The aim of this study was to estimate the radiation-related secondary cancer risks in organs during the treatment of breast cancer with different radiotherapy techniques, such as three-dimensional ...conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT). The treatment plans for 26 patients with breast cancer who received whole-breast irradiation at a dose of 50 Gy included tangential field 3D-CRT with hard-wedges (W-TF), tangential field IMRT (2F-IMRT), multiple field IMRT (6F-IMRT), and double partial arcs (VMAT). Patients were divided into three groups according to the distance between the contralateral breast (CB) and the body of the sternum. Setup error was simulated by moving the isocenter, and the dose distribution was then recalculated without changing the field fluency distribution. Based on the linear-exponential, the plateau, and the full mechanistic dose-response models, the organ equivalent dose and excess absolute risk were calculated from dose-volume histograms to estimate the secondary cancer risks in organs. Compared with 3D-CRT, IMRT and VMAT showed excellent results regarding tumor conformity and homogeneity; however, the low dose volume to organs was considerably higher in 6F-IMRT and VMAT. Secondary cancer risks for 2F-IMRT were comparable or slightly lower than for W-TF, but considerably lower than for 6F-IMRT or VMAT. After setup error simulation, there was a small increase in secondary cancer risk for 2F-IMRT and an increase of 159% and 318% for 6F-IMRT and VMAT, respectively, compared with W-TF. Although these results were obtained in most patients, they did not necessarily apply to every individual. The secondary cancer risks in the CB decreased significantly in correlation with increased distance for all alternative techniques, although they were higher in VMAT and lower in 2F-IMRT regardless of the distance. After setup error simulation, the increased changes in secondary cancer risks in the CB were comparable between 2F-IMRT, 6F-IMRT, and VMAT, suggesting that the secondary cancer risks in the CB mainly depend on radiotherapy techniques and distance, although the effect of setup error cannot be ignored. In the contralateral lung (CL), the secondary cancer risks were almost independent from distance and depended mainly on radiotherapy techniques; they were rarely affected by setup error. VMAT was associated with a higher secondary cancer risk in the CL. For the ipsilateral lung (IL), the secondary cancer risks were higher than those in other organs because the IL receives high doses to achieve tumor control, and they were relatively lower in VMAT. This warrants special consideration when estimating the secondary cancer risk to the IL. The study results suggested that the optimal radiotherapy method for breast cancer should be determined on an individual basis and according to the balance between secondary cancer risks related to anatomic diversity and setup error, which can prevent blind selection of techniques.
Objective
This study aimed to evaluate the quality of locally advanced nasopharyngeal carcinoma (NPC) radiotherapy plans generated by the automated planning module of a commercial treatment planning ...system (TPS).
Methods
Data of 30 patients with locally advanced NPC were retrospectively investigated. For each patient, volumetric modulated arc therapy (VMAT) plans with double arcs were generated manually by experienced physicists and automatically in the Pinnacle
3
Auto-Planning module (Philips Medical Systems, Fitchburg, WI, USA). The anatomic distance between the second clinical target volume (CTV
2
) and the pons of the brainstem, and the T category of disease were factored into the evaluation. Dosimetric verification was evaluated in terms of gamma pass rate. Target coverage, sparing of organs at risk (OARs), and monitor units were evaluated and compared between the manual and automatic VMAT plans.
Results
Not all treatment plans fully met the dose objectives for planning target volumes (PTVs) and OARs, particularly in T4 patients. Overall, automatic VMAT provides a comparable or superior plan quality to manual VMAT in most cases. In stratified analysis, plan quality is mainly independent on T category but is also affected by anatomic distance. If the anatomic distance is less than 5 mm, the automatic VMAT plan quality is equal or even inferior to manual VMAT performed by experienced physicists. Conversely, if the anatomic distance is greater than 5 mm, the automatic VMAT plan quality is superior to manual VMAT. Gamma pass rates for quality assurance are similar between manual and automatic VMAT plans for the former case, but significantly higher in automatic VMAT for the latter.
Conclusion
The selection of manual versus automatic VMAT planning in locally advanced NPC should be made individually based on the anatomic distance, rather than blindly and habitually, since automatic VMAT is not good enough to completely replace manual VMAT.
Purpose
To design and construct a three‐dimensional (3D) anthropomorphic abdominal phantom for geometric accuracy and dose summation accuracy evaluations of deformable image registration (DIR) ...algorithms for adaptive radiation therapy (ART).
Method
Organ molds, including liver, kidney, spleen, stomach, vertebra, and two metastasis tumors, were 3D printed using contours from an ovarian cancer patient. The organ molds were molded with deformable gels made of different mixtures of polyvinyl chloride (PVC) and the softener dioctyl terephthalate. Gels with different densities were obtained by a polynomial fitting curve that described the relation between the Hounsfield unit (HU) and PVC‐softener blending ratio. The rigid vertebras were constructed by molding of white cement and cellulose pulp. The final abdominal phantom was assembled by arranging all the fabricated organs inside a hollow dummy according to their anatomies, and sealed by deformable gel with averaged HU of muscle and fat. Fiducial landmarks were embedded inside the phantom for spatial accuracy and dose accumulation accuracy studies. Two channels were excavated to facilitate ionization chamber insertion for dosimetric measurements. Phantom properties such as deformable gel elasticity and HU stability were studied. The dosimetric measurement accuracy in the phantom was performed, and the DIR accuracies of three DIR algorithms available in the open source DIR toolkit‐DIRART were also validated.
Results
The constructed deformable gel showed elastic behavior and was stable in HU values over times, proving to be a practical material for the deformable phantom. The constructed abdominal phantom consisted of realistic anatomies in terms of both anatomical shapes and densities when compared with its reference patient. The dosimetric measurements showed a good agreement with the calculated doses from the treatment planning system. Fiducial‐based accuracy analysis conducted on the constructed phantom demonstrated the feasibility of applying the phantom for organ‐wise DIR accuracy assessment.
Conclusions
We have designed and constructed an anthropomorphic abdominal deformable phantom with satisfactory elastic property, realistic organ density, and anatomy. This physical phantom can be used for routine validations of DIR geometric accuracy and dose accumulation accuracy in ART.
Radiotherapy is a leading treatment approach of cancer therapy. While it is effective in killing tumor cells, it can also cause serious damage to surrounding normal tissue. Targeted radiotherapy with ...gold nanoparticle-based radiosensitizers is actively being investigated, and considered as a promising means to enhance the efficacy of radiotherapy against tumors under a relatively low and safe radiation dose. In this work, we report a green and one-step strategy to synthesize fluorescent gold nanoclusters by using a commercialized cyclic arginine-glycine-aspartic acid (c(RGDyC)) peptide as the template. The nanoclusters inherit special properties of both the Au core (red/NIR fluorescence emission and strong radiosensitizing effect) and c(RGDyC) shell (active cancer cell-targeting ability and good biocompatibility), and can be applied as fluorescent probes to stain αvβ3 integrin-positive cancer cells, as well as radiosensitizing agents to boost the killing efficacy of radiotherapy. Our data suggest that the as-designed gold nanoclusters have excellent biocompatibility, bright red/NIR fluorescence, active tumor targeting property, and strong radiosensitizing effect, making them highly promising towards potential clinical translation.
Background
Tumour repopulation initiated by residual tumour cells in response to cytotoxic therapy has been described clinically and biologically, but the mechanisms are unclear. Here, we aimed to ...investigate the mechanisms for the tumour‐promoting effect in dying cells and for tumour repopulation in surviving tongue cancer cells.
Methods
Tumour repopulation in vitro and in vivo was represented by luciferase activities. The differentially expressed cytokines in the conditioned medium (CM) were identified using a cytokine array. Gain or loss of function was investigated using inhibitors, neutralising antibodies, shRNAs and ectopic overexpression strategies.
Results
We found that dying tumour cells undergoing cytotoxic therapy increase the growth of living tongue cancer cells in vitro and in vivo. Dying tumour cells create amphiregulin (AREG)‐ and basic fibroblast growth factor (bFGF)‐based extracellular environments via cytotoxic treatment‐induced endoplasmic reticulum stress. This environment stimulates growth by activating lysine acetyltransferase 6B (KAT6B)‐dependent nuclear factor‐kappa B (NF‐κB) signalling in living tumour cells. As direct targets of NF‐κB, miR‐22 targets KAT6B to repress its expression, but long noncoding RNAs (lncRNAs) (XLOC_003973 and XLOC_010383) counter the effect of miR‐22 to enhance KAT6B expression. Moreover, we detected increased AREG and bFGF protein levels in the blood of tongue cancer patients with X‐box binding protein‐1 (XBP1) activation in tumours under cytotoxic therapy and found that XBP1 activation is associated with poor prognosis of patients. We also detected activation of miR‐22/lncRNA/KAT6B/NF‐κB signalling in recurrent cancers compared to paired primary tongue cancers.
Conclusions
We identified the molecular mechanisms of cell death‐induced tumour repopulation in tongue cancer. Such insights provide new avenues to identify predictive biomarkers and effective strategies to address cancer progression.
MKK4 is a candidate tumor suppressor, which acts as a critical mediator of Epstein–Barr Virus (EBV)‐induced c‐Jun N‐terminal kinase (JNK) activation. Functional polymorphism MKK4 −1304T>G has been ...showed to be protective in colorectal cancer or lung cancer. We hypothesized that genetic variants in the MKK4 promoter were associated with the risk of nasopharyngeal carcinoma (NPC). Two common polymorphisms in MKK4, −1304T>G and −1044A>T were genotyped in two independent case‐control panels of Eastern and Southern Chinese populations, totally containing 1237 NPC and 1328 controls. We found that compared to the most common −1304TT genotype, carriers of variant genotypes (−1304TG+GG) were associated with a significantly reduced risk for NPC in total subjects (adjusted OR = 0.78; 95%CI = 0.67–0.94). Further stratification analysis showed that the protective effect was more pronounced in EBV negative status (adjusted OR = 0.51; 95%CI = 0.41–0.68) but restrained in those with EBV infection (adjusted OR = 1.05; 95%CI = 0.88–1.26), and that the −1304GG variant genotypes interacted with EBV negative status on reducing cancer risk (p = 0.011). However, no significant association was observed between the −1044A>T polymorphism and risk of NPC. Our data suggest that the protective role of genetic variant MKK4 −1304T>G is restrained in NPC with EBV infection. These findings implicate the role of EBV and MKK4 −1304 T>G interaction as a causative factor for the NPC.
Metformin, one of the most widely used antidiabetic drugs, has recently been associated with potential antitumorigenic effects. In this study, we evaluated the possible cytotoxic impact of combined ...low doses of metformin and ionizing radiation (IR) on 2 human hepatoma cell lines. The cytotoxic effect of metformin combined with IR was subsequently determined by clonogenic survival and cell cycle assays, assessment of mitochondrial complex I and lactate dehydrogenase (LDH) activity, measurement of cellular adenosine triphosphate (ATP) levels, comet assay and analyses of the formation and disappearance of phosphorylated histone H2AX (γ-H2AX) protein. The combination of metformin and IR caused a much stronger cytotoxicity than the treatment with metformin or IR alone, leading to an ~80% decrease in cell viability and ~35% increase in the accumulation of cells in the G2/M phase of the cell cycle in the 2 hepatoma cell lines. In addition, a reduction in mitochondrial complex I activity (~70%) and a significant increase in LDH activity, as well as lactate production were observed in the cells exposed to metformin. Interestingly, a severe depletion in ATP, increased olive tail moment and the delayed disappearance of γ-H2AX expression were detected in the hepatoma cells treated by metformin plus IR. These findings show that the combination of a low concentration of metformin and IR results in the considerable enhancement of cytotoxic effects in human hepatoma cell lines, leading to decreased DNA repair by reducing ATP production. The data provided in this study may elucidate the remarkable efficiency of this combination treatment and suggest that metformin may be used as a potential adjunct to the radiotherapy of hepatocellular carcinoma.
•Pelvic (active) bone marrow (BM) sparing radiotherapy plans reduced pelvic (active) BM irradiation dose.•Pooled analysis found that pelvic BM-sparing radiotherapy decreased the incidence of G2+ and ...G3+ hematological toxicity (OR 0.31/0.42, P < 0.0001).•No significant differences in gastrointestinal and urological toxicity were observed between pelvic BM-sparing and non-sparing radiotherapy.•Pelvic active BM-sparing radiotherapy also decreased hematologic toxicity (OR 0.42/0.21, P < 0.01).•Clinical benefits of pelvic active BM-sparing radiotherapy over pelvic BM-sparing remains to be further investigated.
Concurrent chemo-radiotherapy in patients with locally advanced cervical cancer has significant hematologic toxicities (HT), leading to treatment disruption and affecting patient prognosis. We performed the meta-analysis to assess the clinical benefit of pelvic (active) bone marrow (BM) sparing radiotherapy.
A systematic methodological search of six primary electronic databases was performed. This systematic review mainly assessed the differences in pelvic (active) BM dose-volume parameters (DVP), hematologic toxicity of pelvic (active) BM sparing versus non-sparing radiotherapy plans. The secondary objective was to explore optimal dose limitation regimens and evaluate other radiation-induced toxicities (gastrointestinal and urological toxicity (GT/UT)). Random-effects models were used for meta-analysis.
Final 65 publications that met inclusion criteria were included in the meta-analysis and descriptive tables. Meta-analysis of mean pelvic BM-DVP differences showed that pelvic BM-V10,20,40,50 (Vx: volume of BM receiving ≥ X Gy) were reduced by −4.6% 95% CI: −6.6, −2.6, −10.9% −13.2, −8.6, −7.3% −9.5, −5.2 and −3.4% −4.3, −2.4 in pelvic BM-sparing plans. Pelvic BM sparing radiotherapy decreased G2/3+ HT odds ratio (OR) 0.31, (0.23, 0.41)/0.42, (0.28, 0.63), without increasing GT G2/3+: OR 0.76, (0.51, 1.14)/0.90, (0.47, 1.74) and UT G2/3+: OR 0.91, (0.57, 1.46)/0.54, (0.25, 1.17). Pelvic active BM sparing radiotherapy also reduced HT G2/3+ HT: OR 0.42, (0.23, 0.77)/0.34, (0.16, 0.72). There were significant variations between publications in dose restriction regimens.
The pelvic BM protection radiotherapy can decrease BM dose and HT. Moreover, it does not increase GT and UT. The clinical benefit of pelvic active BM protection needs to be further validated in randomized controlled trials.
Background
4DCT (four-dimensional computed tomography) can effectively obtain functional lung ventilation images for patients and integrate them into radiotherapy treatment planning. Studies have not ...been performed on esophageal cancer, and there is no clear consensus on the optimal functional lung threshold for functional lung.
Methods
Functional lung images were generated for 11 patients with esophageal cancer. The correlation between the dose–volume parameters of functional lung (FL) as defined by different thresholds and the change of PFT/PDFT (pulmonary diffusion function test) metrics before and after radiotherapy were evaluated. FL-sparing planning was generated for each patient to preserve the functional lung and compared to conventional anatomical CT (non-sparing) planning.
Results
There was a significant positive correlation between the FL0.8 (defined Jacobian value ≤ 0.8), FL0.84, and FL0.9 dose–volume parameters and ΔFEV1/FVC (reduction before and after radiotherapy), and the FL0.8‑V
30
correlation was the strongest (r = 0.819,
P
< 0.01). The FL-sparing planning had a target area conformity index and homogeneity index comparable to the non-sparing planning (
P
> 0.05). For FL, the FL-sparing planning achieved lower FL-MLD (6.30 ± 2.14 Gy vs. 7.83 ± 2.70 Gy), V
10
(17.13 ± 7.70% vs. 27.40 ± 9.48%), and V
20
(6.96 ± 3.85% vs. 11.63 ± 7.19%) compared to the non-sparing planning (
P
< 0.05), while heart and spinal cord doses were not significantly different between the two planning groups.
Conclusion
The 4DCT-based FL irradiation dose for esophageal cancer was significantly associated with a decrease in FEV1/FVC. The optimal FL defined as a Jacobian value ≤ 0.8 or about 21% of the whole lung volume may be a good choice. FL-sparing planning significantly reduced the FL dose without compromising target area coverage.
Classifier diversity and fusion architecture are two critical characteristics stressed in homogeneous and heterogeneous ensemble learning methods and they are equally important for building a ...successful multi-classifier system. In this study, we introduced a two-level framework, namely hierarchical fusion of homogeneous and heterogeneous multi-classifiers (HF2HM), to integrate the diversified classification models produced by feeding heterogeneous classifiers with homogeneous random-projected training datasets. The proposed hierarchical fusion scheme was comprehensively validated using fifteen public UCI datasets and three clinical datasets. The experimental results demonstrated the superiority of the proposed HF2HM framework over the base classifiers and the state-of-the-art benchmark ensemble methods, verifying it as a potential tool to assist in medical decision making in practical clinical settings.
•A hierarchical framework for multi-classifiers fusion is proposed.•It is a hybrid integration of heterogeneous and homogeneous classifiers.•The proposed framework is a potential tool to assist in medical decision-making.
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