Toxicity, Disease Control, and Survival Outcomes of Intensified Preoperative Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer: A Single-Institution Study.

Purpose: The standard treatment regimen of preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) is still controversial. The purpose of this study was to analyze the efficacy and safety of preoperative intensive CRT in our institution. Methods: A retrospective data collection and analysis of 181 LARC patients receiving oxaliplatin (85%) of standard doses in capecitabine-based preoperative CRT and two additional cycle of neoadjuvant chemotherapy between the end of concurrent CRT and surgery. Results: The compliance of the preoperative CRT was satisfactory with 99.4%patients completed radiotherapy and 97.19%patients completed all 2 cycles of concurrent chemotherapy. Except for 20 patients diagnosed clinical complete remission (cCR) managed according to watch and wait strategy, 160 patients received R0 radical surgery. The pathological complete response (pCR) rate was 23.75% (38/160) and tumor regression grade (TRG) 0/1 was 40% (72/180). In terms of tumor downstaging, 89 (55.63%) had T downstaging while 115 (71.88%) had N downstaging. The 1-overall survival (OS),2-OS,3-OS and 5-OS were 98.7%, 96.5%, 91.4% and 81.5%, respectively. The total rate of sphincter preservation was 86.25% (138/160) and the rate of patients with low rectal cancer was 73.0% (54/74) without affecting local control rates and survival rates. Both acute adverse reactions to preoperative CRT and postoperative complications were tolerable and controllable. Conclusion: In this retrospective study, preoperative intensive CRT of patients with LARC achieved satisfied disease control and survival outcomes and well acquired the sphincter retention rate in recent years in our institution. On the basis of these findings, a Phase III study to definitively test the intensified preoperative CRT strategy is warranted.

A deep learning based automatic segmentation approach for anatomical structures in intensity modulation radiotherapy.

OBJECTIVE: To evaluate the automatic segmentation approach for organ at risk (OARs) and compare the parameters of dose volume histogram (DVH) in radiotherapy. METHODOLOGY: Thirty-three patients were selected to contour OARs using automatic segmentation approach which based on U-Net, applying them to a number of the nasopharyngeal carcinoma (NPC), breast, and rectal cancer respectively. The automatic contours were transferred to the Pinnacle System to evaluate contour accuracy and compare the DVH parameters. RESULTS: The time for manual contour was 56.5 ± 9, 23.12 ± 4.23 and 45.23 ± 2.39min for the OARs of NPC, breast and rectal cancer, and for automatic contour was 1.5 ± 0.23, 1.45 ± 0.78 and 1.8 ± 0.56 min. Automatic contours of Eye with the best Dice-similarity coefficients (DSC) of 0.907 ± 0.02 while with the poorest DSC of 0.459 ± 0.112 of Spinal Cord for NPC; And Lung with the best DSC of 0.944 ± 0.03 while with the poorest DSC of 0.709 ± 0.1 of Spinal Cord for breast; And Bladder with the best DSC of 0.91 ± 0.04 while with the poorest DSC of 0.43 ± 0.1 of Femoral heads for rectal cancer. The contours of Spinal Cord in H & N had poor results due to the division of the medulla oblongata. The contours of Femoral head, which different from what we expect, also due to manual contour result in poor DSC. CONCLUSION: The automatic contour approach based deep learning method with sufficient accuracy for research purposes. However, the value of DSC does not fully reflect the accuracy of dose distribution, but can cause dose changes due to the changes in the OARs volume and DSC from the data. Considering the significantly time-saving and good performance in partial OARs, the automatic contouring also plays a supervisory role.

Metformin inhibits hepatocellular carcinoma development by inducing apoptosis and pyroptosis through regulating FOXO3.

This study aimed to expand our understanding of metformin (Met) in inhibiting hepatocellular carcinoma (HCC) progression and to investigate its underlying mechanism. Met was administrated to HCC cells at 5, 10, and 20 µM, after which the cell phenotype was evaluated. RNA-seq cluster analysis was used to screen for target genes modulated by Met. Luciferase activity and ChIP assays were performed to detect the effect of FOXO3 on the transcriptional activation of NLRP3. We evaluated the effect of Met and FOXO3 and on the growth of HCC cells in vivo. Met inhibited HCC cell proliferation and promoted apoptosis. Met also induced pyroptosis of HCC cells. FOXO3 was significantly upregulated by Met treatment, and FOXO3 activated transcription of NLRP3. Cells after Met treatment together with FOXO3 knockdown have a stronger colony formation and migration ability but a lower apoptosis rate compared to the Met treatment alone group. In vivo, Met inhibited HCC tumor growth. The tumors in Met treatment and FOXO3 knockdown group grew faster than in Met treatment group. Thus, Met attenuates HCC cell development by inducing apoptosis and pyroptosis. This effect of metformin is partially dependent on FOXO3 which can activate the transcription of NLRP3.

Efficacy and Prognostic Factors of Trans-Arterial Chemoembolization Combined With Stereotactic Body Radiation Therapy for BCLC Stage B Hepatocellular Carcinoma.

PURPOSE: This study aimed to evaluate the efficacy and safety of trans-arterial chemoembolization (TACE) followed by stereotactic body radiation therapy (SBRT) in treating Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) not amenable to resection and radiofrequency ablation (RFA). METHODS: From February 2012 to January 2017, a total of 57 BCLC stage B HCC patients who were unsuitable candidates for resection and RFA treated with TACE combined with CyberKnife SBRT were included in this retrospective study. Patients underwent TACE for a median of two times (1-5 times) before SBRT. SBRT prescription doses ranged from 30 Gy to 50 Gy in 3-5 fractions. RESULTS: The median follow-up time was 42 months. The objective response rate (CR + PR) was 85.9%, and the disease control rate (CR + PR + SD) was 96.5%. The local control (LC) rates were 91.1% and 84.3% at 1 and 2 years, respectively. The 1-, 2-, 3-year overall survival (OS) and the median survival time were 73.2%, 51.4%, 32.4% and 26.6 months, respectively. The 1-, 2-, and 3-year progression-free survival (PFS) were 34.2%, 21.6%, and 9%, respectively, with a median PFS time of 9.7 months. A subgroup analysis was conducted in 32 patients with AFP ≥ 200 ng/ml before TACE. OS was significantly prolonged in those with AFP that decreased by more than 75% than those with AFP that decreased by less than 75% (P = 0.018) after SBRT. The treatment was well tolerated with only one patient (1.8%) developed grade 3 gastrointestinal toxicity, and another patient developed non-classical RILD. In multivariate analysis, tumor length ≥ 10 cm and AFP ≥ 200 ng/ml were independent poor prognostic factors for OS. CONCLUSION: The combination of TACE and Cyberknife SBRT showed optimal efficacy with acceptable toxicity for BCLC stage B HCC.

Combined inhibition of AURKA and HSF1 suppresses proliferation and promotes apoptosis in hepatocellular carcinoma by activating endoplasmic reticulum stress.

PURPOSE: In this study we aimed to assess the anti-tumor effect of co-inhibition of Aurora kinase A (AURKA) and heat shock transcription factor 1 (HSF1) on hepatocellular carcinoma (HCC), as well as to explore the mechanism involved. METHODS: Expression of AURKA and HSF1 in primary HCC tissues and cell lines was detected by immunohistochemistry (IHC), qRT-PCR and Western blotting. AURKA was knocked down in HepG2 and BEL-7402 HCC cells using lentivirus-mediated RNA interference. Next, CCK-8, clone formation, transwell and flow cytometry assays were used to assess their viability, migration, invasion and apoptosis, respectively. The expression of proteins related to cell cycle progression, apoptosis and endoplasmic reticulum stress (ERS) was analyzed using Western blotting. In addition, in vivo tumor growth of HCC cells was assessed using a nude mouse xenograft model, and the resulting tumors were evaluated using HE staining and IHC. RESULTS: Both AURKA and HSF1 were highly expressed in HCC tissues and cells, while being negatively related to HCC prognosis. Knockdown of AURKA significantly inhibited the colony forming and migrating capacities of HCC cells. In addition, we found that treatment with an AURKA inhibitor (Danusertib) led to marked reductions in the proliferation and migration capacities of the HCC cells, and promoted their apoptosis. Notably, combined inhibition of AURKA and HSF1 induced HCC cell apoptosis, while increasing the expression of ERS-associated proteins, including p-eIF2α, ATF4 and CHOP. Finally, we found that co-inhibition of AURKA and HSF1 elicited an excellent in vivo antitumor effect in a HCC mouse model with a relatively low cytotoxicity. CONCLUSIONS: Combined inhibition of AURKA and HSF1 shows an excellent anti-tumor effect on HCC cells in vitro and in vivo, which may be mediated by ERS. These findings suggest that both AURKA and HSF1 may serve as targets for HCC treatment.

Clinical Effects of Stereotactic Body Radiation Therapy Targeting the Primary Tumor of Liver-Only Oligometastatic Pancreatic Cancer.

AIM: To investigate the efficacy and safety of stereotactic body radiotherapy (SBRT) targeting the primary tumor for liver-only oligometastatic pancreatic cancer. METHODS: We compared the efficacy and safety of SBRT plus chemotherapy with chemotherapy alone in patients with liver-only oligometastatic pancreatic cancer. The populations were balanced by propensity score-weighted and propensity score-matched analyses based on baseline variables. The primary outcome was overall survival (OS). The secondary outcomes included progression free survival (PFS), local progression, metastatic progression and symptomatic local control. RESULTS: This is a retrospective study of 89 pancreatic cancer patients with liver-only oligometastasis. Overall, 34 (38.2%) and 55 (61.8%) patients received SBRT plus chemotherapy and chemotherapy alone, respectively. After propensity score matching, 1-year OS rate was 34.0% (95%CI, 17.8-65.1%) in the SBRT plus chemotherapy group and 16.5% (95%CI, 5.9-46.1%) in chemotherapy alone group (P=0.115). The 6-month PFS rate was 29.4% (95%CI, 15.4-56.1) in SBRT plus chemotherapy and 20.6% (95%CI, 8.8-48.6) in chemotherapy alone group (P=0.468), respectively. Further subgroup analysis indicated that the addition of SBRT improved OS in patients with primary tumor located in the head of pancreas (stratified HR, 0.28; 95% CI, 0.09 to 0.90) or good performance status (stratified HR, 0.24; 95% CI, 0.07 to 0.86). In terms of disease control, SBRT delayed local progression of pancreas (P=0.008), but not distant metastatic progression (P=0.56). Besides, SBRT offered significant abdominal/back pain relief (P=0.016) with acceptable toxicities. CONCLUSIONS: The addition of SBRT to chemotherapy in patients with liver-only oligometastatic pancreatic cancer improves the OS of those with primary tumor located in the head of pancreas or good performance status. In addition, it is a safe and effective method for local progression control and local symptomatic palliation in patients with metastatic pancreatic cancer.

Role of thoracic radiotherapy in extensive stage small cell lung cancer: a systemic review and meta-analysis.

BACKGROUND: The role of thoracic consolidation radiotherapy in patients with extensive stage small cell lung cancer (ES-SCLC) remains controversial. This study aimed to evaluate the efficacy of thoracic radiotherapy (TRT) in these patients. METHODS: A systematic literature search was performed in PubMed, Embase, and the Cochrane library to identify qualified clinical studies. The hazard ratios (HRs) and 95% confidence intervals (CIs) of overall survival (OS), progression-free survival (PFS) and local recurrence-free survival (LRFS) were extracted, and toxicity of the TRT group versus non-TRT group was analyzed. RESULTS: A total of 12 studies were included in this meta-analysis, including 936 patients in the TRT group and 1,059 patients in the non-TRT group. The combined results showed that TRT significantly improved OS (HR =0.65; 95% CI: 0.55-0.77, P<0.00001), PFS (HR =0.64; 95% CI: 0.56-0.72, P<0.00001) and LRFS (HR =0.38, 95% CI: 0.26-0.53, P<0.00001). Subgroup analysis showed that OS benefits were observed in patients receiving sequential TRT (HR =0.67; 95% CI: 0.54-0.84, P=0.0006). The addition of TRT significantly improved OS in patients over 65 years of age (HR =0.55; 95% CI: 0.40-0.74, P=0.0001). For patients with only one organ metastasis, there was no significant difference in OS between the two groups (HR =0.61; 95% CI: 0.36-1.01, P=0.06). There was no statistical difference in hematologic toxicity (leukopenia, thrombocytopenia, anemia) and non-hematologic toxicity (nausea or vomiting) between the two groups. The incidence of grade ≥3 esophageal toxicity was 4.6% in the TRT group and 0% in the non-TRT group (P=0.0001). Grade ≥3 bronchopulmonary toxicity was 2.9% in the TRT group and 0.8% in the non-TRT group (P=0.02). CONCLUSIONS: TRT improves OS, PFS and LRFS in patients with ES-SCLC, with a low increase in esophageal and bronchopulmonary toxicity. More randomized controlled trials (RCTs) are expected to confirm our conclusions. PROSPERO REGISTRATION NUMBER: CRD42020190575.

Genetic analysis of rapidly progressing esophageal squamous cell carcinoma: A case report.

INTRODUCTION: Numerous investigations have been performed to explore candidate biomarker proteins in esophageal squamous cell carcinoma (ESCC) patients, which could predict the response to chemoradiotherapy (CRT). Here we report a patient with unresectable ESCC who had unsatisfactory effects with radiotherapy, chemotherapy and immunotherapy. We performed genetic analysis in this patient to gain insights about the cause of the rapid progression. PATIENT CONCERNS: A 65-year-old man presented with food obstruction, hoarse voice and choking on drinking water for 2 months, and pain behind the breastbone for 1 month. DIAGNOSIS: The patient was clinically diagnosed with ESCC and staged as T4N1M1 Stage IV. INTERVENTIONS: The patient was treated with CRT and immunotherapy. Mutational analyses through high throughput DNA sequencing methodology (next generation sequencing; NGS) was performed on the patient's blood sample. OUTCOMES: The tumor progressed rapidly during the treatment period, and the patient passed away only 3 months from the onset of symptoms. CONCLUSION: Although the role of TP53 gene and PIK3CA gene in the progression, treatment and sensitivity of esophageal cancer has been studied, the mechanism of their simultaneous appearance has not been demonstrated in relevant studies. We speculate that the reason for the rapid progression in this patient during active treatment might be related to this. Further studies are needed to validate our observations.

Concurrent chemoradiotherapy with raltitrexed and nedaplatin regimen for esophageal squamous cell carcinoma.

BACKGROUND: The aim of the study reported here was to evaluate the feasibility and safety of raltitrexed and nedaplatin with concurrent radiotherapy in patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Eligible patients were adults with newly diagnosed untreated, unresectable esophageal cancer in stages I to IV with lymph node metastases or cervical esophageal cancer. Patients received nedaplatin 25 mg/m per day on day 1-3, raltitrexed 3 mg/m on days 1 repeated every 21 days for 2 cycles, and combined concurrent radiotherapy (2 Gy/fraction, total dose of 60 Gy). RESULT: Thirty patients were included with squamous cell carcinoma. The median follow-up duration was 24 months. The overall response rate was 90%. The 1-year and 2-year overall survival rates for all patients were 70.4% and 55.7% with a median survival time of 30 months, and the median progression free survival was 20 month. The major toxicities were leukopenia and thrombopenia, with grade 3 to 4 leukopenia and thrombopenia were 50% and 30% of patients. CONCLUSION: Concurrent chemoradiotherapy with raltitrexed and nedaplatin agents frequently caused myelosuppression but was highly active and suggested to be a promising treatment option for locally advanced ESCC.

Outcomes of Stereotactic Body Radiotherapy for Metastatic Colorectal Cancer With Oligometastases, Oligoprogression, or Local Control of Dominant Tumors.

AIM: To evaluate the clinical outcomes of metastatic colorectal cancer (mCRC) patients with oligometastases, oligoprogression, or local control of dominant tumors after stereotactic body radiotherapy (SBRT) and establish a nomogram model to predict the prognosis for these patients. METHODS AND MATERIALS: A cohort of 94 patients with 162 mCRC metastases was treated with SBRT at a single institution. Treatment indications were oligometastases, oligoprogression, and local control of dominant tumors. End points of this study were the outcome in terms of progression-free survival (PFS), overall survival (OS), local progression (LP), and cumulative incidence of starting or changing systemic therapy (SCST). In addition, univariate and multivariable analyses to assess variable associations were performed. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. RESULTS: Median PFS were 12.6 months, 6.8 months, and 3.7 months for oligometastases, oligoprogression, and local control of dominant tumors, respectively. 0-1 performance status, < 10 ug/L pre-SBRT CEA, and ≤ 2 metastases were significant predictors of higher PFS on multivariate analysis. Median OS were 40.0 months, 26.1 months, and 6.5 months for oligometastases, oligoprogression, and local control of dominant tumors, respectively. In the multivariate analysis of the cohort, the independent factors for survival were indication, performance status, pre-SBRT CEA, and PTV, all of which were selected into the nomogram. The calibration curve for probability of survival showed the good agreement between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.848. CONCLUSIONS: SBRT for metastases derived from colorectal cancer offered favorable survival and symptom palliation without significant complications. The proposed nomogram could provide individual prediction of OS for patients with mCRC after SBRT.

Clinical outcomes and prognostic factors of stereotactic body radiation therapy combined with gemcitabine plus capecitabine for locally advanced unresectable pancreatic cancer.

PURPOSE: This study aimed to evaluate the clinical outcomes, toxicity, and prognostic factors of SBRT combined with gemcitabine plus capecitabine (GEM-CAP) in treating locally advanced pancreatic cancer (LAPC). METHODS: A total of 56 patients with LAPC treated with SBRT combined with GEM-CAP were reviewed from October 2010 to October 2016. The median total prescription dose at five fractions was 40 Gy (30-50 Gy). The patients were subjected to two cycles of GEM-CAP before SBRT. GEM-CAP chemotherapy was then offered for four cycles or until disease tolerance or progression. The primary endpoints included overall survival (OS) and progression-free survival (PFS). RESULTS: The median OS and PFS from the date of diagnosis was 19 (95% CI 14.6-23.4) and 12 months (95% CI 8.34-15.66), respectively. The 1-year and 2-year survival rates were 82.1% and 35.7%, whereas the 1-year and 2-year PFS rates were 48.2% and 14.3%, respectively. The median carbohydrate antigen 19-9-determined PFS time was 11 months (95% CI 5.77-16.24). Multivariate analysis demonstrated that tumor diameter, lymph node metastasis, pre-treatment CA19-9 level, and post-treatment CA19-9 decline were independent prognostic factors (p < 0.05). Acute toxicity was minimal, with two cases (3.6%) experiencing grade 3 duodenal obstruction. No adverse events greater than grade 3 occurred. In late toxicity, three patients (5.4%) developed grade 3 gastrointestinal toxicity and two (3.6%) suffered from perforation caused by grade 4 radiation enteritis and intestinal fistula. CONCLUSIONS: The combination of Cyberknife SBRT and GEM-CAP achieved excellent efficacy with acceptable toxicity for LAPC.

Aurora-a confers radioresistance in human hepatocellular carcinoma by activating NF-κB signaling pathway.

BACKGROUND: Radiotherapy failure is a significant clinical challenge due to the development of resistance in the course of treatment. Therefore, it is necessary to further study the radiation resistance mechanism of HCC. In our early study, we have showed that the expression of Aurora-A mRNA was upregulated in HCC tissue samples or cells, and Aurora-A promoted the malignant phenotype of HCC cells. However, the effect of Aurora-A on the development of HCC radioresistance is not well known. METHODS: In this study, colony formation assay, MTT assays, flow cytometry assays, RT-PCR assays, Western blot, and tumor xenografts experiments were used to identify Aurora-A promotes the radioresistance of HCC cells by decreasing IR-induced apoptosis in vitro and in vivo. Dual-luciferase reporter assay, MTT assays, flow cytometry assays, and Western blot assay were performed to show the interactions of Aurora-A and NF-κB. RESULTS: We established radioresistance HCC cell lines (HepG2-R) and found that Aurora-A was significantly upregulated in those radioresistant HCC cells in comparison with their parental HCC cells. Knockdown of Aurora-A increased radiosensitivity of radioresistant HCC cells both in vivo and in vitro by enhancing irradiation-induced apoptosis, while upregulation of Aurora-A decreased radiosensitivity by reducing irradiation-induced apoptosis of parental cells. In addition, we have showed that Aurora-A could promote the expression of nuclear IkappaB-alpha (IκBα) protein while enhancing the activity of NF-kappaB (κB), thereby promoted expression of NF-κB pathway downstream effectors, including proteins (Mcl-1, Bcl-2, PARP, and caspase-3), all of which are associated with apoptosis. CONCLUSIONS: Aurora-A reduces radiotherapy-induced apoptosis by activating NF-κB signaling, thereby contributing to HCC radioresistance. Our results provided the first evidence that Aurora-A was essential for radioresistance in HCC and targeting this molecular would be a potential strategy for radiosensitization in HCC.

[Cyberknife stereotactic body radiotherapy for liver metastases from prostate cancer].

OBJECTIVE: To investigate the effectiveness and adverse effects of Cyberknife stereotactic body radiotherapy (SBRT) on liver metastases from PCa. METHODS: From June 2009 to September 2016, we treated 20 cases of PCa liver metastases by Cyberknife SBRT, at a total dose of 36 (30－50) Gy, on 1－3 liver metastatic lesions, for 3－5 times, with a prescription isodose line of 70－92%. We assessed the therapeutic effect according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), calculated the survival and disease-control rates using the Kaplan-Meier method, and analyzed the adverse events based on the National Cancer Institute Common Terminology Criteria for Adverse Events－Version 4.0 (CTCAE 4.0). RESULTS: Of all the cases treated, complete response (CR) was found in 8 (40.0%), partial response (PR) in 9 (45.0%), stable disease (SD) in 2 (10.0%), and progressive disease (PD) in 1 (5.0%), with a local control rate (CR+PR) of 85.0% and a disease-control rate (CR+PR+SD) of 95.0%. Among the 14 patients with elevated PSA, 10 (71.4%) showed a significant decrease after treatment. The median follow-up time was 17 months, the 1- and 2-year survival rates were 85.0% and 15.0%, respectively, and the median survival time of the 20 patients was 16.5 months (95% CI: 12.12－22.88). Cyberknife SBRT was well tolerated in all the patients, with only a few mild adverse events (mainly grades 1 and 2 but no 4 and 5) during the whole course of treatment. CONCLUSIONS: Cyberknife SBRT is safe and effective in the treatment of PCa liver metastases, with a high local control rate, and capable of reducing the PSA level and raising the long-term survival rate of the patients.

CYP2E1 Rsa Ι/Pst Ι polymorphism and lung cancer susceptibility: A meta-analysis involving 10,947 subjects.

The above article, published in the Journal of Cellular and Molecular Medicine on 14 September 2016 in Wiley Online Library (wileyonlinelibrary.com), and in Volume 19, pp. 2136-2142, has been retracted by agreement between the authors, the journal Editor in Chief, Stefan Constantinescu, and John Wiley & Sons Ltd. The retraction has been agreed due to unattributed overlap of the language used in the "Materials and method" and "Discussion" sections of this study and the following article published in Lung Cancer: "CYP2E1 Rsa I/Pst I polymorphism is associated with lung cancer risk among Asians" by Ping Zhan, Jing Wang, Yu Zhang, Li-Xin Qiu, Su-feng Zhao, Qian Qian, Shu-Zhen Wei, Li-Ke Yu and Yong Song, Volume 69, 2010, pages 19-25. REFERENCE Shen Z-T, Wu X-H, Li B, Shen J-S, Wang Z, Li J, Zhu X-X. CYP2E1 Rsa Ι/Pst Ι polymorphism and lung cancer susceptibility: a meta-analysis involving 10,947 subjects. J Cell Mol Med. 2015;19:2136-2142. https://doi.org/10.1111/jcmm.12579.

CXCL14 and NOS1 expression in specimens from patients with stage I-IIIA nonsmall cell lung cancer after curative resection.

Many studies show that CXC chemokine ligand 14 (CXCL14) is highly expressed in tumor-associated stromal cells, promoting tumor cell growth, and invasion. Because of its unclear receptors, CXCL14-initiated intracellular signal cascades remain largely unknown. However, CXCL14 can regulate nitric oxide synthase 1 (NOS1) as its intracellular molecular target. In this paper, we investigated the expression of CXCL14 and NOS1 in specimens from patients with stage I-IIIA nonsmall cell lung cancer (NSCLC) after curative resection, and evaluated the prognostic significance of this gene expression in stromal fibroblasts and cancer cells.Immunohistochemistry was used to detect the expression of CXCL14 and NOS1 in 106 formalin fixed, paraffin-embedded specimens from patients with stage I-IIIA NSCLC. The chi-square test was performed to examine the correlation of CXCL14 and NOS1 expression level with clinicopathological features. The effects of the expression of CXCL14 or NOS1 on progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier and Cox hazard proportional model.The percentages of high CXCL14 expression in stromal fibroblasts and that in cancer cells were 46.2% (49/106) and 23.6% (25/106), respectively. The positive expression rates of NOS1 in cancer cells were 42.5% (45/106). The result indicated that there was a significant positive correlation between CXCL14 expression level in stromal fibroblasts and that in cancer cells (χ = 4.158, P = .041). In addition, the expression of CXCL14 in stromal fibroblasts was significantly correlated with NOS1 expression in cancer cells (χ = 16.156, P < .001). The 5-year PFS rates with low and high CXCL14 expression in stromal fibroblasts were 66.7% and 14.3% (χ = 44.008, P < .001), respectively, and the 5-year OS rates with those were 87.1% and 43.5% (χ = 21.531, P < .001), respectively. The 5-year PFS rates with negative and positive expression of NOS1 in cancer cells were 62.3% and 15.6% (χ = 33.756, P < .001), respectively, and the 5-year OS rates with those were 86.4% and 40.1% (χ = 24.430, P < 0.01), respectively.Both the high expression of CXCL14 in stromal fibroblasts and the positive expression of NOS1 in cancer cells are independent negative predictors of PFS and OS in patients with stage I-IIIA NSCLC after curative resection.

Long non-coding RNA ROR promotes radioresistance in hepatocelluar carcinoma cells by acting as a ceRNA for microRNA-145 to regulate RAD18 expression.

Radiotherapy plays a limited role in the treatment of hepatocellular carcinoma (HCC) due to the development of resistance. Therefore, further investigation of underlying mechanisms involved in HCC radioresistance is warranted. Increasing evidence shows that long non-coding RNAs (linc-RNAs) are involved in the pathology of various tumors, including HCC. Previously, we have shown that long noncoding RNA regulator of reprogramming (linc-ROR) promotes HCC metastasis via induction of epithelial-mesenchymal transition (EMT). However, the roles of linc-ROR in HCC radioresistance and its possible mechanisms are unclear. Here, we established two radioresistant HCC cell lines (HepG2-R and SMMC-7721-R) and found that linc-ROR was significantly upregulated in radioresistant HCC cells. Knockdown of linc-ROR reduces in vitro and in vivo radiosensitivity of parental HCC cells by reducing DNA repair capacity, while ectopic expression of linc-ROR enhances radiosensitivity of radioresistant HCC cells. Further mechanistic investigations revealed that lincRNA-ROR exerted its biological effects by acting as a competing endogenous RNA (ceRNA) for miR-145 to regulate RAD18 expression, thereby promoting DNA repair. Collectively, our findings demonstrate that linc-ROR promotes HCC radioresistance and targeting it will be a promising strategy for enhancing the efficacy of radiotherapies in HCC.

Clinical outcomes and prognostic factors of stereotactic body radiation therapy for intrahepatic cholangiocarcinoma.

Stereotactic body radiation therapy (SBRT) has been an emerging non-invasive treatment modality for patients with intrahepatic cholangiocarcinoma (ICC) when surgical treatment cannot be applied. The CyberKnife® is a SBRT system that allows for real-time tracking of the tumor. The purpose of this study was to evaluate the clinical outcomes and prognostic factors for ICC patients receiving this treatment. Twenty-eight patients with ICC were enrolled in the present study. The median prescription dose was 45 Gy (range, 36-54 Gy), fractionated 3 to 5 times with a 70% to 92% isodose line. Local control, overall survival, progression-free survival and toxicity were studied. The median follow-up time was 16 months (3-42 months). Based on modified Response Evaluation and Criteria in Solid Tumors (mRECIST), response rate and disease control rate of SBRT in ICC were 46.4% (13/28) and 89.3% (25/28), respectively. Median overall survival was 15 months (95% CI, 7.22-22.78). 1- and 2-years survival rates were 57.1% and 32.1%, and 1- and 2- years Progression-free Survival rates were 50.0 % and 21.4 %. Multivariate analysis revealed that number of lesions (solitary vs. multiple nodules), CA19-9 levels (≤37 U/mL vs. 37-600/>600) and TNM stage (AJCC stage) were independent prognostic factors for ICC patients treated with SBRT. Toxicity was mostly transient and tolerable. No greater than grade 3 toxicity was observed. These results suggested that CyberKnife SBRT might be a good alternative treatment for unresectable ICC.

A Bayesian network meta-analysis of whole brain radiotherapy and stereotactic radiotherapy for brain metastasis.

This study was conducted to compare the effects of whole brain radiotherapy (WBRT) and stereotactic radiotherapy (SRS) in treatment of brain metastasis.A systematical retrieval in PubMed and Embase databases was performed for relative literatures on the effects of WBRT and SRS in treatment of brain metastasis. A Bayesian network meta-analysis was performed by using the ADDIS software. The effect sizes included odds ratio (OR) and 95% confidence interval (CI). A random effects model was used for the pooled analysis for all the outcome measures, including 1-year distant control rate, 1-year local control rate, 1-year survival rate, and complication. The consistency was tested by using node-splitting analysis and inconsistency standard deviation. The convergence was estimated according to the Brooks-Gelman-Rubin method.A total of 12 literatures were included in this meta-analysis. WBRT + SRS showed higher 1-year distant control rate than SRS. WBRT + SRS was better for the 1-year local control rate than WBRT. SRS and WBRT + SRS had higher 1-year survival rate than the WBRT. In addition, there was no difference in complication among the three therapies.Comprehensively, WBRT + SRS might be the choice of treatment for brain metastasis.

Prognostic Significance of microRNA-7 and its Roles in the Regulation of Cisplatin Resistance in Lung Adenocarcinoma.

BACKGROUND: Previously, microRNA (miR)-7 has been reported to function as a tumor suppressor in human cancers, but the correlations of miR-7 expression with prognosis and cisplatin (CDDP) resistance in lung adenocarcinoma (LA) are unclear. Here, our aim is to determine the prognostic significance of miR-7 and its roles in the regulation of CDDP resistance in LA. METHODS: Quantitative real-time PCR (qRT-PCR) assay was performed to determine miR-7 expression in 108 paired of LA tissues and analyze its correlations with clinicopathological factors of patients. The patient survival data were collected retrospectively by Kaplan-Meier analyses, and multivariate analysis was performed using the Cox proportional hazards model to determine the prognostic significance of miR-7 expression. The effects of miR-7 expression on the chemosensitivity of LA cells to CDDP and its possible mechanisms were evaluated by MTT, flow cytometry, Western blot and luciferase assays. RESULTS: It was observed that the relative expression level of miR-7 in LA tissues was significantly lower than that in the adjacent normal tissues and low miR-7 expression level was closely associated with poorer tumor differentiation, advanced pathological T-factor, higher incidence of lymph node metastasis and advanced p-TNM stage. Also, patients with low miR-7 expression showed a shorter overall survival than those with high miR-7 expression, and multivariate analysis indicated that status of miR-7 expression was an independent molecular biomarker for predicting the overall survival (OS) of LA patients. In addition, upregulation of miR-7 increases the sensitivity of LA cells to CDDP via induction of apoptosis by targeting Bcl-2. CONCLUSIONS: Our finding for the first time demonstrates that low miR-7 expression may be an independent poor prognostic factor and targeting miR-7 may be a potential strategy for the reversal of CDDP resistance in LA.

TGF-ß1 rs1982073 polymorphism contributes to radiation pneumonitis in lung cancer patients: a meta-analysis.

Transforming growth factor beta 1(TGF-ß1) polymorphism was associated with radiation pneumonitis (RP) susceptibility, but their results have been inconsistent. The PubMed and CNKI were searched for case-control studies published up to Januray 01, 2016 was Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. In this meta-analysis, we assessed eight publications involving 368 radiation pneumonitis cases and 855 controls of the association between TGF-ß1 T869C (rs1982073) and G915C (rs1800471) polymorphism and RP susceptibility. Our analysis suggested that TGF-ß1 T869C rs1982073 polymorphism was associated with lower RP risk for CT combined CC versus TT model (OR = 0.58, 95% CI = 0.43-0.77). However, for the G915C rs1800471 polymorphism, no association was found between the polymorphism and the susceptibility to RP in GC combined CC versus GG model (OR = 0.82, 95% CI = 0.50-1.35). These results from the meta-analysis suggest that T869C rs1982073 polymorphism of TGF-ß1 may be associated with RP risk, and there may be no association between G915C polymorphism and RP risk.