scholarly journals Optimizing proton minibeam radiotherapy by interlacing and heterogeneous tumor dose on the basis of calculated clonogenic cell survival

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Matthias Sammer ◽  
Stefanie Girst ◽  
Günther Dollinger
Keyword(s):  
Side Effects ◽  
Cell Survival ◽  
Therapeutic Index ◽  
Heavy Ion ◽  
Dose Distributions ◽  
Normal Tissues ◽  
The Mean ◽  
Clonogenic Cell ◽  
Tissue Sparing ◽  
Heterogeneous Tumor

AbstractProton minibeam radiotherapy (pMBRT) is a spatial fractionation method using sub-millimeter beams at center-to-center (ctc) distances of a few millimeters to widen the therapeutic index by reduction of side effects in normal tissues. Interlaced minibeams from two opposing or four orthogonal directions are calculated to minimize side effects. In particular, heterogeneous dose distributions applied to the tumor are investigated to evaluate optimized sparing capabilities of normal tissues at the close tumor surrounding. A 5 cm thick tumor is considered at 10 cm depth within a 25 cm thick water phantom. Pencil and planar minibeams are interlaced from two (opposing) directions as well as planar beams from four directions. An initial beam size of σ0 = 0.2 mm (standard deviation) is assumed in all cases. Tissue sparing potential is evaluated by calculating mean clonogenic cell survival using a linear-quadratic model on the calculated dose distributions. Interlacing proton minibeams for homogeneous irradiation of the tumor has only minor benefits for the mean clonogenic cell survival compared to unidirectional minibeam irradiation modes. Enhanced mean cell survival, however, is obtained when a heterogeneous dose distribution within the tumor is permitted. The benefits hold true even for an elevated mean tumor dose, which is necessary to avoid cold spots within the tumor in concerns of a prescribed dose. The heterogeneous irradiation of the tumor allows for larger ctc distances. Thus, a high mean cell survival of up to 47% is maintained even close to the tumor edges for single fraction doses in the tumor of at least 10 Gy. Similar benefits would result for heavy ion minibeams with the advantage of smaller minibeams in deep tissue potentially offering even increased tissue sparing. The enhanced mean clonogenic cell survival through large ctc distances for interlaced pMBRT with heterogeneous tumor dose distribution results in optimum tissue sparing potential. The calculations show the largest enhancement of the mean cell survival in normal tissue for high-dose fractions. Thus, hypo-fractionation or even single dose fractions become possible for tumor irradiation. A widened therapeutic index at big cost reductions is offered by interlaced proton or heavy ion minibeam therapy.

scholarly journals Predictors of radiation-induced complications in radiation oncology based on cell survival tests after ex vivo exposure: literature review

2021 ◽  
Vol 29 (1) ◽  
pp. 89-118
Author(s):  
V. A. Vinnikov ◽  
T. V. Rubleva
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Radiation Oncology ◽  
Radiation Effects ◽  
Ex Vivo ◽  
Radiation Toxicity ◽  
Normal Tissues ◽  
Intrinsic Radiosensitivity ◽  
Radiation Induced ◽  
Clonogenic Cell

Background. Among cancer patients receiving radiotherapy about 5–15 % may have adverse reactions in normal tissues and organs that limit their treatment in a full, originally scheduled regimen. The development of biomarkers and assays for radiation oncology allowing the prediction of patients’ normal tissue toxicity requires a lot of resourses, threfore its current status amd potential directions for future research have to be periodically analyzed and re-evaluated. Purpose – this review summarizes the methodological approaches and developments in the area of functional laboratory assays based on ex vivo cell survival for the prediction of the individual clinical radiosensitivity. Materials and methods. Data for the analysis and systematization were obtained from the full-text articles published in peer review international scientific journals (in English) in 1990–2020, which were selected by the extensive search in PubMed information database and cross references on the topic “Functional cellular tests for intrinsic radiosensitivity to predict adverse radiation effects and radiotherapy complications”. Results. In theory, it might be expected that clonogenic cell survival after ex vivo irradiation can surve as the best individual predictor of radiation toxicity, as it is an integral indicator of cell damage and decline of their regenerative potential. Tendentially, fibroblasts, as a test system for such studies, did not show significant advantages over lymphocytes either in detecting inter-individual variations in the intrinsic cellular radiosensitivity or in predicting clinical radiation toxicity, even for that in skin. It was found that clonogenic cell survival assay, being very time consuming and technically demanding, also suffers from the lack of sensitivity and specificity, essential uncertainty and low reproducibility of the results, and thus is not suitable for the sceening for the abnormal intrinsic radiosensitivity. However, this type of assays is applicable for the radiobiological expertise post factum in individual cases with unexpected, extreme radiation lesions. Radiation-induced lymphocyte apoptosis assay seems to be more promising however still requires further fundamental research for better understanding of its background and more validation studies in order to assess the optimum patient groups, radiotherapy regimens and adverse effects for its confident use in clinical practice. Changes in the regulation of cell cycle check-points (radiationinduced delay) ex vivo can have either positive or inverted association, or no correlation with clinical radiation responses in tissues, thus so far cannot be included in the toolbox of applied radiobiological tests. Conclusions. To date, in the practice of clinical radiobiology, there are no fully validated and standardized functional tests based on the cell survival after ex vivo irradiation, which would allow a sufficiently accurate prediction of adverse radiation effects in normal tissues of radiotherapy patients. In general, ex vivo tests based on the evaluation of only one form of cell death in one cell type are not fully reliable as a “stand alone” assay, because different pathways of cell death probably play different roles and show different dose response within the overal reaction of the irradiated tissue or critical organ. Such tests should become a part of the multiparametric predictive platforms.

scholarly journals Radiobiology Experiments With Ultra-high Dose Rate Laser-Driven Protons: Methodology and State-of-the-Art

2021 ◽  
Vol 9 ◽  
Author(s):  
Pankaj Chaudhary ◽  
Giuliana Milluzzo ◽  
Hamad Ahmed ◽  
Boris Odlozilik ◽  
Aaron McMurray ◽  
...  
Keyword(s):  
Dose Rate ◽  
Biological Effects ◽  
Therapeutic Index ◽  
High Dose Rate ◽  
High Dose ◽  
Particle Accelerators ◽  
Dose Rates ◽  
Normal Tissues ◽  
Multiple Pulses ◽  
Tissue Sparing

The use of particle accelerators in radiotherapy has significantly changed the therapeutic outcomes for many types of solid tumours. In particular, protons are well known for sparing normal tissues and increasing the overall therapeutic index. Recent studies show that normal tissue sparing can be further enhanced through proton delivery at 100 Gy/s and above, in the so-called FLASH regime. This has generated very significant interest in assessing the biological effects of proton pulses delivered at very high dose rates. Laser-accelerated proton beams have unique temporal emission properties, which can be exploited to deliver Gy level doses in single or multiple pulses at dose rates exceeding by many orders of magnitude those currently used in FLASH approaches. An extensive investigation of the radiobiology of laser-driven protons is therefore not only necessary for future clinical application, but also offers the opportunity of accessing yet untested regimes of radiobiology. This paper provides an updated review of the recent progress achieved in ultra-high dose rate radiobiology experiments employing laser-driven protons, including a brief discussion of the relevant methodology and dosimetry approaches.

Nanoparticle-based Drug Delivery Systems for Targeted Epigenetics Cancer Therapy

2020 ◽  
Vol 21 (11) ◽  
pp. 1084-1098
Author(s):  
Fengqian Chen ◽  
Yunzhen Shi ◽  
Jinming Zhang ◽  
Qi Liu
Keyword(s):  
Drug Delivery ◽  
Side Effects ◽  
Cancer Therapy ◽  
Drug Delivery Systems ◽  
Therapeutic Index ◽  
Delivery Systems ◽  
Epigenetic Therapy ◽  
Cancer Therapies ◽  
Therapeutic Benefits ◽  
High Therapeutic Index

This review summarizes the epigenetic mechanisms of deoxyribonucleic acid (DNA) methylation, histone modifications in cancer and the epigenetic modifications in cancer therapy. Due to their undesired side effects, the use of epigenetic drugs as chemo-drugs in cancer therapies is limited. The drug delivery system opens a door for minimizing these side effects and achieving greater therapeutic benefits. The limitations of current epigenetic therapies in clinical cancer treatment and the advantages of using drug delivery systems for epigenetic agents are also discussed. Combining drug delivery systems with epigenetic therapy is a promising approach to reaching a high therapeutic index and minimizing the side effects.

Cytoprotective Agents to Avoid Chemotherapy Induced Sideeffects on Normal Cells: A Review

2019 ◽  
Vol 19 (10) ◽  
pp. 765-781
Author(s):  
Seema Rohilla ◽  
Harish Dureja ◽  
Vinay Chawla
Keyword(s):  
Adverse Effects ◽  
Anticancer Agents ◽  
Therapeutic Index ◽  
Chemotherapeutic Agents ◽  
Vital Role ◽  
Normal Cells ◽  
Normal Tissues ◽  
Organ Specific ◽  
Delay In Treatment

Anticancer agents play a vital role in the cure of patients suffering from malignancy. Though, the chemotherapeutic agents are associated with various adverse effects which produce significant toxic symptoms in the patients. But this therapy affects both the malignant and normal cells and leads to constricted therapeutic index of antimalignant drugs which adversely impacts the quality of patients’ life. Due to these adversities, sufficient dose of drug is not delivered to patients leading to delay in treatment or improper treatment. Chemoprotective agents have been developed either to minimize or to mitigate the toxicity allied with chemotherapeutic agents. Without any concession in the therapeutic efficacy of anticancer drugs, they provide organ specific guard to normal tissues.

Cancer Nanotheranostics: A Nanomedicinal Approach for Cancer Therapy and Diagnosis

2020 ◽  
Vol 20 (11) ◽  
pp. 1288-1299
Author(s):  
Paromita Kundu ◽  
Deepika Singh ◽  
Abhalaxmi Singh ◽  
Sanjeeb K. Sahoo
Keyword(s):  
Drug Delivery ◽  
Side Effects ◽  
Cancer Diagnosis ◽  
Specific Drug ◽  
Novel Therapies ◽  
Future Directions ◽  
Normal Tissues ◽  
Cancer Management ◽  
Single Probe ◽  
Therapy And Diagnosis

The panorama of cancer treatment has taken a considerable leap over the last decade with the advancement in the upcoming novel therapies combined with modern diagnostics. Nanotheranostics is an emerging science that holds tremendous potential as a contrivance by integrating therapy and imaging in a single probe for cancer diagnosis and treatment thus offering the advantage like tumor-specific drug delivery and at the same time reduced side effects to normal tissues. The recent surge in nanomedicine research has also paved the way for multimodal theranostic nanoprobe towards personalized therapy through interaction with a specific biological system. This review presents an overview of the nano theranostics approach in cancer management and a series of different nanomaterials used in theranostics and the possible challenges with future directions.

scholarly journals AB0287 HEMATOLOGICAL SIDE EFFECTS OF BIOLOGICAL THERAPY IN RHEUMATOLOGY: DATA FROM THE TUNISIAN REGISTER

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1442.2-1442
Author(s):  
H. Bettaieb ◽  
S. Boussaid ◽  
S. Jemmali ◽  
S. Rekik ◽  
E. Cheour ◽  
...  
Keyword(s):  
Side Effects ◽  
Biological Treatment ◽  
Blood Count ◽  
Biological Therapy ◽  
National Registry ◽  
Close Monitoring ◽  
Female Ratio ◽  
Therapy Initiation ◽  
Male Female Ratio ◽  
The Mean

Background:During the last decade, the treatment of chronic inflammatory rheumatism (CIR) has been greatly improved with the advent of biotherapy.However, the use of biological treatment can lead to a number of side effects including abnormalities in the blood count.Objectives:The aim of this study was to assess the different hematological side effects of biological treatment in patients with rheumatoid arthritis (RA) and spondyloarthitis (SA).Methods:This study included patients with RA (ACR/EULAR 2010) and SA (ASAS 2009) registred with the Tunisian Biologic National Registry (BINAR).Patients were followed and treated with biologics for 2 years of less. Clinical data relative to biological treatment, including haematological side effects, have been collected.Results:Two hundred and ninety-eight patients (178 women and 111 men) were included in the study.The mean age was 49.2 ± 14.1 years. The male/female ratio was 0.6. The mean diseases durations for RA and SA were respectively 6.7 ± 3.5 years and 6.5 ±3.6 years.Anti-TNFα agents were prescribed in 87.9% of patients (n = 263) with respectively: Infliximab (20.4%) Etanercept (23.1%), Adalimumab (24.6%) and Certolizumab (26.5%).Tocilizumab and Rituximab were prescribed in 10.4% and 5% of the patients, respectively.Blood count abnormalities were noted in 15.4 % of patients (n=46).Neutropenia was the most frequently anomaly met on the hemogram (9.1%) followed by anemia (3.4%) and thrombocytopenia (3%). Pancytopenia was found in 11.4% of patients (n=34).The median time between biological therapy initiation and the onset of hematologic manifestations was 4.8 months [1-12]. Biological treatment was interrupted in two patients.In the other cases, the biological treatment was maintained with close monitoring of blood cell count. No case of death related to these hematological disturbances has been reported.Conclusion:In our registry, hematological side effects of biological treatment were found in 15.4% of cases and were noted with a median delay of 4.8 [1-12] months after the treatment initiation. Further studies are needed to confirm our preliminary results.Disclosure of Interests:None declared

scholarly journals Suramin Targets the Conserved Ligand-Binding Pocket of Human Raf1 Kinase Inhibitory Protein

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1151
Author(s):  
Chenyun Guo ◽  
Zhihua Wu ◽  
Weiliang Lin ◽  
Hao Xu ◽  
Ting Chang ◽  
...  
Keyword(s):  
Side Effects ◽  
Ligand Binding ◽  
Mapk Pathway ◽  
Regulatory Protein ◽  
Therapeutic Index ◽  
Binding Pocket ◽  
Biological Macromolecules ◽  
Inhibitory Protein ◽  
Ligand Binding Pocket ◽  
Raf1 Kinase

Suramin was initially used to treat African sleeping sickness and has been clinically tested to treat human cancers and HIV infection in the recent years. However, the therapeutic index is low with numerous clinical side-effects, attributed to its diverse interactions with multiple biological macromolecules. Here, we report a novel binding target of suramin, human Raf1 kinase inhibitory protein (hRKIP), which is an important regulatory protein involved in the Ras/Raf1/MEK/ERK (MAPK) signal pathway. Biolayer interference technology showed that suramin had an intermediate affinity for binding hRKIP with a dissociation constant of 23.8 µM. Both nuclear magnetic resonance technology and molecular docking analysis revealed that suramin bound to the conserved ligand-binding pocket of hRKIP, and that residues K113, W173, and Y181 play crucial roles in hRKIP binding suramin. Furthermore, suramin treatment at 160 µM could profoundly increase the ERK phosphorylation level by around 3 times. Our results indicate that suramin binds to hRKIP and prevents hRKIP from binding with hRaf1, thus promoting the MAPK pathway. This work is beneficial to both mechanistically understanding the side-effects of suramin and efficiently improving the clinical applications of suramin.

scholarly journals Efficacy and Safety of Modified Huang-Lian-Jie-Du Decoction Cream on Cancer Patients with Skin Side Effects Caused by EGFR Inhibition

Processes ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 1081
Author(s):  
Ming-Yang Lee ◽  
Mei-Yi Lin ◽  
Yu-Ju Chang ◽  
Yu-Ting Tseng ◽  
I-An Huang ◽  
...  
Keyword(s):  
Side Effects ◽  
Adverse Events ◽  
Kinase Inhibitors ◽  
Target Therapy ◽  
Herbal Medicines ◽  
Skin Toxicity ◽  
Dry Skin ◽  
Egfr Inhibition ◽  
The Mean ◽  
Skin Conditions

(1) Background: The epidermal growth factor inhibitors (EGFRIs)/tyrosine kinase inhibitors (TKIs) are effective for cancer target therapy, but acneiform rashes or so-called inflammatory papulopustular exanthemas are common (50% to 90%). The conventional therapy for EGFRIs/TKIs-induced skin toxicity is steroids and antibacterial drugs, but it is still ineffective for some patients, and EGFRIs/TKIs dose reduction/interruption may be needed. In this study, a modified Chinese herbal medicine, Huang-Lian-Jie-Du decoction cream with Yin-Cold (YC) medicine characteristic, was investigated for the effect on patients suffering EGFRIs/TKIs-induced skin toxicity. (2) Methods: The modified Huang-Lian-Jie-Du (mHLJD) decoction cream was made from 10 herbal medicines, including 4 major medicines (Huanglian, Huangqin, Huangbo, and Zhizi) in traditional HLJD decoction. Patients with EGFRIs/TKIs-induced skin toxicity were enrolled. Patients were excluded if they also used other cream for skin toxicity. Skin conditions were monitored by follow up every 2 weeks. The patients’ characteristics, the skin toxicities, treatment response, and adverse events were recorded and analyzed until skin problems resolved or the study ended. (3) Results: The mHLJD decoction cream and its sub-packages were stored at 4 °C before use. Thirty-four patients who had grade 1–3 skin toxicities after receiving EGFRIs/TKIs were enrolled. Seven patients withdrew or were excluded. Finally, data from 27 patients were analyzed. The mean grade of rash acneiform was significantly decreased from 2.19 (ranged 1 to 3) to 0.88 (ranged 0 to 2) after mHLJD decoction cream treatment for 4 weeks and to 0.55 (ranged 0 to 2) after mHLJD decoction cream treatment for 8 weeks. Additionally, the mean grade of dry skin was also significantly decreased from 1.57 (ranged 1 to 2) to 0.71 (ranged 0 to 1) after mHLJD decoction cream treatment for 4 weeks. The changes of skin toxicity were significant, with no obvious adverse events. (4) Conclusions: In summary, the mHLJD decoction cream provides benefits for alleviation of EGFRIs/TKIs-induced skin rash acneiform and dry skin. Additionally, no obvious side effects were found in patients using mHLJD decoction cream.

scholarly journals GERMLINE HYPERMUTABILITY IN DROSOPHILA AND ITS RELATION TO HYBRID DYSGENESIS AND CYTOTYPE

Genetics ◽  
1981 ◽  
Vol 98 (3) ◽  
pp. 565-587
Author(s):  
William R Engels
Keyword(s):  
Cell Survival ◽  
Chromosomal Rearrangements ◽  
Stable State ◽  
Hybrid Dysgenesis ◽  
Mutation Rates ◽  
Female Sterility ◽  
Genetic Element ◽  
Two Generations ◽  
The Mean ◽  
P Factor

ABSTRACT In its hypermutable state, an unstable singed allele, snw, mutates in the germline to two other alleleic forms at a total frequency usually between 40 and 60%. In its stable state, the mutation rate of snw is essentially zero. Its state depends on an extrachromosomal condition indistinguishable from a property called cytotype previously studied as a component of hybrid dysgenesis. Of the two known systems of hybrid dysgenesis, denoted P-M and I-R, snw hypermutability is determined by the P-M system and appears to be independent of the I-R system. Cytotype, as defined by the control of snw mutability, is self-reproducing in the cytoplasm or nucleoplasm of the germline through at least two generations. However, it is not entirely autonomous, being ultimately determined by the chromosomes after sufficiently many generations of backcrossing. This combination of chromosomal and extrachromosomal transmission agrees well with previous studies on cytotype. Temperature differences have little effect on the mean mutation rates, but they have a pronounced effect on the intrinsic variance among individuals. The latter effect suggests that high temperatures reduce germ-cell survival during the development of dysgenic flies. Chromosomal rearrangements produce no apparent effects on the behavior of snw. Hypermutability is thought to be caused by the excision or other alteration of an inserted genetic element in the snw gene. This element might be a copy of the "P factor," which is though to be a mobile sequence capable of causing female sterility and other dysgenic traits in the P-M system.

Sign in / Sign up

Export Citation Format

Share Document