Integration of dosimetric parameters, clinical factors, and radiomics to predict symptomatic radiation pneumonitis in lung cancer patients undergoing combined immunotherapy and radiotherapy.

PURPOSE: This study aimed to combine clinical/dosimetric factors and handcrafted/deep learning radiomic features to establish a predictive model for symptomatic (grade ≥ 2) radiation pneumonitis (RP) in lung cancer patients who received immunotherapy followed by radiotherapy. MATERIALS AND METHODS: This study retrospectively collected data of 73 lung cancer patients with prior receipt of ICIs who underwent thoracic radiotherapy (TRT). Of these 73 patients, 41 (56.2 %) developed symptomatic grade ≥ 2 RP. RP was defined per multidisciplinary clinician consensus using CTCAE v5.0. Regions of interest (ROIs) (from radiotherapy planning CT images) utilized herein were gross tumor volume (GTV), planning tumor volume (PTV), and PTV-GTV. Clinical/dosimetric (mean lung dose and V5-V30) parameters were collected, and 107 handcrafted radiomic (HCR) features were extracted from each ROI. Deep learning-based radiomic (DLR) features were also extracted based on pre-trained 3D residual network models. HCR models, Fusion HCR model, Fusion HCR + ResNet models, and Fusion HCR + ResNet + Clinical models were built and compared using the receiver operating characteristic (ROC) curve with measurement of the area under the curve (AUC). Five-fold cross-validation was performed to avoid model overfitting. RESULTS: HCR models across various ROIs and the Fusion HCR model showed good predictive ability with AUCs from 0.740 to 0.808 and 0.740-0.802 in the training and testing cohorts, respectively. The addition of DLR features improved the effectiveness of HCR models (AUCs from 0.826 to 0.898 and 0.821-0.898 in both respective cohorts). The best performing prediction model (HCR + ResNet + Clinical) combined HCR & DLR features with 7 clinical/dosimetric characteristics and achieved an average AUC of 0.936 and 0.946 in both respective cohorts. CONCLUSIONS: In patients undergoing combined immunotherapy/RT for lung cancer, integrating clinical/dosimetric factors and handcrafted/deep learning radiomic features can offer a high predictive capacity for RP, and merits further prospective validation.

Dosimetric predictors of radiation pneumonitis in patients with prior immunotherapy exposure: A multi-institutional analysis.

BACKGROUND AND PURPOSE: Combining immune checkpoint inhibitors (ICIs) and thoracic radiotherapy (TRT) may magnify the radiation pneumonitis (RP) risk. Dosimetric parameters can predict RP, but dosimetric data in context of immunotherapy are very scarce. To address this knowledge gap, we performed a large multicenter investigation to identify dosimetric predictors of RP in this under-studied population. MATERIALS AND METHODS: All lung cancer patients from five institutions who underwent conventionally-fractionated thoracic intensity-modulated radiotherapy with prior ICI receipt were retrospectively compiled. RP was defined per CTCAE v5.0. Statistics utilized logistic regression modeling and receiver operating characteristic (ROC) analysis. RESULTS: The vast majority of the 192 patients (median follow-up 14.7 months) had non-small cell lung cancer, received PD-1 inhibitors, and did not receive concurrent systemic therapy with TRT. Grades 1-5 RP occurred in 21.9%, 25.0%, 8.3%, 1.6%, and 1.0%, respectively. The mean MLD for patients with grades 1-5 RP was 10.7, 11.6, 12.6, 14.7, and 12.8 Gy, respectively. On multivariable analysis, tumor location and mean lung dose (MLD) significantly predicted for any-grade and grade ≥ 2 pneumonitis. Only MLD significantly predicted for grade ≥ 3 RP. ROC analysis was able to pictorially model RP risk probabilities for a variety of MLD thresholds, which can be an assistive tool during TRT treatment planning. CONCLUSION: This study, by far the largest to date of dosimetric predictors of RP in the immunotherapy era, illustrates that MLD is the most critical dose-volume parameter influencing RP risk. These data may provide a basis for revising lung dose constraints in efforts to better prevent RP in this rapidly expanding ICI/TRT population.

Long-Term Outcomes of Nasopharyngeal Carcinoma by Epstein-Barr Virus Status in the Chinese Population: A Multicenter Investigation.

Background: Because the vast majority of nasopharyngeal carcinoma (NPC) in Chinese patients is a direct result of Epstein-Barr virus (EBV) infection, there is a dearth of data for EBV-negative patients in this population. This multicenter study sought to examine the clinical characteristics of EBV-negative patients and compare long-term outcomes with a propensity-matched (1:1.5) EBV-positive cohort. Methods: NPC patients with known EBV status from four hospitals were collated (2013-2021). A logistic regression model was conducted to evaluate the relationship between patient characteristics and EBV status. The Kaplan-Meier method and Cox regression analysis were used to analyze survival data. Results: This study analyzed 48 (40%) EBV-negative and 72 (60%) EBV-positive patients. The median follow-up time was 63.5 months. Most EBV-negative NPC patients (77.1%) were diagnosed in advanced stages with a higher rate (87.5%) of positive lymph node disease, and no significant prognostic factors were discerned in this subpopulation. The EBV-negative disease was more associated with the keratinizing subtype (18.8% vs. 1.4%, p < 0.05). Compared to EBV-negative NPC patients, EBV-positive NPC patients were more likely to develop a local recurrence (9.7% vs. 0%, p = 0.026). There was no statistical difference in mortality (EBV-negative vs. EBV- positive, 8.3% vs. 4.2%, p = 0.34) during the follow-up period. Although the median PFS and median OS were not reached, the 3-year PFS rate was 68.8% vs. 70.8% (EBV-negative vs. EBV-positive, p = 0.06), the 3-year OS rate was 70.8% vs. 76.4% (EBV-negative vs. EBV-positive, p = 0.464), the 5-year PFS rate was 56.3% vs. 50% (EBV-negative vs. EBV-positive, p = 0.451), and the 5-year OS rate was 56.3% vs. 58.3% (EBV-negative vs. EBV-positive, p = 0.051), respectively. These data show that EBV-positive NPC patients seem to have a tendency to gain better survival compared with EBV-negative NPC patients. Conclusions: Most of the EBV-negative patients were in the middle and late stages at the time of diagnosis and were more associated with the keratinizing subtype. EBV status may be associated with prognosis in NPC. EBV positivity seems to be associated with better survival in NPC patients. Still, due to the small cohort of patients and the short observation period for a number of patients, further work is required to corroborate these conclusions.

Optimizing induction chemotherapy regimens for radiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: The optimal number of cycles of induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LANPC) remains unresolved. This study aimed to quantitatively assess the changes in gross tumor volumes (GTVs) and to select the most optimal number of IC cycles. METHODS: We analyzed 54 patients who received a three-cycle IC before commencing radiotherapy, with the tumor and nodal responses assessed by a CT scan before IC and after each IC cycle. The gross tumor volumes of the nasopharynx primary lesion (GTV_T), involved retropharyngeal lymph node (GTV_RP), and involved cervical lymph node (GTV_N) were contoured on each scan. The volume change following each IC cycle was evaluated with Wilcoxon signed-rank test. The three-dimensional vector displacements of target centers were also calculated and compared. RESULTS: The volume reductions of GTVs following IC varied across different patients and showed different trends for the three GTV types. GTV_T and GTV_RP did not display further volume reduction after two IC cycles, whereas GTV_N showed monotonic volume decreases. For GTV_T and GTV_RP following the three IC cycles, the total volume reduction relative to the initial volume before IC was 12.0%, 22.5%, and 20.1% and 26.0%, 44.1%, and 42.2%, respectively. In contrast, for GTV_N, continuing volume reduction was observed with a total reduction of 25.3%, 43.2%, and 54.7% following the three cycles, and the reductions were all significant. Average displacements of the GTVs were <1.5 mm in all directions; their average three-dimensional displacements were 2.6, 4.0, and 1.7 mm, respectively. Acceptable toxicity was observed in most patients. CONCLUSION: This study supports two cycles of IC before radiotherapy for patients with LANPC if the initial metastatic cervical lymph node volume is not dominating. Otherwise, three cycles of IC is recommended to further reduce the cervical node volume.

Exploration of prognostic biomarkers in head and neck squamous cell carcinoma microenvironment from TCGA database.

Background: Immune checkpoint blockade (ICB) therapies have redefined human cancer treatment, including for head and neck squamous cell carcinoma (HNSCC). However, clinical responses to various immune checkpoint inhibitors are often accompanied by immune-related adverse events (irAEs). Therefore, it is crucial to obtain a comprehensive understanding of the association between different immune tumor microenvironments (TMEs) and the immunotherapeutic response. Methods: The research data were obtained from The Cancer Genome Atlas (TCGA) database. We applied RNA-seq genomic data from tumor biopsies to assess the immune TME in HNSCC. As the TME is a heterogeneous system that is highly associated with HNSCC progression and clinical outcome, we relied on the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm to calculate immune and stromal scores that were evaluated based on the immune or stromal components in the TME. Then, the Tumor Immune Dysfunction and Exclusion algorithm (TIDE) was used to predict the benefits of ICB to each patient. Finally, we identified specific prognostic tumor-infiltrating immune cells (TIICs) by quantifying the cellular composition of the immune response in HNSCC and its association to survival outcome, using the CIBERSORT algorithm. Results: Utilizing the HNSCC cohort of the TCGA database and TIDE and ESTIMATE algorithm-derived immune scores, we obtained a list of microenvironment-associated lncRNAs that predicted different clinical outcomes in HNSCC patients. We validated these correlations in a different HNSCC cohort available from the TCGA database and provided insight into the prediction of response to ICB therapies in HNSCC. Conclusions: This study confirmed that CD8+ T cells were significantly associated with better survival in HNSCC and verified that the top five significantly mutated genes (SMGs) in the TCGA HNSCC cohort were TP53, TTN, FAT1, CDKN2A, and MUC16. A high level of CD8+ T cells and high immune and stroma scores corresponded to a better survival probability in HNSCC.

Bone collision detection method for robot assisted fracture reduction based on vibration excitation.

BACKGROUND AND OBJECTIVE: In the process of robotic fracture reduction, there is a risk of unintended collision of broken bones, which is not conducive to ensuring the safety of the reduction system. In order to solve this problem, this paper proposed a vibration-based collision detection method for fracture reduction process. METHODS: Based on the two degree-of-freedom vibration response model, the factors affecting the respond of the vibration, including the excitation voltage, the clamping length at the proximal and distal ends, the mass and tensile force of the soft tissue, were obtained. The effects of these factors on the vibration transfer performance of broken bones and soft tissue were investigated by single factor experiments. RESULTS: The results showed that, in terms of peak value, the increase of excitation voltage would make the vibration amplitude increase linearly, and the increase of soft tissue mass and tension increased the vibration transmission capacity of soft tissue in the frequency range of 500-1000 Hz. In terms of peak frequency, the clamping length at the distal end had the greatest influence, which reached 74 Hz, followed by 45 Hz at the proximal end. While the influence of other factors was little. According to single factor experiments, the excitation frequency in the verification experiments was determined as 677 Hz. Under the vibration interference with the acceleration amplitude of 1.2 G, this method achieved correct detection. CONCLUSION: This research developed a broken bone collision detection method based on vibration excitation. The method can correctly detect the collision of broken bones with strong anti-interference ability. It is of great significance to improve the safety of fracture reduction process.

SETD3 Methyltransferase Regulates PLK1 Expression to Promote In Situ Hepatic Carcinogenesis.

Background: The development of a new strategy to overcome chemoresistance to hepatocellular carcinoma (HCC) treatment is a long-standing issue. We have previously found that upregulated SETD3 levels are closely correlated with HCC. This study aims to explore the mechanism underlying how upregulation of SETD3 promotes liver carcinogenesis. Methods: RNA-Sequencing analysis was used to explore the correlation of SETD3 with regulatory targets. In vitro assays including cell proliferation and migration were performed to study the oncogenic roles of SETD3 and PLK1. Western blotting, immunohistochemical staining, and blood biochemical assays were performed to examine protein expression or pathological index in tumor tissues and mice liver tissues. Luciferase reporter system and chromatin immunoprecipitation assays were used to explore the mechanism. Results: We revealed that SETD3 regulates gene expression in subgroups, including cell division, cell proliferation, and cell cycle, in hepatocellular tumor cells. We found that SETD3 upregulation is associated with elevated PLK1 level in both hepatic tumor cells and clinical liver tissues. We further showed that overexpression of SETD3 promoted tumor cell proliferation and migration, whereas inhibition of PLK1 activity attenuated these phenotypes caused by SETD3. By taking advantage of the Sleep Beauty transposase system, we confirmed that upregulated mouse Setd3 promoted hepatic carcinogenesis in situ, but knockdown of mouse Plk1 mitigated Setd3-promoted tumorigenesis in mice. Mechanistically, we showed that SETD3 could be recruited to the promoter of PLK1 gene to facilitate PLK1 transcription. Conclusions: Our data demonstrate that elevated SETD3 may promote HCC by enhancing PLK1 expression, which suggests that SETD3 may act as a potential drug target combined with PLK1 inhibition to treat HCC.

Efficacy and safety of apatinib combined with whole-brain radiation therapy with a simultaneous integrated boost for brain metastases from non-small cell lung cancer: a multicenter retrospective study.

Background: Brain metastases (BMs) develop in 20-65% of non-small cell lung cancer (NSCLC) patients and are associated with a poor prognosis. Apatinib, a tyrosine kinase inhibitor (TKI) that selectively inhibits the vascular endothelial growth factor receptor 2, is safe and significantly prolongs the survival of chemotherapy-refractory gastric cancer patients. This retrospective study evaluated the safety and efficacy of apatinib combined with concurrent brain radiotherapy in NSCLC patients with BMs. Methods: This trial enrolled patients with non-recurrent BM from histologically-confirmed NSCLC without any limits regarding the BM size/quantity. Eligibility criteria were patients 18-75 years old with measurable BM from histologically-confirmed NSCLC (including both newly-diagnosed and previously treated NSCLC) and expected survival time greater than 3 months. Oral apatinib (500 or 250 mg/day) was started within 1 week prior to commencing whole brain radiotherapy with simultaneous integrated boost (WBRT-SIB) and continued until one week after radiotherapy completion. In addition to toxicities, analyzed outcomes included intracranial overall response rate (iORR), intracranial disease control rate (iDCR), intracranial progression free survival (iPFS), and overall survival (OS). Results: From July 2016 to January 2020, 16 patients were enrolled in this retrospective study. After 3 months of brain radiotherapy, the iORR was 75%, the iDCR was 100%, and the brain edema index (EI) was significantly reduced compared to that before brain radiation therapy (4.2 vs. 1.9; P=0.02). The median iPFS was 16.5 months [95% confidence interval (CI): 15.1-37.4 months]. The median OS was 26 months (95% CI: 17.0-54.0 months). Most of the patients tolerated apatinib well, but 7 patients had side effects, most commonly grade 1 or 2. Only 2 patients experienced grade 3 adverse events (hypertension and oral mucositis), and no grade 4 or 5 toxicities were observed. Conclusions: Apatinib combined with WBRT-SIB appears to be safe and effective in treating BMs in NSCLC patients.

A pilot study of function-based radiation therapy planning for lung cancer using hyperpolarized xenon-129 ventilation MRI.

PURPOSE: Radiation-induced lung injury (RILI) is a common side effect in patients with non-small cell lung cancer (NSCLC) treated with radiotherapy. Minimizing irradiation into highly functional areas of the lung may reduce the occurrence of RILI. The aim of this study is to evaluate the feasibility and utility of hyperpolarized xenon-129 magnetic resonance imaging (MRI), an imaging tool for evaluation of the pulmonary function, to guide radiotherapy planning. METHODS: Ten locally advanced NSCLC patients were recruited. Each patient underwent a simulation computed tomography (CT) scan and hyperpolarized xenon-129 MRI, then received 64 Gyin 32 fractions for radiotherapy. Clinical contours were drawn on CT. Lung regions with good ventilation were contoured based on the MRI. Two intensity-modulated radiation therapy plans were made for each patient: an anatomic plan (Plan-A) based on CT alone and a function-based plan (Plan-F) based on CT and MRI results. Compared to Plan-A, Plan-F was generated with two additional steps: (1) beam angles were carefully chosen to minimize direct radiation entering well-ventilated areas, and (2) additional optimization criteria were applied to well-ventilated areas to minimize dose exposure. V20Gy , V10Gy , V5Gy , and the mean dose in the lung were compared between the two plans. RESULTS: Plan-A and Plan-F were both clinically acceptable and met similar target coverage and organ-at-risk constraints (p > 0.05) except for the ventilated lungs. Compared with Plan-A, V5Gy (Plan-A: 30.7 ± 11.0%, Plan-F: 27.2 ± 9.3%), V10Gy (Plan-A: 22.0 ± 8.6%, Plan-F: 19.3 ± 7.0%), and V20Gy (Plan-A: 12.5 ± 5.6%, Plan-F: 11.0 ± 4.1%) for well-ventilated lung areas were significantly reduced in Plan-F (p < 0.05). CONCLUSION: In this pilot study, function-based radiotherapy planning using hyperpolarized xenon-129 MRI is demonstrated to be feasible in 10 patients with NSCLC with the potential to reduce radiation exposure in well-ventilated areas of the lung defined by hyperpolarized xenon-129 MRI.

A radiomics model predicts the response of patients with advanced gastric cancer to PD-1 inhibitor treatment.

Programmed cell death 1 (PD1) inhibitors have shown promising treatment effects in advanced gastric cancer, the beneficiary population not definite. This study aimed to construct an individualized radiomics model to predict the treatment benefits of PD-1 inhibitors in gastric cancer. Patients with advanced gastric cancer treated with PD-1 inhibitors were randomly divided into a training set (n = 58) and a validation set (n = 29). CT imaging data were extracted from medical records, and an individual radiomics nomogram was generated based on the imaging features and clinicopathological risk factors. Discrimination performance was evaluated by Harrell's c-index and receiver operator characteristic (ROC) curve analyses. The areas under the ROC curves (AUCs) were analyzed to predict anti-PD-1 efficacy and survival. We found that the radiomics nomogram could predict the response of gastric cancer to anti-PD-1 treatment. The AUC was 0.865 with a 95% CI of 0.812-0.828 in the training set, while the AUC was 0.778 with a 95% CI of 0.732-0.776 in the validation set. The diagnostic performance of the radiomics was significantly higher than that of the clinical factors (p < 0.01). Patients with a low risk of disease progression discriminated by the radiomics nomogram had longer progression-free survival than those with a high risk (6.5 vs. 3.2 months, HR 1.99, 95% CI: 1.19-3.31, p = 0.009). The radiomics nomogram based on CT imaging features and clinical risk factors could predict the treatment benefits of PD-1 inhibitors in advanced gastric cancer, enabling it to guide decision-making regarding clinical treatment.

Management and Outcomes of Patients With Radiotherapy Interruption During the COVID-19 Pandemic.

PURPOSE: This retrospective observational study examined patients who experienced radiotherapy (RT) interruption during the Wuhan lockdown for the novel coronavirus disease 2019 (COVID-19) pandemic. MATERIALS AND METHODS: The data of all patients whose RT was interrupted during the Wuhan lockdown from January 23 to April 8, 2020 were collected. Patient-, cancer-, and treatment-related characteristics were analyzed, along with interruption time, disease progression type, and survival status. The methods employed in order to compensate for RT interruption were also described. RESULTS: There were altogether 129 cancer patients whose RT was interrupted. Nineteen (14.7%) patients experienced a total interruption time of at most 7 days; the interruption time was 8-14 days for 27 (20.9%) patients, and 15 or more days for 47 (36.4%) patients. The remaining 36 (27.9%) patients did not come back to our hospital for further RT. We first describe our experience with re-immobilization and/or re-planning (n = 17) as well as dose compensation/adjustment. Of the 40 definitive radiotherapy patients, 37 had squamous cell carcinoma of nasopharyngeal, lung, or cervical origin. Most patients (85/93, 91.4%) were followed up for more than one year. Among the 40 patients who received definitive radiotherapy, nine patients experienced disease progression and five patients died. Three of the seven (42.9%) patients who did not finish radiotherapy after interruption died, as compared to only two of the 33 (6.1%) patients who completed radiotherapy. EQD2 (equivalent dose in 2 Gy fractions) at the time point of RT interruption was calculated. Five of the six patients (83.3%) who received EQD2 ≤10 Gy suffered from disease progression, compared with four of the 34 (11.8%) patients who received EQD2 >10 Gy. For the seven definitive radiotherapy cases who did not finish radiotherapy, three received systemic anti-cancer treatments and three died (all of whom did not receive further systemic therapies). CONCLUSIONS: This study provides the longest follow-up for the outcomes of RT interruption during COVID-19 pandemic to date. It cannot imply causation but implies that completing RT is important, along with the utility of having patients remain on systemic therapies if RT is to be interrupted.

Bone collision detection method for robot assisted fracture reduction based on force curve slope.

BACKGROUND AND OBJECTIVE: The application of robot technology in fracture reduction ensures the minimal invasiveness and accurate operation process. Most of the existing robot assisted fracture reduction systems don't have the function of bone collision detection, which is very important for system safety. In view of the deficiencies in the research of this field, a broken bone collision detection method based on the slope ratio of force curve was proposed in this paper, which could realize the real-time detection. METHODS: In order to analyze the factors influencing the slope of force curve, a collision mechanical model based on three-element viscoelastic model was established. The effects of four factors on the slope ratio of the force curve were studied based on the mechanical model. The proposed collision detection model was analyzed in detail. By drawing slope ratio curves under various experimental conditions, the universality of the collision detection model was proved; by comparative simulation, the differences between the slope ratio curves before and after optimization were analyzed. The factors that affect the performance of the detection model were also analyzed. RESULTS: The results of collision experiments show that the increase of moving speed of distal bone and soft tissue mass reduces the slope ratio, while the increase of collision angle increases the slope ratio. In the verification experiment, the minimum main peak of KRopt curve is 14.16 and the maximum is 220.7, the maximum interference value before the peak is 6.1. When the detection threshold is 10, the model can detect the collision state of the broken bone. It is also proved that after optimization, the model can effectively filter out invalid waveforms and reduce the occurrence of false detections. When a=5 and b=40, the detection model has sufficient stability and a low detection time delay. CONCLUSION: This research developed a broken bone collision detection method based on the slope ratio of the force curve. After optimization, the method has good adaptability under a variety of experimental conditions. The collision of broken bones can be judged by setting an appropriate detection threshold. The application of this method in the robot fracture reduction system will improve the safety of the system.

Upregulation of PAIP1 promotes the gallbladder tumorigenesis through regulating PLK1 level.

BACKGROUND: Increasing evidence suggests that elevated expression of polyA-binding protein-interacting protein 1 (PAIP1) is associated with cancer development and progression. However, how PAIP1 promotes gallbladder cancer (GBC) is still unclear. METHODS: Two GBC tissue-derived cell lines, NOZ and GBC-SD cells, were used in this study. Assays of cell proliferation, colony formation, apoptosis, and xenograft tumor model were performed to examine the tumorigenic effects of PAIP1. Immunohistochemical (IHC) staining was used to examine the expression level of PAIP1 in both patient GBC tissues and mouse tumors. Microarray and bioinformatics analysis were used to explore the targets of PAIP1. Quantitative polymerase chain reaction (qPCR) and western blot analysis were used to validate PAIP1-mediated targets. RESULTS: We found that upregulated PAIP1 expression was correlated with GBC. Knockdown of PAIP1 in gallbladder cells alleviated cell proliferation, promoted apoptosis, and inhibited xenograft tumor growth. Gene microarray analysis showed that stable silencing of PAIP1 altered various gene expressions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that PAIP1 regulates cell cycle progression. Finally, we found that the PLK1 kinase, a key regulator of cell cycle, was regulated by PAIP1 at the transcriptional and protein levels. PLK1 level was positively correlated with PAIP1 level in both mouse tumors and GBC tissues. PAIP1 interacted with PLK1, and rescue of PAIP1 could recover PLK1 protein level and inhibit apoptosis. CONCLUSIONS: Our data suggest that PAIP1 contributes to GBC progression likely through regulating PLK1 level. Since upregulated PAIP1 expression is positively associated with GBC, PAIP1 may act as a clinical prognostic biomarker of GBC.

Concurrent Apatinib and Brain Radiotherapy in Patients With Brain Metastases From Driver Mutation-negative Non-small-cell Lung Cancer: Study Protocol for an Open-label Randomized Controlled Trial.

Brain radiotherapy (BR) is a well-recognized approach for multiple brain metastases (BMs) from non-small-cell lung cancer (NSCLC). However, the prognosis for these patients remains poor. Apatinib, an antiangiogenic agent targeting vascular endothelial growth factor receptor-2, has shown excellent efficacy in multiple solid tumors. This phase II (WWW. ClinicalTrials.gov Identifier: VEGFR-2 NCT03801200) randomized trial aims to evaluate the efficacy and safety of this combined modality paradigm in patients with BMs from driver mutation-negative NSCLC. This is a multicenter, open-label, randomized controlled clinical trial. A total of 90 eligible patients will be allocated in a 1:1 ratio, to either the experimental group (concurrent apatinib and BR) or the control group (BR alone). The primary endpoint is intracranial progression-free survival. The secondary endpoints include intracranial objective response rate, intracranial disease control rate, intracranial time to progression, overall survival, and occurrence of peritumoral brain edema using standardized measurement. Quality of life and adverse events will also be evaluated. Assessments will be carried out before enrollment (baseline) along with 4 and 12 weeks after radiotherapy, followed by every 12 weeks thereafter and up to 24 months. In summary, the aim of this trial is to demonstrate the clinical efficacy and safety of concurrent BR and apatinib in patients with driver mutation-negative NSCLC with multiple BMs, in efforts to expand management options for this population with poor prognosis.

Dosimetric Risk Factors for Acute Radiation Pneumonitis in Patients With Prior Receipt of Immune Checkpoint Inhibitors.

Purpose: Dosimetric parameters (e.g., mean lung dose (MLD), V20, and V5) can predict radiation pneumonitis (RP). Constraints thereof were formulated before the era of combined immune checkpoint inhibitors (ICIs) and radiotherapy, which could amplify the RP risk. Dosimetric predictors of acute RP (aRP) in the context of ICIs are urgently needed because no data exist thus far. Methods and Materials: All included patients underwent thoracic intensity-modulated radiotherapy, previously received ICIs, and followed-up at least once. Logistic regression models examined predictors of aRP (including a priori evaluation of MLD, V20, and V5), and their discriminative capacity was assessed by receiver operating characteristic analysis. Results: Median follow-up of the 40 patients was 5.3 months. Cancers were lung (80%) or esophageal (20%). ICIs were PD-1 (85%) or PD-L1 (15%) inhibitors (median 4 cycles). Patients underwent definitive (n=19), consolidative (n=14), or palliative (n=7) radiotherapy; the median equivalent dose in 2 Gy fractions (EQD2) was 60 Gy (IQR, 51.8-64 Gy). Grades 1-5 aRP occurred in 25%, 17.5%, 15%, 2.5%, and 5%, respectively. The only variables associated with any-grade aRP were V20 (p=0.014) and MLD (p=0.026), and only V20 with grade ≥2 aRP (p=0.035). Neither the number of prior ICI cycles nor the delivery of concurrent systemic therapy significantly associated with aRP risk. Graphs were constructed showing the incrementally increasing risk of aRP based on V20 and MLD (continuous variables). Conclusions: This is the first study illustrating that V20 and MLD may impact aRP in the setting of prior ICIs. However, these data should not be extrapolated to patients without pre-radiotherapy receipt of prior ICIs, or to evaluate the risk of chronic pulmonary effects. If these results are validated by larger studies with more homogeneous populations, the commonly accepted V20/MLD dose constraints could require revision if utilized in the setting of ICIs.