Bevacizumab for radiation necrosis following radiotherapy of brain metastatic disease: a systematic review & meta-analysis.

BACKGROUND: Radiotherapy is the mainstay of brain metastasis (BM) management. Radiation necrosis (RN) is a serious complication of radiotherapy. Bevacizumab (BV), an anti-vascular endothelial growth factor monoclonal antibody, has been increasingly used for RN treatment. We systematically reviewed the medical literature for studies reporting the efficacy and safety of bevacizumab for treatment of RN in BM patients. MATERIALS AND METHODS: PubMed, Medline, EMBASE, and Cochrane library were searched with various search keywords such as "bevacizumab" OR "anti-VEGF monoclonal antibody" AND "radiation necrosis" OR "radiation-induced brain necrosis" OR "RN" OR "RBN" AND "Brain metastases" OR "BM" until 1st Aug 2020. Studies reporting the efficacy and safety of BV treatment for BM patients with RN were retrieved. Study selection and data extraction were carried out by independent investigators. Open Meta Analyst software was used as a random effects model for meta-analysis to obtain mean reduction rates. RESULTS: Two prospective, seven retrospective, and three case report studies involving 89 patients with RN treated with BV were included in this systematic review and meta-analysis. In total, 83 (93%) patients had a recorded radiographic response to BV therapy, and six (6.7%) had experienced progressive disease. Seven studies (n = 73) reported mean volume reductions on gadolinium-enhanced T1 (mean: 47.03%, +/- 24.4) and T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI images (mean: 61.9%, +/- 23.3). Pooling together the T1 and T2 MRI reduction rates by random effects model revealed a mean of 48.58 (95% CI: 38.32-58.85) for T1 reduction rate and 62.017 (95% CI: 52.235-71.799) for T2W imaging studies. Eighty-five patients presented with neurological symptoms. After BV treatment, nine (10%) had stable symptoms, 39 (48%) had improved, and 34 (40%) patients had complete resolution of their symptoms. Individual patient data was available for 54 patients. Dexamethasone discontinuation or reduction in dosage was observed in 30 (97%) of 31 patients who had recorded dosage before and after BV treatment. Side effects were mild. CONCLUSIONS: Bevacizumab presents a promising treatment strategy for patients with RN and brain metastatic disease. Radiographic response and clinical improvement was observed without any serious adverse events. Further class I evidence would be required to establish a bevacizumab recommendation in this group of patients.

Can Prognostic Nutritional Index be a Prediction Factor in Esophageal Cancer?: A Meta-Analysis.

Objective: Prognostic nutritional index (PNI) can be used for survival predication in patients with esophageal cancer (EC). However, the prognostic value of PNI in EC is inconclusive in accordance to the literature. This meta-analysis aimed to evaluate the prediction value of PNI in EC.Methods: Studies focus on the association of PNI and EC were retrieved from the electronic databases. Standard meta-analysis methods were used for data evaluation.Results: Our search yield 12 studies, involving 3118 patients with EC for data analysis. The pooled data suggested that low PNI was correlated with worse overall survival (hazard ratio (HR) = 1.29, 95% confidence interval (CI):1.11-1.50, P = 0.001) and cancer-specific survival (HR = 2.18, 95% CI: 1.68-2.83, P < 0.0001). Moreover, lower PNI was associated with unfavorable prognostic factors (the presence of lymph node metastasis, deeper tumor invasion and advanced TNM stages).Conclusion: The lower PNI was correlated with unfavorable prognostic factor and poor prognosis in patients with EC.

Comparative analysis of robotic gastrectomy and laparoscopic gastrectomy for gastric cancer in terms of their long-term oncological outcomes: a meta-analysis of 3410 gastric cancer patients.

BACKGROUND: Data regarding the long-term oncological outcomes of robotic gastrectomy (RG) are limited despite the increased commonality of this method as an alternative for gastric cancer treatment. Here, we conducted a meta-analysis to evaluate the long-term oncological outcomes of RG in comparison to that of laparoscopic gastrectomy (LG). METHODS: The PubMed, ISI Web of Science, EMBASE, and Cochrane Library databases were comprehensively searched for studies that compared RG and LG in terms of their long-term survival outcomes. The hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS), and relapse-free survival (RFS) were obtained, while the odds ratio (OR) was recorded for the recurrence rate. A sensitivity analysis was performed. Egger's test and Begg's test were applied to evaluate publication bias. RESULTS: Eight studies were identified and involved 3410 gastric cancer patients (RG, 1009; LG, 2401). The two groups had no significant differences in OS (HR, 0.98; 95% CI, 0.80-1.20; P = 0.81), DFS (HR, 1.36; 95% CI, 0.33-5.59; P = 0.67), RFS (HR, 0.92; 95% CI, 0.72-1.19; P = 0.53), or recurrence rate (OR, 0.92; 95% CI, 0.71-1.19; P = 0.53). Moreover, the two techniques were comparable in length of hospital stay (LOS), postoperative complication rate, 30-day mortality rate, and rate of conversion to open surgery. CONCLUSIONS: The long-term oncological outcomes, expressed as OS, DFS, RFS, and recurrence rate, were similar between RG and LG. However, more randomized controlled trials with rigorous study designs and patient cohorts are needed to evaluate the oncologic outcomes of RG in patients with gastric cancer.

Comparison of WBRT alone, SRS alone, and their combination in the treatment of one or more brain metastases: Review and meta-analysis.

Whole brain radiotherapy has been a standard treatment of brain metastases. Stereotactic radiosurgery provides more focal and aggressive radiation and normal tissue sparing but worse local and distant control. This meta-analysis was performed to assess and compare the effectiveness of whole brain radiotherapy alone, stereotactic radiosurgery alone, and their combination in the treatment of brain metastases based on randomized controlled trial studies. Electronic databases (PubMed, MEDLINE, Embase, and Cochrane Library) were searched to identify randomized controlled trial studies that compared treatment outcome of whole brain radiotherapy and stereotactic radiosurgery. This meta-analysis was performed using the Review Manager (RevMan) software (version 5.2) that is provided by the Cochrane Collaboration. The data used were hazard ratios with 95% confidence intervals calculated for time-to-event data extracted from survival curves and local tumor control rate curves. Odds ratio with 95% confidence intervals were calculated for dichotomous data, while mean differences with 95% confidence intervals were calculated for continuous data. Fixed-effects or random-effects models were adopted according to heterogeneity. Five studies (n = 763) were included in this meta-analysis meeting the inclusion criteria. All the included studies were randomized controlled trials. The sample size ranged from 27 to 331. In total 202 (26%) patients with whole brain radiotherapy alone, 196 (26%) patients receiving stereotactic radiosurgery alone, and 365 (48%) patients were in whole brain radiotherapy plus stereotactic radiosurgery group. No significant survival benefit was observed for any treatment approach; hazard ratio was 1.19 (95% confidence interval: 0.96-1.43, p = 0.12) based on three randomized controlled trials for whole brain radiotherapy only compared to whole brain radiotherapy plus stereotactic radiosurgery and hazard ratio was 1.03 (95% confidence interval: 0.82-1.29, p = 0.81) for stereotactic radiosurgery only compared to combined approach. Local control was best achieved when whole brain radiotherapy was combined with stereotactic radiosurgery. Hazard ratio 2.05 (95% confidence interval: 1.36-3.09, p = 0.0006) and hazard ratio 1.84 (95% confidence interval: 1.26-2.70, p = 0.002) were obtained from comparing whole brain radiotherapy only and stereotactic radiosurgery only to whole brain radiotherapy + stereotactic radiosurgery, respectively. No difference in adverse events for treatment difference; odds ratio 1.16 (95% confidence interval: 0.77-1.76, p = 0.48) and odds ratio 0.92 (95% confidence interval: 0.59-1.42, p = 71) for whole brain radiotherapy + stereotactic radiosurgery versus whole brain radiotherapy only and whole brain radiotherapy + stereotactic radiosurgery versus stereotactic radiosurgery only, respectively. Adding stereotactic radiosurgery to whole brain radiotherapy provides better local control as compared to whole brain radiotherapy only and stereotactic radiosurgery only with no difference in radiation related toxicities.

MiR-451 increases radiosensitivity of nasopharyngeal carcinoma cells by targeting ras-related protein 14 (RAB14).

Radioresistance severely impedes the treatment of nasopharyngeal carcinoma (NPC). Recent evidence has shown that the abnormal expression of microRNAs (miRNAs) contributes to radiosensitivity. The aim of this study, therefore, was to investigate whether expression of the miRNAs correlated with radiosensitivity in the context of NPC. Quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to quantify miR-451 expression in two representative NPC cell lines. The role of miR-451 in NPC radiosensitivity was analyzed using a colony formation assay and an immunofluorescence assay with overexpression of miR-451 in NPC cells. Luciferase reporter assays, RT-PCR, and Western blot were performed to confirm the target of miR-451. High levels of miR-451 expression enhanced radiosensitivity in NPC cells by inhibiting the repair of irradiation-induced double-strand breaks (DSBs) and increasing apoptosis. The results also demonstrated that miR-451 directly targeted ras-related protein 14 (RAB14). Downregulation of RAB14 partially replicated the miR-451-mediated DSBs induced by ionizing radiation (IR). MiR-451 could be a potential target for enhancing radiosensitivity of NPC cells by targeting RAB14.

Robotic-assisted versus laparoscopic colorectal surgery: a meta-analysis of four randomized controlled trials.

BACKGROUND: Robotic-assisted laparoscopy is popularly performed for colorectal disease. The objective of this meta-analysis was to compare the safety and efficacy of robotic-assisted colorectal surgery (RCS) and laparoscopic colorectal surgery (LCS) for colorectal disease based on randomized controlled trial studies. METHODS: Literature searches of electronic databases (Pubmed, Web of Science, and Cochrane Library) were performed to identify randomized controlled trial studies that compared the clinical or oncologic outcomes of RCS and LCS. This meta-analysis was performed using the Review Manager (RevMan) software (version 5.2) that is provided by the Cochrane Collaboration. The data used were mean differences and odds ratios for continuous and dichotomous variables, respectively. Fixed-effects or random-effects models were adopted according to heterogeneity. RESULTS: Four randomized controlled trial studies were identified for this meta-analysis. In total, 110 patients underwent RCS, and 116 patients underwent LCS. The results revealed that estimated blood losses (EBLs), conversion rates and times to the recovery of bowel function were significantly reduced following RCS compared with LCS. There were no significant differences in complication rates, lengths of hospital stays, proximal margins, distal margins or harvested lymph nodes between the two techniques. CONCLUSIONS: RCS is a promising technique and is a safe and effective alternative to LCS for colorectal surgery. The advantages of RCS include reduced EBLs, lower conversion rates and shorter times to the recovery of bowel function. Further studies are required to define the financial effects of RCS and the effects of RCS on long-term oncologic outcomes.

Prediction of pathologic complete response to neoadjuvant chemoradiation in locally advanced rectal cancer.

Purpose: To investigate the predictive factors of pathologic complete response (pCR) in locally advanced rectal cancer (LARC) patients who had been treated with neoadjuvant chemoradiation (nCRT). Methods and materials: For this retrospective study, 53 LARC patients (37 males and 16 females; age range 25 to 79 years) were selected. Clinical characteristics, baseline mrTNM staging, MR gross tumor volumes (GTV), and pCR were evaluated. The diagnostic accuracy of GTV for predicting pCR was calculated. Results: Among 53 LARC patients, 15 patients achieved pCR (28.3%), while 38 patients achieved non-pCR. Only three (5.7%) out of 53 patients did not downstage after nCRT. GTV and tumor differentiation were the significant prognostic parameters for predicting pCR. A tumor volume threshold of 21.1 cm3 was determined as a predictor for pCR, with a sensitivity of 84% and specificity of 47%. In addition, GTV was associated with mrN stage, circumferential resection margin (CRM) status, extramural vascular invasion (EMVI) status, and pretreatment serum CEA level. Conclusion: Tumor volume and tumor differentiation have significant predictive values in preoperative assessment of pCR among LARC patients. These findings aid clinicians to discriminate those patients who may likely benefit from preoperative regimens and to make optimal treatment plans.

The predictive role of soluble programmed death ligand 1 in digestive system cancers.

Introduction: The prognostic role of soluble programmed death ligand 1 (sPD-L1) in digestive system cancers (DSCs) remains inconclusive. This study aimed to explore the predictive value of sPD-L1 expression in DSCs. Methods: Comprehensive searches were run on the electronic databases (PubMed, Web of Science, EMBASE, and the Cochrane Library) to identify studies that assessed the prognostic role of sPD-L1 in DSCs. Review Manager software (version 5.3) was used for all analyses. Pooled data for survival outcomes were measured as hazard ratios (HRs), 95% confidence intervals (CIs), and odds ratios and their 95% CIs. Results: The search identified 18 studies involving 2,070 patients with DSCs. The meta-outcome revealed that a high level of sPD-L1 was related to poorer overall survival (HR, 3.06; 95% CI: 2.22-4.22, p<0.001) and disease-free survival (HR, 2.53; 95% CI: 1.67-3.83, p<0.001) in DSCs. Individually, the prognostic significance of high level of sPD-L1 expression was the highest in hepatic cell carcinoma (HR, 4.76; p<0.001) followed by gastric cancer (HR=3.55, p<0.001). Conclusion: sPD-L1 may be a prognostic factor in DSCs for overall survival and disease-free survival. Inflammatory cytokines, treatment approaches, and other factors may affect the expression of sPD-L1. Therefore, the prognostic value of sPD-L1 for recurrence and metastasis should be further investigated. sPD-L1 may also predict response to treatment. Well-designed prospective studies with standard assessment methods should be conducted to determine the prognostic value of sPD-L1 in DSCs.

Case Report: Radiotherapy Plus Immunotherapy and Lenvatinib for the Treatment of Recurrent Hepatocellular Carcinoma With a Right Atrium and Inferior Vena Cava Tumor Thrombus.

Background: The treatment of hepatocellular carcinoma (HCC) with right atrium (RA) and inferior vena cava (IVC) tumor thrombi is challenging, with the standard treatment being not well established. Immunotherapy plus antiangiogenic therapy is a potentially effective treatment for patients with advanced HCC. Here, we described the case of a patient with HCC with RA and IVC tumor thrombi who achieved a successful response from radiotherapy and targeted therapy plus immunotherapy. Case Summary: A 62-year-old women presented with severe bilateral lower extremity edema identified as recurrent HCC with RA and IVC tumor thrombi based on past medical history and computed tomography. The patient received palliative radiotherapy plus pembrolizumab and lenvatinib treatment and was relieved of disease symptoms of bilateral lower extremity edema. The HCC with RA and IVC tumor thrombi shrunk, and the progression-free survival of this patient was > seven months. Conclusion: Tumor thrombus-directed radiotherapy plus concurrent immunotherapy and targeted therapy might be a feasible and safe approach for patients with HCC with RA and IVC tumor thrombi.

The effect of respiratory capacity for dose sparing in left-sided breast cancer irradiation with active breathing coordinator technique.

Background and aim: A subsequent cardiac toxicity is deemed to be dose-dependent for left-sided breast cancer irradiation. This study aims to demonstrate the effect of respiratory capacity for dose sparing when the deep inspiration breath hold with Active Breathing Coordinator technique (ABC-DIBH) is used in left-sided breast cancer irradiation. Methods: 74 left-sided breast cancer patients, who received whole breast or post-mastectomy chest wall radiotherapy with ABC-DIBH between 2020 and 2021 in our center, were retrospectively reviewed in this study. CT scans of free breath (FB) and ABC-DIBH were done for each patient, and two treatment plans with a prescription dose of 5000 cGy/25 Fr were designed separately. The dose to heart, left anterior descending artery (LAD) and lungs was compared between FB and ABC-DIBH. The correlation between individual parameters (dose to organs at risk (OARs) and minimum heart distance (MHD)) was analyzed, and the effect of respiratory capacity for dose sparing was assessed. Results: The plans with ABC-DIBH achieved lower Dmean for heart (34.80%, P < 0.01) and LAD (29.33%, P < 0.01) than those with FB. Regression analysis revealed that both Dmean and D2 of heart were negatively correlated with MHD in the plans with FB and ABC-DIBH, which decreased with the increase in MHD by 37.8 cGy and 309.9 cGy per 1mm, respectively. Besides, a lower Dmean of heart was related to a larger volume of ipsilateral lung in plans with FB. With the increase in volume of ipsilateral lung, the linear correlation was getting weaker and weaker until the volume of ipsilateral lung reached 1700 cc. Meanwhile, a negative linear correlation between Dmean of LAD and MHD in plans with FB and ABC-DIBH was observed, whose slope was 162.5 and 135.9 cGy/mm, respectively. Furthermore, when the respiratory capacity of ABC-DIBH reached 1L, and the relative ratio (ABC-DIBH/FB) reached 3.6, patients could obtain the benefit of dose sparing. The larger difference in respiratory capacity had no significant effect in the larger difference of MHD, Dmean of heart and Dmean of LAD between FB and ABC-DIBH. Conclusion: This study demonstrates the sufficiently good effect of ABC-DIBH when utilizing for cardiac sparing. It also reveals the correlations among individual parameters and the effect of respiratory capacity for dose sparing. This helps take optimal advantage of the ABC-DIBH technique and predict clinical benefits.

Impact of Previous Local Treatment for Brain Metastases on Response to Molecular Targeted Therapy in BRAF-Mutant Melanoma Brain Metastasis: A Systematic Review and Meta-Analysis.

Background: Melanoma brain metastases (BMs) are associated with poor prognosis and are the main cause of mortality in melanoma patients. BRAF inhibitors have shown intracranial activity in both treatment-naïve and previously treated BM patients. We aimed to investigate if there was any difference in response of BRAF inhibitors in these two cohorts. Materials and Methods: Electronic database search included PubMed, Medline, and Cochrane library until March 2021 for studies with desired comparative outcomes. Outcomes of interest that were obtained for meta-analysis included intracranial response rate as the primary outcome and survival and safety outcomes as the secondary outcomes. Review Manager version 5.4 was used for data analysis. Results: Three studies comprising 410 BRAF-mutated melanoma patients with BMs were included according to eligibility criteria. The comparative cohort included patients with treatment-naïve BMs (TN cohort; n = 255) and those who had progressive disease after receiving local brain treatment for BMs (PT cohort; n = 155). Meta-analysis revealed that BRAF inhibitors (vemurafenib and dabrafenib) and BRAF/MEK inhibitor combination (dabrafenib and trametinib) induced significantly higher intracranial disease control (OR 0.58 [95% CI: 0.34, 0.97], p = 0.04) and a trend toward improved progression-free survival (PFS) (HR 1.22 [95% CI: 0.98, 1.52], p = 0.08) in the PT cohort as compared to the TN cohort. Overall survival was not significantly different between the cohorts (HR 1.16 [95% CI: 0.89, 1.51], p = 0.28). Subgroup analysis revealed that PFS was significantly improved (HR 1.67 [95% CI: 1.06, 2.62], p = 0.03), and a trend toward improved OS (HR 1.62 [95% CI: 0.95, 2.75], p = 0.08) was achieved in patients receiving BRAF/MEK inhibitor combination and patients with BRAFv600K mutation receiving dabrafenib alone. No increase in overall adverse events (AEs), grade 3/4 AEs, and severe adverse events (SAEs) was observed between the cohorts. Conclusions: BRAF inhibitors (plus MEK inhibitor) may achieve better intracranial disease stability in BRAF-mutant melanoma patients who have received previous local treatment for BMs. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/), identifier CRD42020185984.

Anti-PD1 Therapy Plus Whole-Brain Radiation Therapy May Prolong PFS in Selected Non-Small Cell Lung Cancer Patients with Brain Metastases: A Retrospective Study.

BACKGROUND: Whole-brain radiotherapy (WBRT) remains an essential modality of treatment for brain metastases (BMs) derived from non-small cell lung cancer (NSCLC) patients and anti-PD-1 therapy has demonstrated intracranial responses in these patients. We aimed to evaluate if the combination of the two treatments could yield additive efficacy. METHODS: A retrospective review of our institution's database was carried out to identify NSCLC patients with BMs who had been treated with anti-PD1 therapy and/or WBRT between 2015 and 2020. Patient characteristics, main outcomes, including progression-free survival (PFS) and overall survival (OS), and factors affecting these outcomes were analyzed. SPSS 24 was used for statistical analysis. Appropriate statistical tests were employed according to the type of data. RESULTS: Overall, 21 NSCLC BM patients were identified that had received WBRT. Of these, ten had been additionally treated with anti-PD1 therapy within 30 days of WBRT initiation. Median PFS was 3 (95% CI 0.8-5.1) months with WBRT alone versus 11 (95% CI 6.3-15.6) months with combined treatment. Risk of disease progression was 71% lower with the combined approach (HR 0.29, 95% CI 0.11-0.80; p=0.016). A trend toward improved OS was also observed with the combined approach (HR 0.33, 95% CI 0.08-1.12; p=0.107). Concurrent treatment (p=0.028) and male sex (p=0.052) were associated with improved PFS, while OS was associated only with age (p=0.02). CONCLUSION: Concurrent WBRT and anti-PD1 therapy may delay progression and improve survival in BM patients with confirmed EGFR- and ALK-negative NSCLC histology. Prospective studies are warranted to validate and elucidate on the additive effect of the two modalities.

Bevacizumab Treatment of Radiation-Induced Brain Necrosis: A Systematic Review.

BACKGROUND: Radiation brain necrosis (RBN) is a serious complication in patients receiving radiotherapy for intracranial disease. Many studies have investigated the efficacy and safety of bevacizumab in patients with RBN. In the present study, we systematically reviewed the medical literature for studies reporting the efficacy and safety of bevacizumab, as well as for studies comparing bevacizumab with corticosteroids. MATERIALS AND METHODS: We searched PubMed, Cochrane library, EMBASE, and ClinicalTrials.gov from their inception through 1 March, 2020 for studies that evaluated the efficacy and safety of bevacizumab in patients with RBN. Two investigators independently performed the study selection, data extraction, and data synthesis. RESULTS: Overall, the present systematic review included 12 studies (eight retrospective, two prospective, and two randomized control trials [RCTs]) involving 236 patients with RBN treated who were treated with bevacizumab. The two RCTs also had control arms comprising patients with RBN who were treated with corticosteroids/placebo (n=57). Radiographic responses were recorded in 84.7% (200/236) of patients, and radiographic progression was observed in 15.3% (36/236). Clinical improvement was observed in 91% (n=127) of responding patients among seven studies (n=113). All 12 studies reported volume reduction on T1 gadolinium enhancement MRI (median: 50%, range: 26%-80%) and/or T2 FLAIR MRI images (median: 59%, range: 48%-74%). In total, 46 responding patients (34%) had recurrence. The two RCTs revealed significantly improved radiographic response in patients treated with bevacizumab (Levin et al.: p = 0.0013; Xu et al.: p < 0.001). Both also showed clinical improvement (Levin et al.: NA; Xu et al.: p = 0.039) and significant reduction in edema volume on both T1 gadolinium enhancement MRI (Levin et al.: p=0.0058; Xu et al.: p=0.027) and T2 FLAIR MRI (Levin et al.: p=0.0149; Xu et al.: p < 0.001). Neurocognitive improvement was significantly better after 2 months of treatment in patients receiving bevacizumab than in those given corticosteroids, as assessed by the MoCA scale (p = 0.028). The recurrence rate and side effects of the treatments showed no significant differences. CONCLUSIONS: Patients with RBN respond to bevacizumab, which can improve clinical outcomes and cognitive function. Bevacizumab appears to be more efficacious than corticosteroid-based treatment. The safety profile was comparable to that of the corticosteroids.

Efficacy and Safety of Actively Personalized Neoantigen Vaccination in the Management of Newly Diagnosed Glioblastoma: A Systematic Review.

PURPOSE: Glioblastoma (GBM) shows frequent relapse and is highly resistant to treatment; therefore, it is considered fatal. Various vaccination protocols that have been tested in patients with GBM, which is the most common and aggressive primary brain tumor, have indicated safety and efficacy, to some extent, when used alone or in combination with standard of care. Recently, neoantigen-based personalized vaccines have shown tremendous immunogenicity and safety in GBM. We aimed to systematically review the medical literature for clinical trials to evaluate the efficacy and safety of neoantigen-based personalized vaccines for newly diagnosed GBM. METHODS: We conducted a literature search for clinical trials on PubMed, Cochrane Library, China National Knowledge Infrastructure, and ClinicalTrials.gov until March 20, 2021. The primary outcomes of interest were immunogenicity and safety of the therapy. Efficacy outcomes, such as progression-free survival and overall survival, were secondary outcomes of interest. RESULTS: Two clinical trials involving 24 patients were included in this review. High immunogenicity was observed in both studies. The GAPVAC-101 trial reported 50% APVAC1-induced and 84.7% APVAC2-induced immunogenicity with CD8+ and CD4+ T cell responses in 92% (12/13) and 80% (8/10) immune responders, respectively. Two out of five patients showed CD4+ and CD8+ T cell responses in the study by Keskin et al. Dexamethasone use had limited immunogenicity in a trial by Keskin et al (6/8). No serious treatment-related adverse events were reported. CONCLUSION: Actively personalized vaccines aimed at unmutated peptides and neoantigens for patients with GBM are safe and highly immunogenic, particularly when administered in combination. Larger studies are warranted to investigate the role.

Radiation Plus Anti-PD-1 Therapy for NSCLC Brain Metastases: A Retrospective Study.

BACKGROUND: Radiation therapy (RT) is the mainstay of brain metastases (BMs), and anti-PD-1 blockade has led to intracranial responses in non-small cell lung carcinoma (NSCLC) patients with BMs. OBJECTIVE: This study aimed to evaluate the efficacy and safety of adding anti-PD-1 blockade to RT in the management of NSCLC patients with BM in terms of survival outcome. MATERIALS AND METHODS: We retrospectively reviewed 70 NSCLC patients with BMs who were treated with whole brain radiation therapy (WBRT) between January 2016 and January 2021. Of the 70 patients, 29 additionally received anti-PD-1 therapy within 30 days of WBRT initiation. Baseline characteristics of the patients and efficacy outcomes such as progression-free survival (PFS) and overall survival (OS) were statistically compared using SPSS v26. Results were obtained using the Chi-square test/Fisher exact test, t-test, Kaplan-Meier, and Cox regression survival analyses. RESULTS: The median survival for the entire cohort was 24 months (95% CI, 19.5-28.5). The median survival times for WBRT alone and WBRT plus anti-PD-1 therapy cohorts were 20 months (95% CI, 11.6-28.3) and 27 months (95% CI, 19.5-28.5), respectively (p=0.035). There was no statistical difference in PFS for the treatment cohorts (median PFS for WBRT alone: 7 months vs. 12 months for WBRT plus anti-PD-1, p=0.247). In EGFR wild-type subgroup (n=31), both PFS (p=0.037) and OS (p=0.012) were significantly improved. Only the treatment group (WBRT plus anti-PD-1) was a significant predictor of OS on univariate and multivariate analyses (p=0.040). There were no significant differences in adverse events among the treatment groups. CONCLUSIONS: NSCLC patients with BM receiving additional anti-PD-1 therapy may derive better OS than WBRT alone without any increase in adverse events. Prospective well-designed studies are warranted to validate and elucidate the additive effects of the two modalities in this group of patients.

Prognostic Role of Soluble Programmed Death Ligand 1 in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: The objective of this study was to explore whether soluble programmed death ligand 1 (sPD-L1) is a potential prognostic biomarker in patients with non-small cell lung cancer (NSCLC). METHODS: A comprehensive search of electronic databases was carried out. Original studies with inclusion of sPD-L1, progression-free survival, and overall survival in NSCLC were eligible. The primary endpoints were overall survival and progression-free survival. Hazard ratios (HRs) and 95% confidence intervals (CIs) were applied for data analysis. RESULTS: Eight studies involving 710 patients with NSCLC were included in the analysis. A pooled data analysis revealed that high levels of sPD-L1 were correlated with poorer overall survival (HR = 2.34; 95% CI = 1.82-3.00; P < 0.001) and progression-free survival (HR = 2.35; 95% CI = 1.62-3.40, P < 0.001). A subgroup analysis revealed that high levels of sPD-L1 were correlated with poor overall survival in patients treated with immunotherapy (HR = 2.40; 95% CI = 1.79-3.22; P < 0.001). CONCLUSION: This pooled analysis of published data suggests that sPD-L1 may serve as a readily available biomarker for survival in NSCLC patients treated with ICI based treatment. Prospective studies with well-designed standard assessment methods should be conducted to validate the prognostic role of sPD-L1 in NSCLC. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021283177.

Honokiol ameliorates radiation-induced brain injury via the activation of SIRT3.

OBJECTIVE: Sirtuin 3 (SIRT3) plays a vital role in regulating oxidative stress in tissue injury. The aim of this study was to evaluate the radioprotective effects of honokiol (HKL) in a zebrafish model of radiation-induced brain injury and in HT22 cells. METHODS: The levels of reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1ß) were evaluated in the zebrafish brain and HT22 cells. The expression levels of SIRT3 and cyclooxygenase-2 (COX-2) were measured using western blot assays and real-time polymerase chain reaction (RT-PCR). RESULTS: HKL treatment attenuated the levels of ROS, TNF-α, and IL-1ß in both the in vivo and in vitro models of irradiation injury. Furthermore, HKL treatment increased the expression of SIRT3 and decreased the expression of COX-2. The radioprotective effects of HKL were achieved via SIRT3 activation. CONCLUSIONS: HKL attenuated oxidative stress and pro-inflammatory responses in a SIRT3-dependent manner in radiation-induced brain injury.

Impact of Tyrosine Kinase Inhibitors (TKIs) Combined With Radiation Therapy for the Management of Brain Metastases From Renal Cell Carcinoma.

Background: Targeted therapy has transformed the outcome for patients with metastatic renal cell carcinoma. Their efficacy and safety have also been demonstrated in brain metastatic RCC. Preclinical evidence suggests synergism of radiation and tyrosine kinase inhibitors. Consequently, several studies have compared their efficacy in the treatment of RCC brain metastases to the era of brain management with surgery/radiation only. Objectives: We seek to systematically review and meta-analyze the results of those studies that involved comparative intervention groups of brain management; TKIs, and never used TKIs. Methods and Materials: Online databases (PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov) were searched for comparative studies. Overall survival as the primary outcome of interest, and local brain control, distant control, and adverse events as secondary outcomes of interest were recorded for meta-analysis. Hazard ratios were pooled together using Review Manager 5.3. Fixed effects or random effects model were adopted according to the level of heterogeneity. Subgroup analysis included studies that involved SRS as the local treatment of management. Results: Overall 7 studies (n = 897) were included for meta-analysis. TKI use was associated with better survival (HR 0.60 [0.52, 0.69], p < 0.00001) and local brain control (HR 0.34 [0.11, 0.98], p = 0.05). SRS subgroup also revealed significantly better survival (HR 0.61 [0.44, 0.83], p = 0.002) and local brain control (HR 0.19 [0.08, 0.45], p = 0.0002). Distant brain control (HR 0.95 [0.67, 1.35], p = 0.79) and brain progression free survival were unaffected (HR 0.94 [0.56, 1.56], p = 0.80). Only one study (n = 376) reported significantly greater 12-months cumulative incidence of radiation necrosis with TKI use within 30 days of SRS (10.9 vs. 6.4%, p = 0.04). Conclusions: TKIs use in combination with SRS is safe and effective for treating RCC brain metastases. Larger randomized controlled trials are warranted to validate the results.

Soluble PD-1: Predictive, Prognostic, and Therapeutic Value for Cancer Immunotherapy.

Programmed death protein 1 (PD-1) interaction with PD-L1 deliver immunosuppressive environment for tumor growth, and its blockade with directed monoclonal antibodies (anti-PD-1/anti-PD-L1) has shown remarkable clinical outcome. Lately, their soluble counterparts, sPD-1 and sPD-L1, have been detected in plasma, and elevated levels have been associated with advanced disease, clinical stages, and worst prognosis for cancer patients. Elevated plasma levels of sPD-L1 have been correlated with worst prognosis in several studies and has displayed a persistent outlook. On the other hand, sPD-1 levels have been inconsistent in their predictive and prognostic ability. Pretherapeutic higher sPD-1 plasma levels have shown to predict advanced disease state and to a lesser extent worst prognosis. Any increase in sPD-1 plasma level post therapeutically have been correlated with improved survival for various cancers. In vitro and in vivo studies have shown sPD-1 ability to bind PD-L1 and PD-L2 and block PD-1/PD-L1 interaction. Local delivery of sPD-1 in cancer tumor microenvironment through local gene therapy have demonstrated an increase in tumor specific CD8+ T cell immunity and tumor growth reduction. It had also exhibited enhancement of T cell immunity induced by vaccination and other gene therapeutic agents. Furthermore, it may also lessen the inhibitory effect of circulating sPD-L1 and enhance the effects of mAb-based immunotherapy. In this review, we highlight various aspects of sPD-1 role in cancer prediction, prognosis, and anti-cancer immunity, as well as, its therapeutic value for local gene therapy or systemic immunotherapy in blocking the PD-1 and PD-L1 checkpoint interactions.

Efficacy of BRAF Inhibitors in Combination With Stereotactic Radiosurgery for the Treatment of Melanoma Brain Metastases: A Systematic Review and Meta-Analysis.

BACKGROUND: BRAF inhibitors have improved the outcome for patients with BRAF mutant metastatic melanoma and have shown intracranial responses in melanoma brain metastases. Stereotactic radiosurgery (SRS) is being used as a local treatment for melanoma brain metastasis (MBM) with better local control and survival. We searched for studies comparing the combination of two treatments with SRS alone to detect any clinical evidence of synergism. MATERIALS AND METHODS: PubMed, EMBASE, Medline, and Cochrane library were searched until May 2020 for studies with desired comparative outcomes. Outcomes of interest that were obtained for meta-analysis included survival as the primary, and local control as the secondary outcome. RESULTS: A total of eight studies involving 976 patients with MBM were selected. Survival was significantly improved for patients receiving BRAF inhibitor plus SRS in comparison to SRS alone as assessed from the time of SRS induction (SRS survival: hazard ratio [HR] 0.67 [0.58-0.79], p <0.00001), from the time of brain metastasis diagnosis (BM survival: HR 0.65 [0.54, 0.78], p < 0.00001), or from the time of primary diagnosis (PD survival: HR 0.74 [0.57-0.95], p = 0.02). Dual therapy was also associated with improved local control, indicating an additive effect of the two treatments (HR 0.53 [0.31-0.93], p=0.03). Intracranial hemorrhage was higher in patients receiving BRAF inhibitors plus SRS than in those receiving SRS alone (OR, 3.16 [1.43-6.96], p = 0.004). CONCLUSIONS: BRAF inhibitors in conjunction with SRS as local treatment appear to be efficacious. Local brain control and survival improved in patients with MBM receiving dual therapy. Safety assessment would need to be elucidated further as the incidence of intracranial hemorrhage was increased.