A Modified NAR Scoring Model Incorporating Immune Infiltration Characteristics to Better Predict Long-Term Survival Following Neoadjuvant Radiotherapy in Rectal Cancer.

(1) Background: The neoadjuvant rectal (NAR) score has been developed as a prognostic tool for survival in locally advanced rectal cancer (LARC). However, the NAR score only incorporates weighted cT, ypT, and ypN categories. This long-term follow-up study aims to modify a novel prognostic scoring model and identify a short-term endpoint for survival. (2) Methods: The prognostic factors for overall survival (OS) were explored through univariate and multivariate analyses. Based on Cox regression modeling, nomogram plots were constructed. Area under the curve (AUC) and concordance indices were used to evaluate the performance of the nomogram. Receiver operating characteristic (ROC) analysis was conducted to compare the efficiency of the nomogram with other prognostic factors. (3) Results: After a long-term follow-up, the 5-year OS was 67.1%. The mean NAR score was 20.4 ± 16.3. Multivariate analysis indicated that CD8+ T-cell, lymphovascular invasion, and the NAR score were independent predictors of OS. The modified NAR scoring model, incorporating immune infiltration characteristics, exhibited a high C-index of 0.739 for 5-year OS, significantly outperforming any individual factor. Moreover, the predictive value of the nomogram was superior to the AJCC stage and pathological complete regression at 3-year, 5-year, and 10-year time points, respectively. Over time, the model's predictions of long-term survival remained consistent and improved in accuracy. (4) Conclusions: The modified NAR scoring model, incorporating immune infiltration characteristics, demonstrates high accuracy and consistency in predicting OS.

Vinpocetine enhances cisplatin sensitivity of non-small cell lung cancer cells by reducing the nuclear factor erythroid 2-related factor 2 signaling.

Vinpocetine exerts pharmacological effects against cardiovascular diseases, while few studies focused on its roles in cancer. The present study investigated the roles of vinpocetine in non-small cell lung cancer (NSCLC) and its relationship with cisplatin resistance. A549 cisplatin-resistant cells (A549/DDP) and nuclear factor erythroid 2-related factor 2 (Nrf2)-overexpressing cell lines were established. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay was conducted to determine cell viability. Annexin V-propidium iodide assay was conducted to determine cell apoptosis. RT-quantitative PCR and western blot analysis were conducted to determine the levels of mRNA and protein, respectively. NSCLC cell tumor-bearing model was constructed to determine the effects of vinpocetine on tumor growth. Treatment with vinpocetine inhibited cell proliferation and promoted cisplatin-induced cell apoptosis. In addition, treatment with vinpocetine suppressed protein expression of Nrf2 and inhibited messenger RNA levels of heme oxygenase 1 and NAD(P)H dehydrogenase quinone 1 induced by cisplatin. Interestingly, the overexpression of Nrf2 abolished the antiproliferative effects of vinpocetine on NSCLC cells. In vivo data suggested that vinpocetine (50 mg/kg) inhibited tumor growth and enhanced the antitumor effects of cisplatin in the NSCLC cell tumor-bearing model. Vinpocetine enhances cisplatin sensitivity of NSCLC cells in part by suppressing Nrf2 signaling.

Knockdown of circ-RAD23B inhibits non-small cell lung cancer progression via the miR-142-3p/MAP4K3 axis.

BACKGROUND: The development of non-small cell lung cancer (NSCLC) is associated with the deregulation of circRNAs. The objective of this study was to investigate the effects of circ-RAD23B in NSCLC. METHODS: Circ-RAD23B expression, miR-142-3p and MAP4K3 was detected by qPCR. Cell proliferation was investigated by CCK-8 assay and colony formation assay. Cell migration and invasion were assessed by transwell assay. Angiogenesis ability was assessed by tube formation assay. Cell cycle distribution and cell apoptosis were monitored by flow cytometry. The predicted binding relationship between miR-142-3p and circ-RAD23B or MAP4K3 was verified by dual-luciferase reporter assay. The protein level of MAP4K3 was detected by western blot. Animal models were established to determine the role of circ-RAD23B in vivo. RESULTS: Circ-RAD23B was shown to be upregulated in NSCLC tissues and cells. Knockdown of circ-RAD23B inhibited proliferation, migration, invasion, angiogenesis and promoted cell cycle arrest and apoptosis in NSCLC cells, and circ-RAD23B knockdown also impeded tumor growth in vivo. Circ-RAD23B acted as miR-142-3p sponge to inhibit miR-142-3p expression and thus enrich the expression of MAP4K3, a target of miR-142-3p. Rescue experiments presented that miR-142-3p inhibition reversed the effects of circ-RAD23B knockdown, and MAP4K3 overexpression abolished the effects of miR-142-3p restoration. In addition, we found that circ-RAD23B knockdown led to decreased phosphorylation expression of ERK1/2, JNK and p38, three key groups of the MAPK signaling pathway. CONCLUSIONS: Circ-RAD23B knockdown inhibited NSCLC development by regulating the miR-142-3p/MAP4K3 axis, which might be associated with the inactivation of the MAPK signaling pathway.

Patterns of supraclavicular area failure after mastectomy in breast cancer patients: implications for target volume delineation.

PURPOSE: To characterize the pattern of post-mastectomy supraclavicular lymph node (LN) metastases in patients with breast cancer (BC) and to provide insights for individualized clinical target volume delineation for radiotherapy. METHODS: We retrospectively analyzed 88 patients with BC who developed post-mastectomy regional LN metastases. The affected regional LNs were categorized as the ipsilateral medial supraclavicular LN area (IMSC-LN), ipsilateral lateral supraclavicular LN area (ILSC-LN), ipsilateral infraclavicular LN area (IIC-LN), and ≥2 groups in the ipsilateral clavicular LN area (MMIC-LN). Clinical characteristics were included in a multivariate analysis to identify risk factors for clavicular LN metastases. RESULTS: The ILSC-LNs (68.2%) were the most common metastatic site. IMSC-LN metastases showed a significant association with estrogen-receptor (ER) negative status, left-sided BC, and positive axillary LNs. Tumor size ≥2.4 cm and Her2 type were predictors of ILSC-LN metastases. Additionally, tumor size ≥2.4 cm, and level I ipsilateral axillary metastases were associated with MMIC-LN metastasis. CONCLUSION: ILSC-LN was the most frequently affected group of supraclavicular lymph nodes. ER-negative status, left-sided BC, tumor size, and positive ipsilateral axillary LNs are potentially associated with the pattern of supraclavicular LN metastatic involvement.

High Biologically Effective Dose Radiotherapy for Brain Metastases May Improve Survival and Decrease Risk for Local Relapse Among Patients With Small-Cell Lung Cancer: A Propensity-Matching Analysis.

To evaluate whether high biologically effective dose (BED) radiotherapy improves local control and survival outcomes for patients with brain metastases (BMs) from small-cell lung cancer (SCLC) and to determine possible prognostic factors. From January 1998 to June 2018, 250 patients with BM from SCLC were retrospectively analyzed. The Cutoff Finder program was used to classify patients by BED. Overall survival (OS) and BM progression-free survival (BM-PFS) were analyzed using the Kaplan-Meier method and log-rank test. A Cox regression model was used to calculate the hazard ratio and 95% CI for prognostic factors for OS among the study population and propensity score (PS)-matched patients. A BED of 47.4 was taken as the optimal cutoff value. Both OS and BM-PFS were significantly improved in the high-BED (>47.4 Gy) than in the low-BED (≤47.4 Gy) group (median OS: 17.5 months vs 9.5 months, P < .001, median BM-PFS: 14.4 months vs 8.3 months, P < .001). Biologically effective dose (P < .001), Eastern Cooperative Oncology Group performance status (P = .047), smoking (P = .005), and pleural effusion (P = .004) were independent prognostic factors for OS. Propensity score matching with a ratio of 1:2 resulted in 57 patients in the high-BED group and 106 patients in the low-BED group. In the PS-matched cohort, OS and BM-PFS were significantly prolonged in the high-BED group compared with the low-BED group (P < .001). Biologically effective dose >47.4 Gy improves survival among patients with BM from SCLC. Eastern Cooperative Oncology Group score, smoking, and pleural effusion independently affect OS of SCLC patients with BM.

Prognostic nomogram based on the metastatic lymph node ratio for gastric neuroendocrine tumour: SEER database analysis.

OBJECTIVE: The prediction of survival of gastric neuroendocrine tumours (g-NETs) is controversial. Prognostic effects of the metastatic lymph node ratio (LNR) in patients with g-NET were explored, and a nomogram was plotted to predict the survival rates of patients. METHODS: A longitudinal study conducted on the basis of the Surveillance, Epidemiology, and End Results database. The association between LNR and survival were investigated by using Pearson correlation and Cox regression. Overall survival (OS) and cancer-specific survival (CSS) rates were predicted with the help of nomograms. RESULTS: A total of 315 patients with g-NET diagnosed from 2004 to 2015 were included in this study. LNR was discovered to have a negative correlation with OS and CSS (Pearson correlation coefficients: 0.343 (p<0.001) and 0.389 (p<0.001), respectively). The multivariate analyses indicated age, tumour site, differentiation, T staging, M staging, chemotherapy and LNR to be independent prognostic factors for both OS and CSS. Surgery was also a prognostic determinant for CSS (p=0.003). Concordance indices of the nomograms for OS and CSS were higher than those of the TNM classification (0.772 vs 0.730 and 0.807 vs 0.768, respectively). As per the area under the receiver operating characteristic curve, predictive ability of the nomograms for survival of 1, 3 and 5 years was all better than that of TNM classification. CONCLUSIONS: LNR is an independent predictor of g-NETs. The nomograms plotted in this study have a satisfying predictive ability of survival risks and are capable of guiding tailored treatment strategies for patients with g-NET.

Radiation-induced small extracellular vesicles as "carriages" promote tumor antigen release and trigger antitumor immunity.

Rationale: Accumulating evidence supports the importance of radiation therapy in the induction of antitumor immunity. Small extracellular vesicles (sEVs) play essential roles in tumor antigen loading and delivery. However, the role of sEVs in radiation-induced antitumor immunity remains unclear. It is therefore important to determine the role and regulatory mechanisms of sEVs in radiation-induced immunity. Methods: Tumor cells were irradiated (8 Gy), and sEVs were purified via ultracentrifugation. Primary tumor and experimental lung metastasis models were established in mice to evaluate antitumor immunity triggered by immunization with sEVs. Proteomic and bioinformatic analyses were performed to identify altered cargos in sEVs induced by radiation. Peptides derived from up-regulated proteins in sEVs were designed and synthesized as vaccines according to major histocompatibility complex (MHC) I binding and immunogenicity. Results: Here, we demonstrated that sEVs derived from irradiated tumor cells could trigger antitumor immunity against primary tumor and experimental lung metastasis by enhancing CD8+ and CD4+ T cell infiltration. Radiation may also enrich sEVs with tumor antigens and heat-shock proteins. Furthermore, CUB domain-containing protein 1 (CDCP1) derived from radiation-induced sEVs was identified as a novel tumor-associated antigen and developed as a peptide vaccine that may generate antitumor immune responses. Conclusions: Our results demonstrate that the use of sEVs secreted by irradiated tumor cells constitutes an efficient approach for tumor antigen delivery and presentation and highlight the role of sEVs in radiation-triggered antitumor immunity.

Mortal Obligate RNA Transcript Inhibits Cancer Cell Invasion and Migration in Lung Adenocarcinoma by Downregulating miRNA-223.

Background: Mortal obligate RNA transcript (MORT), a long noncoding RNA, has been reported as a potential tumor suppressor in many types of cancer. The functions of MORT involved in lung adenocarcinoma (LUAD) were investigated in this study. Materials and Methods: A total of 67 patients with LUAD (adenocarcinoma) were recruited in this study. Quantitative reverse transcription-polymerase chain reaction was used to assess gene expression. Cell transfections were used to analyze gene interactions. Transwell migration and invasion assay were carried out to analyze cell migration and invasion. Results: MORT was downregulated, whereas miRNA-223 was upregulated in LUAD. Expression of MORT was significantly affected by tumor metastasis but not by the size of tumors. Expression of miRNA-223 and MORT was inversely correlated in LUAD tissue samples. LUAD cells overexpressing MORT showed downregulated miRNA-223, whereas the expression of MORT was not significantly affected by overexpression of miRNA-223. Besides, overexpression of MORT inhibited, whereas overexpression of miRNA-223 promoted the invasion and migration of LUAD cells. Overexpression of miRNA-223 inhibited the effects of overexpressing MORT on cell invasion and migration. Conclusions: Therefore, MORT may inhibit cancer cell invasion and migration in LUAD by downregulating miRNA-223.

Role of postoperative radiotherapy in pT3N0 rectal cancer: A risk-stratification system based on population analyses.

The impact of adjuvant radiotherapy in pT3N0 rectal cancer is controversial. We aimed to determine the risk factors for cancer-specific survival (CSS) among these patients and to develop a risk-stratification system to identify which of these patients would benefit from adjuvant radiotherapy. In this review of the Surveillance, Epidemiology, and End Results database (2010-2014), we analyzed the data of pT3N0 rectal cancer patients who had not undergone neoadjuvant radiotherapy. Prognostic factors were identified using the Cox proportional hazards model, and risk scores were derived according to the ß regression coefficient. A total of 1021 patients were identified from the database search. The overall 5-year CSS was 86.31%. Multivariate analysis showed that age (P < 0.001), tumor differentiation (P = 0.044), number of nodes resected (P = 0.032), marital status (P = 0.005), and radiotherapy (P = 0.006) were independent prognostic factors for CSS. A risk-stratification system composed of age, tumor differentiation, and number of nodes resected was generated. Low-risk patients had better CSS than high-risk patients (92.13% vs 72.55%, P < 0.001). The addition of radiotherapy to surgery doubled the CSS among the high-risk patients (42.06% vs 91.26%, P = 0.001) but produced no survival benefit among the low-risk patients (93.36% vs 96.38%, P = 0.182). Our risk-stratification model based on age, tumor differentiation, and number of nodes resected predicted the outcomes of pT3N0 rectal cancer patients. This model could help identify patients who may benefit from adjuvant radiotherapy.

Role of postoperative radiotherapy in dermatofibrosarcoma protuberans: a propensity score-matched analysis.

OBJECTIVE: This study aimed to evaluate the role of postoperative radiotherapy (RT) in dermatofibrosarcoma protuberans (DFSP) and identify the prognostic factors influencing the disease-free survival (DFS). METHODS: A total of 184 patients with DFSP were analyzed from 2000 to 2016. The regression model was used to examine the prognostic factors for DFS. Baseline covariates were balanced using a propensity score model. The role of RT was assessed by comparing the DFS of the surgery + RT group with that of the surgery group. RESULTS: The median follow-up was 58 months (range, 6-203 months). The 5-year DFS rate was 89.8%. The univariate analysis showed that age ≥ 50 years, presence of fibrosarcoma, margins < 2 cm, and tumor size ≥5 cm were associated with worse DFS (P = 0.002, P <  0.001, P = 0.030, and P = 0.032, respectively). The multivariate Cox regression model revealed that age, margin width, lesion number, and histological subtype independently affected DFS. The Ki-67 expression was related to age and histological subtype. Patients with Ki-67 ≥ 17% showed a worse DFS than those with Ki-67 < 17% (35.8% vs 87.8%, P = 0.002). In the matched cohort, DFS was significantly higher in the S + RT group than in the S group (5-year DFS, 88.1% vs 56.2%, P = 0.044). CONCLUSIONS: Age, margin width, lesion number, and histological subtype were independent risk factors for DFS in patients with DFSP. The high expression of Ki-67 could predict a poor prognosis. Postoperative RT could improve DFS for patients with DFSP.

Association of markers of systemic and local inflammation with prognosis of patients with rectal cancer who received neoadjuvant radiotherapy.

PURPOSE: The inflammatory status of patients with cancer appears to affect cancer progression and patient prognosis. We examined the characteristics of cancer-associated systemic and local inflammation and its impact on the overall survival (OS) of patients with locally advanced rectal cancer (LARC) who received neoadjuvant radiotherapy (nRT). PATIENTS AND METHODS: Seventy-six consecutive LARC patients who received nRT from February 2012 to September 2015 were retrospectively analyzed. The peripheral neutrophil-to-lymphocyte ratio (NLR) was determined at diagnosis, and the CD8+ T-cell count was determined from surgical specimens. Factors associated with OS were identified by univariate and multivariate Cox regression. RESULTS: The median follow-up time was 23.0 months (range: 2-59), and the overall 5-year OS rate was 68.6% (95% CI =46.06-91.14). Patients with a high NLR (≥2.0) and a low CD8+ T-cell count (<9%) had a significantly worse 5-year OS than those with a low NLR and a high CD8+ T-cell count (P=0.005). NLR was also associated with lymphovascular invasion (P=0.014) and T stage (P=0.047), and the CD8+ T-cell count was associated with mucinous adenocarcinoma (P=0.005) and T stage (P=0.049). An NLR <2.0 was associated with pathological complete regression after nRT (P=0.039). Multivariate Cox regression indicated that NLR (P=0.025), CD8+ T-cell count (P=0.018), age (P=0.020), lymphovascular invasion (P=0.038), and T stage (P=0.011) were independently associated with OS. CONCLUSION: A high NLR and a low CD8+ T-cell count were significantly associated with poor survival in our population of patients with LARC. Measurement of markers of systemic and local inflammation might help to predict the prognosis of patients with LARC after nRT.

Prolyl hydroxylase domain 3 influences the radiotherapy efficacy of pancreatic cancer cells by targeting hypoxia-inducible factor-1α.

PURPOSE: Pancreatic cancer is characterized by a hypoxic microenvironment and resistance to most currently available treatment modalities. Prolyl hydroxylase domain 3 (PHD3) is a rate-limiting enzyme that regulates the degradation of hypoxia-inducible factors (HIFs) and is deregulated in pancreatic cancer cells. Whether such alteration of PHD3 expression contributes to the sustained growth and radioresistance of pancreatic cancer cells remains largely unknown. MATERIALS AND METHODS: PHD3 was overexpressed in pancreatic cancer Mia-paca2 cells via lentiviral expression. Cell cycle progression and apoptosis were assayed by flow cytometry. HIF-1α, EGFR, and PHD3 protein expression was assessed by Western blotting. Cell survival was determined in a colony formation assay. RESULTS: PHD3 overexpression suppressed HIF-1α protein expression and EGFR phosphorylation and enhanced the 2 Gy irradiation-mediated reductions in HIF-1α and phosphorylated (p)-EGFR under either normoxic or hypoxic conditions. PHD3 overexpression inhibited the growth and colony formation of Mia-paca2 cells in response to irradiation under either normoxic or hypoxic conditions. PHD3 overexpression exacerbated irradiation-induced apoptosis, with a greater effect under hypoxia than normoxia. Cell cycle distribution analysis demonstrated that PHD3 overexpression resulted in further shortened S phase and lengthened G2/M phase in response to irradiation. CONCLUSION: PHD3 expression may contribute to the radiotherapy efficacy of pancreatic cancer cells and serve as a novel biomarker for improving radiotherapy efficacy in pancreatic cancer.

Survival benefit of re-irradiation in esophageal Cancer patients with Locoregional recurrence: a propensity score-matched analysis.

BACKGROUND: To investigate the treatment failure pattern and factors influencing locoregional recurrence of esophageal squamous cell carcinoma (ESCC) and examine patient survival with re-irradiation (re-RT) after primary radiotherapy. METHODS: We retrospectively analyzed 87 ESCC patients treated initially with radiotherapy. Failure patterns were classified into regional lymph node recurrence only (LN) and primary failure with/without regional lymph node recurrence (PF). Patients received either re-RT or other treatments (non-re-RT group). Baseline covariates were balanced by a propensity score model. Overall survival (OS) and toxicities were assessed as outcomes. RESULTS: The median follow-up time was 87 months. Thirty-nine patients received re-RT. Failure pattern and re-RT were independent prognostic factors for OS (P = 0.040 and 0.015) by Cox multivariate analysis. Re-RT with concomitant chemotherapy showed no survival benefit over re-RT alone (P = 0.70). No differences in characteristics were found between the groups by Chi-square tests after propensity score matching. The Cox model showed that failure pattern and re-RT were prognostic factors with hazard ratios (HR) of 0.319 (P = 0.025) and 0.375 (P = 0.002), respectively, in the matched cohort. Significant differences in OS were observed according to failure pattern (P = 0.004) and re-RT (P < 0.001). In the re-RT and non-re-RT groups, 9.09% and 3.03% of patients experienced tracheoesophageal fistulas, and 15.15% and 3.03% of patients developed pericardial/pleural effusion, respectively (P > 0.05). The incidence of radiation pneumonitis was higher in the re-RT group (24.24% vs. 6.06%, P = 0.039), but no cases of pneumonia-related death occurred. CONCLUSIONS: Re-RT improved long-term survival in patients with locoregional recurrent ESCC. Despite a high incidence of radiation pneumonitis, toxicities were tolerable.