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issn:2234-943
1.  MicroRNA Targeting to Modulate Tumor Microenvironment 
Communication between stromal cells and tumor cells initiates tumor growth, angiogenesis, invasion, and metastasis. Stromal cells include cancer-associated fibroblasts, tumor-associated macrophages, pericytes, endothelial cells, and infiltrating immune cells. MicroRNAs (miRNAs) in the tumor microenvironment have emerged as key players involved in the development of cancer and its progression. miRNAs are small endogenous non-protein-coding RNAs that negatively regulate the expression of multiple target genes at post-transcriptional level and thereby control many cellular processes. In this review, we provide a comprehensive overview of miRNAs dysregulated in different stromal cells and their impact on the regulation of intercellular crosstalk in the tumor microenvironment. We also discuss the therapeutic significance potential of miRNAs to modulate the tumor microenvironment. Since miRNA delivery is quite challenging and the biggest hurdle for clinical translation of miRNA therapeutics, we review various non-viral miRNA delivery systems that can potentially be used for targeting miRNA to stromal cells within the tumor microenvironment.
doi:10.3389/fonc.2016.00003
PMCID: PMC4717414  PMID: 26835418
tumor microenvironment; tumor stroma; microRNA; gene delivery; cancer-associated fibroblasts; tumor-associated macrophages
2.  The Influence of C-Ions and X-rays on Human Umbilical Vein Endothelial Cells 
Damage to the endothelium of blood vessels, which may occur during radiotherapy, is discussed as a potential precursor to the development of cardiovascular disease. We thus chose human umbilical vein endothelial cells as a model system to examine the effect of low- and high-linear energy transfer (LET) radiation. Cells were exposed to 250 kV X-rays or carbon ions (C-ions) with the energies of either 9.8 MeV/u (LET = 170 keV/μm) or 91 MeV/u (LET = 28 keV/μm). Subculture of cells was performed regularly up to 46 days (~22 population doublings) post-irradiation. Immediately after exposure, cells were seeded for the colony forming assay. Additionally, at regular intervals, mitochondrial membrane potential (MMP) (JC-1 staining) and cellular senescence (senescence-associated β-galactosidase staining) were assessed. Cytogenetic damage was investigated by the micronucleus assay and the high-resolution multiplex fluorescence in situ hybridization (mFISH) technique. Analysis of radiation-induced damage shortly after exposure showed that C-ions are more effective than X-rays with respect to cell inactivation or the induction of cytogenetic damage (micronucleus assay) as observed in other cell systems. For 9.8 and 91 MeV/u C-ions, relative biological effectiveness values of 2.4 and 1.5 were obtained for cell inactivation. At the subsequent time points, the number of micronucleated cells decreased to the control level. Analysis of chromosomal damage by mFISH technique revealed aberrations frequently involving chromosome 13 irrespective of dose or radiation quality. Disruption of the MMP was seen only a few days after exposure to X-rays or C-ions. Cellular senescence was not altered by radiation at any time point investigated. Altogether, our data indicate that shortly after exposure C-ions were more effective in damaging endothelial cells than X-rays. However, late damage to endothelial cells was not found for the applied conditions and endpoints.
doi:10.3389/fonc.2016.00005
PMCID: PMC4718996  PMID: 26835420
cardiovascular disease; endothelial cells; high-LET radiation; carbon ions; carbon ion therapy; chromosome 13; micronucleus formation; senescence-associated β-galactosidase
3.  O-GlcNAcylation and the Metabolic Shift in High-Proliferating Cells: All the Evidence Suggests that Sugars Dictate the Flux of Lipid Biogenesis in Tumor Processes 
Cancer cells are characterized by their high capability to proliferate. This imposes an accelerated biosynthesis of membrane compounds to respond to the need for increasing the membrane surface of dividing cells and remodeling the structure of lipid microdomains. Recently, attention has been paid to the upregulation of O-GlcNAcylation processes observed in cancer cells. Although O-GlcNAcylation of lipogenic transcriptional regulators is described in the literature (e.g., FXR, LXR, ChREBP), little is known about the regulation of the enzymes that drive lipogenesis: acetyl co-enzyme A carboxylase and fatty acid synthase (FAS). The expression and catalytic activity of both FAS and O-GlcNAc transferase (OGT) are high in cancer cells but the reciprocal regulation of the two enzymes remains unexplored. In this perspective, we collected data linking FAS and OGT and, in so doing, pave the way for the exploration of the intricate functions of these two actors that play a central role in tumor growth.
doi:10.3389/fonc.2016.00006
PMCID: PMC4722119  PMID: 26835421
FAS; O-GlcNAcylation; OGT; cancer; cell proliferation
5.  Medical Applications at CERN and the ENLIGHT Network 
State-of-the-art techniques derived from particle accelerators, detectors, and physics computing are routinely used in clinical practice and medical research centers: from imaging technologies to dedicated accelerators for cancer therapy and nuclear medicine, simulations, and data analytics. Principles of particle physics themselves are the foundation of a cutting edge radiotherapy technique for cancer treatment: hadron therapy. This article is an overview of the involvement of CERN, the European Organization for Nuclear Research, in medical applications, with specific focus on hadron therapy. It also presents the history, achievements, and future scientific goals of the European Network for Light Ion Hadron Therapy, whose co-ordination office is at CERN.
doi:10.3389/fonc.2016.00009
PMCID: PMC4724719  PMID: 26835422
particle physics; imaging; radiotherapy; detectors; accelerators; hadron therapy
6.  Mutant p53 Drives Cancer by Subverting Multiple Tumor Suppression Pathways 
The tumor suppressor p53 normally acts as a brake to halt damaged cells from perpetrating their genetic errors into future generations. If p53 is disrupted by mutation, it may not only lose these corrective powers, but counterproductively acquire new capacities that drive cancer. A newly emerging manner in which mutant p53 executes its cancer promoting functions is by harnessing key proteins, which normally partner with its wild type, tumor-inhibiting counterpart. In association with the subverted activities of these protein partners, mutant p53 is empowered to act across multiple fundamental cellular pathways (regulating cell division and metabolism) and corrupt them to become cancer promoting.
doi:10.3389/fonc.2016.00012
PMCID: PMC4728204  PMID: 26858938
p53 mutations; gain of function; metabolism; cell cycle; transcriptional regulation
7.  Clinical Overview of MDM2/X-Targeted Therapies 
MDM2 and MDMX are the primary negative regulators of p53, which under normal conditions maintain low intracellular levels of p53 by targeting it to the proteasome for rapid degradation and inhibiting its transcriptional activity. Both MDM2 and MDMX function as powerful oncogenes and are commonly over-expressed in some cancers, including sarcoma (~20%) and breast cancer (~15%). In contrast to tumors that are p53 mutant, whereby the current therapeutic strategy restores the normal active conformation of p53, MDM2 and MDMX represent logical therapeutic targets in cancer for increasing wild-type (WT) p53 expression and activities. Recent preclinical studies suggest that there may also be situations that MDM2/X inhibitors could be used in p53 mutant tumors. Since the discovery of nutlin-3a, the first in a class of small molecule MDM2 inhibitors that binds to the hydrophobic cleft in the N-terminus of MDM2, preventing its association with p53, there is now an extensive list of related compounds. In addition, a new class of stapled peptides that can target both MDM2 and MDMX have also been developed. Importantly, preclinical modeling, which has demonstrated effective in vitro and in vivo killing of WT p53 cancer cells, has now been translated into early clinical trials allowing better assessment of their biological effects and toxicities in patients. In this overview, we will review the current MDM2- and MDMX-targeted therapies in development, focusing particularly on compounds that have entered into early phase clinical trials. We will highlight the challenges pertaining to predictive biomarkers for and toxicities associated with these compounds, as well as identify potential combinatorial strategies to enhance its anti-cancer efficacy.
doi:10.3389/fonc.2016.00007
PMCID: PMC4728205  PMID: 26858935
p53; MDM2; MDMX; cancer therapy; nutlin
8.  Cancer Care Delivery and Women’s Health: The Role of Patient Navigation 
Background
Patient navigation (PN) is a patient-centered health-care service delivery model that assists individuals, particularly the medically underserved, in overcoming barriers (e.g., personal, logistical, and system) to care across the cancer care continuum. In 2012, the American College of Surgeons Commission on Cancer (CoC) announced that health-care facilities seeking CoC-accreditation must have PN processes in place starting January 1, 2015. The CoC mandate, in light of the recent findings from centers within the Patient Navigation Research Program and the influx of PN interventions, warrants the present literature review.
Methods
PubMed and Medline were searched for studies published from January 2010 to October 2015, particularly those recent articles within the past 2 years, addressing PN for breast and gynecological cancers, and written in English. Search terms included patient navigation, navigation, navigator, cancer screening, clinical trials, cancer patient, cancer survivor, breast cancer, gynecological cancer, ovarian cancer, uterine cancer, vaginal cancer, and vulvar cancer.
Results
Consistent with prior reviews, PN was shown to be effective in helping women who receive cancer screenings, receive more timely diagnostic resolution after a breast and cervical cancer screening abnormality, initiate treatment sooner, receive proper treatment, and improve quality of life after cancer diagnosis. However, several limitations were observed. The majority of PN interventions focused on cancer screening and diagnostic resolution for breast cancer. As observed in prior reviews, methodological rigor (e.g., randomized controlled trial design) was lacking.
Conclusion
Future research opportunities include testing PN interventions in the post-treatment settings and among gynecological cancer patient populations, age-related barriers to effective PN, and collaborative efforts between community health workers and patient navigators as care goes across segments of the cancer control continuum. As PN programs continue to develop and become a standard of care, further research will be required to determine the effectiveness of cancer PN across the cancer care continuum, and in different patient populations.
doi:10.3389/fonc.2016.00002
PMCID: PMC4729879  PMID: 26858934
patient navigation; breast cancer; cervical cancer; gynecological cancers; women’s health; cancer disparities
9.  Protons, Photons, and the Prostate – Is There Emerging Evidence in the Ongoing Discussion on Particle Therapy for the Treatment of Prostate Cancer? 
Proton therapy is actively and repeatedly discussed within the framework of particle therapy for the treatment of prostate cancer (PC). The argument in favor of treating the prostate with protons is partly financial: given that small volumes are treated, treatment times are low, resulting in a hypothetical high patient throughput. However, such considerations should not form the basis of medical decision-making. There are also physical and biological arguments which further support the use of particle therapy for PC. The only relevant randomized data currently available is the study by Zietman and colleagues, comparing a high to a low proton boost, resulting in a significant increase in PSA-free survival in the experimental (high dose) arm (1). With modern photon treatments and image-guided radiotherapy (IGRT), equally high doses can be applied with photons and, thus, a randomized trial comparing high-end photons to protons is warranted. For high-linear energy transfer (LET) particles, such as carbon ions, the increase in relative biological effectiveness could potentially convert into an improvement in outcome. Additionally, through the physical differences of protons and carbon ions, the steeper dose gradient with carbon ions and the lack of beam broadening in the carbon beam lead to a superior dose distribution supporting the idea of hypofractionation. Biological and clinical data are emerging, however, has practice-changing evidence already arrived?
doi:10.3389/fonc.2016.00008
PMCID: PMC4729886  PMID: 26858936
protons; prostate cancer; carbon ions; clinical trials; IMRT
10.  Assessment of Geant4 Prompt-Gamma Emission Yields in the Context of Proton Therapy Monitoring 
Monte Carlo tools have been long used to assist the research and development of solutions for proton therapy monitoring. The present work focuses on the prompt-gamma emission yields by comparing experimental data with the outcomes of the current version of Geant4 using all applicable proton inelastic models. For the case in study and using the binary cascade model, it was found that Geant4 overestimates the prompt-gamma emission yields by 40.2 ± 0.3%, even though it predicts the prompt-gamma profile length of the experimental profile accurately. In addition, the default implementations of all proton inelastic models show an overestimation in the number of prompt gammas emitted. Finally, a set of built-in options and physically sound Geant4 source code changes have been tested in order to try to improve the discrepancy observed. A satisfactory agreement was found when using the QMD model with a wave packet width equal to 1.3 fm2.
doi:10.3389/fonc.2016.00010
PMCID: PMC4729887  PMID: 26858937
proton therapy; hadrontherapy; prompt gammas; Geant4; online monitoring; in-beam monitoring; collimated camera; nuclear fragmentation models
11.  Optimizing Cancer Care Delivery through Implementation Science 
The 2013 Institute of Medicine report investigating cancer care concluded that the cancer care delivery system is in crisis due to an increased demand for care, increasing complexity of treatment, decreasing work force, and rising costs. Engaging patients and incorporating evidence-based care into routine clinical practice are essential components of a high-quality cancer delivery system. However, a gap currently exists between the identification of beneficial research findings and the application in clinical practice. Implementation research strives to address this gap. In this review, we discuss key components of high-quality implementation research. We then apply these concepts to a current cancer care delivery challenge in women’s health, specifically the implementation of a surgery decision aid for women newly diagnosed with breast cancer.
doi:10.3389/fonc.2016.00001
PMCID: PMC4729951  PMID: 26858933
implementation science; dissemination and implementation research; cancer care delivery; breast cancer; knowledge-to-action; decision aid
12.  Impact of Freezing Delay Time on Tissue Samples for Metabolomic Studies 
Introduction
Metabolic profiling of intact tumor tissue by high-resolution magic angle spinning (HR MAS) MR spectroscopy (MRS) provides important biological information possibly useful for clinical diagnosis and development of novel treatment strategies. However, generation of high-quality data requires that sample handling from surgical resection until analysis is performed using systematically validated procedures. In this study, we investigated the effect of postsurgical freezing delay time on global metabolic profiles and stability of individual metabolites in intact tumor tissue.
Materials and methods
Tumor tissue samples collected from two patient-derived breast cancer xenograft models (n = 3 for each model) were divided into pieces that were snap-frozen in liquid nitrogen at 0, 15, 30, 60, 90, and 120 min after surgical removal. In addition, one sample was analyzed immediately, representing the metabolic profile of fresh tissue exposed neither to liquid nitrogen nor to room temperature. We also evaluated the metabolic effect of prolonged spinning during the HR MAS experiments in biopsies from breast cancer patients (n = 14). All samples were analyzed by proton HR MAS MRS on a Bruker Avance DRX600 spectrometer, and changes in metabolic profiles were evaluated using multivariate analysis and linear mixed modeling.
Results
Multivariate analysis showed that the metabolic differences between the two breast cancer models were more prominent than variation caused by freezing delay time. No significant changes in levels of individual metabolites were observed in samples frozen within 30 min of resection. After this time point, levels of choline increased, whereas ascorbate, creatine, and glutathione (GS) levels decreased. Freezing had a significant effect on several metabolites but is an essential procedure for research and biobank purposes. Furthermore, four metabolites (glucose, glycine, glycerophosphocholine, and choline) were affected by prolonged HR MAS experiment time possibly caused by physical release of metabolites caused by spinning or due to structural degradation processes.
Conclusion
The MR metabolic profiles of tumor samples are reproducible and robust to variation in postsurgical freezing delay up to 30 min.
doi:10.3389/fonc.2016.00017
PMCID: PMC4730796  PMID: 26858940
cancer; freezing time delay; HR MAS; metabolic profile; MR spectroscopy; metabolomics; snap-freezing; degradation
13.  Genetics and Epigenetics of Glioblastoma: Applications and Overall Incidence of IDH1 Mutation 
Glioblastoma is the most fatal brain cancer found in humans. Patients suffering from glioblastoma have a dismal prognosis, with a median survival of 15 months. The tumor may develop rapidly de novo in older patients or through progression from anaplastic astrocytomas in younger patients if glioblastoma is primary or secondary, respectively. During the past decade, significant advances have been made in the understanding of processes leading to glioblastoma, and several important genetic defects that appear to be important for the development and progression of this tumor have been identified. Particularly, the discovery of recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) gene has shed new light on the molecular landscape in glioblastoma. Indeed, emerging research on the consequences of mutant IDH1 protein expression suggests that its neomorphic enzymatic activity catalyzing the production of the oncometabolite 2-hydroxyglutarate influences a range of cellular programs that affect the epigenome and contribute to glioblastoma development. One of the exciting observations is the presence of IDH1 mutation in the vast majority of secondary glioblastoma, while it is almost absent in primary glioblastoma. Growing data indicate that this particular mutation has clinical and prognostic importance and will become a critical early distinction in diagnosis of glioblastoma.
doi:10.3389/fonc.2016.00016
PMCID: PMC4731485  PMID: 26858939
glioblastoma; genetics; epigenetics; IDH1 mutation
14.  Potential of Induced Metabolic Bioluminescence Imaging to Uncover Metabolic Effects of Antiangiogenic Therapy in Tumors 
Tumor heterogeneity at the genetic level has been illustrated by a multitude of studies on the genomics of cancer, but whether tumors can be heterogeneous at the metabolic level is an issue that has been less systematically investigated so far. A burning-related question is whether the metabolic features of tumors can change either following natural tumor progression (i.e., in primary tumors versus metastasis) or therapeutic interventions. In this regard, recent findings by independent teams indicate that antiangiogenic drugs cause metabolic perturbations in tumors as well as metabolic adaptations associated with increased malignancy. Induced metabolic bioluminescence imaging (imBI) is an imaging technique that enables detection of key metabolites associated with glycolysis, including lactate, glucose, pyruvate, and ATP in tumor sections. Signals captured by imBI can be used to visualize the topographic distribution of these metabolites and quantify their absolute amount. imBI can be very useful for metabolic classification of tumors as well as to track metabolic changes in the glycolytic pathway associated with certain therapies. Imaging of the metabolic changes induced by antiangiogenic drugs in tumors by imBI or other emerging technologies is a valuable tool to uncover molecular sensors engaged by metabolic stress and offers an opportunity to understand how metabolism-based approaches could improve cancer therapy.
doi:10.3389/fonc.2016.00015
PMCID: PMC4733917  PMID: 26870694
angiogenesis; metabolism; imaging; glycolysis; cancer; mouse models
15.  Validation of Claims Algorithms for Progression to Metastatic Cancer in Patients with Breast, Non-small Cell Lung, and Colorectal Cancer 
Background
Validated algorithms for identifying progression to metastatic cancer could permit the use of administrative claims databases for research in this area.
Objective
To identify simple algorithms that could accurately detect cancer progression to metastatic breast, non-small cell lung, and colorectal cancer (CRC) using medical and pharmacy claims data.
Methods
Adults with stage I–III breast, non-small cell lung cancer (NSCLC), or CRC in the Geisinger Health System from 2004 to 2011 were selected. Evidence of progression was extracted via manual chart review as the reference standard. In addition to secondary malignancy diagnosis (ICD-9 code for metastases), diagnoses, procedures, and treatments were selected with clinician input as indicators of cancer progression. Random forests models provided variable importance scores. In addition to codes for secondary malignancy, several more complex algorithms were constructed and performance measures calculated.
Results
Among those with breast cancer [17/502 (3.4%) progressed], the performance of a secondary malignancy code was suboptimal [sensitivity: 64.7%; specificity: 86.0%; positive predictive value (PPV): 13.9; negative predictive value (NPV): 98.6%]; requiring malignancy at another site or initiation of immunotherapy increased PPV and specificity but decreased sensitivity. For NSCLC [61/236 (25.8%) progressed], codes for secondary malignancy alone (PPV: 47.4%; NPV: 84.8%; sensitivity: 60.7%; specificity: 76.6%) performed similarly or better than more complex algorithms. For CRC [33/276 (12.0%) progressed], secondary malignancy codes had good specificity (92.7%) and NPV (92.3%) but low sensitivity (42.4%) and PPV (43.8%); an algorithm with change in chemotherapy increased sensitivity but decreased other metrics.
Conclusion
Selected algorithms performed similarly to the presence of a secondary tumor diagnosis code, with low sensitivity/PPV and higher specificity/NPV. Accurate identification of cancer progression likely requires verification through chart review.
doi:10.3389/fonc.2016.00018
PMCID: PMC4733924  PMID: 26870695
cancer progression; metastatic cancer; claims algorithm; oncology; random forests
16.  Preventing Cervical Cancer in the United States: Barriers and Resolutions for HPV Vaccination 
Human papillomavirus (HPV) vaccination rates for preadolescent and adolescent girls in the United States are far behind those of other developed nations. These rates differ substantially by region and state, socioeconomic status, and insurance status. In parents and young women, a lack of awareness and a misperception of the risk of this vaccine drive low vaccination rates. In physicians, lack of comfort with discussion of sexuality and the perception that the vaccine should be delayed to a later age contribute to low vaccination rates. Patient- and physician-targeted educational campaigns, systems-based interventions, and school-based vaccine clinics offer a variety of ways to address the barriers to HPV vaccination. A diverse and culturally appropriate approach to promoting vaccine uptake has the potential to significantly improve vaccination rates in order to reach the Healthy People 2020 goal of over 80% vaccination in adolescent girls. This article reviews the disparities in HPV vaccination rates in girls in the United States, the influences of patients’, physicians’, and parents’ attitudes on vaccine uptake, and the proposed interventions that may help the United States reach its goal for vaccine coverage.
doi:10.3389/fonc.2016.00019
PMCID: PMC4733925  PMID: 26870696
HPV; vaccination; cervical cancer; disparities; health policy
17.  First Images of a Three-Layer Compton Telescope Prototype for Treatment Monitoring in Hadron Therapy 
A Compton telescope for dose monitoring in hadron therapy is under development at IFIC. The system consists of three layers of LaBr3 crystals coupled to silicon photomultiplier arrays. 22Na sources have been successfully imaged reconstructing the data with an ML-EM code. Calibration and temperature stabilization are necessary for the prototype operation at low coincidence rates. A spatial resolution of 7.8 mm FWHM has been obtained in the first imaging tests.
doi:10.3389/fonc.2016.00014
PMCID: PMC4735841  PMID: 26870693
Compton camera; Compton telescope; hadron therapy; treatment monitoring; LaBr3
18.  Radiation Metabolomics: Current Status and Future Directions 
Human exposure to ionizing radiation (IR) disrupts normal metabolic processes in cells and organs by inducing complex biological responses that interfere with gene and protein expression. Conventional dosimetry, monitoring of prodromal symptoms, and peripheral lymphocyte counts are of limited value as organ- and tissue-specific biomarkers for personnel exposed to radiation, particularly, weeks or months after exposure. Analysis of metabolites generated in known stress-responsive pathways by molecular profiling helps to predict the physiological status of an individual in response to environmental or genetic perturbations. Thus, a multi-metabolite profile obtained from a high-resolution mass spectrometry-based metabolomics platform offers potential for identification of robust biomarkers to predict radiation toxicity of organs and tissues resulting from exposures to therapeutic or non-therapeutic IR. Here, we review the status of radiation metabolomics and explore applications as a standalone technology, as well as its integration in systems biology, to facilitate a better understanding of the molecular basis of radiation response. Finally, we draw attention to the identification of specific pathways that can be targeted for the development of therapeutics to alleviate or mitigate harmful effects of radiation exposure.
doi:10.3389/fonc.2016.00020
PMCID: PMC4736121  PMID: 26870697
ionizing radiation; metabolomics; biomarkers
19.  Targeting of Mutant p53 and the Cellular Redox Balance by APR-246 as a Strategy for Efficient Cancer Therapy 
TP53 is the most frequently mutated gene in cancer. The p53 protein activates transcription of genes that promote cell cycle arrest or apoptosis, or regulate cell metabolism, and other processes. Missense mutations in TP53 abolish specific DNA binding of p53 and allow evasion of apoptosis and accelerated tumor progression. Mutant p53 often accumulates at high levels in tumor cells. Pharmacological reactivation of mutant p53 has emerged as a promising strategy for improved cancer therapy. Small molecules that restore wild type activity of mutant p53 have been identified using various approaches. One of these molecules, APR-246, is a prodrug that is converted to the Michael acceptor methylene quinuclidinone (MQ) that binds covalently to cysteines in p53, leading to refolding and restoration of wild type p53 function. MQ also targets the cellular redox balance by inhibiting thioredoxin reductase (TrxR1) and depleting glutathione. This dual mechanism of action may account for the striking synergy between APR-246 and platinum compounds. APR-246 is the only mutant p53-targeting compound in clinical development. A phase I/IIa clinical trial in hematological malignancies and prostate cancer showed good safety profile and clinical effects in some patients. APR-246 is currently tested in a phase Ib/II trial in patients with high-grade serous ovarian cancer.
doi:10.3389/fonc.2016.00021
PMCID: PMC4737887  PMID: 26870698
APR-246; mutant p53; apoptosis; thioredoxin reductase; glutathione; redox balance; clinical trial; cancer therapy
20.  The Significance of a Common Idiotype (1F7) on Antibodies against Human Immune Deficiency Virus Type 1 and Hepatitis C Virus 
In this review, we trace the concept and potential functional role of regulatory idiotypes in the immune response to human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus, and hepatitis C virus (HCV). A major idiotype involved in these viral infections is recognized and defined by a murine monoclonal antibody (1F7). Antibodies expressing the idiotype defined by 1F7 are dominant in HIV-1 infection and are also found on many broadly neutralizing antibodies against HIV-1. This regulatory idiotypic axis offers opportunities for exploitation in vaccine development for HIV-1, HCV, and other chronic viral infections.
doi:10.3389/fonc.2016.00011
PMCID: PMC4742788  PMID: 26904499
idiotype; 1F7; HIV; SIV; HCV
21.  Analysis of Prognostic Factors in High-Grade Osteosarcoma of the Extremities in Children: A 15-Year Single-Institution Experience 
Background
The aim of this retrospective study was to define clinical and pathological features and prognostic factors among children and adolescents diagnosed with high-grade osteosarcoma of the extremities.
Methods
A total of 73 patients younger than 18 years diagnosed with primary osteosarcoma of the extremities between January 1998 and December 2013 were retrospectively evaluated. Prognostic factors, such as age, gender, primary tumor site, alkaline phosphatase and lactate dehydrogenase levels, metastatic disease, pathological fracture, histological response, and surgery type, were analyzed to evaluate their effects on overall survival (OS) and event-free survival (EFS).
Results
At a median follow-up of 30 months (1.5–152), OS and EFS at 5 years were 64.5 ± 8.1 and 48.5 ± 8.7% for patients with localized disease; and 16.2 ± 7.9 and 14.4 ± 7.3% for patients with initial metastatic disease, respectively. In patients with localized disease, conservative surgery was performed on 22 of 46 patients (43.5%), and there was no significant difference in survival rates among patients who had conservative vs. radical surgery (p = 0.65). Although tumor size (>12 cm) was significant prognostic factor in univariate analysis; multivariate analysis identified elevated levels of alkaline phosphatase (p = 0.033) and poor response to neoadjuvant chemotherapy (p < 0.001) only as independent prognostic factors. Age, histological type, pathological fracture, and primary tumor site did not significantly affect prognosis.
Conclusion
Initial elevated presence of alkaline phosphatase in serum and poor histological response after neoadjuvant chemotherapy were significant factors for unfavorable prognosis. It is necessary to optimize staging and treatment intensification to improve survival rates, especially among patients with metastasis at initial presentation.
doi:10.3389/fonc.2016.00022
PMCID: PMC4745606  PMID: 26904501
osteosarcoma; children; prognostic factors
22.  Ramadan Fasting and Patients with Cancer: State-of-the-Art and Future Prospects 
Ramadan fasting represents one of the five pillars of the Islam creed. Even though some subjects (among which patients) are exempted from observing this religious duty, they may be eager to share this particular moment of the year with their family and peers. However, there are no guidelines or standardized protocols that can help physicians to properly address the issue of patients with cancer fasting in Ramadan and correctly advising them. Moreover, in a more interconnected and globalized society, in which more and more Muslim patients live in the Western countries, this topic is of high interest also for the general practitioner. For this purpose, we carried out a systematic review on the subject. Our main findings are that (1) very few studies have been carried out, addressing this issue, (2) evidence concerning quality of life and compliance to treatment is contrasting and scarce, and (3) generally speaking, few patients ask their physicians whether they can safely fast or not. For these reasons, further research should be performed, given the relevance and importance of this topic.
doi:10.3389/fonc.2016.00027
PMCID: PMC4748028  PMID: 26904505
cancer; drug compliance and adherence; quality of life; Ramadan fasting; stomia
23.  The Value of Ultrasound Monitoring of Adnexal Masses for Early Detection of Ovarian Cancer 
Although ultrasound has so far been found to be ineffective as a screening tool for ovarian cancer, it is commonly used as a means of evaluating or following ovarian or adnexal masses once they are detected. We review the use of serial ultrasound for the management of adnexal masses and propose an approach to monitoring based on an understanding of the overall risk of cancer among the population in question and an assessment of how the potential benefit of monitoring compares with potential risk. In our approach, masses that are symptomatic, large (>10 cm), associated with an elevated CA 125 level or overt signs of malignancy, or that are determined to have a worrisome appearance by stringent ultrasound criteria should be evaluated surgically. Women with masses that have none of these characteristics should be offered monitoring. Short-term initial ultrasound monitoring carries significant potential benefit in terms of aiding detection of early malignancy and avoidance of unnecessary surgery. However, if a mass remains stable but persistent, the potential benefit of ongoing monitoring wanes with time, whereas the potential harms, in terms of patient anxiety, cost, and the risk of incidental findings and unnecessary surgery increase. Therefore, monitoring of stable lesions should be limited in duration in order to limit potential harms from overtreatment and overdiagnosis.
doi:10.3389/fonc.2016.00025
PMCID: PMC4748035  PMID: 26904503
ultrasound detection; adnexal diseases; ovarian neoplasms; early detection of cancer; overtreatment
24.  A Review of Radiotherapy-Induced Late Effects Research after Advanced Technology Treatments 
The number of incident cancers and long-term cancer survivors is expected to increase substantially for at least a decade. Advanced technology radiotherapies, e.g., using beams of protons and photons, offer dosimetric advantages that theoretically yield better outcomes. In general, evidence from controlled clinical trials and epidemiology studies are lacking. To conduct these studies, new research methods and infrastructure will be needed. In the paper, we review several key research methods of relevance to late effects after advanced technology proton-beam and photon-beam radiotherapies. In particular, we focus on the determination of exposures to therapeutic and stray radiation and related uncertainties, with discussion of recent advances in exposure calculation methods, uncertainties, in silico studies, computing infrastructure, electronic medical records, and risk visualization. We identify six key areas of methodology and infrastructure that will be needed to conduct future outcome studies of radiation late effects.
doi:10.3389/fonc.2016.00013
PMCID: PMC4748041  PMID: 26904500
late effects; dose; risk; measurement; calculation; proton; photon
25.  Plan Quality and Treatment Efficiency for Radiosurgery to Multiple Brain Metastases: Non-Coplanar RapidArc vs. Gamma Knife 
Objectives
This study compares the dosimetry and efficiency of two modern radiosurgery [stereotactic radiosurgery (SRS)] modalities for multiple brain metastases [Gamma Knife (GK) and LINAC-based RapidArc/volumetric modulated arc therapy], with a special focus on the comparison of low-dose spread.
Methods
Six patients with three or four small brain metastases were used in this study. The size of targets varied from 0.1 to 10.5 cc. SRS doses were prescribed according to the size of lesions. SRS plans were made using both Gamma Knife® Perfexion and a single-isocenter, multiple non-coplanar RapidArc®. Dosimetric parameters analyzed included RTOG conformity index (CI), gradient index (GI), 12 Gy isodose volume (V12Gy) for each target, and the dose “spread” (Dspread) for each plan. Dspread reflects SRS plan’s capability of confining radiation to within the local vicinity of the lesion and to not spread out to the surrounding normal brain tissues. Each plan has a dose (Dspread), such that once dose decreases below Dspread (on total tissue dose–volume histogram), isodose volume starts increasing dramatically. Dspread is defined as that dose when volume increase first exceeds 20 cc/0.1 Gy dose decrease.
Results
RapidArc SRS has smaller CI (1.19 ± 0.14 vs. 1.50 ± 0.16, p < 0.001) and larger GI (4.77 ± 1.49 vs. 3.65 ± 0.98, p < 0.01). V12Gy results were comparable (2.73 ± 1.38 vs. 3.06 ± 2.20 cc, p = 0.58). Moderate to lower dose spread, V6, V4.5, and V3, were also equivalent. GK plans achieved better very low-dose spread (≤3 Gy) and also had slightly smaller Dspread, 1.9 vs. 2.5 Gy. Total treatment time for GK is estimated between 60 and 100 min. GK treatments are between 3 and 5 times longer compared to RapidArc treatment techniques.
Conclusion
Dosimetric parameters reflecting prescription dose conformality (CI), dose fall off (GI), radiation necrosis indicator (V12Gy), and dose spread (Dspread) were compared between GK SRS and RapidArc SRS for multi-mets. RapidArc plans have smaller CI but larger GI. V12Gy are comparable. GK appears better at reducing only very low-dose spread (<3 Gy). The treatment time of RapidArc SRS is significantly reduced compared to GK SRS.
doi:10.3389/fonc.2016.00026
PMCID: PMC4749694  PMID: 26904504
VMAT; RapidArc; Gamma Knife; SRS; brain metastasis

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