Dynamic circulating tumor DNA during chemoradiotherapy predicts clinical outcomes for locally advanced non-small cell lung cancer patients.

The value of circulating tumor DNA (ctDNA) during chemoradiotherapy (CRT) remains unclear but is critical for detecting molecular residual disease (MRD). In this prospective study, we sequenced 761 blood samples from 139 patients with locally advanced non-small cell lung cancer treated with definitive radiation therapy (RT). ctDNA concentrations showed a significantly declining trend as CRT progressed at on-RT and after-RT time points versus baseline. Thirty-eight (27.3%) patients with early undetectable ctDNA at both on-RT (RT reached 40 Gy) and after-RT time points, indicating early response to CRT, had better survival outcomes for both with or without consolidation immune checkpoint inhibitors. Longitudinal undetectable MRD was found in 20.1% patients. The 2-year cancer-specific progression-free survival of these patients was 88.4%, corresponding to a potentially cured population. Further analysis revealed that pretreatment ctDNA variants serve as an essential MRD informed source. These data provide clinical insights for ctDNA-MRD detection.

[Secondary or Second Primary Endotracheal Cancer after Surgery for Primary Lung Cancer: Case Series and Review of the Literature].

BACKGROUND: The clinical feature, treatment and outcomes of the patients with endotracheal cancer after radical surgery for primary lung cancer are unclear. This article will provide a detailed explanation of the above issues by summarizing the relevant cases. METHODS: We retrospectively reviewed five patients in Guangdong Provincial People's Hospital and retrieved 9 cases from other literatures by searching PubMed. RESULTS: For five patients in out institute, 4 endotracheal cancers were considered as secondary to lung cancers. Radical stump resection (n=2), concurrent chemoradiotherapy (CCRT) (n=1), chemotherapy (n=1) and palliative care (n=1) were performed separately in 5 patients. The patient underwent CCRT achieved the longest progression-free survival of 29.5 months. For 9 patients retrieved from other studies, 8 endotracheal cancers were defined as metastases. Radiotherapy alone (n=4), CCRT (n=2), chemotherapy alone (n=2) or surgery (n=2) were performed separately in 10 lesions of 9 patients. 1 patient with radiotherapy alone and 1 patient with CCRT achieved complete response. CONCLUSIONS: More attention should be paid to the abnormality of the trachea after surgery of lung cancer. CCRT may be a good choice for endotracheal cancers after primary lung cancer.

Legacy and novel perfluoroalkyl substances in raw and cooked squids: Perspective from health risks and nutrient benefits.

Perfluoroalkyl substance (PFAS) existed ubiquitously in the environment and could be ingested unconsciously with food which posed a disease risk to human health. Swordtip squid (Uroteuthis edulis) is one of the most popular and highly consumed seafood worldwide, with wide distribution and abundant biomass. Therefore, it is of great importance to the health of the public by reducing the health risks of squid consumption while preserving the benefits of squid to humans. In this study, the PFAS and fatty acids in squids were tested from the southeast coastal regions of China, a major habitat for squids. Relative higher concentrations of PFAS in squid were found in the subtropical zone of southern China (mean: 15.90 ng/g·dw) compared to those of the temperate zone of northern China (mean: 11.77 ng/g·dw). The digestive system had high tissue/muscle ratio (TMR) values, and the pattern of TMR among the same carbon-chain PFAS was similar. Cooking methods have a significant contribution to eliminating PFAS (in squids). PFAS were transferred from squids to other mediums after cooking, so juice and oil should be poured out to minimize PFAS exposure into body. The result showed that squids can be regarded as a healthy food by health benefits associated with fatty acids. Estimated daily intake (EDI) had the highest level in Korea via consuming squids through cooking processes compared with other countries. Based on the assessment of the hazard ratios (HRs), there was a high exposure risk of perfluoropentanoic acid (PFPeA) via taking squids for human health. This research provided the theoretical guidance of aquatic product processing in improving nutrition and reducing harmful substances.

Melatonin reduces radiation-induced ferroptosis in hippocampal neurons by activating the PKM2/NRF2/GPX4 signaling pathway.

Ferroptosis is a type of regulated cell death that is dependent on iron and reactive oxygen species (ROS). Melatonin (N-acetyl-5-methoxytryptamine) reduces hypoxic-ischemic brain damage via mechanisms that involve free radical scavenging. How melatonin regulates radiation-induced ferroptosis of hippocampal neurons is yet to be elucidated. In this study, the mouse hippocampal neuronal cell line HT-22 was treated with 20µM melatonin before being stimulated with a combination of irradiation and 100 µM FeCl3. Furthermore, in vivo experiments were performed in mice treated with melatonin via intraperitoneal injection, which was followed by radiation exposure. A series of functional assays, including CCK-8, DCFH-DA kit, flow cytometry, TUNEL staining, iron estimations, and transmission electron microscopy, were performed on cells as well as hippocampal tissues. The interactions between PKM2 and NRF2 proteins were detected using a coimmunoprecipitation (Co-IP) assay. Moreover, chromatin immunoprecipitation (ChIP), a luciferase reporter assay, and an electrophoretic mobility shift assay (EMSA) were performed to explore the mechanism by which PKM2 regulates the NRF2/GPX4 signaling pathway. The spatial memory of mice was evaluated using the Morris Water Maze test. Hematoxylin-eosin and Nissl staining were performed for histological examination. The results revealed that melatonin protected HT-22 neuronal cells from radiation-induced ferroptosis, as inferred from increased cell viability, decreased ROS production, reduced number of apoptotic cells, and less cristae, higher electron density in mitochondria. In addition, melatonin induced PKM2 nuclear transference, while PKM2 inhibition reversed the effects of melatonin. Further experiments demonstrated that PKM2 bound to and induced the nuclear translocation of NRF2, which regulated GPX4 transcription. Ferroptosis enhanced by PKM2 inhibition was also converted by NRF2 overexpression. In vivo experiments indicated that melatonin alleviated radiation-induced neurological dysfunction and injury in mice. In conclusion, melatonin suppressed ferroptosis to decrease radiation-induced hippocampal neuronal injury by activating the PKM2/NRF2/GPX4 signaling pathway.

Risk Factors for Refractory Immune Checkpoint Inhibitor-related Pneumonitis in Patients With Lung Cancer.

Checkpoint inhibitor-related pneumonitis (CIP) is one of the most important immune checkpoint inhibitors side effects, and it is rare but fatal. Identifying patients at risk of refractory CIP before the start of CIP therapy is important for controlling CIP. We retrospectively analyzed the clinical data of 60 patients with lung cancer who developed CIP. Refractory CIP was defined as CIP with poor response to corticosteroid treatment, including CIP not relieved with corticosteroid administration or CIP recurrence during the corticosteroid tapering period. We analyzed clinical characteristics, peripheral blood biomarkers, treatment, and outcomes in nonrefractory and refractory CIP. Risk factors associated with refractory CIP were assessed. Among 60 patients with CIP, 16 (26.7%) had refractory CIP. The median onset time for patients with nonrefractory and those with refractory CIP was 16.57 (interquartile range [IQR], 6.82-28.14) weeks and 7.43 (IQR, 2.71-19.1) weeks, respectively. The level of lactate dehydrogenase (LDH) was significantly higher in the refractory CIP group at baseline (255 [222, 418] vs. 216 [183, 252], P =0.031) and at CIP onset (321.5 [216.75, 487.5] vs. 219 [198. 241], P =0.019). An LDH level >320 U/L at CIP onset was an independent risk factor of refractory CIP (odds ratio [OR], 8.889; 95% confidence interval [CI]: 1.294-61.058; P =0.026). The incidence of refractory CIP is high among patients with CIP. An increased LDH level at CIP onset is independently associated with refractory CIP. Monitoring LDH levels during immune checkpoint inhibitors treatment is recommended.

The Efficacy and Safety of Intraoperative Radiotherapy in the Treatment of Recurrent High-Grade Glioma: A Single-Center Prospective Study.

BACKGROUND: High-grade gliomas are treated following a standard protocol; however, tumor recurrence is almost inevitable. Recurrent high-grade gliomas have an extremely poor prognosis, and there are no clear treatment guidelines. In this stud, we evaluated the safety and effectiveness of intraoperative radiotherapy (IORT) for recurrent high-grade glioma. METHODS: In this prospective randomized study begun in April 2018, patients ≥18 years of age with a Karnofsky Performance Status >50 and recurrent high-grade glioma were randomly assigned in a 1:1 ratio to tumor resection and IORT or tumor resection alone. RESULTS: Twenty-two patients were allocated to the IORT group and 21 to receive surgery only (operation group). Clinical data of 42 enrolled patients were involved in the analysis. The progression-free survival of the IORT group was 9.6 months and of the operation group was 7.3 months (P = 0.018), and the overall survival of the 2 groups was 13.5 months and 10.2 months, respectively (P = 0.054). Univariate and multivariate analysis indicated that preoperative Karnofsky Performance Status >70 and IORT were protective factors for patients with recurrent high-grade glioma. A patient who underwent conventional fractionated radiotherapy within 6 months of receiving IORT died on the ninth day after undergoing tumor resection and IORT because of severe cerebral edema. The total operation time was longer in the IORT group, but there were no differences in intraoperative bleeding or adverse events between the 2 groups. CONCLUSIONS: IORT with low-energy radiography at a dose of 30-40 Gy is generally safe and effective for patients with recurrent glioma. However, IORT should not be performed for patients who have received conventional fractionated radiotherapy within 6 months.

Deep learning predicts immune checkpoint inhibitor-related pneumonitis from pretreatment computed tomography images.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer, including both non-small cell lung cancer and small cell lung cancer. Despite the promising results of immunotherapies, ICI-related pneumonitis (ICIP) is a potentially fatal adverse event. Therefore, early detection of patients at risk for developing ICIP before the initiation of immunotherapy is critical for alleviating future complications with early interventions and improving treatment outcomes. In this study, we present the first reported work that explores the potential of deep learning to predict patients who are at risk for developing ICIP. To this end, we collected the pretreatment baseline CT images and clinical information of 24 patients who developed ICIP after immunotherapy and 24 control patients who did not. A multimodal deep learning model was constructed based on 3D CT images and clinical data. To enhance performance, we employed two-stage transfer learning by pre-training the model sequentially on a large natural image dataset and a large CT image dataset, as well as transfer learning. Extensive experiments were conducted to verify the effectiveness of the key components used in our method. Using five-fold cross-validation, our method accurately distinguished ICIP patients from non-ICIP patients, with area under the receiver operating characteristic curve of 0.918 and accuracy of 0.920. This study demonstrates the promising potential of deep learning to identify patients at risk for developing ICIP. The proposed deep learning model enables efficient risk stratification, close monitoring, and prompt management of ICIP, ultimately leading to better treatment outcomes.

Skeletal Muscle Mass Measurement Using Cone-Beam Computed Tomography in Patients With Head and Neck Cancer.

Background and purpose: Head and neck cancer (HNC) patients usually present with malnutrition during radiotherapy, leading to loss of skeletal muscle mass (SMM) and poor clinical outcomes. CT has been used in clinical practice for measuring SMM in cancer patients. However, its clinical application for monitoring SMM is limited by the expensive price and high radiation exposure. This study aimed to investigate the feasibility of cone-beam computed tomography (CBCT) for assessing SMM and its changes in HNC patients undergoing radiotherapy. Materials and methods: This study was divided into two parts. In part 1 (n = 32), the cross-sectional of skeletal muscle area (SMA) at the third cervical vertebra (C3) based on CBCT and computed tomography (CT) was assessed. In part 2 (n = 30), CT and CBCT were performed, and patients' weight was measured before and at four different time points during radiotherapy. SMAs at C3 were independently identified by three senior radiation oncologists. The interobserver agreement of SMA on CBCT (SMACBCT) findings was analyzed using the intraclass correlation coefficient (ICC). One-way analysis of variance was used to evaluate the interobserver variability and statistical significance for SMA measurements. CBCT and CT measurement differences and correlations were analyzed using paired sample t-test and Pearson correlation analysis, respectively. The Krouwer variant of the Bland-Altman plot was used to analyze the agreement of SMA measurements between CBCT and CT. A simple linear regression model was used to analyze the relationship of SMA measurements between the two imaging techniques, and the equation was established. A repeated-measures ANOVA was performed to evaluate the effects and interactions between weight loss, SMA loss, and time. Results: SMACBCT demonstrated excellent interobserver reliability; no significant difference between SMACBCT and SMA on CT (SMACT) at C3 was observed in all patients. The SMACBCT and SMACT were highly correlated (r = 0.966; 95% confidence interval = 0.955-0.975; p < 0.001). Bland-Altman analysis revealed that SMACBCT was generally higher than SMACT. The predicted SMA value at C3 on CT using CBCT was similar to the actual value. Moreover, significant differences between SMA and weight loss (F =10.99, p = 0.002), groups (weight loss and SMA loss) and times (4 time points) (F = 3.93, p = 0.013), and mean percent loss over time (F = 7.618, p < 0.001) were noted. Conclusion: CBCT may be used as an alternative for CT to measure SMA in HNC patients during radiotherapy.

Comprehensive Analysis of Expression and Prognostic Value of MS4As in Glioma.

Glioma is the most common malignancy of the nervous system with high mortality rates. The MS4A family members have been reported as potential prognostic biomarkers in several cancers; however, the relationship between the MS4A family and glioma has not been clearly confirmed. In our study, we explored the prognostic value of MS4As as well as their potential pro-cancer mechanisms of glioma. Using bioinformatics analysis methods based on the data from public databases, we found that the expression of MS4A4A, MS4A4E, MS4A6A, MS4A7, TMEM176A, and TMEM176B was significantly overexpressed in glioma tissues compared with that of normal tissues. The Kaplan-Meier method and Cox proportional hazards models revealed that high levels of MS4As can be associated with a poorer prognosis; TMEM176A, TMEM176B, age, WHO grade, and IDH status were identified as independent prognostic factors. Enrichment analysis predicted that MS4As were related to tumor-related pathways and immune response, which might regulate the process of MS4As promoting tumorigenesis. Additionally, we analyzed the correlations of MS4A expression with immune cells and immune inhibitory molecules. Finally, data from the cell culture suggested that knockdown of the TMEM176B gene contributes to the decreased proliferation and migration of glioma cells. In conclusion, MS4A4A, MS4A4E, MS4A6A, MS4A7, TMEM176A, and TMEM176B may act as potential diagnostic or prognostic biomarkers in glioma and play a role in forming the immune microenvironment in gliomas.

Integrative Dissection of Novel Lactate Metabolism-Related Signature in the Tumor Immune Microenvironment and Prognostic Prediction in Breast Cancer.

The outcomes of some breast cancer patients remain poor due to being susceptible to recurrence, metastasis and drug resistance, and lactate metabolism has been described as a hallmark of cancer and a contributor to cancer progression and immune escape. Hence, it is worthy of seeking potentially novel biomarkers from lactate metabolism relevant perspectives for this particular cohort of patients. In this context, 205 available lactate metabolism-related genes (LMGs) were obtained by a search of multiple genesets, and the landscape of somatic mutation, copy number variation, and mRNA expression levels was investigated among these genes. Crucially, 9 overall survival-related LMGs were identified through univariate Cox regression analysis in The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases. Subsequently, a prognostic signature, defined as Lactate Metabolism Index (LMI), was established with 5 OS-related LMGs using Least Absolute Shrinkage and Selection Operator (LASSO) Cox hazard regression analysis in TCGA training set, and then validated in two external cohorts (METABRIC and GSE96058). From the comprehensive results, breast cancer patients with high LMI had considerably poorer survival probability across all cohorts, and the degree of clinical features tended to be more severe as the LMI value increased. Furthermore, a prognostic nomogram incorporating LMI, age, and AJCC stage was constructed and demonstrated great prediction performance for OS of breast cancer patients, which was evaluated by the calibration plot and the decision curve analysis. Moreover, the potential effect of different LMI values on levels of immune checkpoints, tumor-infiltrating immune cells, and cytokines were explored ultimately, and patients with higher LMI values might gain an immunosuppressive tumor microenvironment that contributed to immune escape of breast cancer and inferior prognosis. Collectively, all findings in the study indicated the potential prognostic value of LMI in breast cancer, providing further implications for the role of lactate metabolism in breast cancer prognosis, tumor immune microenvironment, and immunotherapy.

Differentiation between immune checkpoint inhibitor-related and radiation pneumonitis in lung cancer by CT radiomics and machine learning.

PURPOSE: Consolidation immunotherapy after completion of chemoradiotherapy has become the standard of care for unresectable locally advanced non-small cell lung cancer and can induce potentially severe and life-threatening adverse events, including both immune checkpoint inhibitor-related pneumonitis (CIP) and radiation pneumonitis (RP), which are very challenging for radiologists to diagnose. Differentiating between CIP and RP has significant implications for clinical management such as the treatments for pneumonitis and the decision to continue or restart immunotherapy. The purpose of this study is to differentiate between CIP and RP by a CT radiomics approach. METHODS: We retrospectively collected the CT images and clinical information of patients with pneumonitis who received immune checkpoint inhibitor (ICI) only (n = 28), radiotherapy (RT) only (n = 31), and ICI+RT (n = 14). Three kinds of radiomic features (intensity histogram, gray-level co-occurrence matrix [GLCM] based, and bag-of-words [BoW] features) were extracted from CT images, which characterize tissue texture at different scales. Classification models, including logistic regression, random forest, and linear SVM, were first developed and tested in patients who received ICI or RT only with 10-fold cross-validation and further tested in patients who received ICI+RT using clinicians' diagnosis as a reference. RESULTS: Using 10-fold cross-validation, the classification models built on the intensity histogram features, GLCM-based features, and BoW features achieved an area under curve (AUC) of 0.765, 0.848, and 0.937, respectively. The best model was then applied to the patients receiving combination treatment, achieving an AUC of 0.896. CONCLUSIONS: This study demonstrates the promising potential of radiomic analysis of CT images for differentiating between CIP and RP in lung cancer, which could be a useful tool to attribute the cause of pneumonitis in patients who receive both ICI and RT.

Dynamic changes in the radiologic manifestation of a recurrent checkpoint inhibitor related pneumonitis in a non-small cell lung cancer patient: A case report.

BACKGROUND: As immune checkpoint inhibitors (ICIs) have become widely used in lung cancer treatment, immune-related adverse events (irAEs) warrant sufficient attention. Checkpoint inhibitor-related pneumonitis (CIP) is one of the most concerning adverse events as it is uncommon but life threatening. CASE SUMMARY: The patient whose case is reported here experienced three episodes of CIP in a span of 4 mon. Interestingly, the three episodes of CIP involved different regions of the lung separately. Taking these pneumonitis areas together makes nearly a whole lung area. CONCLUSION: This case showed that recurrent CIPs may occur repeatedly until the whole lung is involved, suggesting that the follow-up period of CIP should be long enough, and the rechallenge of ICI should be done with due caution.

Hydrophobically modified chitin/halloysite nanotubes composite sponges for high efficiency oil-water separation.

A high-performance oil-water separation device that built by environment-friendly materials is a promising strategy to solve water pollution problem. In this study, we developed an oil-water separation system with chitin/halloysite nanotubes (C/HNTs) composites. C/HNTs were crosslinked by epichlorohydrin and freeze-dried, then a porous sponge was formed. The C/HNTs sponge was modified to be hydrophobic via immersing into bromohexadecane ethanol solution. The surface structure, mechanical properties, microstructure, oil absorption and oil-water separation ability of the C/HNTs sponge were investigated. The addition of HNTs significantly increased the compressive strength of chitin sponge without influence on porous structure. IR spectra indicated the successful coating of bromohexadecane on the C/HNTs sponge surface, which enabled the hydrophobicity and lipophilicity of this construct. The inside construct of the C/HNTs sponges were full of interconnected pores, and the pore size ranged from 250 to 500 µm. The absorption capability for various oil and grease were measured, including methylbenzene, sunflower seed oil, carbon dichloride, n-hexane, chloroform and acetone. It is found that the total amount of chloroform absorbed by a C/HNTs sponge was ~11.23 times of the sponge's weight, and the absorption for hexane was ~3.94 times of the sponge's weight. The sponge also exhibited an excellent oil-water separation ability with as high as 98.7% separation efficiency. All the results suggested that the chitin/HNTs sponges with improved mechanical property would have a great potential in oil-water separation.

Radiation-induced Cochlea hair cell death: mechanisms and protection.

Cochlea hair cell death is regarded to be responsible for the radiation-induced sensorineural hearing loss (SNHL), which is one of the principal complications of radiotherapy (RT) for head and neck cancers. In this mini- review, we focus on the current progresses trying to unravel mechanisms of radiation-induced hair cell death and find out possible protection. P53, reactive oxygen species (ROS) and c-Jun N-terminal kinase (JNK) pathways have been proposed as pivotal in the processes leading to radiation hair cell death. Potential protectants, such as amifostine, N-acetylcysteine (NAC) and epicatechin (EC) , are claimed to be effective at reducing radiation- inducedhair cell death. The RT dosage, selection and application of concurrent chemotherapy should be pre- examined in order to minimize the damage to cochlea hair cells.

Protective effect of tanshinone IIA against radiation-induced ototoxicity in HEI-OC1 cells.

Radiotherapy is a highly efficient treatment method for nasopharyngeal carcinoma that is often accompanied by significant ototoxic side-effects. The inner ear hair cells are particularly prone to serious injury following radiotherapy. Tanshinone IIA is a transcription factor inhibitor that is extracted from the traditional herbal medicine, Salvia miltiorrhiza Bunge. The present study investigated the effects of tanshinone IIA treatment on radiation-induced toxicity in the HEI-OC1 hair cell line. Using an MTT assay and flow cytometry, the radiation-induced weakening of the cells was observed to be alleviated when the cells were pre-treated with tanshinone IIA. Radiation exposure promoted p65/nuclear factor (NF)-κB nuclear translocation and activated the p53/p21 pathway, two processes which play a significant role in radiation-induced cell apoptosis. However, pre-treatment of the cells with tanshinone IIA inhibited p65/NF-κB nuclear translocation and p53/p21 pathway activation. These results demonstrate that tanshinone IIA is capable of protecting cochlear cells from radiation-induced injury through the suppression of p65/NF-κB nuclear translocation and the p53/p21 signaling pathway.