Response Prediction to Concurrent Chemoradiotherapy in Esophageal Squamous Cell Carcinoma Using Delta-Radiomics Based on Sequential Whole-Tumor ADC Map.

Purpose: The purpose of this study was to investigate the association between the radiomics features (RFs) extracted from a whole-tumor ADC map during the early treatment course and response to concurrent chemoradiotherapy (cCRT) in patients with esophageal squamous cell carcinoma (ESCC). Methods: Patients with ESCC who received concurrent chemoradiotherapy were enrolled in two hospitals. Whole-tumor ADC values and RFs were extracted from sequential ADC maps before treatment, after the 5th radiation, and after the 10th radiation, and the changes of ADC values and RFs were calculated as the relative difference between different time points. RFs were selected and further imported to a support vector machine classifier for building a radiomics signature. Radiomics signatures were obtained from both RFs extracted from pretreatment images and three sets of delta-RFs. Prediction models for different responders based on clinical characteristics and radiomics signatures were built up with logistic regression. Results: Patients (n=76) from hospital 1 were randomly assigned to training (n=53) and internal testing set (n=23) in a ratio of 7 to 3. In addition, to further test the performance of the model, data from another institute (n=17) were assigned to the external testing set. Neither ADC values nor delta-ADC values were correlated with treatment response in the three sets. It showed a predictive effect to treatment response that the AUC values of the radiomics signature built from delta-RFs over the first 2 weeks were 0.824, 0.744, and 0.742 in the training, the internal testing, and the external testing set, respectively. Compared with the evaluated response, the performance of response prediction in the internal testing set was acceptable (p = 0.048). Conclusions: The ADC map-based delta-RFs during the early course of treatment were effective to predict the response to cCRT in patients with ESCC.

Adverse events of immunotherapy in non-small cell lung cancer: A systematic review and network meta-analysis.

BACKGROUND: Immune checkpoint inhibitors have yielded significant treatment progress in non-small cell lung cancer (NSCLC), while some special adverse events (AEs) named immune-related adverse events (irAEs) were observed in clinical trials. We aimed to systematically assess the incidences of AEs in immunotherapy of NSCLC. METHODS: We searched randomized controlled trials (RCTs) in PubMed/MEDLINE, Embase, Cochrane, and ClinicalTrail.gov before May 2021, and grouped arms into 10 treatment categories. We extracted AEs as serious (grade 3-5) or others (grade1-2) from all systems, and we pooled their incidences by random effects model. For arm-based pair-wise comparisons, we employed Bayesian network meta-analysis. Meta-regression was used to assess the contribution of coefficients. RESULTS: Totally 23,322 patients from 52 RCTs were included. The overall incidences of serious AEs were 37.0% in chemotherapy arm, 33.0% in PD1 arm, and 37.0% in PDL1 arm, while in combined groups it was 47.0% in PDL1_Chemo arm, 43.0% in PD1_CTLA4 arm, and 48.0% in ICI_Target arm. The incidence of each serious AE was less than 4% in monotherapy, and slightly higher in combined groups. In network meta-analysis, the immunotherapeutic groups presented a significant higher incidence rank in colitis, hepatobiliary disorders, pneumonitis, and rash compared with chemotherapy. There was a significantly positive correlation between the occurrence of serious hepatitis (p < 0.0001) and PFS in PDL1 arm, likewise serious pneumonitis (p = 0.0049) and rash (p < 0.0001) in PD1 arm. CONCLUSIONS: The overall incidences of AEs were similar in immune monotherapy compared with chemotherapy in NSCLC. Some irAEs were more common in immune therapy and their frequencies were positively associated with clinical efficacy.

Development and validation of a radiomics signature on differentially expressed features of 18F-FDG PET to predict treatment response of concurrent chemoradiotherapy in thoracic esophagus squamous cell carcinoma.

BACKGROUND AND PURPOSE: To investigate potential image markers for early prediction of treatment response on thoracic esophagus squamous cell carcinoma (ESCC) treated with concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: 159 thoracic ESCC patients enrolled from two institutions were divided into training and validation sets. A total of 944 radiomics features were extracted from pretreatment 18F-FDG PET images. We first performed the inter-observer reproducibility test in 10 pairs of patients (responders vs. nonresponders), and the limma package was used to identify differentially expressed features (DEFs). Then the least absolute shrinkage and selection operator (LASSO) logistic regression model with 10-fold cross-validation was used to construct a treatment response related radiomics signature. Finally, the performance was assessed in both sets with receiver operating characteristic (ROC) curves and Kaplan-Meier analysis. RESULTS: After the inter-observer test, 691 features were considered reproducible and been retained (ICC > 0.9). 61 DEFs were selected from limma and entered into the LASSO logistic regression model. The radiomics signature was significantly associated with treatment response in the training (p < 0.001) and validation set (p = 0.026), which achieved area under curve (AUC) values of 0.844 and 0.835, respectively. Delong test results of two ROCs showed no significant difference (p = 0.918). The cut-off value of the radiomics signature could successfully divide patients into high-risk and low-risk groups in both sets. CONCLUSION: This study indicated that the proposed radiomics signature could be a useful image marker to predict the therapeutic response of thoracic ESCC patients treated with CCRT.

MicroRNA-27a downregulates the expression of Hsp90 and enhances the radiosensitivity in esophageal squamous cell carcinoma.

PURPOSE: Accumulating evidence suggests that microRNAs (miRNAs) possess diverse cellular regulatory roles in radiation responses. In this study, we aimed to identify the role of miR-27a in esophageal squamous cell carcinoma (ESCC) radiosensitivity by exploring the relationship between miR-27a and heat shock protein 90 (Hsp90). MATERIALS AND METHODS: We performed quantitative real-time polymerase chain reaction (qRT-PCR) to detect miR-27a expression in the plasma of ESCC patients and healthy volunteers. The expression of Hsp90 and its key client proteins associated with radioresistance were analyzed by Western blotting. Then, the effects of miR-27a on proliferation, apoptosis, cell cycle and radiosensitivity in ESCC cell lines were determined by CCK-8, flow cytometry, and clonogenic survival assay. We also generated subcutaneous tumors to explore whether miR-27a enhanced radiosensitivity in vivo. RESULTS: In our current study, we found that miR-27a expression was downregulated in the plasma of ESCC patients compared with that of healthy volunteers. Overexpression of miR-27a in ESCC cell lines caused a reduction of Hsp90 mRNA and protein. We also demonstrated that upregulation of miR-27a induced degradation of Hsp90 key client proteins associated with radioresistance. In related functional experiments, miR-27a significantly inhibited growth, increased radiation-induced apoptosis, induced cell cycle arrest in G0/G1 phase and enhanced ESCC radiosensitivity both in vitro and in vivo. CONCLUSION: From these findings, we concluded that miR-27a may contribute to radiosensitivity by modulating Hsp90 expression. Moreover, miR-27a-based therapy utilized to target Hsp90 could be contemplated as a compelling alternative for sensitize ESCC to radiotherapy with fewer side effects.

Extracellular Hsp90α clinically correlates with tumor malignancy and promotes migration and invasion in esophageal squamous cell carcinoma.

PURPOSE: Extracellular Hsp90α (eHsp90α) is known to be involved in tumor invasiveness and metastasis, and its prognostic value in many kinds of tumors has been identified. We aimed to evaluate the clinical and functional role of eHsp90α in esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: A total of 193 patients with newly diagnosed ESCC were retrospectively evaluated. The relationship between serum Hsp90α levels before treatment and ESCC malignancy of the patients was analyzed. To test the role of eHsp90α in migration and invasion of ESCC cell lines, transwell assay was performed. Western blotting was used to explore the possible mechanism in which eHsp90α promotes ESCC migration and invasion. RESULTS: We found that the serum Hsp90α level before treatment is positively correlated with ESCC malignancy. Moreover, high serum Hsp90α level before treatment was significantly correlated with positive lymph node (LN) metastasis, which is the main prognostic factor for ESCC patients. Meanwhile, we demonstrated that eHsp90α promoted migration and invasion of ECA109 and ECA9706 in vitro. Further investigations revealed that eHsp90α stabilized MMP-2 and promoted epithelial-to-mesenchymal transition evidenced by downregulation of E-cadherin and upregulation of N-cadherin. On the other hand, Hsp90α neutralizing antibody functionally blocked the secreted Hsp90α and reversed those effects. CONCLUSION: Our findings prove the critical role of eHsp90α in promoting ESCC migration and invasion, indicating it can be not only a promising predictor for ESCC LN status, but also an effective target in ESCC therapeutics, especially in preventing LN metastasis.

Human papillomavirus infection increases the chemoradiation response of esophageal squamous cell carcinoma based on P53 mutation.

BACKGROUND AND PURPOSE: A retrospective study was carried out to analyze multiple prognostic predictors, including human papillomavirus (HPV) infection for chemoradiation treatment of esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: DNA extracted from a total of 192 patients treated with chemoradiation for locally advanced ESCC was examined to determine HPV status by polymerase chain reaction (PCR) and P53 gene mutation by genetic sequencing. The relationships between the chemoradiation response (CRR) and overall survival (OS) rate with HPV status and P53 gene mutation were analyzed. RESULTS: Thirty-two of the 108 patients with P53 mutated tumors were stained positive for HPV, while thirty-five of the 84 P53 wild-type tumors were HPV positive. P53 mutation and HPV infection were two independent events (p=0.083, Kappa=0.083). HPV infection increased the CRR (p=0.017) and 3-year OS (p=0.047) compared with the HPV negative group. This difference was more significant in the P53 mutation subgroup (CRR p=0.019; OS p=0.025). However, HPV infection led to no difference in the P53 wild-type subgroup (CRR p=0.802; OS p=0.468). The P53 mutation status was an independent prognostic factor (CRR p=0.034; OS p<0.001). Age was another significant prognostic factor for OS (p=0.001). CONCLUSIONS: Depending on P53 mutation status, HPV infection can contribute to a higher tumor response and better prognosis of ESCC treated with chemoradiation therapy.

The clinical significance of isocitrate dehydrogenase 2 in esophageal squamous cell carcinoma.

Isocitrate dehydrogenase 2 (IDH2) is the rate-limiting enzyme in the tricarboxylic acid (TCA) cycle in cellular metabolism. Growing evidence indicates that IDH2 plays a crucial role in the development of cancer. We aimed to investigate the expression level of IDH2 and its prognostic value in esophageal squamous cell cancer (ESCC). We evaluate the IDH2 expression and prognostic value in ESCC by immunohistochemical (IHC) staining, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The cell counting kit-8 (CCK8), clonogenic and invasion assays were performed to verify the IDH2 function in vitro. The protein expression level of IDH2 was significantly upregulated in ESCC tissues (IHC, Western blotting, all P<0.001) despite no significant difference at mRNA expression level (P>0.05). Kaplan-Meier analysis showed that IDH2 overexpression in ESCC patients was significantly related to worse overall survival (OS) and progression-free survival (PFS), P = 0.003 and 0.002, respectively. The univariate and multivariate analyses revealed that IDH2 overexpression served as an independent prognostic factor for OS and PFS (all P<0.005) in ESCC. The OD450 value, colony formation and invasive cell number were decreased in the shIDH2 groups (all P<0.0001). The upregulation of IDH2 in ESCC cells showed opposite effects (all P<0.05). Additionally, IDH2 knockdown phenotype can be rescued by shRNA-resistant IDH2 (all P<0.05). These results demonstrated that IDH2 was upregulated in ESCC and could be used as a valuable prognostic marker for ESCC patients.

Comparison of long-term survival between temozolomide-based chemoradiotherapy and radiotherapy alone for patients with low-grade gliomas after surgical resection.

PURPOSE: This study was designed to compare the survival outcomes of temozolomide-based chemoradiotherapy (TMZ + RT) vs radiotherapy alone (RT-alone) for low-grade gliomas (LGGs) after surgical resection. PATIENTS AND METHODS: In this retrospective analysis, we reviewed postoperative records of 69 patients with LGGs treated with TMZ + RT (n=31) and RT-alone (n=38) at the Shandong Cancer Hospital Affiliated to Shandong University between June 2011 and December 2013. Patients in the TMZ + RT group were administered 50-100 mg oral TMZ every day until the radiotherapy regimen was completed. RESULTS: The median follow-up since surgery was 33 months and showed no significant intergroup differences (P=0.06). There were statistically significant intergroup differences in the progression-free survival rate (P=0.037), with 83.9% for TMZ-RT group and 60.5% for RT-alone group. The overall 2-year overall survival (OS) rate was 89.86%. Age distribution (≥45 years and <45 years) and resection margin (complete resection or not) were significantly associated with OS (P=0.03 and P=0.004, respectively). CONCLUSION: Although no differences were found in the 2-year OS between the TMZ + RT and RT-alone groups, there was a trend toward increased 2-year progression-free survival in the TMZ + RT group. With better tolerability, concurrent TMZ chemoradiotherapy may be beneficial for postoperative patients with LGGs. Age distribution and surgical margin are likely potential indicators of disease prognosis. The possible differences in long-term survival between the two groups and the links between prognostic factors and long-term survival may be worthy of further investigation.

Intratumoral Heterogeneity of Subcutaneous Nodules in a Never-Smoker Woman of Lung Squamous Cell Carcinoma Detected on 18F-Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography: A Case Report.

Subcutaneous tissue is a rare site of metastasis, accounting for only 1-2% of all lung neoplasms. Positron emission tomography (PET) using ¹8F-fluorodeoxyglucose (FDG) has been reported to increase the diagnostic accuracy of subcutaneous metastasis. A 58-year-old woman presented with complaints of dry coughing, in which three positive subcutaneous nodules were found on ¹8F-FDG positron emission tomography and computed tomography (PET/CT). Pathologic examination confirmed that each of the nodules contained 1) necrotic fat, 2) small amounts of blood cells and glandular epithelium, and 3) subcutaneous metastasis of moderately differentiated lung squamous cell carcinoma, respectively. Although PET/CT is useful for the detection of subcutaneous metastasis of primary lung cancer, we noted heterogeneous accumulation of ¹8F-FDG in subcutaneous tumors. This case highlights the importance of obtaining histological confirmation of malignant diseases whenever possible.

Dinner-to-bed time and post-dinner walk: new potential independent factors in esophageal cancer development.

PURPOSE: Esophageal squamous cell carcinoma (ESCC) remains a significant cause of morbidity and mortality worldwide. The aim of the study was to investigate the effects of shorter dinner-to-bed time and post-dinner walk on ESCC risk. METHODS: A matched case-control study with 232 ESCC patients and 286 age- and gender-matched healthy controls enrolled was conducted. Conditional logistic regression was used to calculated odds ratio (OR) and 95 % confidence intervals (95 % CI). RESULTS: The adjusted ORs of ESCC for subjects with shorter dinner-to-bed time (<3 h) were 2.84 (95 % CI 1.64-4.29), relative to those with longer dinner-to-bed time (≥4 h). While post-dinner walk was associated with a decreased ESCC risk (adjusted OR 0.64; 95 % CI 0.41-0.89). What's more, when reflux symptom was added into the multivariate models, risk estimate for shorter dinner-to-bed time still remained statistically significant (p = 0.003), and risk estimate for post-dinner walk changed slightly. In the subgroup analysis stratified by post-dinner walk, subjects with shorter dinner-to-bed time experienced similar risk (adjusted ORs 2.71 vs. 2.82). CONCLUSIONS: Shorter dinner-to-bed time is a potential risk factor for ESCC and post-dinner walk is a protective factor, providing evidence for the effect of lifestyle factors on ESCC risk.