Visible-Light-Promoted Cascade Coupling of 2-Isocyanonaphthalenes with Elemental Sulfur and Amines to Construct Naphtho[2,1-d]thiazol-2-Amines.

A visible-light-induced strategy has been explored for the synthesis of naphtho[2,1-d]thiazol-2-amines through ortho-C-H sulfuration of 2-isocyanonaphthalenes with elemental sulfur and amines under external photocatalyst-free conditions. This three-component reaction, which utilizes elemental sulfur as the odorless sulfur source, molecular oxygen as the clean oxidant, and visible light as the clean energy source, provides a mild and efficient approach to construct a series of naphtho[2,1-d]thiazol-2-amines. Preliminary mechanistic studies indicated that visible-light-promoted photoexcitation of reaction intermediates consisting of thioureas and DBU might be involved in this transformation.

Magnetization of amorphous FeOOH chrysanthemum-like nanosheets under ambient conditions.

The conversion of paramagnetic solid iron oxides to magnetic iron oxides has drawn considerable interest, but it's still challenging to carry out without heat treatment or irradiation. In this work, solid amorphous iron oxide chrysanthemum-like nanosheets synthesized by a smart redox strategy at the interface of a soap-free emulsion are magnetized at room temperature and under ambient pressure. An amorphous FeOOH hollow shell with needles towards water is produced by the reaction of cumyl hydroperoxide (CHPO) and iron(II) sulfate (FeSO4) at the interface of the emulsion generated by ultrasound and torn up into chrysanthemum-like nanosheets simultaneously. With the presence of noble metal ions, such as Au3+, the magnetization of the nanosheets was carried out as soon as sodium borohydride (NaBH4) was introduced into the dispersion. The magnetic chrysanthemum-like nanosheets present saturation magnetization (Ms) of 32 emu g-1 and can be placed linearly in a magnetic field.

Transfer learning enables prediction of myocardial injury from continuous single-lead electrocardiography.

OBJECTIVE: Chest pain is common, and current risk-stratification methods, requiring 12-lead electrocardiograms (ECGs) and serial biomarker assays, are static and restricted to highly resourced settings. Our objective was to predict myocardial injury using continuous single-lead ECG waveforms similar to those obtained from wearable devices and to evaluate the potential of transfer learning from labeled 12-lead ECGs to improve these predictions. METHODS: We studied 10 874 Emergency Department (ED) patients who received continuous ECG monitoring and troponin testing from 2020 to 2021. We defined myocardial injury as newly elevated troponin in patients with chest pain or shortness of breath. We developed deep learning models of myocardial injury using continuous lead II ECG from bedside monitors as well as conventional 12-lead ECGs from triage. We pretrained single-lead models on a pre-existing corpus of labeled 12-lead ECGs. We compared model predictions to those of ED physicians. RESULTS: A transfer learning strategy, whereby models for continuous single-lead ECGs were first pretrained on 12-lead ECGs from a separate cohort, predicted myocardial injury as accurately as models using patients' own 12-lead ECGs: area under the receiver operating characteristic curve 0.760 (95% confidence interval [CI], 0.721-0.799) and area under the precision-recall curve 0.321 (95% CI, 0.251-0.397). Models demonstrated a high negative predictive value for myocardial injury among patients with chest pain or shortness of breath, exceeding the predictive performance of ED physicians, while attending to known stigmata of myocardial injury. CONCLUSIONS: Deep learning models pretrained on labeled 12-lead ECGs can predict myocardial injury from noisy, continuous monitor data early in a patient's presentation. The utility of continuous single-lead ECG in the risk stratification of chest pain has implications for wearable devices and preclinical settings, where external validation of the approach is needed.

Contrastive learning of heart and lung sounds for label-efficient diagnosis.

Data labeling is often the limiting step in machine learning because it requires time from trained experts. To address the limitation on labeled data, contrastive learning, among other unsupervised learning methods, leverages unlabeled data to learn representations of data. Here, we propose a contrastive learning framework that utilizes metadata for selecting positive and negative pairs when training on unlabeled data. We demonstrate its application in the healthcare domain on heart and lung sound recordings. The increasing availability of heart and lung sound recordings due to adoption of digital stethoscopes lends itself as an opportunity to demonstrate the application of our contrastive learning method. Compared to contrastive learning with augmentations, the contrastive learning model leveraging metadata for pair selection utilizes clinical information associated with lung and heart sound recordings. This approach uses shared context of the recordings on the patient level using clinical information including age, sex, weight, location of sounds, etc. We show improvement in downstream tasks for diagnosing heart and lung sounds when leveraging patient-specific representations in selecting positive and negative pairs. This study paves the path for medical applications of contrastive learning that leverage clinical information. We have made our code available here: https://github.com/stanfordmlgroup/selfsupervised-lungandheartsounds.

Preclinical Efficacy of Pro- and Anti-Angiogenic Peptide Hydrogels to Treat Age-Related Macular Degeneration.

Pro-angiogenic and anti-angiogenic peptide hydrogels were evaluated against the standard of care wet age-related macular degeneration (AMD) therapy, Aflibercept (Eylea®). AMD was modeled in rats (laser-induced choroidal neovascularization (CNV) model), where the contralateral eye served as the control. After administration of therapeutics, vasculature was monitored for 14 days to evaluate leakiness. Rats were treated with either a low or high concentration of anti-angiogenic peptide hydrogel (0.02 wt% 8 rats, 0.2 wt% 6 rats), or a pro-angiogenic peptide hydrogel (1.0 wt% 7 rats). As controls, six rats were treated with commercially available Aflibercept and six with sucrose solution (vehicle control). Post lasering, efficacy was determined over 14 days via fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT). Before and after treatment, the average areas of vascular leak per lesion were evaluated as well as the overall vessel leakiness. Unexpectedly, treatment with pro-angiogenic peptide hydrogel showed significant, immediate improvement in reducing vascular leak; in the short term, the pro-angiogenic peptide performed better than anti-angiogenic peptide hydrogel and was comparable to Aflibercept. After 14 days, both the pro-angiogenic and anti-angiogenic peptide hydrogels show a trend of improvement, comparable to Aflibercept. Based on our results, both anti-angiogenic and pro-angiogenic peptide hydrogels may prove good therapeutics in the future to treat wet AMD over a longer-term treatment period.

Calculating the Eroded Thickness Corresponding to a Short-Term Tectonic Uplift with Milankovitch Theory: A Case Study of the Middle Permian Maokou Formation in Southeastern Sichuan Basin, Southwest China.

The Middle Permian Maokou Formation in the southeastern Sichuan Basin is a typical carbonate karst reservoir. At the end of the Middle Permian, a short-term tectonic uplift (Tungwu movement) occurred in the upper Yangtze region, causing the formation of dissolved fissures and holes. To determine the location of the high-quality reservoir, this paper calculated the eroded thickness using the Milankovitch theory. Based on the gamma logging data of the six wells in the southeastern Sichuan Basin, the dominant frequency and the astronomical time scale were evaluated via frequency spectrum analysis, continuous wavelet transform, and empirical mode decomposition. In addition, we analyzed the relationship between Fischer curve characteristics and the variation of lithology. Last, four methods were used to calculate the eroded thickness, and the rationality was analyzed. Consequently, we identified four levels of Milankovitch cycles, i.e., middle eccentricity (e2), short eccentricity (e3), long obliquity (o1), and short obliquity (o2). Also, the Fischer curves of the six wells were divided into two forms related to local structural uplift. The residual strata of the Maokou Formation comprised three complete third-order cycles, and the boundaries were the 15th, 34th, and 54th e3 cycles. The deposition rate of bioclastic limestone was the lowest (2.12-5.36 cm/ka with an average of 3.30 cm/ka), whereas the deposition rate of argillaceous limestone was the largest (2.27-5.25 cm/ka with an average of 4.09 cm/ka). Among the four methods, the missing formation deposition rate method exhibited the most precise calculation results, while that of the seismic data method was relatively low. Generally, the eroded thickness of the Maokou Formation in southeastern Sichuan was in the range of 0-140 m, i.e., the eroded thickness in the west and south of X14 was relatively large (>100 m), while the area north of LS1 experienced the weakest denudation (eroded thickness < 40 m).

Artificial intelligence in global ophthalmology: using machine learning to improve cataract surgery outcomes at Ethiopian outreaches.

Differences between target and implanted intraocular lens (IOL) power in Ethiopian cataract outreach campaigns were evaluated, and machine learning (ML) was applied to optimize the IOL inventory and minimize avoidable refractive error. Patients from Ethiopian cataract campaigns with available target and implanted IOL records were identified, and the diopter difference between the two was measured. Gradient descent (an ML algorithm) was used to generate an optimal IOL inventory, and we measured the models performance across varying surplus levels. Only 45.6% of patients received their target IOL power and 23.6% received underpowered IOLs with current inventory (50% surplus). The ML-generated IOL inventory ensured that more than 99.5% of patients received their target IOL when using only 39% IOL surplus. In Ethiopian cataract campaigns, most patients have avoidable postoperative refractive error secondary to suboptimal IOL inventory. Optimizing the IOL inventory using this ML model might eliminate refractive error from insufficient inventory and reduce costs.

Impact of proton radiotherapy on treatment timing in pediatric and adult patients with CNS tumors.

BACKGROUND: Despite putative benefits associated with proton radiotherapy in the setting of CNS tumors, numerous barriers limit treatment accessibility. Given these challenges, we explored the association of proton use with variations in treatment timing. METHODS: Pediatric and adult patients with histologically confirmed CNS tumors were identified from the National Cancer Database (2004-2015). Univariable and multivariable regression models were constructed to assess factors impacting radiation timing. Multivariable Cox regression was used to evaluate the effect of treatment delay on survival. RESULTS: A total of 76 157 patients received photon or proton radiotherapy. Compared to photons, time to proton administration was longer in multiple pediatric (embryonal, ependymal, nonependymal glial, and other) and adult (ependymal, nonependymal glial, meningeal, other) tumor histologies. On adjusted analysis, proton radiotherapy was associated with longer delays in radiotherapy administration in pediatric embryonal tumors (+3.00 weeks, P = .024) and in all adult tumors (embryonal [+1.36 weeks, P = .018], ependymal [+3.15 weeks, P < .001], germ cell [+2.65 weeks, P = .024], glial [+2.15 weeks, P < .001], meningeal [+5.05 weeks, P < .001], and other [+3.06 weeks, P < .001]). In patients with high-risk tumors receiving protons, delays in adjuvant radiotherapy were independently associated with poorer survival (continuous [weeks], adjusted hazard ratio = 1.09, 95% CI = 1.02-1.16). CONCLUSIONS: Proton radiotherapy is associated with later radiation initiation in pediatric and adult patients with CNS tumors. In patients with high-risk CNS malignancies receiving protons, delayed adjuvant radiotherapy is associated with poorer survival. Further studies are needed to understand this discrepancy to maximize the potential of proton radiotherapy for CNS malignancies.

Responsive polymeric Janus cage.

A robust thermo-responsive polymeric Janus cage with a PNIPAM-cPVBC-PEO sandwiched shell is synthesized. The Janus cage provides a general method of thermally triggered separation of oil/water emulsions independent of the type of surfactant and emulsion. It can selectively capture organic compounds at a higher temperature and release them at a lower temperature.

Stereotactic Radiosurgery for Resected Brain Metastases: Does the Surgical Corridor Need to be Targeted?

PURPOSE: Although consensus guidelines for postresection stereotactic radiosurgery (SRS) for brain metastases recommend the surgical corridor leading to the resection cavity be included in the SRS plan, no study has reported patterns of tumor recurrence based on inclusion or exclusion of the corridor as a target. We reviewed tumor control and toxicity outcomes of postresection SRS for deep brain metastases based on whether or not the surgical corridor was targeted. MATERIALS AND METHODS: We retrospectively reviewed patients who had resected brain metastases treated with SRS between 2007 and 2018 and included only "deep" tumors (defined as located ≥1.0 cm from the pial surface before resection). RESULTS: In 66 deep brain metastases in 64 patients, the surgical corridor was targeted in 43 (65%). There were no statistical differences in the cumulative incidences of progression at 12 months for targeting versus not targeting the corridor, respectively, for overall local failure 2% (95% confidence interval [CI], 0%-11%) versus 9% (95% CI, 1%-25%; P = .25), corridor failure 0% (95% CI, 0%-0%) versus 9% (95% CI, 1%-25%; P = .06), cavity failure 2% (95% CI, 0%-11%) versus 0% (95% CI, 0%-0%; P = .91), and adverse radiation effect 5% (95% CI, 1%-15%) versus 13% (95% CI, 3%-30%; P = .22). Leptomeningeal disease (7%; 95% CI, 2%-18%) versus 26% (95% CI, 10%-45%; P = .03) was higher in those without the corridor targeted. CONCLUSIONS: Omitting the surgical corridor in postoperative SRS for resected brain metastases was not associated with statistically significant differences in corridor or cavity recurrence or adverse radiation effect. As seen in recent prospective trials of postresection SRS, the dominant pattern of progression is within the resection cavity; omission of the corridor would yield a smaller SRS volume that could allow for dose escalation to potentially improve local cavity control.

Neurological adverse effects due to programmed death 1 (PD-1) inhibitors.

PURPOSE: PD-1 Immunotherapy is integral in treating multiple cancers, but has been associated with neurological adverse events (nAEs). Our study was aimed at identifying the clinical spectrum of nAEs associated with pembrolizumab and nivolumab. METHODS: We performed an IRB approved single-center retrospective cohort study on patients receiving either pembrolizumab or nivolumab. Patients that developed nAEs within 12 months of treatment were identified. Descriptive statistics were conducted, and differences between groups were analyzed by the Chi-square or t test method. RESULTS: In total, 649 patients were identified. Seventeen patients (2.6%) developed nAEs. Eight of those were on pembrolizumab and nine were on nivolumab. Average age was 62.1 years. Ten were males and 7 were females. Most patients had melanoma (6, 35.3%). Patients who developed nAEs more frequently had intracranial lesions at initiation of anti PD-1 therapy compared to those who did not develop nAEs (76.5% vs 27.8%; p-value < 0.001). Fifteen patients (88.2%) permanently stopped PD-1 therapy. In 8 patients, treatment termination resolved symptoms attributed to immune checkpoint blockade. The majority of patients developed grade 3 or 4 nAEs (10 patients, 58.8%), and required hospitalization (11 patients, 64.7%). Eight patients died for nAEs referable causes. CONCLUSION: Pembrolizumab and nivolumab are associated with the development of nAEs associated with increased risk of permanent discontinuation of treatment, hospitalization, and death. Melanoma patients might be at a particularly high risk of such side effects. Future studies are still required to better assess which patients benefit most from such therapies, while minimizing the risk of complications.

Evaluating Surgical Resection Extent and Adjuvant Therapy in the Management of Gliosarcoma.

Introduction: Gliosarcomas are clinically aggressive tumors, histologically distinct from glioblastoma. Data regarding the impact of extent of resection and post-operative adjuvant therapy on gliosarcoma outcomes are limited. Methods: Patients with histologically confirmed gliosarcoma diagnosed between 1999 and 2019 were identified. Clinical, molecular, and radiographic data were assembled based on historical records. Comparisons of categorical variables used Pearson's Chi-square and Fisher's exact test while continuous values were compared using the Wilcoxon signed-rank test. Survival comparisons were assessed using Kaplan-Meier statistics and Cox regressions. Results: Seventy-one gliosarcoma patients were identified. Secondary gliosarcoma was not associated with worse survival when compared to recurrent primary gliosarcoma (median survival 9.8 [3.8 to 21.0] months vs. 7.6 [1.0 to 35.7], p = 0.7493). On multivariable analysis, receipt of temozolomide (HR = 0.02, 95% CI 0.001-0.21) and achievement of gross total resection (GTR; HR = 0.13, 95% CI 0.02-0.77) were independently prognostic for improved progression-free survival (PFS) while only receipt of temozolomide was independently associated with extended overall survival (OS) (HR = 0.03, 95% CI 0.001-0.89). In patients receiving surgical resection followed by radiotherapy and concomitant temozolomide, achievement of GTR was significantly associated with improved PFS (median 32.97 [7.1-79.6] months vs. 5.45 [1.8-26.3], p = 0.0092) and OS (median 56.73 months [7.8-104.5] vs. 14.83 [3.8 to 29.1], p = 0.0252). Conclusion: Multimodal therapy is associated with improved survival in gliosarcoma. Even in patients receiving aggressive post-operative multimodal management, total surgical removal of macroscopic disease remains important for optimal outcomes.

Evolving role of biomaterials in diagnostic and therapeutic radiation oncology.

Radiation therapy to treat cancer has evolved significantly since the discovery of x-rays. Yet, radiation therapy still has room for improvement in reducing side effects and improving control of cancer. Safer and more effective delivery of radiation has led us to novel techniques and use of biomaterials. Biomaterials in combination with radiation and chemotherapy have started to appear in pre-clinical explorations and clinical applications, with many more on the horizon. Biomaterials have revolutionized the field of diagnostic imaging, and now are being cultivated into the field of theranostics, combination therapy, and tissue protection. This review summarizes recent development of biomaterials in radiation therapy in several application areas.

Tyrosine Kinase Inhibitor Resistance Increased the Risk of Cerebral Radiation Necrosis After Stereotactic Radiosurgery in Brain Metastases of Non-small-Cell Lung Cancer: A Multi-Institutional Retrospective Case-Control Study.

Objective: This study aimed to investigate the relationship between the timing of stereotactic radiosurgery (SRS) intervention and the complications of cerebral radiation necrosis (CRN) in patients with brain metastases of lung adenocarcinoma who received tyrosine kinase inhibitor (TKI) treatment. Methods: A total of 361 targets from 257 patients with brain oligometastases of lung adenocarcinoma who received CyberKnife treatment between 2010 and 2017 were retrospectively collected from three CyberKnife centers. The difference in brain necrosis between patients with or without TKI application was statistically counted. Logistic regression analysis was used to analyze the effect of applying TKI on the occurrence of CRN in patients and the effect of SRS before and after TKI resistance on CRN. Results: The rate of CRN in the TKI group was significantly higher than that in the non-TKI group. The incidence of brain necrosis in patients undergoing SRS after drug resistance was significantly higher than that in patients undergoing SRS before drug resistance. Regression analysis showed that combination of TKI with SRS, and SRS after TKI resistance were important influencing factors for CRN. Conclusion: Performing the SRS for brain metastases after TKI resistance worsened the occurrence of CRN of patients treated with TKI. Clinical Trial Registration: Chinese clinical trial registry, http://www.chictr.org.cn/edit.aspx?pid=38395&htm=4, Registration number: ChiCTR1900022750.

Patterns of Care and Age-Specific Impact of Extent of Resection and Adjuvant Radiotherapy in Pediatric Pineoblastoma.

BACKGROUND: Pediatric pineoblastomas are highly aggressive tumors that portend poor outcomes despite multimodal management. Controversy remains regarding optimal disease management. OBJECTIVE: To evaluate patterns of care and optimal clinical management of pediatric pineoblastoma. METHODS: A total of 211 pediatric (age 0-17 yr) histologically confirmed pineoblastoma patients diagnosed between 2004 and 2015 were queried from the National Cancer Database. Wilcoxon rank-sum statistics and chi-squared analyses were used to compare continuous and categorical variables, respectively. Univariable and multivariable Cox regressions were used to evaluate prognostic impact of covariates. Propensity-score matching was used to balance baseline characteristics. RESULTS: Older patients (age ≥ 4 yr) experienced improved overall survival compared to younger patients (age < 4 yr) (hazard ratio [HR] = 0.41; 95% CI 0.25-0.66). Older patients (adjusted odds ratio [aOR] = 5.21; 95% CI 2.61-10.78) and those residing in high-income regions (aOR = 3.16; 95% CI 1.21-8.61) received radiotherapy more frequently. Radiotherapy was independently associated with improved survival in older (adjusted HR [aHR] = 0.31; 95% CI 0.12-0.87) but not younger (aHR = 0.64; 95% CI 0.20-1.90) patients. The benefits of radiotherapy were more pronounced in patients receiving surgery than in those not receiving surgery (aHR [surgical patients] = 0.23; 95% CI 0.08-0.65; aHR [nonsurgical patients] = 0.46; 95% CI 0.22-0.97). Older patients experienced improved outcomes associated with aggressive resection (P = .041); extent of resection was not associated with survival in younger patients (P = .880). CONCLUSION: Aggressive tumor resection was associated with improved survival only in older pediatric patients. Radiotherapy was more effective in patients receiving surgery. Age-stratified approaches might allow for improved disease management of pediatric pineoblastoma.

Stereotactic Radiosurgery for Resected Brain Metastases: Single-Institutional Experience of Over 500 Cavities.

PURPOSE: Postoperative stereotactic radiosurgery (SRS) has less detrimental effect on cognition and quality of life compared with whole brain radiation therapy (WBRT) and is increasingly used for resected brain metastases (BMs). Postoperative SRS techniques are not standardized, and there is a concern for a different pattern of failure after postoperative SRS compared with WBRT. We aim to study the efficacy, toxicity, and failure pattern of postoperative SRS. METHODS AND MATERIALS: We retrospectively reviewed outcomes of patients with resected BMs treated with postoperative SRS between 2007 and 2018. Overall survival and cumulative incidences of local failure, overall distant intracranial failure (distant parenchymal failure, nodular leptomeningeal disease [nLMD], classical leptomeningeal disease [cLMD]), and adverse radiation effect were reported. Neurologic death was determined for patients with leptomeningeal disease (LMD). RESULTS: A total of 442 patients with 501 resected BMs were treated over 475 total SRS courses. Median clinical follow-up and overall survival after SRS were 10.1 months (interquartile range, 3.6-20.7 months) and 13.9 months (95% confidence interval [CI], 11.8-15.2 months), respectively. At 12 months, event rates were 7% (95% CI, 5%-10%) for local failure, 9% (95% CI, 7%-12%) for adverse radiation effect, 44% (95% CI, 40%-49%) for overall distant intracranial failure, 37% (95% CI, 33%-42%) for distant parenchymal failure, and 13% (95% CI, 10%-17%) for LMD. The overall incidence of LMD was 15.8% (53% cLMD, 46% nLMD). cLMD was associated with shorter survival than nLMD (2.0 vs 11.2 months, P < .01) and a higher proportion of neurologic death (67% vs 41%, P = .02). A total of 15% of patients ultimately received WBRT. CONCLUSIONS: We report the largest clinical experience of postoperative SRS for resected BMs, showing excellent local control and low toxicity. Intracranial failure was predominantly distant, with a rising incidence of LMD.

Stereotactic Radiosurgery for Pediatric and Adult Intracranial and Spinal Ependymomas.

OBJECTIVE/BACKGROUND: We report efficacy and toxicity outcomes with stereotactic radiosurgery (SRS) for intracranial and spinal ependymoma. METHODS: We analyzed adult and pediatric patients with newly diagnosed or recurrent intracranial or spinal ependymoma lesions treated with SRS at our institution. Following SRS, local failure (LF) was defined as failure within or adjacent to the SRS target volume, while distant failure (DF) was defined as failure outside of the SRS target volume. Time to LF and DF was analyzed using competing risk analysis with death as a competing risk.Overall survival (OS) was calculated from the date of first SRS to the date of death or censored at the date of last follow-up using the Kaplan-Meier method. RESULTS: Twenty-one patients underwent SRS to 40 intracranial (n = 30) or spinal (n = 10) ependymoma lesions between 2007 and 2018, most commonly with 18 or 20 Gy in 1 fraction. Median follow-up for all patients after first SRS treatment was 54 months (range 2-157). The 1-year, 2-year, and 5-year rates of survival among patients with initial intracranial ependymoma were 86, 74, and 52%, respectively. The 2-year cumulative incidences of LF and DF after SRS among intracranial ependymoma patients were 25% (95% CI 11-43) and 42% (95% CI 22-60), respectively. No spinal ependymoma patient experienced LF, DF, or death within 2 years of SRS. Three patients had adverse radiation effects. CONCLUSIONS: SRS is a viable treatment option for intracranial and spinal ependymoma with excellent local control and acceptable toxicity.

Ultra-Low-Dose Bevacizumab For Cerebral Radiation Necrosis: A Prospective Phase II Clinical Study.

OBJECTIVE: To investigate the treatment efficacy of ultra-low-dose bevacizumab for cerebral radiation necrosis. METHODS: Patients with cerebral radiation necrosis after stereotactic radiotherapy (SRT) confirmed by imaging were included. Bevacizumab (1 mg/kg, once every three weeks, for at least three continuous treatments) was administered. The primary endpoints included change in cerebral necrosis symptoms, volume of intracranial edema, and changes in MRI signals. The secondary endpoints were adverse reactions of bevacizumab treatment. RESULTS: In total, 21 patients were included in this study, all of whom received SRT between December 2016 and February 2019, developed cerebral radiation necrosis, and were treated with bevacizumab. Twenty patients were symptomatic from radiation necrosis, and the symptoms were alleviated in 18 patients (90%). Twenty patients had intracranial edema, and the grade of edema index (EI) was improved in 19 patients (95%). The intensity of the intracranial-enhanced MRI signals was significantly reduced in 20 patients (95.24%). The adverse reactions of bevacizumab treatment were mild, and no adverse reactions more severe than grade 2 were found. CONCLUSION: The preliminary results showed that ultra-low-dose bevacizumab had high efficacy for treating cerebral radiation necrosis, and could be a valid alternative to the standard-dose bevacizumab. CLINICAL REGISTRY: Chinese clinical trial registry (ChiCTR-IOD-16009803).

Increase of secondary mutations may be a drug-resistance mechanism for lung adenocarcinoma after radiation therapy combined with tyrosine kinase inhibitor.

Objective: To investigate changes in the secondary mutations of tumor in a drug-resistance mechanism for lung adenocarcinoma after radiation therapy combined with tyrosine kinase inhibitor (TKI). Methods: Lung adenocarcinoma cell line PC9 in vitro and xenograft model in nude mice were used to observe tumor inhibitory effects and drug-resistance under the effect of radiation therapy combined with erlotinib through apoptosis detection through in vitro survival curve and in vivo growth curve; changes in gene mutations before and after drug-resistance in nude mice xenografts were observed by the next generation sequencing, and the relationship between cancer drug-resistance and radiation therapy combined with TKI was observed. Results: Radiation therapy combined with erlotinib had a more reliable radio-sensitizing effect in vitro and in vivo, however, there were several drug-resistant tumor cells. Meanwhile, radiation therapy combined with erlotinib could significantly increase the number of mutations in tumor genes. The whole genome sequencing showed that the secondary mutation in the combined treatment group significantly increased in comparison with those of the single treatment group and the blank control group. Conclusion: The increase of secondary mutations may be an important drug-resistance mechanism for lung adenocarcinoma after radiation therapy combined with TKI, which provided further space exploration under the combined action of radiation and TKI.