MiR-30a-5p inhibits cell behaviors in esophageal cancer via modulating CBX2.

BACKGROUND: This investigation studied the impacts of the miR-30a-5p/CBX2 axis on esophageal cancer (EC). METHODS: Research objects were ascertained using The Cancer Genome Atlas database. Followed by qRT-PCR, western blot, dual-luciferase reporter, MTT, Transwell, and wound healing approaches, we tested gene expression and varying cell behaviors RESULTS: Conspicuously miR-30 family members (miR-30a-5p, miR-30b-5p, miR-30c-5p, miR-30d-5p, miR-30e-5p) downregulation and CBX2 upregulation were discovered in EC cells. miR-30 family members target CBX2 and inhibited CBX2 expression. EC cell behaviors were inhibited by miR-30a-5p/CBX2 axis. CONCLUSION: MiR-30a-5p draws a new inspiration for EC treatment.

miR-3942-3p Increases the radiosensitivity of nasopharyngeal carcinoma through negatively regulating BARD1.

Nasopharyngeal carcinoma (NPC) has high incidence in China and East and Southeast Asia. The study was performed to investigate the effect of microRNA3942-3p (miR-3942-3p) on the radiosensitivity of NPC. Compared with non-cancer tissue, NPC had significantly lower miR-3942-3p expression. X-irradiation (IR) reduced the expression of miR-3942-3p in a dose-dependent way in NPC cells. Down-regulation of miR-3942-3p using miR-3942-3p inhibitor resulted in significantly increased cell viability, decreased apoptosis of CNE1 cells. Bax decreased and Bcl2 increased after IR. The expression of BARD1, a cancer predisposing gene, was elevated in NPC tissue. It was confirmed to be a target of miR-3942-3p using luciferase reporter assay. Down-regulation of BARD1 using siRNA significantly reduced cell viability and significantly increased apoptosis both before and after IR. The same response was observed when miR-3942-3p mimics was used to transfect BARD1-overexpressing CNE1 cells, suggesting the up-regulation of miR-3942-3p could sensitize CNE1 cells to X-rays via BARD1. Our data demonstrate that up-regulation of miR-3942-3p could sensitize NPC to X-rays via a downstream target BARD1, offering potential new strategies for radiotherapy of NPC.

Endostar, an Antiangiogenesis Inhibitor, Combined With Chemoradiotherapy for Locally Advanced Cervical Cancer.

This phase II randomized clinical trial aimed to assess the efficacy and toxicity of Endostar, an antiangiogenesis inhibitor, combined with concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC). Patients with LACC were randomly assigned to either CCRT plus Endostar (CCRT+E arm) or CCRT alone (CCRT arm). All patients received pelvic intensity-modulated radiation therapy (IMRT) and brachytherapy. Weekly cisplatin was administered concurrently with IMRT. Patients in the CCRT+E arm also received concurrent Endostar every 3 weeks for two cycles. The primary endpoint was progression-free survival (PFS) and acute toxicities. The exploratory endpoint was the impact of vascular endothelial growth factor receptor-2 (VEGFR2) expression on long-term survival. A total of 116 patients were enrolled. Patients in the CCRT+E arm and in the CCRT arm had similar acute and late toxicity profile. The 1- and 2-year PFS were 91.4% versus 82.1% and 80.8% versus 63.5% (p=0.091), respectively. The 1- and 2-year distance metastasis-free survival (DMFS) were 92.7% versus 81.1% and 86.0% versus 65.1% (p=0.031), respectively. Patients with positive VEGFR2 expression had significant longer PFS and overall survival (OS) compared with those with negative VEGFR2 expression. Patients in the CCRT+E arm had significantly longer PFS, OS, and DMFS than those in the CCRT arm when VEGFR2 expression was positive. In conclusion, CCRT plus Endostar significantly improved DMFS but not PFS over CCRT alone. The addition of Endostar could significantly improve survival for patients with positive VEGFR2 expression.

Hyperprogression After Immunotherapy for Primary Small Cell Neuroendocrine Carcinoma of the Ureter: A Case Report.

BACKGROUND: Primary small cell neuroendocrine carcinoma (SCNEC) in the ureter is extremely rare and has been sporadically reported in case reports. Its incidence, diagnosis, treatment, and outcomes have not yet been thoroughly understood. Here we present a patient with advanced SCNEC in the ureter who was treated by multimodal strategies. To the best of our knowledge, this is the first literature report about the clinical outcomes of the combination of programmed death ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) and radiotherapy in patient with primary ureteral SCNEC. CASE PRESENTATION: A 71-year old male presented with right flank pain and gross hematuria. A laparoscopic right nephroureterectomy was performed. He was diagnosed with primary ureteral SCNEC, pT3N0M0. Following the surgery, 4 cycles of adjuvant chemotherapy with carboplatin and etoposide (CE) were administered, with disease-free survival (DFS) of 10.1 months. He was then offered 4 cycles of palliative first-line chemotherapy with nedaplatin and irinotecan. The disease was continuously progressed, with progression-free survival (PFS) of 3.7 months. The patient subsequently received second-line treatment with PD-L1 ICI combined with radiotherapy. Unfortunately, hyperprogressive disease was found at the end of treatment. MRI and CT scan showed bilateral pubic bones, right acetabulum, and liver metastases. Without further intervention, the patient died from extensive metastatic disease 2 months after diagnosis, with overall survival (OS) of 18.2 months. CONCLUSION: Physicians must be aware of this rare and aggressive carcinoma at its initial presentation. Special attention should be paid to the potential likelihood of hyperprogression during the treatment.

Long-Term Results of Concurrent Chemoradiotherapy Combined with Anti-EGFR Monoclonal Antibody Prior to Surgery in Locally Advanced Cervical Cancer: A Single-Institute Prospective Study.

PURPOSE: We aimed to evaluate the long-term survival outcomes of concurrent chemoradiotherapy (CCRT) combined with nimotuzumab followed by surgery in patients with locally advanced cervical cancer (LACC). PATIENTS AND METHODS: Patients received whole pelvic intensity-modulated radiation therapy (IMRT) and concomitantly with weekly cisplatin (40 mg/m2) or nedaplatin (30 mg/m2) and weekly nimotuzumab (200 mg). After assessment of the treatment response, patients then underwent radical surgery. RESULTS: Between June 2013 and July 2016, 33 patients with FIGO IB2-IIIB cervical cancer were recruited. Clinical complete response and partial response were observed in 8 (24.3%) and 23 patients (69.7%), respectively. Twenty-seven patients (81.8%) were successfully treated with radical hysterectomy and pelvic lymphadenectomy: 9 (33.3%) showed pathological complete response; 10 (37.1%) showed partial response and 8 (29.6%) presented with persistent macroscopic/microscopic residual carcinoma. For the intention-to-treat population, the median follow-up time was 53.7 months. Locoregional recurrence and distant metastases were observed in three and seven patients, respectively. The 5-year overall survival, progression-free survival, locoregional recurrence-free survival, and distant metastasis-free survival were 81.5%, 72.7%, 90.9%, and 78.3%, respectively. Both acute and late toxicities were manageable and mainly limited to grade 1 or 2. CONCLUSION: Concurrent chemoradiotherapy combined with nimotuzumab followed by surgery for patients with LACC is safe and results in excellent long-term treatment outcomes. Further randomized controlled studies are warranted to confirm the findings.

A prospective study on neoadjuvant chemoradiotherapy plus anti-EGFR monoclonal antibody followed by surgery for locally advanced cervical cancer.

BACKGROUND: To investigate the efficacy and safety of neoadjuvant chemoradiotherapy plus anti-epidermal growth factor receptor monoclonal antibody followed by surgery for locally advanced cervical cancer (LACC). PATIENTS AND METHODS: Patients with histologically proven LACC were enrolled into this prospective study. All patients received intensity-modulated radiation therapy with conventional fractionation. Weekly cisplatin or nedaplatin was administered concurrently with intensity-modulated radiation therapy. Nimotuzumab, a humanized anti-epidermal growth factor receptor monoclonal antibody, was given at a dose of 200 mg per week for 6 cycles. Approximately 1 month after the completion of neoadjuvant treatment, the patients were assessed for clinical tumor response and operability based on MRI and gynecological examination. For those who were considered to be candidates for surgery, radical hysterectomy, and pelvic lymph node dissection were performed 5-6 weeks after the completion of neoadjuvant therapy. RESULTS: Twenty-eight patients were enrolled. Clinical complete response and partial response were found in 8 (28.5%) and 20 (71.5%) patients, respectively. Four patients were not eligible for surgery and 2 patients refused surgery although they were assessed as surgical candidates. They were not included in this analysis. Radical hysterectomy and pelvic lymph node dissection were performed for the remaining 22 patients. Among them, 8 (36.4%) had complete pathology response, 9 (40.9%) presented with persistent atypical cells or cervical intraepithelial neoplasia, and 5 (22.7%) presented with macroscopic and/or microscopic residual disease, according to the pathological evaluation. Median follow-up time was 22 months (range, 5-39 months). The 2-year locoregional control rate, progression-free survival rate, distant metastasis-free survival rate, and overall survival rate were 95.0%, 85.2%, 84.0%, and 90.0%, respectively. Acute toxicities were mild in general and easily manageable. Chronic toxicities were mainly limited to grade 1. No severe late toxicities were observed. CONCLUSION: Concurrent chemoradiotherapy plus nimotuzumab followed by surgery is highly effective and safe in LACC. Further studies are warranted to confirm the findings.

Three-Phase Adaptive Radiation Therapy for Patients With Nasopharyngeal Carcinoma Undergoing Intensity-Modulated Radiation Therapy: Dosimetric Analysis.

Patients with nasopharyngeal carcinoma undergoing intensity-modulated radiation therapy may experience significant anatomic changes throughout the entire treatment course, and adaptive radiation therapy may be necessary to maintain optimal dose delivered both to the targets and to the critical structures. The timing of adaptive radiation therapy, however, is largely unknown. This study was to evaluate the dosimetric benefits of a 3-phase adaptive radiation therapy technique for nasopharyngeal carcinoma. Twenty patients with nasopharyngeal carcinoma treated with intensity-modulated radiation therapy were recruited prospectively. After fractions 5 and 15, each patient had repeat computed tomography scans, and adaptive replans with recontouring the targets and organs at risk on the new computed tomography images were generated and used for subsequent treatment (replan 1 and replan 2). Two hybrid intensity-modulated radiation therapy plans (plan 1 and plan 2) were generated by superimposing the initial plan (plan 0) to each repeated new computed tomography image, reflecting the actual dose delivered to the targets and organs at risk if no changes were made to the original plan. Dosimetric comparisons were made between the adaptive replans (adaptive radiation therapy plans: plan 0 + replan 1 + replan 2) and their corresponding nonadaptive radiation therapy plans (plan 0 + plan 1 + plan 2). Comparing with the nonadaptive radiation therapy plans, the adaptive radiation therapy plans resulted in a significant improvement in conformity index for planning target volumes for primary disease, involved lymph node, high-risk clinical target volume, and low-risk clinical target volume (PTVnx, PTVnd, PTV1, and PTV2, respectively). Median V95 for PTVnx; D95, D99, V100, V95, and V93 for PTVnd; D99 and V100 for PTV1; and D95, D99, V100, V95, and V93 for PTV2 were increased significantly. There were significant dose-volume reductions, including maximum doses to the brainstem and temporal lobes, mean doses to the glottis, V50 for the supraglottis, Dmean and V30 for the left parotid, median dose to the right optic nerve, and V55 for the skin. The 3-phase adaptive intensity-modulated radiation therapy for patients with nasopharyngeal carcinoma results in improvements in target coverage and conformity index and decreased doses to some organs at risk.

Determining appropriate timing of adaptive radiation therapy for nasopharyngeal carcinoma during intensity-modulated radiation therapy.

BACKGROUND: To determine appropriate timing of an adaptive radiation therapy (ART) replan by evaluating anatomic and dosimetric changes of target volumes and organs at risk (OARs) during intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC). METHODS: Nineteen NPC patients were recruited. Each patient had repeat computed tomography (CT) scans after each five fractions and at treatment completion. Automatic re-contouring the targets and OARs by using deformable registration algorithm was conducted through CT-CT fusion. Anatomic changes were assessed by comparing the initial CT and repeated CT. Hybrid plans with re-contouring were generated and the dose-volume histograms (DVH) of the hybrid plan and the original plan were compared. RESULTS: Progressive volume reductions in gross target volume for primary disease (GTVnx), gross target volume for involved lymph nodes (GTVnd), and parotids were observed over time. Comparing with the original plan, each hybrid plan had no significant difference in homogeneity index (HI) for all the targets. Some parameters for planning target volumes for primary disease and high-risk clinical target volume (PTVnx and PTV1, respectively) improved significantly, notably starting from the 10th fraction. These parameters included mean dose (Dmean), dose to 95% of the volume (D95), percentage of the volume receiving 95% of the prescription dose (V95), and conformity index (CI) for PTVnx, and Dmean, D95, and CI for PTV1. The dosimetric parameters for PTVnd remained the same in general except for D95 and V95 which had significant improvement at specific time points; whereas for PTV2, similar trend of dosimetric changes was also observed. Dose to some OARs increased significantly at some time points. CONCLUSIONS: There were significant anatomic and dosimetric changes in the targets and OARs. The target dose coverage in the hybrid plans did not get worse, but overdose occurred in some critical structures. Significant dosimetric changes should be considered as a trigger point at which ART replanning is indicated. D95/V95/CI for PTV2, Dmax for the brain stem, spinal cord, right eyeball and left lens, and Dmean/V30 for the parotids and glottis were taken into account for predicting the need for ART. Two replans at the 5th and 15th fractions were suggested.

Dosimetric study of a respiratory gating technique based on four-dimensional computed tomography in non-small-cell lung cancer.

This study sought to compare the differences in target volumes and dose distributions to the targets and organs at risk (OARs) between a four-dimensional computed tomography (4DCT)-based respiratory-gated intensity-modulated radiation therapy (IMRT) plan (PlanEOE) and a three-dimensional CT (3DCT)-based IMRT plan (Plan3D) in patients with non-small-cell lung cancer (NSCLC). For 17 patients with Stages I-III NSCLC, both 4DCT data and conventional 3DCT data were obtained. The Plan3D and PlanEOE were designed based on 3DCT data and 4DCT data, respectively. The displacements of the gross tumor volume (GTV) centroid were 0.13 ± 0.09 cm, 0.15 ± 0.1 cm, and 0.27 ± 0.27 cm in the right-left, anterior-posterior, and superior-inferior directions, respectively. The volume of the GTVEOE was 3.05 ± 5.17 cm(3) larger than that of the GTV3D. The volume of the PTV3D was 72.82 ± 48.65 cm(3) larger than that of the PTVEOE. There was no significant difference between the PTV3D and PTVEOE for V55.8, V60, V66 and the homogeneity index. The PTV3D had a lower target conformity index than the PTVEOE (P = 0.036). PlanEOE had a significantly lower lung V10, V20, V30, V40 and mean lung dose (MLD) than Plan3D. For the heart, PlanEOE had a significantly lower V30 and mean dose. In conclusion, 4DCT is an appropriate method for assessing the displacement of the GTV centroid in three dimensions. PlanEOE has smaller PTVs and a decreased dose and volume for the normal lung and heart, as compared with Plan3D.

Expression of DNA-PKcs and BRCA1 as prognostic indicators in nasopharyngeal carcinoma following intensity-modulated radiation therapy.

The mechanisms of radiation-induced effects in cancer mainly involve double-strand breaks (DSBs) which are important in maintaining the stability of genes. The DNA repair genes breast cancer 1 (BRCA1) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are capable of maintaining genetic stability through two distinct and complementary repair mechanisms for DNA DSBs, known as repair-homologous recombination (HR) and non-homologous end joining (NHEJ). DNA-PKcs is a member of the phosphatidylinositol 3-kinase (PI3K) family. The PI3K/AKT cell signaling pathway is implicated in cell migration and invasion. The BRCA1 protein is implicated in multiple complex cellular processes that are related to chromosome sensitivity to mutagens. To determine the protein expression and clinical implications of DNA-PKcs and BRCA1 in nasopharyngeal carcinoma (NPC) and cancer progression, we evaluated its expression status by immunohistochemistry in 87 patients who received intensity-modulated radiation therapy (IMRT). In NPC, negative expression of DNA-PKcs was detected in 35 of the 87 (40.2%) cancer types and was significantly associated with poor patient survival (P<0.05). The overexpression of DNA-PKcs and BRCA1 also led to significantly improved distant metastasis-free survival compared with patients who did not overexpress both genes, although the expression level of BRCA1 and distant metastasis-free survival were not closely correlated. In addition, multivariate analysis indicated that DNA-PKcs status is a predictive marker of distant metastasis-free survival. In conclusion, lower expression of DNA-PKcs may be correlated with higher distant metastasis in patients with NPC. DNA-PKcs may be a predictive marker of distant metastasis after IMRT, independent of the classical prognostic marker. BRCA1 may additionally exert a synergistic effect to predict distant metastasis-free survival.

Interfractional and intrafractional errors assessed by daily cone-beam computed tomography in nasopharyngeal carcinoma treated with intensity-modulated radiation therapy: a prospective study.

This prospective study was to assess interfractional and intrafractional errors and to estimate appropriate margins for planning target volume (PTV) by using daily cone-beam computed tomography (CBCT) guidance in nasopharyngeal carcinoma (NPC). Daily pretreatment and post-treatment CBCT scans were acquired separately after initial patient setup and after the completion of each treatment fraction in 10 patients treated with IMRT. Online corrections were made before treatment if any translational setup error was found. Interfractional and intrafractional errors were recorded in the right-left (RL), superior-inferior (SI) and anterior-posterior (AP) directions. For the translational shifts, interfractional errors >2 mm occurred in 21.7% of measurements in the RL direction, 12.7% in the SI direction and 34.1% in the AP direction, respectively. Online correction resulted in 100% of residual errors ≤2 mm in the RL and SI directions, and 95.5% of residual errors ≤2 mm in the AP direction. No residual errors >3 mm occurred in the three directions. For the rotational shifts, a significant reduction was found in the magnitudes of residual errors compared with those of interfractional errors. A margin of 4.9 mm, 4.0 mm and 6.3 mm was required in the RL, SI and AP directions, respectively, when daily CBCT scans were not performed. With daily CBCT, the margins were reduced to 1.2 mm in all directions. In conclusion, daily CBCT guidance is an effective modality to improve the accuracy of IMRT for NPC. The online correction could result in a 70-81% reduction in margin size.

Feasibility and efficacy study of weekly cisplatin with concurrent intensity-modulated radiation therapy for nasopharyngeal carcinoma: preliminary results.

The aim of this study was to assess the feasibility and efficacy of a weekly cisplatin 40 mg/m(2) regimen in patients with nasopharyngeal carcinoma treated concurrently with definitive intensity-modulated radiation therapy (IMRT). The primary endpoints were treatment compliance and acute toxicities. Twenty-two patients with newly diagnosed NPC were recruited in this phase II trial. All patients received definitive IMRT concurrently with weekly cisplatin 40 mg/m(2) for six cycles. The treatment technique was split-field IMRT (SF-IMRT) before August 2009 and whole-field IMRT (WF-IMRT) thereafter. The median follow-up time was 15.1 months (range, 1.5-30 months). No patients experienced regional recurrence or distant metastasis. One patient developed local recurrence. One patient died of non-malignant disease. For all patients, the 1-year overall survival, local recurrence-free survival, regional recurrence-free survival, and distant metastasis-free survival were 95.5%, 95.5%, 100%, and 100%, respectively. All patients received the full dose of RT. Twenty-one patients (95.5%) completed all six cycles of chemotherapy (CHT). Three patients experienced treatment delay. Of them, one had CHT delay, and the other two had IMRT delay. No treatment-related death was found. Acute toxicities were generally mild or moderate. Grade 3 and 4 toxicities accounted for less than 10% of overall occurrence in each corresponding category except for a relatively higher rate in stomatitis (Grade 3, 27%). Renal function impairment was not found. Weekly cisplatin with concurrent IMRT appears to be feasible and effective in treating NPC patients and these findings warrant further investigation.

Intrathoracic Endotracheal Metastasis from Nasopharyngeal Carcinoma: A First Case Report and Review of the Literature.

Intrathoracic endotracheal metastasis from a very distant site is extremely rare. We report the first case of such a disease in a 68-year-old man with nasopharyngeal carcinoma who presented with a cough and hemoptysis 34 months after finishing radiotherapy. Prior to tracheal metastasis, he developed a solitary metastasis in the lung and underwent chemotherapy followed by radiotherapy. Computed tomography showed the presence of an enlarged lymph node in the para-aortic arch. Fiberoptic bronchoscopy revealed an endotracheal tumor 1 cm above the carina. Histological and immunohistochemical analyses confirmed its nasopharyngeal origin. He was treated with conventional radiotherapy and three-dimensional conformal radiotherapy; complete tumor remission was achieved. He died of nonmalignant disease with no signs of tumor recurrence 2 years after treatment completion. Radiotherapy may be an appropriate management approach to achieve long-term tumor control for this disease.

Concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma: a treatment paradigm also applicable to patients in Southeast Asia.

The majority of nasopharyngeal carcinoma (NPC) patients present at locally advanced stage. The poor prognosis has led to increasing interests in exploring the use of chemotherapy (CT). Intergroup-0099 trial was the first randomized trial comparing concurrent chemoradiotherapy (CCRT) with radiotherapy (RT) alone. Its outcome established the treatment standard in the United States as standard of care for locally advanced NPC. However, criticism has been arisen, particularly about its reproducibility and applicability in Southeast Asia where NPC is an endemic disease. Subsequently, new evidence has been provided by a large number of publications from various centers. In this article, through comprehensively analyzing recent meta-analyses and randomized controlled trials performed in Asian centers, we conclude that CCRT as a treatment paradigm is also applicable to patients in Southeast Asia and should be standard of practice in locally advanced disease. However, the CT regimen varied markedly among those trials, and the optimal regimen and scheduling remains to be determined. Moreover, a number of patients experienced toxicities and the treatment compliance was generally poor. With the emergence of new RT techniques such as intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT), the role of concurrent CT with these new techniques needs to be tested. New chemotherapeutics have been investigated in the recurrent or metastatic disease. However, their effectiveness in previously untreated NPC is unclear. Previous efforts have been made for immunotherapy and targeted therapy in palliative setting. Their role in newly diagnosed NPC should be evaluated, particularly when they are combined with CT or RT.