Assessment of different head tilt angles in volumetric modulated arc therapy for hippocampus-avoidance whole-brain radiotherapy.

Purpose: In the field of radiation therapy for brain metastases, whole-brain hippocampus-avoidance treatment is commonly employed. this study aims to examine the impact of different head tilt angles on the dose distribution in the whole-brain target area and organs at risk. It also aims to determine the head tilt angle to achieve optimal radiation therapy outcomes. Methods: CT images were collected from 8 brain metastases patients at 5 different groups of head tilt angle. The treatment plans were designed using the volumetric modulated arc therapy (VMAT) technique. The 5 groups of tilt angle were as follows: [0°,10°), [10°,20°), [20°,30°), [30°,40°), and [40°,45°]. The analysis involved assessing parameters such as the uniformity index, conformity index, average dose delivered to the target, dose coverage of the target, hot spots within the target area, maximum dose, and average dose received by organs at risk. Additionally, the study evaluated the correlation between hippocampal dose and other factors, and established linear regression models. Results: Significant differences in dosimetric results were observed between the [40°,45°] and [0°,10°) head tilt angles. The [40°,45°] angle showed significant differences compared to the [0°,10°) angle in the average dose in the target area (31.49 ± 0.29 Gy vs. 31.99 ± 0.29 Gy, p=0.016), dose uniformity (1.20 ± 0.03 vs. 1.24 ± 0.03, p=0.016), hotspots in the target area (33.64 ± 0.35 Gy vs. 34.42 ± 0.49 Gy, p=0.016), maximum hippocampal dose (10.73 ± 0.36 Gy vs. 11.66 ± 0.59 Gy, p=0.008), maximum dose in the lens (2.82 ± 1.10 Gy vs. 4.99 ± 0.16 Gy, p=0.016), and average dose in the lens (1.93 ± 0.29 Gy vs. 4.22 ± 0.26 Gy, p=0.008). There is a moderate correlation between the maximum dose in the hippocampi and the PTV length (r=0.49, p=0.001). Likewise, the mean dose in the hippocampi is significantly correlated with the hippocampi length (r=0.34, p=0.04). Conclusion: The VMAT plan with a head tilt angle of [40°,45°] met all dose constraints and demonstrated improved uniformity of the target area while reducing the dose to organs at risk. Furthermore, the linear regression models suggest that increasing the head tilt angle within the current range of [0°,45°] is likely to lead to a decrease in the average hippocampal dose.

DNA-Programmed Four-Bit Quaternary Fluorescence Encoding (FLUCO) Enables 51-Colored Bioimaging Analysis.

Color encoding plays a crucial role in painting, digital photography, and spectral analysis. Achieving accurate, target-responsive color encoding at the molecular level has the potential to revolutionize scientific research and technological innovation, but significant challenges persist. Here, we propose a multibit DNA self-assembly system based on computer-aided design (CAD) technology, enabling accurate, target-responsive, amplified color encoding at the molecular level, termed fluorescence encoding (FLUCO). As a model, we establish a quaternary FLUCO system using four-bit DNA self-assembly, which can accurately encode 51 colors, presenting immense potential in applications such as spatial proteomic imaging and multitarget analysis. Notably, FLUCO enables the simultaneous imaging of multiple targets exceeding the limitations of channels using conventional imaging equipment, and marks the integration of computer science for molecular encoding and decoding. Overall, our work paves the way for target-responsive, controllable molecular encoding, facilitating spatial omics analysis, exfoliated cell analysis, and high-throughput liquid biopsy.

Tumor-associated antigen-specific cell imaging based on upconversion luminescence and nucleic acid rolling circle amplification.

Tumor-associated antigen (TAA)-based diagnosis has gained prominence for early tumor screening, treatment monitoring, prognostic assessment, and minimal residual disease detection. However, limitations such as low sensitivity and difficulty in extracting non-specific binding membrane proteins still exist in traditional detection methods. Upconversion luminescence (UCL) exhibits unique physical and chemical properties under wavelength near-infrared light excitation. Rolling circle amplification (RCA) is an efficient DNA amplification technique with amplification factors as high as 105. Therefore, the above two excellent techniques can be employed for highly accurate imaging analysis of tumor cells. Herein, we developed a novel nanoplatform for TAA-specific cell imaging based on UCL and RCA technology. An aptamer-primer complex selectively binds to Mucin 1 (MUC1), one of TAA on cell surface, to trigger RCA reaction, generating a large number of repetitive sequences. These sequences provide lots of binding sites for complementary signal probes, producing UCL from lanthanide-doped upconversion nanoparticles (UCNPs) after releasing quencher group. The experimental results demonstrate the specific attachment of upconversion nanomaterials to cancer cells which express a high level of MUC1, indicating the potential of UCNPs and RCA in tumor imaging.

Spectral CT assists differentiation of osteoblastic bone metastasis from bone island in newly diagnosed cancer patients.

OBJECTIVES: To investigate measurements derived from plain and enhanced spectral CT in differentiating osteoblastic bone metastasis (OBM) from bone island (BI). MATERIALS AND METHODS: From January to November 2020, 73 newly diagnosed cancer patients with 201 bone lesions (OBM = 92, BI = 109) having received spectral CT were retrospectively enrolled. Measurements including CT values of 40-140 keV, slope of the spectral curve, effective atomic number (Zeff), water (calcium) density, calcium (water) density, and Iodine (calcium) density were derived from manually segmented lesions on plain and enhanced spectral CT, and then analyzed using Student t-test and Pearson's correlation. Multivariate analysis was performed to build models (plain spectral model, enhanced spectral CT model, and combined model) for the discrimination of OBM and BI with performance evaluated using receiver operator characteristics curve and DeLong test. RESULTS: All features were significantly different between the BI group and OBM group (all p < 0.05), highly correlated with the corresponding features between plain and enhanced spectral CT both in OBM (r: 0.392-0.763) and BI (r: 0.430-0.544). As for the model performance, the combined model achieved the best performance (AUC = 0.925, 95% CI: 0.879 to 0.957), which significantly outperformed the plain spectral CT model (AUC = 0.815, 95% CI: 0.754 to 0.866, p < 0.001) and enhanced spectral CT model (AUC = 0.901, 95% CI: 0.852 to 0.939, p = 0.024) in differentiating OBM and BI. CONCLUSION: In addition to plain spectral CT measurements, enhanced spectral CT measurements would further significantly benefit the differential diagnosis. CLINICAL RELEVANCE STATEMENT: Measurements derived either from plain or enhanced spectral CT could provide additional valuable information to improve the differential diagnosis between OBM and BI in newly diagnosed cancer patients. KEY POINTS: • We intend to investigate plain and enhanced spectral CT measurements in differentiating OBM from BI. • Both plain and enhanced spectral CT help in discriminating OBM and BI in newly diagnosed cancer patients. • Enhanced spectral CT measurements further improve plain spectral CT measurements-based differential diagnosis.

Evaluation of the Yield of DNA Double-Strand Breaks for Carbon Ions Using Monte Carlo Simulation and DNA Fragment Distribution.

PURPOSE: The aim of this work was to provide a method to evaluate the yield of DNA double-strand breaks (DSBs) for carbon ions, overcoming the bias in existing methods due to the nonrandom distribution of DSBs. METHODS AND MATERIALS: A previously established biophysical program based on the radiation track structure and a multilevel chromosome model was used to simulate DNA damage induced by x-rays and carbon ions. The fraction of activity retained (FAR) as a function of absorbed dose or particle fluence was obtained by counting the fraction of DNA fragments larger than 6 Mbp. Simulated FAR curves for the 250 kV x-rays and carbon ions at various energies were compared with measurements using constant-field gel electrophoresis. The doses or fluences at the FAR of 0.7 based on linear interpolation were used to estimate the simulation error for the production of DSBs. RESULTS: The relative difference of doses at the FAR of 0.7 between simulation and experiment was -8.5% for the 250 kV x-rays. The relative differences of fluences at the FAR of 0.7 between simulations and experiments were -17.5%, -42.2%, -18.2%, -3.1%, 10.8%, and -14.5% for the 34, 65, 130, 217, 2232, and 3132 MeV carbon ions, respectively. In comparison, the measurement uncertainty was about 20%. Carbon ions produced remarkably more DSBs and DSB clusters per unit dose than x-rays. The yield of DSBs for carbon ions, ranging from 10 to 16 Gbp-1Gy-1, increased with linear energy transfer (LET) but plateaued in the high-LET end. The yield of DSB clusters first increased and then decreased with LET. This pattern was similar to the relative biological effectiveness for cell survival for heavy ions. CONCLUSIONS: The estimated yields of DSBs for carbon ions increased from 10 Gbp-1Gy-1 in the low-LET end to 16 Gbp-1Gy-1 in the high-LET end with 20% uncertainty.

Lantern-shaped flexible RNA origami for Smad4 mRNA delivery and growth suppression of colorectal cancer.

mRNA delivery has shown high application value in the treatment of various diseases, but its effective delivery is still a major challenge at present. Herein, we propose a lantern-shaped flexible RNA origami for mRNA delivery. The origami is composed of a target mRNA scaffold and only two customized RGD-modified circular RNA staples, which can compress the mRNA into nanoscale and facilitate its endocytosis by cells. In parallel, the flexible structure of the lantern-shaped origami allows large regions of the mRNA to be exposed and translated, exhibiting a good balance between endocytosis and translation efficiency. The application of lantern-shaped flexible RNA origami in the context of the tumor suppressor gene, Smad4 in colorectal cancer models demonstrates promising potential for accurate manipulation of protein levels in in vitro and in vivo settings. This flexible origami strategy provides a competitive delivery method for mRNA-based therapies.

Artificial general intelligence for radiation oncology.

The emergence of artificial general intelligence (AGI) is transforming radiation oncology. As prominent vanguards of AGI, large language models (LLMs) such as GPT-4 and PaLM 2 can process extensive texts and large vision models (LVMs) such as the Segment Anything Model (SAM) can process extensive imaging data to enhance the efficiency and precision of radiation therapy. This paper explores full-spectrum applications of AGI across radiation oncology including initial consultation, simulation, treatment planning, treatment delivery, treatment verification, and patient follow-up. The fusion of vision data with LLMs also creates powerful multimodal models that elucidate nuanced clinical patterns. Together, AGI promises to catalyze a shift towards data-driven, personalized radiation therapy. However, these models should complement human expertise and care. This paper provides an overview of how AGI can transform radiation oncology to elevate the standard of patient care in radiation oncology, with the key insight being AGI's ability to exploit multimodal clinical data at scale.

Monte Carlo simulation of linac using PRIMO.

BACKGROUND: Monte Carlo simulation is considered as the most accurate method for dose calculation in radiotherapy. PRIMO is a Monte-Carlo program with a user-friendly graphical interface. MATERIAL AND METHOD: A VitalBeam with 6MV and 6MV flattening filter free (FFF), equipped with the 120 Millennium multileaf collimator was simulated by PRIMO. We adjusted initial energy, energy full width at half maximum (FWHM), focal spot FWHM, and beam divergence to match the measurements. The water tank and ion-chamber were used in the measurement. Percentage depth dose (PDD) and off axis ratio (OAR) were evaluated with gamma passing rates (GPRs) implemented in PRIMO. PDDs were matched at different widths of standard square fields. OARs were matched at five depths. Transmission factor and dose leaf gap (DLG) were simulated. DLG was measured by electronic portal imaging device using a sweeping gap method. RESULT: For the criterion of 2%/2 mm, 1%/2 mm and 1%/1 mm, the GPRs of 6MV PDD were 99.33-100%, 99-100%, and 99-100%, respectively; the GPRs of 6MV FFF PDD were 99.33-100%, 98.99-99.66%, and 97.64-98.99%, respectively; the GPRs of 6MV OAR were 96.4-100%, 90.99-100%, and 85.12-98.62%, respectively; the GPRs of 6MV FFF OAR were 95.15-100%, 89.32-100%, and 87.02-99.74%, respectively. The calculated DLG matched well with the measurement (6MV: 1.36 mm vs. 1.41 mm; 6MV FFF: 1.07 mm vs. 1.03 mm, simulation vs measurement). The transmission factors were similar (6MV: 1.25% vs. 1.32%; 6MV FFF: 0.8% vs. 1.12%, simulation vs measurement). CONCLUSION: The calculated PDD, OAR, DLG and transmission factor were all in good agreement with measurements. PRIMO is an independent (with respect to analytical dose calculation algorithm) and accurate Monte Carlo tool.

Label-free single-particle imaging approach for ultra-rapid detection of pathogenic bacteria in clinical samples.

Rapid detection of pathogenic bacteria within a few minutes is the key to control infectious disease. However, rapid detection of pathogenic bacteria in clinical samples is quite a challenging task due to the complex matrix, as well as the low abundance of bacteria in real samples. Herein, we employ a label-free single-particle imaging approach to address this challenge. By tracking the scattering intensity variation of single particles in free solution, the morphological heterogeneity can be well identified with particle size smaller than the diffraction limit, facilitating the morphological identification of single bacteria from a complex matrix in a label-free manner. Furthermore, the manipulation of convection in free solution enables the rapid screening of low-abundance bacteria in a small field of view, which significantly improves the sensitivity of single-particle detection. As a proof of concept demonstration, we are able to differentiate the group B streptococci (GBS)-positive samples within 10 min from vaginal swabs without using any biological reagents. This is the most rapid and low-cost method to the best of our knowledge. We believe that such a single-particle imaging approach will find wider applications in clinical diagnosis and disease control due to its high sensitivity, rapidity, simplicity, and low cost.

Sperm-like nanocarriers for ultrafast delivery of antisense DNA.

Although various nanomaterials have been designed as intracellular delivery tools, the following aspects have become obstacles to limit their development, like a complex and time-consuming synthesis process, as well as relatively limited application areas (i.e. biosensing or cell imaging). Here, we developed a novel nano-delivery system called "nano-sperm" with low cytotoxicity and high biocompatibility. In this system, we used DNA oligonucleotides as a backbone to synthesize a nanostructure with silver nanoclusters in the head and functional fragments in the tail, which is shaped like a sperm, to achieve dual functions of ultrafast delivery and imaging/therapy. As a model, we analyzed the possibility of the "nano-sperm" carrying DNA with different structures for imaging or survivin-asDNA for tumor therapy. Therefore, this work reports a novel bifunctional high-speed delivery vehicle, which successfully fills the gap in the field of tumor therapy using DNA-templated nanoclusters as a delivery vehicle.

Evaluation of Plan Robustness Using Hybrid Intensity-Modulated Radiotherapy (IMRT) and Volumetric Arc Modulation Radiotherapy (VMAT) for Left-Sided Breast Cancer.

PURPOSE: We aim to evaluate the robustness of multi-field IMRT and VMAT plans to target motion for left-sided BC radiotherapy. METHODS: The 7-field hybrid IMRT (7F-H-IMRT) and 2-arc VMAT (2A-VMAT) plans were generated for ten left-sided BC patients. Shifts of 3 mm, 5 mm, and 10 mm in six directions were introduced and the perturbed dose distributions were recalculated. The dose differences (∆D) of the original plan and perturbed plan corresponded to the plan robustness for the structure. RESULTS: Higher ∆D98%, ∆D95%, and ∆Dmean of CTV were observed in 2A-VMAT plans, which induced higher tumor control probability reductions. A higher ∆Dmean of CTV Boost was found in 7F-H-IMRT plans despite lower ∆D98% and ∆D95%. Shifts in the S-I direction exerted the largest effect on CTV and CTV Boost. Regarding OARs, shifts in R, P, and I directions contributed to increasing the received dose. The 2A-VMAT plans performed better dose sparing, but had a higher robustness in a high-dose volume of the left lung and heart. The 2A-VMAT plans decreased the max dose of LAD but exhibited lower robustness. CONCLUSION: The 2A-VMAT plans showed higher sensitivity to position deviation. Shifts in the S-I direction exerted the largest effect for CTV and CTV Boost.

Serum exosomal miR-34a as a potential biomarker for the diagnosis and prognostic of hepatocellular carcinoma.

Background: Circulating exosomal microRNAs (miRNAs) are considered as potentially non-invasive biomarkers for early detection and prognosis of cancers. Due to the lack of highly sensitive and specific molecular markers, a lot of patients with hepatocellular carcinoma are diagnosed in advanced stages. This study aims to explore the expression mode and clinical detection value of serum exosomal miR-34a in HCC, providing new potential targets and theoretical basis for the early diagnosis and prognosis monitoring of hepatocellular carcinoma. Methods: The expression of serum exosomal miR-34a in 60 HCC patients before and after operation and 60 healthy examiners was abstracted and detected by ultracentrifugation and real-time quantitative PCR. Using ROC analysis, Kaplan-Meier survival analysis and Cox regression analysis, the value of serum exosomal miR-34a on diagnosis and prognosis in HCC patients was assessed. Results: The expression level of serum exosomal miR-34a in preoperative patients was reduced significantly comparing with that in healthy examiners and postoperative patients (P<0.01; P<0.05). Moreover, the decrease of serum exosomal miR-34a was correlated significantly with differentiation degree, TNM stage, tumor infiltration depth and lymph node metastasis(P<0.05), but had no statistical differences with gender, age, ALT, AST, viral infection, cirrhosis and tumor size of HCC patients (P>0.05). At the same time, the combination of serum exosomal miR-34a and α-fetoprotein (AFP) showed high capability on diagnosis to distinguish healthy examiners and HCC patients through ROC analysis. The overall survival of patients with lower expression of serum exosomal miR-34a was worse than that of patients with high level expression by Kaplan-Meier survival analysis (P<0.05). Univariate and multivariate Cox regression analysis both showed that serum exosomal miR-34a was independently related to OS. Conclusions: Collectively, serum exosomal miR-34a is significantly down-regulated in HCC patients and might be a novel noninvasive biomarker for diagnosis and prognosis of HCC.

Predicting machine's performance record using the stacked long short-term memory (LSTM) neural networks.

PURPOSE: The record of daily quality control (QC) items shows machine performance patterns and potentially provides warning messages for preventive actions. This study developed a neural network model that could predict the record and trend of data variations quantitively. METHODS AND MATERIALS: The record of 24 QC items for a radiotherapy machine was investigated in our institute. The QC records were collected daily for 3 years. The stacked long short-term memory (LSTM) model was used to develop the neural network model. A total of 867 records were collected to predict the record for the next 5 days. To compare the stacked LSTM, the autoregressive integrated moving average model (ARIMA) was developed on the same data set. The accuracy of the model was quantified by the mean absolute error (MAE), root-mean-square error (RMSE), and coefficient of determination (R2 ). To validate the robustness of the model, the record of four QC items was collected for another radiotherapy machine, which was input into the stacked LSTM model without changing any hyperparameters and ARIMA model. RESULTS: The mean MAE, RMSE, and R 2 ${\rm{\;}}{R^2}$ with 24 QC items were 0.013, 0.020, and 0.853 in LSTM, while 0.021, 0.030, and 0.618 in ARIMA, respectively. The results showed that the stacked LSTM outperforms the ARIMA. Moreover, the mean MAE, RMSE, and R 2 ${\rm{\;}}{R^2}$ with four QC items were 0.102, 0.151, and 0.770 in LSTM, while 0.162, 0.375, and 0.550 in ARIMA, respectively. CONCLUSIONS: In this study, the stacked LSTM model can accurately predict the record and trend of QC items. Moreover, the stacked LSTM model is robust when applied to another radiotherapy machine. Predicting future performance record will foresee possible machine failure, allowing early machine maintenance and reducing unscheduled machine downtime.

A Critical Review of LET-Based Intensity-Modulated Proton Therapy Plan Evaluation and Optimization for Head and Neck Cancer Management.

In this review article, we review the 3 important aspects of linear-energy-transfer (LET) in intensity-modulated proton therapy (IMPT) for head and neck (H&N) cancer management. Accurate LET calculation methods are essential for LET-guided plan evaluation and optimization, which can be calculated either by analytical methods or by Monte Carlo (MC) simulations. Recently, some new 3D analytical approaches to calculate LET accurately and efficiently have been proposed. On the other hand, several fast MC codes have also been developed to speed up the MC simulation by simplifying nonessential physics models and/or using the graphics processor unit (GPU)-acceleration approach. Some concepts related to LET are also briefly summarized including (1) dose-weighted versus fluence-weighted LET; (2) restricted versus unrestricted LET; and (3) microdosimetry versus macrodosimetry. LET-guided plan evaluation has been clinically done in some proton centers. Recently, more and more studies using patient outcomes as the biological endpoint have shown a positive correlation between high LET and adverse events sites, indicating the importance of LET-guided plan evaluation in proton clinics. Various LET-guided plan optimization methods have been proposed to generate proton plans to achieve biologically optimized IMPT plans. Different optimization frameworks were used, including 2-step optimization, 1-step optimization, and worst-case robust optimization. They either indirectly or directly optimize the LET distribution in patients while trying to maintain the same dose distribution and plan robustness. It is important to consider the impact of uncertainties in LET-guided optimization (ie, LET-guided robust optimization) in IMPT, since IMPT is sensitive to uncertainties including both the dose and LET distributions. We believe that the advancement of the LET-guided plan evaluation and optimization will help us exploit the unique biological characteristics of proton beams to improve the therapeutic ratio of IMPT to treat H&N and other cancers.

Exosomal microRNAs in hepatocellular carcinoma.

Hepatocellular carcinoma is one of the most common malignant tumors worldwide and the fourth leading cause of cancer-related deaths. The prognosis of hepatocellular carcinoma patients is extremely poor due to the occult onset and high metastasis of hepatocellular carcinoma. Therefore, biomarkers with high specificity and sensitivity are of great importance in early screening, diagnosis prognosis, and treatment of hepatocellular carcinoma patients. Exosomes are tiny vesicles secreted by various types of cells, which can serve as mediators of intercellular communication to regulate the tumor microenvironment, and play a key role in the occurrence, development, prognosis, monitor and treatment of hepatocellular carcinoma. As microRNA deliverer, exosomes are involved in multiple life activities by regulating target genes of recipient cells such as proliferation, invasion, metastasis and apoptosis of cancer cells. In this review, we summarized the composition, active mechanism and function of exosomal microRNAs in hepatocellular carcinoma, and elaborated on their potential application value of early diagnosis and treatment in hepatocellular carcinoma.

Exosome in Hepatocellular Carcinoma: an update.

Hepatocellular carcinoma (HCC) is a common malignant tumor in the digestive tract with limited therapeutic choices. Intercellular communication among cancer cells and their microenvironment is crucial to disease progression. Exosomes are extracellular vesicles secreted by multiple types of cells into the extracellular space, which contain a variety of active components of secretory cells, including lipids, proteins, RNA and DNA. This vesicle structure involves in the exchange of materials and information between cells and plays an important role in the development of many diseases. Studies have shown that exosomes participate in the communication between HCC cells and non-HCC cells and regulate the occurrence and development of hepatocellular carcinoma. Therefore, exosomes may be specific biomarkers for early diagnosis and metastasis of HCC, which are also potential targets for the treatment of HCC. This review summarizes the characteristic, types and biological functions of exosomes and discusses their research progress and application prospects in the diagnosis and treatment of HCC.

MicroRNA-200a and microRNA-141 have a synergetic effect on the suppression of epithelial-mesenchymal transition in liver cancer by targeting STAT4.

MicroRNAs (miRNAs or miRs) are non-coding small RNAs that target specific messenger RNAs to inhibit protein translation. miR-200a and miR-141 function as tumor suppressors by targeting STAT4. These two miRNAs belong to the same family, and their expression is often decreased in various cancer types, but are located on different chromosomes of the human genome. The present study showed that the expression levels of miR-141 and miR-200a in serum and cells of liver cancer are significantly downregulated. The expression levels of miR-141 and miR-200a are closely associated with clinicopathological features of liver cancer, especially metastasis and invasion. It is first reported that STAT4 is the new common target gene of miR-141 and miR-200a. In the present study, miR-141 and miR-200a were confirmed to inhibit the expression of E-cadherin and vimentin synergistically during epithelial-mesenchymal transition to regulate the proliferation, migration and invasion of liver cancer cells by targeting STAT4. Simultaneous overexpression of miR-200a and miR-141 resulted in stronger effects compared with each miRNA alone. In addition, overexpression of STAT4 significantly reversed the tumor suppressive roles of miR-200a and miR-141 in liver cancer cells. These findings enrich the tumor suppressor mechanisms of the miR-200 family, and may also provide new experimental and theoretical basis for the use of miRNAs for early diagnosis, prognosis and thorough treatment of liver cancer.

Impact of Multiple Beams on Plan Quality, Linear Energy Transfer Distribution, and Plan Robustness of Intensity Modulated Proton Therapy for Lung Cancer.

The increase of proton beam number might provide higher degrees of freedom in the optimization of intensity-modulated proton therapy planning. In this study, we aimed to quantitatively explore the potential benefits of the increased beam number, including dose volume histogram (DVH), linear energy transfer volume histogram, and DVH bandwidth metrics. Twelve patients with lung cancer are retrospectively selected. Four plans were created based on internal target volume (ITV) robust optimization for each patient using the RayStation treatment planning system. Four plans were generated using different numbers (three, five, seven, and nine) of evenly separated coplanar beams. The three-beam plan was considered as the reference plan. Biologically equivalent doses were calculated using both constant relative biological effectiveness (RBE) and variable RBE models, respectively. To evaluate plan quality, DVH metrics in the target [ITV: D2%, CI, HI] and organs-at-risk [Lung: V5Gy[RBE], V20Gy[RBE], V30Gy[RBE]; Heart D2%; Spinal cord D2%] were calculated using both RBE models. To evaluate LET distributions, LET volume histogram metrics [ITV LETmean and LET2%; Lung LETmean and LET2%; Heart LET2%; Spinal cord LET2%] were quantified. To evaluate plan robustness, the metrics using DVH bandwidth [ITV: D2%, D99%; Lung: V5Gy[RBE], V20Gy[RBE], V30Gy[RBE]; Heart D2%; Spinal cord D2%] were also reported. For plan quality, the increase of proton beam number resulted in fewer target hot spots, improved target dose conformity, improved target dose homogeneity, lower median-dose lung volume, and fewer hot spots in spinal cord. As to LET distributions, target mean LET increased significantly as the beam number increased to seven or more. Lung LET hot spots were significantly reduced with the increase of proton beams. With respect to plan robustness, the robustness of target dose coverage, target hot spots, and low-dose lung volume were improved, while the robustness of heart hot spots became worse as the beam number increased to nine. The robustness of cord hot spots became worse using five and seven beams compared to that using three beams. As the proton beam number increased, plan quality and LET distributions were comparable or significantly improved. The robustness of target dose coverage, target dose hot spots, and low-dose lung volume were significantly improved.

Acute Toxicities and Short-Term Patient Outcomes After Intensity-Modulated Proton Beam Radiation Therapy or Intensity-Modulated Photon Radiation Therapy for Esophageal Carcinoma: A Mayo Clinic Experience.

PURPOSE: Intensity modulated proton beam radiation therapy (IMPT) has a clinically significant dosimetric advantage over intensity modulated photon radiation therapy (IMRT) for the treatment of patients with esophageal cancer, particularly for sparing the heart and lungs. We compared acute radiation therapy-related toxicities and short-term clinical outcomes of patients with esophageal cancer who received treatment with IMPT or IMRT. METHODS AND MATERIALS: We retrospectively reviewed the electronic health records of consecutive adult patients with esophageal cancer who underwent concurrent chemoradiotherapy with IMPT or IMRT in the definitive or neoadjuvant setting from January 1, 2014, through June 30, 2018, with additional follow-up data collected through January 31, 2019. Treatment-related toxicities were evaluated per the Common Terminology Criteria for Adverse Events, version 4. Survival outcomes were estimated with the Kaplan-Meier method. RESULTS: A total of 64 patients (32 per group) were included (median follow-up time: 10 months for IMPT patients vs 14 months for IMRT patients). The most common radiation therapy regimen was 45 Gy in 25 fractions, and 80% of patients received a simultaneous integrated boost to a median cumulative dose of 50 Gy. Similar numbers of IMPT patients (n = 15; 47%) and IMRT patients (n = 18; 56%) underwent surgery (P = .07), with no difference in pathologic complete response rates (IMPT: n = 5; 33% vs IMRT: n = 7; 39%; P = .14). At 1 year, the clinical outcomes also were similar for IMPT and IMRT patients, respectively. Local control was 92% versus 84% (P = .87), locoregional control 92% versus 80% (P = .76), distant metastasis-free survival 87% versus 65% (P = .08), progression-free survival 71% versus 45% (P = .15), and overall survival 74% versus 71% (P = .62). The rate of acute treatment-related grade 3 toxicity was similar between the groups (P = .71). CONCLUSIONS: In our early experience, IMPT is a safe and effective treatment when administered as part of definitive or trimodality therapy. Longer follow-up is required to evaluate the effectiveness of IMPT.

Early Outcomes of Patients With Locally Advanced Non-small Cell Lung Cancer Treated With Intensity-Modulated Proton Therapy Versus Intensity-Modulated Radiation Therapy: The Mayo Clinic Experience.

PURPOSE: There are very little data available comparing outcomes of intensity-modulated proton therapy (IMPT) to intensity-modulated radiation therapy (IMRT) in patients with locally advanced NSCLC (LA-NSCLC). METHODS: Seventy-nine consecutively treated patients with LA-NSCLC underwent definitive IMPT (n = 33 [42%]) or IMRT (n = 46 [58%]) from 2016 to 2018 at our institution. Survival rates were calculated using the Kaplan-Meier method and compared with the log-rank test. Acute and subacute toxicities were graded based on Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: Median follow-up was 10.5 months (range, 1-27) for all surviving patients. Most were stage III (80%), received median radiation therapy (RT) dose of 60 Gy (range, 45-72), and had concurrent chemotherapy (65%). At baseline, the IMPT cohort was older (76 vs 69 years, P < .01), were more likely to be oxygen-dependent (18 vs 2%, P = .02), and more often received reirradiation (27 vs 9%, P = .04) than their IMRT counterparts. At 1 year, the IMPT and IMRT cohorts had similar overall survival (68 vs 65%, P = .87), freedom from distant metastasis (71 vs 68%, P = .58), and freedom from locoregional recurrence (86 vs 69%, P = .11), respectively. On multivariate analyses, poorer pulmonary function and older age were associated with grade +3 toxicities during and 3 months after RT, respectively (both P ≤ .02). Only 5 (15%) IMPT and 4 (9%) IMRT patients experienced grade 3 or 4 toxicities 3 months after RT (P = .47). There was 1 treatment-related death from radiation pneumonitis 6 months after IMRT in a patient with idiopathic pulmonary fibrosis. CONCLUSIONS: Compared with IMRT, our early experience suggests that IMPT resulted in similar outcomes in a frailer population of LA-NSCLC who were more often being reirradiated. The role of IMPT remains to be defined prospectively.