chamber array detector for each field delivered at the planned gantry angles with the electronic medical record (EMR) system in the QA mode and the accelerator control system (ACS) in the treatment mode, and additional measurements at depths for each field with the ACS in physics mode and without the EMR system. Dose distributions for each field in a water phantom were calculated independently using a recently developed in-house pencil beam algorithm and compared with those obtained using the treatment planning system (TPS). The treatment log file for each field was analyzed in terms of deviations in delivered spot positions from their planned positions using various statistical methods. Using this improved PSQA program, we were able to verify the integrity of the data transfer from the TPS to the EMR to the ACS, the dose calculation of the TPS, and the treatment delivery, including the dose delivered and spot positions. On the basis of this experience, we estimate that the in-room measurement time required for each complex IMPT case (e.g., a patient receiving bilateral IMPT for head and neck cancer) is less than 1 h using the improved PSQA program. Our experience demonstrates that it is possible to develop an efficient and effective PSQA program for IMPT with the equipment and resources available in the clinic. Full article
(This article belongs to the Special Issue Proton Therapy for Cancer)
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22 pages, 623 KiB  
Review
PP2A: The Wolf in Sheep’s Clothing?
by Maeve Kiely 1 and Patrick A. Kiely 1,2,*
1 Department of Life Sciences, and Materials and Surface Science Institute, University of Limerick, Limerick 78666, Ireland
2 Stokes Institute, University of Limerick 78666, Limerick, Ireland
Cancers 2015, 7(2), 648-669; https://doi.org/10.3390/cancers7020648 - 10 Apr 2015
Cited by 61 | Viewed by 16397
Abstract
Protein Phosphatase 2A (PP2A) is a major serine/threonine phosphatase in cells. It consists of a catalytic subunit (C), a structural subunit (A), and a regulatory/variable B-type subunit. PP2A has a critical role to play in homeostasis where its predominant function is as a [...] Read more.
Protein Phosphatase 2A (PP2A) is a major serine/threonine phosphatase in cells. It consists of a catalytic subunit (C), a structural subunit (A), and a regulatory/variable B-type subunit. PP2A has a critical role to play in homeostasis where its predominant function is as a phosphatase that regulates the major cell signaling pathways in cells. Changes in the assembly, activity and substrate specificity of the PP2A holoenzyme have a direct role in disease and are a major contributor to the maintenance of the transformed phenotype in cancer. We have learned a lot about how PP2A functions from specific mutations that disrupt the core assembly of PP2A and from viral proteins that target PP2A and inhibit its effect as a phosphatase. This prompted various studies revealing that restoration of PP2A activity benefits some cancer patients. However, our understanding of the mechanism of action of this is limited because of the complex nature of PP2A holoenzyme assembly and because it acts through a wide variety of signaling pathways. Information on PP2A is also conflicting as there are situations whereby inactivation of PP2A induces apoptosis in many cancer cells. In this review we discuss this relationship and we also address many of the pertinent and topical questions that relate to novel therapeutic strategies aimed at altering PP2A activity. Full article
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9 pages, 259 KiB  
Article
A Possible Association between Melanoma and Prostate Cancer. Results from a Case-Control-Study
by Alina Goldenberg 1,†, Shang I. Brian Jiang 2,3,† and Philip R. Cohen 3,*,†
1 School of Medicine, University of California, San Diego, CA 92093, USA
2 Mohs Micrographic and Dermatologic Surgery, University of California, San Diego, CA 92122, USA
3 Department of Dermatology, University of California, San Diego, CA 92122, USA
These authors contributed equally to this work.
Cancers 2015, 7(2), 670-678; https://doi.org/10.3390/cancers7020670 - 15 Apr 2015
Cited by 7 | Viewed by 6488
Abstract
Melanoma and prostate cancer are the fifth and first most common cancers in men within the United States, respectively. The association between the two cancers lies in the mutual androgen-dependence. However, the relationship between prostate cancer history and melanoma development remains to be [...] Read more.
Melanoma and prostate cancer are the fifth and first most common cancers in men within the United States, respectively. The association between the two cancers lies in the mutual androgen-dependence. However, the relationship between prostate cancer history and melanoma development remains to be further elucidated. We aim to determine the odds of history of prostate cancer among men with melanoma as compared to time-frame, clinic, and provider-matched controls without melanoma within a single academic surgical center. We present a case-control study comparing men treated for melanoma and non-melanoma cancer by a single provider between 2010 and 2014 within an academic dermatologic surgical center. Overall, there were nine cases of prostate cancer among the melanoma group and two cases amongst the controls—a statistically significant difference in both uni- and multivariable analyses (p = 0.057 [95% CI 1, 23.5], p = 0.042 [95% CI 1.1, 129], respectively). Body mass index, alcohol use, and skin type II were significant risk factors for melanoma (p = 0.011 [95% CI 1, 1.3], 0.005 [95% CI 1.4, 7], 0.025 [95% CI 1.1, 3.3], respectively). There were more immunosuppressed controls (p = 0.002); however, the melanoma patients had a significantly longer duration of immunosuppression (11.6 vs. 1.9 years, p < 0.001 [95% CI 0.03, 0.5]). Melanoma screenings for men should include questions on prostate cancer history. Prostate cancer patients may benefit from more frequent and comprehensive melanoma screening. Full article
(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)
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9 pages, 392 KiB  
Communication
Cardiometabolic and Skeletal Risk Factors in Black Men with Prostate Cancer Starting Androgen Deprivation Therapy
by Orvar Gunnarsson 1,*, Shehzad Basaria 2 and Gretchen A. Gignac 3
1 Department of Medicine, Division of Hematology and Oncology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 16 Penn Tower, Philadelphia, PA 19104, USA
2 Department of Medicine, Section of Men's Health, Aging and Metabolism, Brigham and Women's Hospital, Boston, MA 02115, USA
3 Department of Medicine, Section of Hematology and Oncology, Boston University School of Medicine, Boston, MA 02118, USA
Cancers 2015, 7(2), 679-687; https://doi.org/10.3390/cancers7020679 - 22 Apr 2015
Viewed by 5463
Abstract
Background: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to [...] Read more.
Background: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI), vitamin-D status, bone mineral density (BMD), dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between −1 to −2.5 and osteoporosis when T scores ≤−2.5. Results: Of the initial cohort of 130 black men, 111 (85.4%) patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. Conclusions: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications. Full article
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18 pages, 1251 KiB  
Article
Reducing the Cost of Proton Radiation Therapy: The Feasibility of a Streamlined Treatment Technique for Prostate Cancer
by Wayne D. Newhauser 1,2,*, Rui Zhang 1,2,3,4, Timothy G. Jones 3,4,5,†, Annelise Giebeler 3,4,‡, Phillip J. Taddei 3,4,#, Robert D. Stewart 6, Andrew Lee 3 and Oleg Vassiliev 1,2
1 Department of Physics and Astronomy, Louisiana State University, 202 Nicholson Hall, Baton Rouge, LA 70803, USA
2 Department of Physics, Mary Bird Perkins Cancer Center, 4950 Essen Lane, Baton Rouge, LA 70809, USA
3 Departments of Radiation Physics and Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
4 The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA
5 Department of Physics, Abilene Christian University, ACU Box 27963, Abilene, TX 79699, USA
6 Department of Radiation Oncology, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356043, Seattle, WA 98195, USA
Current address: 343 Van Gordan St 18-503, Lakewood, CO 80228, USA.
Current address: Scripps Proton Therapy Center, 9730 Summers Ridge Road, San Diego, CA 92121, USA.
# Current address: Department of Radiation Oncology, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon.
Cancers 2015, 7(2), 688-705; https://doi.org/10.3390/cancers7020688 - 24 Apr 2015
Cited by 8 | Viewed by 10310
Abstract
Proton radiation therapy is an effective modality for cancer treatments, but the cost of proton therapy is much higher compared to conventional radiotherapy and this presents a formidable barrier to most clinical practices that wish to offer proton therapy. Little attention in literature [...] Read more.
Proton radiation therapy is an effective modality for cancer treatments, but the cost of proton therapy is much higher compared to conventional radiotherapy and this presents a formidable barrier to most clinical practices that wish to offer proton therapy. Little attention in literature has been paid to the costs associated with collimators, range compensators and hypofractionation. The objective of this study was to evaluate the feasibility of cost-saving modifications to the present standard of care for proton treatments for prostate cancer. In particular, we quantified the dosimetric impact of a treatment technique in which custom fabricated collimators were replaced with a multileaf collimator (MLC) and the custom range compensators (RC) were eliminated. The dosimetric impacts of these modifications were assessed for 10 patients with a commercial treatment planning system (TPS) and confirmed with corresponding Monte Carlo simulations. We assessed the impact on lifetime risks of radiogenic second cancers using detailed dose reconstructions and predictive dose-risk models based on epidemiologic data. We also performed illustrative calculations, using an isoeffect model, to examine the potential for hypofractionation. Specifically, we bracketed plausible intervals of proton fraction size and total treatment dose that were equivalent to a conventional photon treatment of 79.2 Gy in 44 fractions. Our results revealed that eliminating the RC and using an MLC had negligible effect on predicted dose distributions and second cancer risks. Even modest hypofractionation strategies can yield substantial cost savings. Together, our results suggest that it is feasible to modify the standard of care to increase treatment efficiency, reduce treatment costs to patients and insurers, while preserving high treatment quality. Full article
(This article belongs to the Special Issue Proton Therapy for Cancer)
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17 pages, 176 KiB  
Review
Dosimetric Comparison and Potential for Improved Clinical Outcomes of Paediatric CNS Patients Treated with Protons or IMRT
by Kris S. Armoogum 1,*,† and Nicola Thorp 2,†
1 Department of Radiotherapy Physics, Royal Derby Hospital, Derby Hospitals NHS Foundation Trust, Uttoxeter Road, Derby DE22 3NE, UK
2 The Clatterbridge Cancer Centre NHS Foundation Trust, Clatterbridge Road, Bebington, Wirral CH63 4JY, UK
These authors contributed equally to this work.
Cancers 2015, 7(2), 706-722; https://doi.org/10.3390/cancers7020706 - 28 Apr 2015
Cited by 28 | Viewed by 7908
Abstract
Background: We compare clinical outcomes of paediatric patients with CNS tumours treated with protons or IMRT. CNS tumours form the second most common group of cancers in children. Radiotherapy plays a major role in the treatment of many of these patients but [...] Read more.
Background: We compare clinical outcomes of paediatric patients with CNS tumours treated with protons or IMRT. CNS tumours form the second most common group of cancers in children. Radiotherapy plays a major role in the treatment of many of these patients but also contributes to late side effects in long term survivors. Radiation dose inevitably deposited in healthy tissues outside the clinical target has been linked to detrimental late effects such as neurocognitive, behavioural and vascular effects in addition to endocrine abnormalities and second tumours. Methods: A literature search was performed using keywords: protons, IMRT, CNS and paediatric. Of 189 papers retrieved, 10 were deemed relevant based on title and abstract screening. All papers directly compared outcomes from protons with photons, five papers included medulloblastoma, four papers each included craniopharyngioma and low grade gliomas and three papers included ependymoma. Results: This review found that while proton beam therapy offered similar clinical target coverage, there was a demonstrable reduction in integral dose to normal structures. Conclusions: This in turn suggests the potential for superior long term outcomes for paediatric patients with CNS tumours both in terms of radiogenic second cancers and out-of-field adverse effects. Full article
(This article belongs to the Special Issue Proton Therapy for Cancer)
13 pages, 537 KiB  
Review
Pathologic Cellular Events in Smoking-Related Pancreatitis
by Edwin Thrower 1,2
1 Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
2 Veterans Affairs Connecticut Healthcare, West Haven, CT 06516, USA 
Cancers 2015, 7(2), 723-735; https://doi.org/10.3390/cancers7020723 - 29 Apr 2015
Cited by 13 | Viewed by 8183
Abstract
Pancreatitis, a debilitating inflammatory disorder, results from pancreatic injury. Alcohol abuse is the foremost cause, although cigarette smoking has recently surfaced as a distinct risk factor. The mechanisms by which cigarette smoke and its toxins initiate pathological cellular events leading to pancreatitis, have [...] Read more.
Pancreatitis, a debilitating inflammatory disorder, results from pancreatic injury. Alcohol abuse is the foremost cause, although cigarette smoking has recently surfaced as a distinct risk factor. The mechanisms by which cigarette smoke and its toxins initiate pathological cellular events leading to pancreatitis, have not been clearly defined. Although cigarette smoke is composed of more than 4000 compounds, it is mainly nicotine and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which have been extensively studied with respect to pancreatic diseases. This review summarizes these research findings and highlights cellular pathways which may be of relevance in initiation and progression of smoking-related pancreatitis. Full article
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27 pages, 768 KiB  
Review
Lymphoma: Immune Evasion Strategies
by Ranjan Upadhyay 1, Linda Hammerich 1, Paul Peng 1, Brian Brown 2, Miriam Merad 3 and Joshua D. Brody 1,*
1 Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Cancers 2015, 7(2), 736-762; https://doi.org/10.3390/cancers7020736 - 30 Apr 2015
Cited by 43 | Viewed by 11293
Abstract
While the cellular origin of lymphoma is often characterized by chromosomal translocations and other genetic aberrations, its growth and development into a malignant neoplasm is highly dependent upon its ability to escape natural host defenses. Neoplastic cells interact with a variety of non-malignant [...] Read more.
While the cellular origin of lymphoma is often characterized by chromosomal translocations and other genetic aberrations, its growth and development into a malignant neoplasm is highly dependent upon its ability to escape natural host defenses. Neoplastic cells interact with a variety of non-malignant cells in the tumor milieu to create an immunosuppressive microenvironment. The resulting functional impairment and dysregulation of tumor-associated immune cells not only allows for passive growth of the malignancy but may even provide active growth signals upon which the tumor subsequently becomes dependent. In the past decade, the success of immune checkpoint blockade and adoptive cell transfer for relapsed or refractory lymphomas has validated immunotherapy as a possible treatment cornerstone. Here, we review the mechanisms by which lymphomas have been found to evade and even reprogram the immune system, including alterations in surface molecules, recruitment of immunosuppressive subpopulations, and secretion of anti-inflammatory factors. A fundamental understanding of the immune evasion strategies utilized by lymphomas may lead to better prognostic markers and guide the development of targeted interventions that are both safer and more effective than current standards of care. Full article
(This article belongs to the Special Issue Lymphoma)
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21 pages, 711 KiB  
Review
Mechanisms of Acquired Resistance to ALK Inhibitors and the Rationale for Treating ALK-positive Lung Cancer
by Hideko Isozaki 1, Nagio Takigawa 2,* and Katsuyuki Kiura 3
1 Department of Clinical Pharmaceutics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
2 Department of General Internal Medicine 4, Kawasaki Medical School, Okayama 700-8505, Japan
3 Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan
Cancers 2015, 7(2), 763-783; https://doi.org/10.3390/cancers7020763 - 30 Apr 2015
Cited by 66 | Viewed by 13205
Abstract
The discovery of an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene led to improved clinical outcomes in patients with lung cancer after the development of the first ALK-targeting agent, crizotinib. Some second-generation ALK tyrosine kinase inhibitors (TKIs), which might be [...] Read more.
The discovery of an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene led to improved clinical outcomes in patients with lung cancer after the development of the first ALK-targeting agent, crizotinib. Some second-generation ALK tyrosine kinase inhibitors (TKIs), which might be more potent than crizotinib or effective on crizotinib-resistant patients, have been developed. Although these ALK-TKIs show an excellent response initially, most patients eventually acquire resistance. Therefore, careful consideration of the resistance mechanisms might lead to superior therapeutic strategies. Here, we summarize the history of ALK-TKIs and their underlying resistance mechanisms in both the preclinical and clinical settings. In addition, we discuss potential future treatment strategies in ALK-TKI-naïve and -resistant patients with lung cancer harboring the EML4-ALK fusion gene. Full article
(This article belongs to the Special Issue Non-Small Cell Lung Cancer Therapies)
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11 pages, 381 KiB  
Review
Hedgehog Signaling Inhibitors as Anti-Cancer Agents in Osteosarcoma
by Ram Mohan Ram Kumar * and Bruno Fuchs
Laboratory for Orthopaedic Research, Balgrist University Hospital, Sarcoma Center-UZH University of Zurich, Zurich 8008, Switzerland
Cancers 2015, 7(2), 784-794; https://doi.org/10.3390/cancers7020784 - 13 May 2015
Cited by 38 | Viewed by 7539
Abstract
Osteosarcoma is a rare type of cancer associated with a poor clinical outcome. Even though the pathologic characteristics of OS are well established, much remains to be understood, particularly at the molecular signaling level. The molecular mechanisms of osteosarcoma progression and metastases have [...] Read more.
Osteosarcoma is a rare type of cancer associated with a poor clinical outcome. Even though the pathologic characteristics of OS are well established, much remains to be understood, particularly at the molecular signaling level. The molecular mechanisms of osteosarcoma progression and metastases have not yet been fully elucidated and several evolutionary signaling pathways have been found to be linked with osteosarcoma pathogenesis, especially the hedgehog signaling (Hh) pathway. The present review will outline the importance and targeting the hedgehog signaling (Hh) pathway in osteosarcoma tumor biology. Available data also suggest that aberrant Hh signaling has pro-migratory effects and leads to the development of osteoblastic osteosarcoma. Activation of Hh signaling has been observed in osteosarcoma cell lines and also in primary human osteosarcoma specimens. Emerging data suggests that interference with Hh signal transduction by inhibitors may reduce osteosarcoma cell proliferation and tumor growth thereby preventing osteosarcomagenesis. From this perspective, we outline the current state of Hh pathway inhibitors in osteosarcoma. In summary, targeting Hh signaling by inhibitors promise to increase the efficacy of osteosarcoma treatment and improve patient outcome. Full article
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16 pages, 867 KiB  
Article
An Analytical Model of Leakage Neutron Equivalent Dose for Passively-Scattered Proton Radiotherapy and Validation with Measurements
by Christopher Schneider 1,2, Wayne Newhauser 1,2,* and Jad Farah 3
1 Department of Physics and Astronomy, Louisiana State University and Agricultural and Mechanical College, 202 Nicholson Hall, Baton Rouge, LA 70803, USA
2 Mary Bird Perkins Cancer Center, 4950 Essen Lane, Baton Rouge, LA 70809, USA
3 Institut de Radioprotection et de Sûreté Nucléaire, Service de Dosimétrie Externe, BP-17, 92262 Fontenay-aux-Roses, France
Cancers 2015, 7(2), 795-810; https://doi.org/10.3390/cancers7020795 - 18 May 2015
Cited by 16 | Viewed by 5985
Abstract
Exposure to stray neutrons increases the risk of second cancer development after proton therapy. Previously reported analytical models of this exposure were difficult to configure and had not been investigated below 100 MeV proton energy. The purposes of this study were to test [...] Read more.
Exposure to stray neutrons increases the risk of second cancer development after proton therapy. Previously reported analytical models of this exposure were difficult to configure and had not been investigated below 100 MeV proton energy. The purposes of this study were to test an analytical model of neutron equivalent dose per therapeutic absorbed dose at 75 MeV and to improve the model by reducing the number of configuration parameters and making it continuous in proton energy from 100 to 250 MeV. To develop the analytical model, we used previously published H/D values in water from Monte Carlo simulations of a general-purpose beamline for proton energies from 100 to 250 MeV. We also configured and tested the model on in-air neutron equivalent doses measured for a 75 MeV ocular beamline. Predicted H/D values from the analytical model and Monte Carlo agreed well from 100 to 250 MeV (10% average difference). Predicted H/D values from the analytical model also agreed well with measurements at 75 MeV (15% average difference). The results indicate that analytical models can give fast, reliable calculations of neutron exposure after proton therapy. This ability is absent in treatment planning systems but vital to second cancer risk estimation. Full article
(This article belongs to the Special Issue Proton Therapy for Cancer)
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12 pages, 443 KiB  
Review
Insights into the Molecular Pathogenesis of Activated B-Cell-like Diffuse Large B-Cell Lymphoma and Its Therapeutic Implications
by Georg Lenz 1,2
1 Translational Oncology, Department of Medicine A, Albert-Schweitzer Campus 1, University Hospital Münster, 48149 Münster, Germany
2 Cluster of Excellence EXC 1003, Cells in Motion, 48149 Münster, Germany 
Cancers 2015, 7(2), 811-822; https://doi.org/10.3390/cancers7020812 - 22 May 2015
Cited by 26 | Viewed by 10576
Abstract
Within the last couple of years, the understanding of the molecular mechanisms that drive the pathogenesis of diffuse large B-cell lymphoma (DLBCL) has significantly improved. Large-scale gene expression profiling studies have led to the discovery of several molecularly defined subtypes that are characterized [...] Read more.
Within the last couple of years, the understanding of the molecular mechanisms that drive the pathogenesis of diffuse large B-cell lymphoma (DLBCL) has significantly improved. Large-scale gene expression profiling studies have led to the discovery of several molecularly defined subtypes that are characterized by specific oncogene addictions and significant differences in their outcome. Next generation sequencing efforts combined with RNA interference screens frequently identify crucial oncogenes that lead to constitutive activation of various signaling pathways that drive lymphomagenesis. This review summarizes our current understanding of the molecular pathogenesis of the activated B-cell-like (ABC) DLBCL subtype that is characterized by poor prognosis. A special emphasis is put on findings that might impact therapeutic strategies of affected patients. Full article
(This article belongs to the Special Issue Lymphoma)
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26 pages, 1066 KiB  
Review
The Role of Intracellular Calcium for the Development and Treatment of Neuroblastoma
by Noothan Jyothi Satheesh and Dietrich Büsselberg *
Weill Cornell Medical College in Qatar, Qatar Foundation-Education City, POB 24144, Doha, Qatar
Cancers 2015, 7(2), 823-848; https://doi.org/10.3390/cancers7020811 - 22 May 2015
Cited by 23 | Viewed by 12547
Abstract
Neuroblastoma is the second most common paediatric cancer. It developsfrom undifferentiated simpatico-adrenal lineage cells and is mostly sporadic; however, theaetiology behind the development of neuroblastoma is still not fully understood. Intracellularcalcium ([Ca2+]i) is a secondary messenger which regulates numerous cellular processesand, therefore, its [...] Read more.
Neuroblastoma is the second most common paediatric cancer. It developsfrom undifferentiated simpatico-adrenal lineage cells and is mostly sporadic; however, theaetiology behind the development of neuroblastoma is still not fully understood. Intracellularcalcium ([Ca2+]i) is a secondary messenger which regulates numerous cellular processesand, therefore, its concentration is tightly regulated. This review focuses on the role of[Ca2+]i in differentiation, apoptosis and proliferation in neuroblastoma. It describes themechanisms by which [Ca2+]i is regulated and how it modulates intracellular pathways.Furthermore, the importance of [Ca2+]i for the function of anti-cancer drugs is illuminatedin this review as [Ca2+]i could be a target to improve the outcome of anti-cancer treatmentin neuroblastoma. Overall, modulations of [Ca2+]i could be a key target to induce apoptosisin cancer cells leading to a more efficient and effective treatment of neuroblastoma. Full article
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27 pages, 442 KiB  
Review
Voltage-Gated Ion Channels in Cancer Cell Proliferation
by Vidhya R. Rao 1, Mathew Perez-Neut 1, Simon Kaja 2 and Saverio Gentile 1,*
1 Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago 2160 S. 1s tAve, Maywood, IL 60153, USA
2 Department of Ophthalmology and Vision Research Center, School of Medicine, University of Missouri-Kansas City, 2411 Holmes St., Kansas City, MO 64108, USA
Cancers 2015, 7(2), 849-875; https://doi.org/10.3390/cancers7020813 - 22 May 2015
Cited by 166 | Viewed by 15105
Abstract
Changes of the electrical charges across the surface cell membrane are absolutely necessary to maintain cellular homeostasis in physiological as well as in pathological conditions. The opening of ion channels alter the charge distribution across the surface membrane as they allow the diffusion [...] Read more.
Changes of the electrical charges across the surface cell membrane are absolutely necessary to maintain cellular homeostasis in physiological as well as in pathological conditions. The opening of ion channels alter the charge distribution across the surface membrane as they allow the diffusion of ions such as K+, Ca++, Cl, Na+. Traditionally, voltage-gated ion channels (VGIC) are known to play fundamental roles in controlling rapid bioelectrical signaling including action potential and/or contraction. However, several investigations have revealed that these classes of proteins can also contribute significantly to cell mitotic biochemical signaling, cell cycle progression, as well as cell volume regulation. All these functions are critically important for cancer cell proliferation. Interestingly, a variety of distinct VGICs are expressed in different cancer cell types, including metastasis but not in the tissues from which these tumors were generated. Given the increasing evidence suggesting that VGIC play a major role in cancer cell biology, in this review we discuss the role of distinct VGIC in cancer cell proliferation and possible therapeutic potential of VIGC pharmacological manipulation. Full article
(This article belongs to the Special Issue Cancer Cell Proliferation)
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32 pages, 2352 KiB  
Article
The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells
by Roberto Gomez-Casal 1,2, Chitralekha Bhattacharya 1,2, Michael W. Epperly 1,3, Per H. Basse 1,4, Hong Wang 1,5, Xinhui Wang 6, David A. Proia 7, Joel S. Greenberger 1,3, Mark A. Socinski 1,2 and Vera Levina 1,2,*,†
1 The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
2 Department of Medicine, The University of Pittsburgh, Pittsburgh, PA 15213, USA
3 Department of Radiation Oncology, The University of Pittsburgh, Pittsburgh, PA 15213, USA
4 Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15213, USA
5 Department of Biostatistics, The University of Pittsburgh, Pittsburgh, PA 15213, USA
6 Harvard Medical School, Harvard University, 25 Shattuck Street, Boston, MA 02115, USA
7 Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421, USA
Current address: Hillman Cancer Center, University of Pittsburgh Cancer Institute, Rm. 1.19c, 5117 Center Ave., Pittsburgh, PA 15213, USA.
Cancers 2015, 7(2), 876-907; https://doi.org/10.3390/cancers7020814 - 22 May 2015
Cited by 19 | Viewed by 7025
Abstract
The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated [...] Read more.
The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors. Full article
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22 pages, 1073 KiB  
Review
Effects of Age on the Detection and Management of Breast Cancer
by Andrew McGuire, James A. L. Brown *,†,‡, Carmel Malone, Ray McLaughlin and Michael J. Kerin
1 Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
These authors contributed equally to this work.
ORCID: 0000-0002-3155-0334.
Cancers 2015, 7(2), 908-929; https://doi.org/10.3390/cancers7020815 - 22 May 2015
Cited by 273 | Viewed by 18625
Abstract
Currently, breast cancer affects approximately 12% of women worldwide. While the incidence of breast cancer rises with age, a younger age at diagnosis is linked to increased mortality. We discuss age related factors affecting breast cancer diagnosis, management and treatment, exploring key concepts [...] Read more.
Currently, breast cancer affects approximately 12% of women worldwide. While the incidence of breast cancer rises with age, a younger age at diagnosis is linked to increased mortality. We discuss age related factors affecting breast cancer diagnosis, management and treatment, exploring key concepts and identifying critical areas requiring further research. We examine age as a factor in breast cancer diagnosis and treatment relating it to factors such as genetic status, breast cancer subtype, hormone factors and nodal status. We examine the effects of age as seen through the adoption of population wide breast cancer screening programs. Assessing the incidence rates of each breast cancer subtype, in the context of age, we examine the observed correlations. We explore how age affects patient’s prognosis, exploring the effects of age on stage and subtype incidence. Finally we discuss the future of breast cancer diagnosis and treatment, examining the potential of emerging tests and technologies (such as microRNA) and how novel research findings are being translated into clinically relevant practices. Full article
(This article belongs to the Special Issue Cancers and Aging)
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20 pages, 150 KiB  
Review
Targeted Therapies in Non-Small Cell Lung Cancer—Beyond EGFR and ALK
by Sacha I. Rothschild
Medical Oncology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland
Cancers 2015, 7(2), 930-949; https://doi.org/10.3390/cancers7020816 - 26 May 2015
Cited by 90 | Viewed by 9265
Abstract
Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations [...] Read more.
Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations (so-called “driver mutations”) for their malignant phenotype. Personalized therapy encompasses the strategy of matching these subtypes with effective targeted therapies. EGFR mutations and ALK translocation are the most effectively targeted oncogenes in NSCLC. EGFR mutations and ALK gene rearrangements are successfully being targeted with specific tyrosine kinase inhibitors. The number of molecular subgroups of NSCLC continues to grow. The scope of this review is to discuss recent data on novel molecular targets as ROS1, BRAF, KRAS, HER2, c-MET, RET, PIK3CA, FGFR1 and DDR2. Thereby the review will focus on therapeutic strategies targeting these aberrations. Moreover, the emerging challenge of acquired resistance to initially effective therapies will be discussed. Full article
(This article belongs to the Special Issue Non-Small Cell Lung Cancer Therapies)
13 pages, 210 KiB  
Review
Quality of Life in Patients with NSCLC Receiving Maintenance Therapy
by Achim Rittmeyer
Lungenfachklinik Immenhausen, Thoracic Oncology, Immenhausen 34376, Germany
Cancers 2015, 7(2), 950-962; https://doi.org/10.3390/cancers7020817 - 29 May 2015
Cited by 5 | Viewed by 4835
Abstract
Introduction: In the past few years many trials have evaluated the use of maintenance therapy in the treatment of NSCLC stage IV. Both switch as well as continuation maintenance show an improved PFS and overall survival. HRQoL data was only partially published. The [...] Read more.
Introduction: In the past few years many trials have evaluated the use of maintenance therapy in the treatment of NSCLC stage IV. Both switch as well as continuation maintenance show an improved PFS and overall survival. HRQoL data was only partially published. The aim of this article is to review the published effects of maintenance therapy on HRQoL. Methods: Two PubMed searches were performed using the terms: “maintenance therapy and NSCLC” and “maintenance therapy and NSCLC and HRQoL”. The published data was compared, analysed and evaluated. Results: 272 articles were found dealing with maintenance therapy, and of these 85 articles were found regarding maintenance therapy and HRQoL in NSCLC. Maintenance therapy showed no negative impact on HRQoL but failed to show a real benefit. Some symptoms showed positive trends during maintenance therapy. HRQoL can be used to select patients for maintenance therapy. Conclusions: Maintenance therapy is very safe, improves PFS and OS without impairing HRQoL. Although a positive impact on general QoL could not be demonstrated this is possibly due to the mode of evaluating HRQoL. Patient reported outcomes should be simplified and examined for a longer period of time. Full article
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3 pages, 262 KiB  
Editorial
Cancers Best Paper Award 2015
by Robert H. Weiss
Editor-in-Chief, Division of Nephrology and Cancer Center, University of California, Davis, CA 95616, USA
Cancers 2015, 7(2), 963-965; https://doi.org/10.3390/cancers7020818 - 29 May 2015
Viewed by 4211
Abstract
Cancers has instituted a “Best Paper” award to recognize the most outstanding papers in the area of oncology published in Cancers.[...] Full article
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15 pages, 561 KiB  
Article
New Variants of Tomato Thymidine Kinase 1 Selected for Increased Sensitivity of E. coli KY895 towards Azidothymidine
by Louise Slot Christiansen 1,2,*, Louise Egeblad 2, Birgitte Munch-Petersen 3, Jure Piškur 1,† and Wolfgang Knecht 1,2,*
1 Department of Biology, Lund University, Lund 22362, Sweden
2 Lund Protein Production Platform, Lund University, Lund 22362, Sweden
3 Department of Science, Systems and Models, Roskilde University, Roskilde 4000, Denmark
We would like to dedicate this article to Prof. Jure Piškur, who passed away while this work was in progress.
Cancers 2015, 7(2), 966-980; https://doi.org/10.3390/cancers7020819 - 8 Jun 2015
Cited by 4 | Viewed by 5227
Abstract
Nucleoside analogues (NA) are prodrugs that are phosphorylated by deoxyribonucleoside kinases (dNKs) as the first step towards a compound toxic to the cell. During the last 20 years, research around dNKs has gone into new organisms other than mammals and viruses. Newly discovered [...] Read more.
Nucleoside analogues (NA) are prodrugs that are phosphorylated by deoxyribonucleoside kinases (dNKs) as the first step towards a compound toxic to the cell. During the last 20 years, research around dNKs has gone into new organisms other than mammals and viruses. Newly discovered dNKs have been tested as enzymes for suicide gene therapy. The tomato thymidine kinase 1 (ToTK1) is a dNK that has been selected for its in vitro kinetic properties and then successfully been tested in vivo for the treatment of malignant glioma. We present the selection of two improved variants of ToTK1 generated by random protein engineering for suicide gene therapy with the NA azidothymidine (AZT).We describe their selection, recombinant production and a subsequent kinetic and biochemical characterization. Their improved performance in killing of E. coli KY895 is accompanied by an increase in specificity for the NA AZT over the natural substrate thymidine as well as a decrease in inhibition by dTTP, the end product of the nucleoside salvage pathway for thymidine. The understanding of the enzymatic properties improving the variants efficacy is instrumental to further develop dNKs for use in suicide gene therapy. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
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24 pages, 600 KiB  
Review
Complications from Stereotactic Body Radiotherapy for Lung Cancer
by Kylie H. Kang 1, Christian C. Okoye 2,†, Ravi B. Patel 2,†, Shankar Siva 3, Tithi Biswas 2, Rodney J. Ellis 2, Min Yao 2, Mitchell Machtay 2 and Simon S. Lo 2,*
1 School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
2 Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
3 Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia
These authors contributed equally to this work.
Cancers 2015, 7(2), 981-1004; https://doi.org/10.3390/cancers7020820 - 15 Jun 2015
Cited by 91 | Viewed by 9111
Abstract
Stereotactic body radiotherapy (SBRT) has become a standard treatment option for early stage, node negative non-small cell lung cancer (NSCLC) in patients who are either medically inoperable or refuse surgical resection. SBRT has high local control rates and a favorable toxicity profile relative [...] Read more.
Stereotactic body radiotherapy (SBRT) has become a standard treatment option for early stage, node negative non-small cell lung cancer (NSCLC) in patients who are either medically inoperable or refuse surgical resection. SBRT has high local control rates and a favorable toxicity profile relative to other surgical and non-surgical approaches. Given the excellent tumor control rates and increasing utilization of SBRT, recent efforts have focused on limiting toxicity while expanding treatment to increasingly complex patients. We review toxicities from SBRT for lung cancer, including central airway, esophageal, vascular (e.g., aorta), lung parenchyma (e.g., radiation pneumonitis), and chest wall toxicities, as well as radiation-induced neuropathies (e.g., brachial plexus, vagus nerve and recurrent laryngeal nerve). We summarize patient-related, tumor-related, dosimetric characteristics of these toxicities, review published dose constraints, and propose strategies to reduce such complications. Full article
(This article belongs to the Special Issue Non-Small Cell Lung Cancer Therapies)
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17 pages, 886 KiB  
Review
Sarcoidosis in Melanoma Patients: Case Report and Literature Review
by Bryce D. Beutler 1,*,† and Philip R. Cohen 2,*,†
1 School of Allied Health Sciences, University of Nevada, Las Vegas, 1060 Wiegand Road, Encinitas, CA 92024, USA
2 Department of Dermatology, University of California San Diego, 10991 Twinleaf Court, San Diego, CA 92131, USA
These authors contributed equally to this work.
Cancers 2015, 7(2), 1005-1021; https://doi.org/10.3390/cancers7020821 - 15 Jun 2015
Cited by 36 | Viewed by 11011
Abstract
Sarcoidosis is a systemic inflammatory disease characterized by the development of noncaseating granulomas in multiple organ systems. Many hematologic malignancies and solid tumors, including melanoma, have been associated with sarcoidosis. We describe the clinical and pathologic findings of a 54-year-old man with melanoma-associated [...] Read more.
Sarcoidosis is a systemic inflammatory disease characterized by the development of noncaseating granulomas in multiple organ systems. Many hematologic malignancies and solid tumors, including melanoma, have been associated with sarcoidosis. We describe the clinical and pathologic findings of a 54-year-old man with melanoma-associated sarcoidosis. In addition, we not only review the literature describing characteristics of other melanoma patients with sarcoidosis, but also the features of melanoma patients with antineoplastic therapy-associated sarcoidosis. Sarcoidosis has been described in 80 melanoma patients; sufficient information for analysis was provided in 39 of these individuals. In 43.6% of individuals (17 out of 39), sarcoidosis was directly associated with melanoma; in 56.4% of oncologic patients (22 out of 39), sarcoidosis was induced by antineoplastic therapy that had been administered for the treatment of their metastatic melanoma. The discovery of melanoma preceded the development of sarcoidosis in 12 of the 17 (70.5%) individuals who did not receive systemic treatment. Pulmonary and/or cutaneous manifestations of sarcoidosis were common among both groups of patients. Most patients did not require treatment for sarcoidosis. Melanoma patients—either following antineoplastic therapy or without systemic treatment—may be at an increased risk to develop sarcoidosis. In antineoplastic therapy naive melanoma patients, a common etiologic factor—such as exposure to ultraviolet light—may play a role in their developing melanoma and sarcoidosis. Full article
(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)
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15 pages, 277 KiB  
Review
Involvement of 14-3-3 Proteins in Regulating Tumor Progression of Hepatocellular Carcinoma
by Yi-Ju Wu 1,†, Yee-Jee Jan 2,†, Bor-Sheng Ko 3,†, Shu-Man Liang 1 and Jun-Yang Liou 1,*
1 Institute of Cellular and System Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan 350, Taiwan
2 Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan
3 Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
These authors contributed equally to this work.
Cancers 2015, 7(2), 1022-1036; https://doi.org/10.3390/cancers7020822 - 15 Jun 2015
Cited by 45 | Viewed by 7055
Abstract
There are seven mammalian isoforms of the 14-3-3 protein, which regulate multiple cellular functions via interactions with phosphorylated partners. Increased expression of 14-3-3 proteins contributes to tumor progression of various malignancies. Several isoforms of 14-3-3 are overexpressed and associate with higher metastatic risks [...] Read more.
There are seven mammalian isoforms of the 14-3-3 protein, which regulate multiple cellular functions via interactions with phosphorylated partners. Increased expression of 14-3-3 proteins contributes to tumor progression of various malignancies. Several isoforms of 14-3-3 are overexpressed and associate with higher metastatic risks and poorer survival rates of hepatocellular carcinoma (HCC). 14-3-3β and 14-3-3ζ regulate HCC cell proliferation, tumor growth and chemosensitivity via modulating mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and p38 signal pathways. Moreover, 14-3-3ε suppresses E-cadherin and induces focal adhesion kinase (FAK) expression, thereby enhancing epithelial-mesenchymal transition (EMT) and HCC cell migration. 14-3-3ζ forms complexes with αB-crystallin, which induces EMT and is the cause of sorafenib resistance in HCC. Finally, a recent study has indicated that 14-3-3σ induces heat shock protein 70 (HSP70) expression, which increases HCC cell migration. These results suggest that selective 14-3-3 isoforms contribute to cell proliferation, EMT and cell migration of HCC by regulating distinct targets and signal pathways. Targeting 14-3-3 proteins together with specific downstream effectors therefore has potential to be therapeutic and prognostic factors of HCC. In this article, we will overview 14-3-3's regulation of its downstream factors and contributions to HCC EMT, cell migration and proliferation. Full article
(This article belongs to the Special Issue Cancer Cell Proliferation)
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15 pages, 479 KiB  
Review
Exploring the Mechanisms of Gastrointestinal Cancer Development Using Deep Sequencing Analysis
by Tomonori Matsumoto, Takahiro Shimizu, Atsushi Takai and Hiroyuki Marusawa *
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
Cancers 2015, 7(2), 1037-1051; https://doi.org/10.3390/cancers7020823 - 15 Jun 2015
Cited by 8 | Viewed by 6854
Abstract
Next-generation sequencing (NGS) technologies have revolutionized cancer genomics due to their high throughput sequencing capacity. Reports of the gene mutation profiles of various cancers by many researchers, including international cancer genome research consortia, have increased over recent years. In addition to detecting somatic [...] Read more.
Next-generation sequencing (NGS) technologies have revolutionized cancer genomics due to their high throughput sequencing capacity. Reports of the gene mutation profiles of various cancers by many researchers, including international cancer genome research consortia, have increased over recent years. In addition to detecting somatic mutations in tumor cells, NGS technologies enable us to approach the subject of carcinogenic mechanisms from new perspectives. Deep sequencing, a method of optimizing the high throughput capacity of NGS technologies, allows for the detection of genetic aberrations in small subsets of premalignant and/or tumor cells in noncancerous chronically inflamed tissues. Genome-wide NGS data also make it possible to clarify the mutational signatures of each cancer tissue by identifying the precise pattern of nucleotide alterations in the cancer genome, providing new information regarding the mechanisms of tumorigenesis. In this review, we highlight these new methods taking advantage of NGS technologies, and discuss our current understanding of carcinogenic mechanisms elucidated from such approaches. Full article
(This article belongs to the Special Issue Next Generation Sequencing Approaches in Cancer)
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20 pages, 2248 KiB  
Article
Silencing of Taxol-Sensitizer Genes in Cancer Cells: Lack of Sensitization Effects
by Shang-Lang Huang 1 and Chuck C.-K. Chao 1,2,3,*
1 Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
2 Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
3 Department of Medical Research and Development, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
Cancers 2015, 7(2), 1052-1071; https://doi.org/10.3390/cancers7020824 - 16 Jun 2015
Cited by 10 | Viewed by 5665
Abstract
A previous genome-wide screening analysis identified a panel of genes that sensitize the human non-small-cell lung carcinoma cell line NCI-H1155 to taxol. However, whether the identified genes sensitize other cancer cells to taxol has not been examined. Here, we silenced the taxol-sensitizer genes [...] Read more.
A previous genome-wide screening analysis identified a panel of genes that sensitize the human non-small-cell lung carcinoma cell line NCI-H1155 to taxol. However, whether the identified genes sensitize other cancer cells to taxol has not been examined. Here, we silenced the taxol-sensitizer genes identified (acrbp, atp6v0d2, fgd4, hs6st2, psma6, and tubgcp2) in nine other cancer cell types (including lung, cervical, ovarian, and hepatocellular carcinoma cell lines) that showed reduced cell viability in the presence of a sub-lethal concentration of taxol. Surprisingly, none of the genes studied increased sensitivity to taxol in the tested panel of cell lines. As observed in H1155 cells, SKOV3 cells displayed induction of five of the six genes studied in response to a cell killing dose of taxol. The other cell types were much less responsive to taxol. Notably, four of the five inducible taxol-sensitizer genes tested (acrbp, atp6v0d2, psma6, and tubgcp2) were upregulated in a taxol-resistant ovarian cancer cell line. These results indicate that the previously identified taxol-sensitizer loci are not conserved genetic targets involved in inhibiting cell proliferation in response to taxol. Our findings also suggest that regulation of taxol-sensitizer genes by taxol may be critical for acquired cell resistance to the drug. Full article
(This article belongs to the Special Issue Cancer Cell Proliferation)
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19 pages, 1148 KiB  
Article
Oncogenic BRAF(V600E) Induces Clastogenesis and UVB Hypersensitivity
by Dennis A. Simpson 1,2,*, Nathalay Lemonie 1, David S. Morgan 1, Shobhan Gaddameedhi 3 and William K. Kaufmann 1,2,4
1 Department of Pathology & Laboratory Medicine, University of North Carolina at Chapel Hill, CB7295, Chapel Hill, NC 27599, USA
2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB7295, Chapel Hill, NC 27599, USA
3 Department of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, WA 99210, USA
4 Center for Environmental Health and Susceptibility, University of North Carolina at Chapel Hill, CB7295, Chapel Hill, NC 27599, USA
Cancers 2015, 7(2), 1072-1090; https://doi.org/10.3390/cancers7020825 - 17 Jun 2015
Cited by 2 | Viewed by 7672
Abstract
The oncogenic BRAF(V600E) mutation is common in melanomas as well as moles. The roles that this mutation plays in the early events in the development of melanoma are poorly understood. This study demonstrates that expression of BRAF(V600E) is not only clastogenic, but synergizes [...] Read more.
The oncogenic BRAF(V600E) mutation is common in melanomas as well as moles. The roles that this mutation plays in the early events in the development of melanoma are poorly understood. This study demonstrates that expression of BRAF(V600E) is not only clastogenic, but synergizes for clastogenesis caused by exposure to ultraviolet radiation in the 300 to 320 nM (UVB) range. Expression of BRAF(V600E) was associated with induction of Chk1 pS280 and a reduction in chromatin remodeling factors BRG1 and BAF180. These alterations in the Chk1 signaling pathway and SWI/SNF chromatin remodeling pathway may contribute to the clastogenesis and UVB sensitivity. These results emphasize the importance of preventing sunburns in children with developing moles. Full article
(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)
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