Low- dose Apatinib promotes vascular normalization and hypoxia reduction and sensitizes radiotherapy in lung cancer.

BACKGROUND AND PURPOSE: Abnormal vascular network of tumor can create a hypoxic microenvironment, and reduce radiotherapy sensitivity. Normalization of tumor vasculature can be a new therapeutic strategy for sensitizing radiotherapy. This study aimed to explore the effect of apatinib on vascular normalization, as well as the syngeneic effect with radiotherapy on lung cancer. MATERIALS AND METHODS: Lewis lung carcinoma (LLC) xenograft-bearing female C57BL/6 mice were treated with different doses of apatinib (30, 60, and 120 mg/kg per day) and/or radiation therapy (8 Gy/1F) and then sacrificed to harvest tumor tissue for immunohistochemical test. Further 18 F-FMISO micro- PET in vivo explored the degree of hypoxia. RESULTS: Immunohistochemistry of CD31 and alpha-smooth muscle actin (α-SMA) proved that low-dose apatinib can normalize vasculature in tumor, especially on Day 10. Tissue staining of hypoxyprobe-1 and 18 F-FMISO micro- PET in vivo showed that 60 mg/kg/day of apatinib significantly alleviates hypoxia. Moreover, this study further proved that low-dose apatinib (60 mg/kg/day) can enhance the radio-response of LLC xenograft mice. CONCLUSION: Our data suggested that low- dose apatinib can successfully induce a vascular normalization window and function as a radio- sensitizer in the lung cancer xenografts model.

Is Performance of Fluorine-18-fluorodeoxyglucose Positron Emission Tomography/Computed tomography (CT) or Contrast-enhanced CT Efficient Enough to Guide the Hilar Lymph Node Staging for Patients with Esophageal Squamous Cell Carcinoma?

Introduction: We evaluated the diagnostic performance of fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and contrast-enhanced CT in the detection of hilar lymph node metastasis (LNM) in esophageal squamous cell carcinoma (ESCC) to determine their value in guiding hilar lymph node staging and delineating radiation target volume. Methods: Consecutive patients with ESCC who underwent both PET/CT and contrast-enhanced CT before radical lymphadenectomy and esophagectomy at our institution from September 2009 to November 2018 were enrolled. The sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) of FDG-PET/CT and contrast-enhanced CT for diagnosing hilar LNM were calculated. Results: Of the 174 patients included, contrast-enhanced CT predicted nine positive cases, while PET/CT predicted one, and eight (4.6%) were identified as pathologically positive for their resected hilar lymph nodes. The SE, SP, PPV, and NPV of PET/CT and contrast-enhanced CT were 0.000, 0.994, 0.000, and 0.954; and 0.125, 0.952, 0.111, and 0.958, respectively. The specificity showed a significant difference (P=0.037). PET/CT is slightly more specific than contrast-enhanced CT. Conclusions: PET/CT and contrast-enhanced CT may be useful tools for predicting the negativity of hilar LN status, but they are not recommended for guiding the hilar lymph node staging and the delineating of hilar LNM in radiotherapy planning of ESCC patients based on their low PPV.

Overall survival benefit of osimertinib and clinical value of upfront cranial local therapy in untreated EGFR-mutant nonsmall cell lung cancer with brain metastasis.

Osimertinib, as a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), showed more potent efficacy against brain metastasis (BM) in untreated EGFR-mutant nonsmall cell lung cancer (NSCLC) in the FLAURA study. However, the overall survival (OS) benefit of osimertinib and clinical value of cranial local therapy (CLT) in these patients remain undetermined. Here we conducted a retrospective study involving untreated EGFR-mutant NSCLC patients with BMs receiving first-line osimertinib or first-generation EGFR-TKIs. Upfront CLT was defined as CLT performed before disease progression to the first-line EGFR-TKIs. Pattern of treatment failure and survival outcomes were extensively investigated. Among the 367 patients enrolled, first-generation EGFR-TKI was administered in 265, osimertinib in 102 and upfront CLT performed in 140. Patients receiving osimertinib had more (P < .001) and larger BMs (P = .003) than those receiving first-generation EGFR-TKIs. After propensity score matching, osimertinib was found to prolong OS (37.7 vs 22.2 months, P = .027). Pattern of failure analyses found that 51.8% of the patients without upfront CLT developed their initial progressive disease (PD) in the brain and 59.0% of the cranial PD occurred at the original sites alone, suggesting potential clinical value of upfront CLT. Indeed, upfront stereotactic radiosurgery (SRS) and/or surgery was associated with improved OS among those receiving first-generation EGFR-TKIs (P = .019) and those receiving osimertinib (P = .041). In summary, compared to first-generation EGFR-TKIs, osimertinib is associated with improved OS in untreated EGFR-mutant NSCLC with BMs. Meanwhile, upfront SRS and/or surgery may provide extra survival benefit, which needs to be verified in future studies.

Janus Polypyrrole Nanobelt@Polyvinyl Alcohol Hydrogel Evaporator for Robust Solar-Thermal Seawater Desalination and Sewage Purification.

The state-of-the-art solar-thermal evaporators demonstrating high energy utilization efficiency, a high evaporation rate, and salt rejection are highly desirable in solar-driven low-energy water purification/harvesting. Herein, a novel Janus solar evaporator is constructed by loading polypyrrole (PPy) nanobelts on the polyvinyl alcohol (PVA) hydrogel. The PPy nanobelts present a high solar absorption of 98.3%, leading to a localized solar-thermal efficiency of 82.5% when insulated from bulk water by the PVA hydrogel. The porous PVA hydrogel and the hydrophilic PPy nanobelts enable the efficient three-dimensional water transport. Taking advantages of the synergistic effect in the water-energy nexus, the Janus PPy nanobelt@PVA hydrogel evaporator evaporates water with a high rate of 2.26 kg m-2 h-1 via 80.1% solar energy from 1 sun irradiance with a low PPy loading of ∼3 mg cm-2 even at a rate of 2.64 kg m-2 h-1 via 96.3% solar energy for a biomimetic conical evaporator. The Janus evaporator presents superior salt-resistant desalination and contaminant purification performance in seawater and sewage. Furthermore, a portable solar-thermal purifier equipped with the Janus evaporator desalts real seawater far above the drinking water standard with over a 99.9% salt rejection rate and eliminates 95.8% of chemical oxygen demand in real sewage, highlighting its potential for advanced clean water harvesting.

Identification and Integrated Analysis of circRNA and miRNA of Radiation-Induced Lung Injury in a Mouse Model.

BACKGROUND: Radiation-induced lung injury (RILI) is a main threat to patients who received thoracic radiotherapy. Thus, understanding the molecular mechanism of RILI is of great importance. Circular RNAs (circRNAs) have been found to act as a regulator of multiple biological processes, and the circRNA-microRNA (miRNA)-mRNA axis could play an important role in the signaling pathway of many human diseases including radiation injury. METHODS: First, the circRNA and miRNA of RILI in a mouse model were investigated. The mice received 12 Gy of thoracic irradiation, and the irradiated lung tissues at 48 hours after irradiation were analyzed by RNA sequencing (RNA-seq) compared with normal lung tissues. Then, Gene Ontology analysis of the target mRNAs of the significantly differently expressed circRNAs was performed. RESULTS: In the irradiated group, inflammatory changes in lungs were observed; 21 significantly up-regulated and 33 down-regulated significantly miRNAs were identified (p < 0.05). Among 27 differentially expressed circRNAs, 10 were down-regulated and 17 were up-regulated in the irradiated group [log2 (fold change) > 1 or < -1, p<0.05]. These differentially expressed miRNAs took part in a series of cellular processes, such as positive regulation of alpha-beta T-cell proliferation, interstitial matrix, collagen fibril organization, chemokine receptor activity, cellular defense response, and B-cell receptor signaling pathway. The differentially expressed circRNAs were related to Th1 and Th2 differentiation pathways, and the predicted mRNAs were verified. CONCLUSION: This study revealed immune-related molecular pathways play an important role in the early response after radiotherapy. In the future, research on the target mechanism and early intervention of circRNAs with associated miRNAs such as circRNA5229, circRNA544, and circRNA3340, could benefit the treatment of RILI.

Clinical Value of Upfront Cranial Radiation Therapy in Osimertinib-Treated Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer With Brain Metastases.

PURPOSE: As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib has a powerful ability to penetrate the blood-brain barrier and a high potency for controlling brain metastases (BMs) from EGFR-mutant non-small cell lung cancer (NSCLC). The clinical value of cranial radiation therapy in osimertinib-treated NSCLC with BMs remains largely unknown. METHODS AND MATERIALS: Patients with NSCLC and BMs and receiving osimertinib treatment as the standard of care were retrospectively enrolled from 2 institutions. Cranial radiation therapy (RT; whole-brain radiation therapy [WBRT] or/and stereotactic radiosurgery [SRS]) performed before disease progression (PD) to osimertinib was categorized as upfront cranial radiation therapy (ucRT group), excluding those treatments performed during prior EGFR-TKI treatment. Overall survival (OS), progression-free survival (PFS), and the time to intracranial progression (iTTP) were compared between the 2 groups, with adjustment by covariates in propensity-score matched (PSM) analyses. The state of having 1 to 3 BM lesions, with a maximal size of ≤3 cm, was defined as having oligo-BM; otherwise; the cases were defined as having multiple BMs. RESULTS: Of the 205 patients enrolled, osimertinib was used as first-line therapy in 74 and second-line therapy in 131. There were 48 patients who received ucRTs, including WBRT in 24 and SRS in 24. All patients with oligo-BM in the ucRT group received SRS alone (n = 17), whereas most (n = 28; 90.3%) patients with multiple BMs received WBRT. Failure pattern analyses indicated that in the non-ucRT group, 40.2% of the initial PD involved the brain and 76.9% of the cranial PD involved the original sites, indicating the potential roles of ucRT. Indeed, the iTTP was significantly prolonged (P = .010) in the ucRT group among the whole population. In the PSM oligo-BM cohort, the ucRT group showed superior PFS (P = .033) and OS (P = .026) compared with the non-ucRT group, and the differences remained after multivariate Cox analyses. No such differences were observed in the subpopulation with multiple BMs. CONCLUSIONS: In osimertinib-treated NSCLC patients with BMs, oligo-BM status could be used as a potential factor to select patients for upfront cranial RT. Further investigation by well-designed clinical trials is warranted.

Outcomes for Surgery in Stage IA Large Cell Lung Neuroendocrine Compared With Other Types of Non-Small Cell Lung Cancer: A Propensity Score Matching Study Based on the Surveillance, Epidemiology, and End Results (SEER) Database.

BACKGROUND: Pulmonary large cell neuroendocrine cancer (LCNEC) is commonly classified as non-small cell lung cancer (NSCLC). Even for stage I disease, after surgery the survival is always poor, but clinical research on LCNEC is scant and always with unsatisfying sample sizes. Thus, we conduct the first study using the Surveillance, Epidemiology, and End Results (SEER) database to compare survival after surgery between stage I LCNEC and other types of NSCLC. METHODS: From 2004 to 2016, 473 patients with stage IA LCNEC, 17,669 patients with lung adenocarcinoma (LADC) and 8,475 patients with lung squamous cell cancer (LSCC), all treated with surgery were identified. In addition, 1:1 PSM was used, and overall (OS) and cancer-specific survival (CSS) between groups were compared. RESULTS: The 5-year OS rates and CSS rates for LCNEC were 52.5% and 81.5%, respectively. Overall, both OS and CSS were significantly superior for stage IA LADC than LCNEC (for OS: HR 0.636, 95% CI 0.568-0.712; for CSS: HR 0.688, 95% CI 0.561-0.842, LCNEC as reference), while comparable for LSCC with LCNEC (for OS: HR 0.974, 95% CI 0.869-1.091; for CSS: HR 0.907, 95% CI 0.738-1.115). PSM generated 471 pairs when LCNEC was compared with LADC and both OS and CSS were significantly better in LADC than LCNEC (for OS: HR 0.580, 95% CI 0.491-0.686; for CSS: HR 0.602, 95% CI 0.446-0.814). Of note, for the subgroup of patients ≤ 65 years old, HRs for both OS and CSS were lower (for OS: HR 0.470; for CSS: HR 0.482). As for comparison between LCNEC and LSCC, PSM generated 470 pairs. Differently, only CSS was significantly superior in LSCC than LCNEC (HR 0.563, 95% CI 0.392-0.807), while OS was not. Further grouping by age showed only CSS between two groups for patients with age ≤ 65 years old was significantly different (P = 0.006). CONCLUSIONS: We report the first survival comparison after surgery between stage IA LCNEC and other types of NSCLC by SEER database and PSM. Our results demonstrated after surgery, stage IA LCNEC was worse in survival, especially compared to LADC. Extra clinical care should be paid, especially for younger patients. More studies investigating adjuvant therapy are warranted.

Is clinical target volume necessary?-a failure pattern analysis in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy using intensity-modulated radiotherapy technique.

BACKGROUND: Our previous dosimetric study showed that for locally advanced non-small cell lung cancer (LA-NSCLC), radiotherapy with intensity-modulated radiotherapy (IMRT) technique could deliver sufficient dose coverage to subclinical regions and reduce the dose to normal tissues with the omission of clinical target volume (CTV). To further clinically validate this strategy, we conducted the current study to analyze the failure pattern for patients with LA-NSCLC treated with concurrent chemotherapy and CTV-omitted IMRT. We also investigated the effects of target volumes on lymphopenia during radiotherapy to further test the potential benefits of CTV omission in anti-tumor immunotherapy. METHODS: A total of 63 patients with LA-NSCLC treated with CTV-omitted IMRT with concurrent chemotherapy were enrolled in this study. Their planning target volume (PTV) (also PTV-g) was expanded directly from gross tumor volume (GTV). A virtual CTV was expanded from GTV, and the PTV generated from virtual CTV was named planning target volume with CTV expansion (PTV-c). Treatment failures were divided into local, regional, and distant failures, and local-regional recurrences were classified into inside PTV-g (IN-PTV-g), between PTV-g and PTV-c (PTV-g-c), and outside PTV-c (OUT-PTV-c). The relationship between lymphopenia during radiotherapy and the target volumes was also evaluated using Spearman's correlation analysis. RESULTS: Among the 60 patients with detailed follow-up data for recurrences, 46 (76.7%) experienced recurrences, with 18 (30.0%) being local recurrence, 5 (8.4%) being regional failure, and 33 (55.0%) being distant failure. For the 21 patients with local-regional recurrences, 16, 6, and 1 were IN-PTV-g, OUT-PTV-c, and PTV-g-c recurrences, respectively. Lymphopenia during radiotherapy was associated with both GTV and PTV, with larger volumes linked to severe lymphopenia. CONCLUSIONS: CTV omission is feasible for LA-NSCLC treated with concurrent chemoradiotherapy and does not compromise failure inside the subclinical region. The radiation volumes were associated with lymphopenia during radiotherapy, with larger volumes related to severe lymphopenia. This finding supports the further exploration of CTV omission for immunotherapy.

Radiotherapy for unresectable locally advanced non-small cell lung cancer: a narrative review of the current landscape and future prospects in the era of immunotherapy.

Significant recent advances have occurred in the use of radiation therapy for locally advanced non-small cell lung cancer (LA-NSCLC). In fact, the past few decades have seen both therapeutic gains and setbacks in the evolution of radiotherapy for LA-NSCLC. The PACIFIC trial has heralded a new era of immunotherapy and has raised important questions for future study, such as the future directions of radiation therapy for LA-NSCLC in the era of immunotherapy. Modern radiotherapy techniques such as three-dimensional (3D) conformal radiotherapy and intensity-modulated radiotherapy (IMRT) provide opportunities for improved target conformity and reduced normal-tissue exposure. However, the low-dose radiation volume brought by IMRT and its effects on the immune system deserve particular attention when combing radiotherapy and immunotherapy. Particle radiotherapy offers dosimetric advantages and exhibits great immunoregulatory potential. With the ongoing improvement in particle radiotherapy techniques and knowledge, the combination of immunotherapy and particle radiotherapy has tremendous potential to improve treatment outcomes. Of particular importance are questions on the optimal radiation schedule in the settings of radio-immunotherapy. Strategies for the reduction of the irradiated field such as involved-field irradiation (IFI) and omission of clinical target volume (CTV) hold promise for better preservation of immune function while not compromising locoregional and distant control. In addition, different dose-fractionation regimens can have diverse effects on the immune system. Thus, prospective trials are urgently needed to establish the optimal dose fractionation regimen. Moreover, personalized radiotherapy which allows the tailoring of radiation dose to each individual's genetic background and immune state is of critical importance in maximizing the benefit of radiation to patients with LA-NSCLC.

Survival outcomes and symptomatic central nervous system (CNS) metastasis in EGFR-mutant advanced non-small cell lung cancer without baseline CNS metastasis: Osimertinib vs. first-generation EGFR tyrosine kinase inhibitors.

OBJECTIVES: Central nervous system (CNS) metastases are common complications in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (TKIs). However, for patients without baseline CNS metastasis, data regarding the incidence of symptomatic CNS metastasis with EGFR-TKI treatment and its risk factors are still rare. MATERIALS AND METHODS: Patients with EGFR-mutant advanced NSCLC without baseline CNS metastasis who are receiving first- and/or third-generation EGFR-TKIs were included. Overall survival (OS), cumulative incidence of symptomatic CNS metastasis upon treatment failure, and their risk factors were evaluated. RESULTS: There were 813 patients enrolled, with 562, 106, and 32 received first-line gefitinib, erlotinib, and osimertinib, respectively, while 113 received second-line osimertinib. At a median follow-up of 18.1 months, the median OS was 45.5 months. There were 38 patients developed symptomatic CNS metastases. Osimertinib-treated patients tended to have a lower risk of CNS metastases compared with those treated with first-generation EGFR-TKIs (p = 0.059). However, the cumulative incidence curves of symptomatic CNS metastasis tended to reach a plateau after approximately 3 years regardless of which generation was used, and incidences beyond that period were similar in the two groups. Patients with L858R mutation exhibited a higher risk of developing CNS metastasis than patients with 19del mutation (p = 0.001). Interestingly, the presence of baseline neuroimaging was not associated with the risk of developing CNS metastasis or OS. CONCLUSION: Compared with first-generation EGFR-TKIs, osimertinib can delay but not prevent the development of symptomatic CNS metastasis. L858R mutation is an independent risk factor for CNS metastasis.

LncRNA-RP11 Modulates TGF-ß1-Activated Radiation-Induced Lung Injury Through Downregulating microRNA-29a.

Radiation-induced lung injury (RILI) is one of the most serious complications of thoracic radiation and TGF-ß1 is a central regulator of RILI. However, the molecular mechanism underlying the fine tuning of TGF-ß1 signaling in RILI has not been fully understood. In the current study, differentially expressed long non-coding RNAs (LncRNAs) among human lung fibroblasts cell lines HFL-1 and WI-38 treated with TGF-ß1, were identified by microarray and validated by real time PCR. LncRNA-RP11 was found to be the most increased LncRNA and it mediated the promotion of fibrogenic activity in human lung fibroblasts after TGF-ß1 treatment. Bioinformatic analysis revealed that TGF-ß1 may be associated with the component and structure of extracellular matrix in lung fibroblasts cells, and LncRNA-RP11 was predicted and confirmed to be a competing endogenous RNA by directly binding to miR-29a. Functional experiments investigating the biological role of LncRNA-RP11/miR-29a axis in RILI, were then carried out in human fibroblasts. The results showed that radiation promoted the expression of LncRNA-RP11, but regressed the expression of miR-29a. Furthermore, radiation elevated the expression of various common collagenic proteins, which could be abolished by overexpression of miR-29a.

Regulatory T Cells: An Emerging Player in Radiation-Induced Lung Injury.

Regulatory T cells (Tregs), which have long been recognized as essential regulators of both inflammation and autoimmunity, also impede effective antitumor immune response due to their immunosuppressive properties. Combined radiotherapy and immunotherapeutic interventions focusing on the removal of Tregs have recently garnered interest as a promising strategy to reverse immunosuppression. Meanwhile, Tregs are emerging as a key player in the pathogenesis of radiation-induced lung injury (RILI), a frequent and potentially life-threatening complication of thoracic radiotherapy. Recognition of the critical role of Tregs in RILI raises the important question of whether radiotherapy combined with Treg-targeting immunotherapy offers any beneficial effects in the protection of normal lung tissue. This present review focuses on the contributions of Tregs to RILI, with particular emphasis on the suspected differential role of Tregs in the pneumonitic phase and fibrotic phase of RILI. We also introduce recent progress on the potential mechanisms by which Tregs modulate RILI and the crosstalk among Tregs, other infiltrating T cells, fibrocytes, and resident epithelial cells driving disease pathogenesis. Finally, we discuss whether Tregs also hold promise as a potential target for immunotherapeutic interventions for RILI.

Pattern of Recurrence Analysis in Metastatic EGFR-Mutant NSCLC Treated with Osimertinib: Implications for Consolidative Stereotactic Body Radiation Therapy.

PURPOSE: Despite the impressive response rate to osimertinib, acquired resistance remains an obstacle to achieving long-term tumor control in metastatic epidermal growth factor receptor-mutant non-small cell lung cancer. Stereotactic body radiation therapy (SBRT) plays a growing role in the management of oligometastatic disease. We investigated the patterns of residual disease and progression on osimertinib, as well as the predictors of candidates for consolidative SBRT. METHODS AND MATERIALS: The serial scans of patients with metastatic epidermal growth factor receptor-mutant non-small cell lung cancer treated with osimertinib were retrospectively reviewed. Disease progression in residual sites, new sites, and both residual and new sites were classified as residual-site recurrence (RR), new-site recurrence (NR), and combined RR and NR (RNR), respectively. Logistic regression analysis was performed to identify predictors of candidates for consolidative SBRT. RESULTS: Ninety-seven patients were enrolled. The median time to maximal osimertinib response was 2.6 months. Twenty-six patients (26.8%) with oligoresidual disease were identified as candidates for consolidative SBRT at time of maximal response. Stage T1-2 before initiation of osimertinib (P = .046) was the independent predictor of consolidative SBRT eligibility. During a median follow-up of 10.9 months, disease progression was documented in 50 (51.5%) patients, and 70% of them experienced oligoprogression. Twenty-five (50%) patients developed disease progression in originally involved sites, 11 (22%) had new metastases, and 14 (28%) experienced disease progression in both original and new metastatic sites. Forty-six patients had progressive disease after experiencing initial stable disease or objective response to osimertinib. RR occurred in 20 (43.5%) of these patients, NR in 14 (30.4%), and RNR in 12 (26.1%). Notably, within the subgroup of patients eligible for consolidative SBRT, RR was observed in 6 (54.5%) patients, RNR in 3 (27.3%), and NR in 2 (18.2%). CONCLUSIONS: The majority of progressive disease on osimertinib was within residual lesions in initially involved sites. Consolidative SBRT may prolong time to progression in a selected subgroup of patients, which merits further investigation.

Enhancing Targeted Cancer Treatment by Combining Hyperthermia and Radiotherapy Using Mn-Zn Ferrite Magnetic Nanoparticles.

Radiotherapy (RT) is a major treatment method for non-small-cell lung cancer (NSCLC), and development of new treatment modality is now critical to amplify the negative effects of RT on tumors. In this study, we demonstrated a nanoparticle-loaded block copolymer micellar system for cancer hyperthermia treatment (HT) that can be used for synergistic therapy under alternating magnetic field (AMF) and radiation field. Block copolymer micelles (polyethylene glycol-block-polycaprolactone, or PEG-PCL) containing hyaluronic acid (HA) and Mn-Zn ferrite magnetic nanoparticles (MZF) were fabricated via a two-step preparation. HA-modified Mn-Zn ferrite magnetic nanoparticles (MZF-HA) can be enriched in CD44 highly expressing tumor cells, such as A549 (human lung adenocarcinoma cell line), through an active targeting mechanism via receptor-ligand binding of HA and CD44 (HA receptor). MZF can generate thermal energy under an AMF, leading to a local temperature increase to approximately 43 °C at tumor sites for mild HT, and the increased tumor oxygenation can enhance the therapeutic effect of RT. In vitro experiments show that MZF-HA is able to achieve excellent specific targeting performance toward A549 cells with excellent biocompatibility as well as enhanced therapy performance under HT and RT in vitro by apoptosis flow cytometry. In the A549 subcutaneous tumor xenografts model, MRI confirms the enrichment of MZF-HA in tumor, and hypoxia immunohistochemistry analysis (IHC) proved the increased tumor oxygenation after HT. Furthermore, the tumor volume decreases to 49.6% through the combination of HT and RT in comparison with the 58.8% increase of the untreated group. These results suggest that the application of MZF-HA is able to increase the therapeutic effect of RT on A549 and can be used for further clinical NSCLC treatment evaluation.

A narrative review of evolving roles of radiotherapy in advanced non-small cell lung cancer: from palliative care to active player.

Radiotherapy, along with other loco-regional interventions, is conventionally utilized as a palliative approach to alleviate symptoms and mitigate oncological emergencies in advanced non-small cell lung cancer (NSCLC). Thanks to the ongoing improvement of medical treatments in the last decade, such as targeted therapy and immunotherapy, the survival of patients with advanced NSCLC has been considerably prolonged, making it feasible and clinically beneficial for radiotherapy to play a more active role in highly selected subpopulations. In this review, we will focus on the evolving roles of radiotherapy in advanced NSCLC. First of all, among patients who are initially unable to tolerate aggressive treatment due to severe symptoms caused by metastases and/or tumor emergencies, timely radiotherapy could significantly improve their performance status (PS) and general condition, thus giving them a chance for intensive treatment and prolonged survival. The efficacy, potential candidates, and optimal dose-fractionation regimens of radiotherapy in this clinical scenario will be discussed. Additionally, radiotherapy can play a curative role as a concurrent therapy, consolidation therapy, and salvage therapy for patients with oligo-metastatic, oligo-residual, and oligo-progressive disease, respectively. Accumulating evidence from recent clinical trials, basic research, and translational investigations regarding the potentially curative roles of radiotherapy in NSCLC patients with oligo-metastatic disease will be summarized. Moreover, with the advent of various small molecular tyrosine kinase inhibitors (TKIs), the treatment efficacy and overall survival of oncogene-addicted NSCLC with brain metastases have been significantly improved, and the clinical value and optimal timing of cranial radiotherapy have become topics of much debate. Finally, synergistic antitumor interactions between radiotherapy and immunotherapy have been repeatedly demonstrated. Thus, the immune sensitizing role of radiotherapy in advanced NSCLC is also highlighted in this review.

Identification of lncRNA, MicroRNA, and mRNA-Associated CeRNA Network of Radiation-Induced Lung Injury in a Mice Model.

Radiation-induced lung injury (RILI) can be challenging for thoracic radiotherapy, thus investigating its mechanisms of related pathophysiological process is needed. Long noncoding RNAs (lncRNAs) was found to participate in normal tissue damage induced by ionizing irradiation. Here, we first profiled the dysregulation of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) of RILI in mice model receiving 12 Gy thoracic irradiation. The lung tissue was collected 48 hours after irradiation, after which an RNA library was built by RNA sequencing. Compared with the control group, 461 mRNAs and 401 lncRNAs were significantly upregulated, while 936 mRNAs and 501 lncRNAs were significantly downregulated. Then we predicted target miRNAs of the dysregulated lncRNAs and the target mRNAs of these miRNAs. Next, functional annotations of these target mRNAs were performed. Results showed some pathways apparently dysregulated, such as Th1 and Th2 cell differentiation, Th17 cell differentiation, and hematopoietic cell lineage. Through this study, we also highlighted that T helpers could be vital in RILI through lncRNA-miRNA-mRNA network, therefore causing fibrosis, indicating that RNA dysregulation in early stage of RILI may cause severe late complications. Thus, research on the target mechanism and early intervention of lncRNAs with associated competing endogenous RNA network will benefit the treatment of RILI.

Radiographic Features of Metastatic Brain Tumors from ALK-rearranged Non-small Cell Lung Cancer: Implications for Optimal Treatment Modalities.

Purpose: To investigate the radiological features on magnetic resonance imaging (MRI) of brain metastases (BM) from ALK-rearranged non-small cell lung cancer (NSCLC). Patients and Methods: We retrospectively evaluated data from 40 eligible patients with ALK-rearranged NSCLC. Radiographic features of metastatic brain tumors, including the number, size, location, and peritumoral brain edema size (PBES), were delineated using MRI. Results: 13 patients had metachronous BM (MBM), having developed BM at least 6 months after diagnosis with NSCLC. The remaining patients were categorized as having synchronous BM (SBM). Compared with patients in the SBM group, patients in the MBM group were found to have more favorable values for radiological features including BM number, BM size, and PBES. Ten (76.9%) of the 13 patients with MBM had ≤3 lesions and were asymptomatic, and none had developed a diffuse BM pattern, supporting the adoption of stereotactic radiosurgery (SRS) in the majority of these patients and against the administration of prophylactic cranial irradiation (PCI). Conversely, among the 27 patients with SBM, 15 (55.6%) patients had >3 lesions and 12 (44.4%) patients were symptomatic, highlighting the necessity of rapidly administrating brain radiotherapy, either as SRS or whole brain radiotherapy (WBRT). Importantly, only two patients (5.0%) had metastases in the hippocampus and peri-hippocampus region, and both were in the SBM group, indicating the feasibility of hippocampal avoidance WBRT in ALK-rearranged NSCLC. Conclusions: Both WBRT and SRS are appropriate for the treatment of BM in patients with ALK-rearranged NSCLC. The incidence of BM in the hippocampus and peri-hippocampus region is low in our radiological data. Nearly 80% of patients with metachronous BM have oligo-metastatic lesions, indicating that SRS is the preferred therapy while PCI is not indicated.

Patterns of brain metastasis immediately before prophylactic cranial irradiation (PCI): implications for PCI optimization in limited-stage small cell lung cancer.

BACKGROUND: Prophylactic cranial irradiation (PCI) is indicated for limited-stage small cell lung cancer (LS-SCLC) with good response to chemoradiotherapy (CRT). However, brain metastasis (BM) developed in LS-SCLC before PCI is not rare. In this study, we comprehensively investigated the features of pre-PCI BMs, aiming to explore the potential of PCI optimization for LS-SCLC. METHODS: One-hundred-ten LS-SCLC patients achieving clinical complete remission after definitive CRT with contrast-enhanced cranial magnetic resonance imaging (MRI) at baseline and immediately before PCI were included. The time trend and risk factors for pre-PCI BM were evaluated. Several radiological features, including numbers, sizes, and locations of pre-PCI BMs, were investigated to explore the technical feasibility of stereotactic radiotherapy and hippocampal-avoidance (HA) PCI. RESULTS: Twenty-four (21.8%) of the LS-SCLC patients harbored pre-PCI BM, all except one were asymptomatic. CRT duration (CRT-D) was the only independent risk factor for pre-PCI BM. The pre-PCI BM rate gradually increased in line with a growing time interval between treatment initiation and pre-PCI MRI. Pre-PCI BM and prolonged CRT-D were both correlated with worse overall survival. Of 129 pre-PCI intracranial lesions, 2 (1.5%) were in the HA region. Eight of the 24 (33.3%) pre-PCI BM patients were ineligible for stereotactic radiotherapy. CONCLUSION: Our findings suggest that PCI is still of importance in LS-SCLC, and MRI evaluation before PCI is indispensable. Investigations are warranted to explore the possibility of moving PCI up to before CRT completion in LS-SCLC patients with prolonged CRT-D. HA-PCI could be considered to reduce neurotoxicity.

Immune checkpoint inhibitors: a new era for esophageal cancer.

Introduction: The poor prognosis for patients with esophageal cancer (EC) requires evolving current treatment regimens. Immune checkpoint inhibitors show clinical efficacy and a great safety profile in multiple tumors. And the monoclonal antibodies that target programmed death receptor-1/programmed death receptor ligand-1 or the cytotoxic T lymphocyte antigen-4 pathway has shown potential curable effect of EC. Areas covered: This review article covers the prognostic significance of immune checkpoint expression, the accumulating current clinical studies of checkpoint inhibitors in esophageal cancer patients, and future directions. Expert opinion: Many clinical studies have reported favorable survival results with manageable toxicity of anti-programmed death receptor-1/programmed death receptor ligand-1 and anti-cytotoxic T lymphocyte antigen-4 treatment. More results are expected from future clinical studies. It is believed that combining chemoradiotherapy and immune checkpoint inhibitors can induce safe and efficient anti-tumor immune responses and can be a promising therapeutic strategy.

Predicting the Value of Adjuvant Therapy in Esophageal Squamous Cell Carcinoma by Combining the Total Number of Examined Lymph Nodes with the Positive Lymph Node Ratio.

BACKGROUND: The value of adjuvant therapy for esophageal squamous cell carcinoma (ESCC) has been controversial, at least partially due to the lack of efficient criteria for selecting suitable patients. This study aimed to explore the existence of parameters related to lymph node (LN) status that can predict the value of adjuvant therapy in ESCC. METHODS: The study included 298 patients with ESCC who had undergone radical esophagectomy with lymphadenectomy. Adjuvant therapy was defined as reception of adjuvant chemotherapy, radiotherapy, or chemoradiotherapy. For the study, LN ratio (LNR), total number of resected LNs (TLNs), and pN stage were selected for Cox regression analyses, including their correlations and prognostic values for survival. Log-rank tests were used to compare the survival rates of the patients with and without adjuvant therapy stratified by pN stage, TLNs, LNR, or their combinations. RESULTS: The independent prognostic factors for survival were TLNs, LNR, and pN stage. Whereas pN stage was significantly related to TLNs and LNR, TLNs were not correlated with LNR. The survival rates between the patients with and those without adjuvant therapy stratified by pN stage, TLNs, or LNR did not differ significantly. We used the median values of TLNs and LNR to group the patients into four groups. The patients in the group with fewer TLNs and higher LNR who had undergone adjuvant therapy showed a significantly better survival than those without adjuvant therapy (p = 0.030). CONCLUSIONS: In contrast to TLNs, LNR, and pN stage as single factors, the combination of TLNs and LNR can predict the value of adjuvant therapy.