Curving out a new path: CD28/B7 cis interactions.

Important signaling events at the immunological synapse have increasingly been linked to cis interactions between receptors on T cells. In this issue of Immunity, Zhao et al.1 implicate cis CD28/B7 interactions facilitated by curved membrane invaginations in boosting tumor immunity.

Real-World Survival Outcomes Based on EGFR Mutation Status in Chinese Patients With Lung Adenocarcinoma After Complete Resection: Results From the ICAN Study.

INTRODUCTION: The adjuvant treatment of patients with resected lung adenocarcinoma (LUAD) remains unstandardized. We analyzed the survival outcomes of these patients based on EGFR mutation status and adjuvant chemotherapy treatment. METHODS: This noninterventional real-world study (ICAN) enrolled Chinese patients with resected stages I to III LUAD from April 8, 2010, to December 31, 2010. Tumor EGFR mutation status and 3-year disease-free survival (DFS) were determined. The extension phase provided long-term follow-up with overall survival (OS) as the primary end point. Secondary end points included DFS and prognostic factors of survival. Survival outcomes based on adjuvant chemotherapy treatment, EGFR mutation status, and postoperative stage were analyzed post hoc. RESULTS: Among 568 patients in the ICAN cohort, 472 continued to the extension phase and remained eligible. The 3-year DFS rate was 58.8%. In the extension cohort, 260 patients (55.1%) had EGFR-mutant disease and 207 (43.9%) received adjuvant chemotherapy. At a median follow-up of 109.0 (95% confidence interval [CI]: 106.6-111.4) months, median OS and DFS were 103.3 (95% CI: 101.7-104.9) and 67.4 (95% CI: 49.7-85.2) months, respectively. The 5-year OS and DFS rates were 68.9% (95% CI: 64.3-73.6) and 52.9% (95% CI: 48.2-57.7), respectively. EGFR wild-type disease was a significant independent predictor of worse OS (HR = 1.24, 95% CI: 1.07-1.44, p= 0.004) based on the Cox regression analysis of common factors. Post hoc subgroup analysis revealed that survival outcomes were not significantly different with adjuvant chemotherapy regardless of EGFR mutation status across all postoperative stages. CONCLUSIONS: EGFR mutations are common in operable LUAD, and recurrence and mortality after resection were considerable. Adjuvant chemotherapy did not improve survival outcomes, regardless of EGFR mutation status and postoperative stage.

Final report of a prospective randomized study on thoracic radiotherapy target volume for limited-stage small cell lung cancer with radiation dosimetric analyses.

BACKGROUND: The thoracic radiotherapy (TRT) target volume for limited-stage small-cell lung cancer (SCLC) has been controversial for decades. In this report, the final results of a prospective randomized trial on the TRT target volume before and after induction chemotherapy are presented. METHODS: After 2 cycles of etoposide and cisplatin, patients arm were randomized to receive TRT to the postchemotherapy or prechemotherapy tumor volume in a study arm and a control arm. Involved-field radiotherapy was received in both arms. TRT consisted of 1.5 grays (Gy) twice daily in 30 fractions to up to a total dose of 45 Gy. Lymph node regions were contoured, and intentional and incidental radiation doses were recorded. RESULTS: The study was halted early because of slow accrual. Between 2002 and 2017, 159 and 150 patients were randomized to the study arm or the control arm, respectively; and 21.4% and 19.1% of patients, respectively, were staged using positron emission tomography/computed tomography (P = .31). With a median follow-up of 54.1 months (range, 19.9-165.0 months) in survivors, the 3-year local/regional progression-free probability was 58.2% and 65.5% in the study and control arms, respectively (P = .44), and the absolute difference was -7.3% (95% CI, -18.2%, 3.7%). In the study and control arms, the median overall survival was 21.9 months and 26.6 months, respectively, and the 5-year overall survival rate was 22.8% and 28.1%, respectively (P = .26). Grade 3 esophagitis was observed in 5.9% of patients in the study arm versus 15.5% of those in the control arm (P = .01). The isolated out-of-field failure rate was 2.6% in the study arm versus 4.1% in the control arm (P = .46), and all such failures were located in the supraclavicular fossa or contralateral hilum. The regions 7, 3P, 4L, 6, 4R, 5, and 2L received incidental radiation doses >30 Gy. CONCLUSIONS: TRT could be limited to the postchemotherapy tumor volume, and involved-field radiotherapy could be routinely applied for limited-stage SCLC.

PIM1 gene silencing inhibits proliferation and promotes apoptosis of human esophageal cancer cell line Eca-109.

We aimed to study the effect of PIM1 gene silencing on the proliferation and apoptosis of human esophageal cancer cell line Eca109. Cultured Eca109 cells were transfected with the recombinant plasmids in mediation of Lipofectamine TM 2000 Reagent. The Eca109 cells in logarithmic growth phase were collected and assigned into three groups: the PIM1 siRNA group (stably transfected with PIM1-shRNA plasmids), the negative control (NC) group (transfected with vacant plasmids), and the blank group (Eca109 cells without any transfection). The PIM1 mRNA expression was determined by real-time quantitative polymerase chain reaction (RT-qPCR). Cell cycle was analyzed by flow cytometry. Cell proliferation was evaluated using the Cell Counting Kit-8 (CCK-8). Cell apoptosis was assessed by Annexin V-FITC/PI double-staining and TUNEL assays. The PIM1 mRNA expression of Eca109 cells in the PIM1 siRNA group was significantly lower than that in the NC and blank groups. Compared with the NC and blank groups, the viability and proliferation of the Eca109 cells in the PIM1 siRNA group were significantly decreased at 48 h, 72 h and 96 h after transfection. The cell growth inhibition rate of the PIM1 siRNA group was higher than that of the NC and blank groups after transfection. Furthermore, the apoptotic rate of the PIM1 siRNA group was also higher than that of the NC and blank groups. In conclusion, our preliminary findings suggest that PIM1 gene silencing could inhibit proliferation and promote apoptosis of esophageal cancer cells.

Chemokine receptor CXCR4 expression and lung cancer prognosis: a meta-analysis.

The chemokine receptor CXCR4 is a G protein-coupled receptor that plays an important role in several biological processes, such as trafficking and homeostasis of immune cells (like T lymphocytes), alteration of cell skeleton rearrangement and cell migration. To investigate whether the CXCR4 protein impacts on lung cancer prognosis, a meta-analysis was performed. Our meta-analysis study involved 2,037 lung cancer patients from 24 studies by a comprehensive search from PubMed, Embase and CNKI databases up to September 2014. Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) were used to evaluate the relationship. We found that the CXCR4 expression was significantly associated with lymph node metastasis (OR = 3.79, 95% CI: 2.15-6.68), distant metastasis (OR = 3.67, 95% CI: 1.84-7.32), tumor stage (OR = 2.78, 95% CI: 1.77-4.39) and overall survival (HR = 1.63, 95% CI: 1.16-2.30). In conclusion, CXCR4 might be a new prognostic biomarker, and it might become a new diagnosis and therapeutic target in lung cancer.

MiR-133a modulates osteogenic differentiation of vascular smooth muscle cells.

Arterial calcification is a key pathologic component of vascular diseases such as atherosclerosis, coronary artery disease, and peripheral vascular disease. A hallmark of this pathological process is the phenotypic transition of vascular smooth muscle cells (VSMCs) to osteoblast-like cells. Several studies have demonstrated that microRNAs (miRNAs) regulate osteoblast differentiation, but it is unclear whether miRNAs also regulate VSMC-mediated arterial calcification. In the present study, we sought to characterize the role of miR-133a in regulating VSMC-mediated arterial calcification. Northern blotting analysis of VSMCs treated with ß-glycerophosphate demonstrated that miR-133a was significantly decreased during osteogenic differentiation. Overexpression of miR-133a inhibited VSMC transdifferentiation into osteoblast-like cells as evidenced by a decrease in alkaline phosphatase activity, osteocalcin secretion, Runx2 expression, and mineralized nodule formation. Conversely, the knockdown of miR-133a using an miR-133a inhibitor promoted osteogenic differentiation of VSMCs by increasing alkaline phosphatase activity, osteocalcin secretion, and Runx2 expression. Runx2 was identified as a direct target of miR-133a by a cotransfection experiment in VSMCs with luciferase reporter plasmids containing wild-type or mutant 3'-untranslated region sequences of Runx2. Furthermore, the pro-osteogenic effects of miR-133a inhibitor were abrogated in Runx2-knockdown cells, and the inhibition of osteogenic differentiation by pre-miR-133a was reversed by overexpression of Runx2, providing functional evidence that the effects of miR-133a in osteogenic differentiation were mediated by targeting Runx2. These results demonstrate that miR-133a is a key negative regulator of the osteogenic differentiation of VSMCs.

[Clinicopathological features and prognostic analysis of esophageal sarcomatoid carcinoma].

OBJECTIVE: To analyze the clinicopathological characteristics and prognosis of a rare histological type of esophageal cancer-sarcomatoid carcinoma. METHODS: Clinicopathological data of 31 patients with esophageal sarcomatoid carcinoma who underwent surgery in the Department of Thoracic Surgery of Zhejiang Cancer Hospital from Jan 2000 to Dec 2009 were collected and analyzed. The survival analysis was performed using Kaplan-Meier method. RESULTS: All the patients underwent surgery. Of the 31 patients, one received preoperative chemoradiotherapy and postoperative chemotherapy, and 8 received postoperative chemotherapy. All the tumors were located in the middle or lower esophagus. Microscopically, the tumors were composed of both carcinomatous and sarcomatous components, and there was a transition between the two components, but no obvious heterogenous elements such as osteosarcoma, chondrosarcoma or rhabdomyosarcoma were found. In the carcinomatous components, positive expression of CK and EMA was found in all the 31 cases, and positive expression of vimentin in 5 of the 31 cases. In the sarcomatous components, positive expression of CK, EMA and vimentin was found in 29, 28 and 23 cases, respectively. The 1-, 3-, and 5-year survival rates were 80.6%, 55.9% and 33.4%, respectively, and the median survival time was 40 months. CONCLUSIONS: Esophageal sarcomatoid carcinoma is a particular type of esophageal malignancy with unique clinicopathological features. The diversity and complexity of the carcinomatous and sarcomatous components and their potential of transformation and differentiation lead to different prognosis from each other.

[Related factors of right recurrent nerve nodal involvement in esophageal cancer].

OBJECTIVE: To study the related factors of right recurrent nerve nodal involvement in esophageal cancer. METHODS: 280 patients with thoracic esophageal cancer received esophagectomy and right recurrent nerve node dissection. The clinicopathological data were analyzed retrospectively. Univariate data were analyzed by chi-square test, and multivariate data were analyzed by logistic regression. RESULTS: The right recurrent nerve nodal metastasis was found in 76 cases (27.1%, 76/280). In the 979 excised right recurrent nerve nodes, metastases were found in 118 nodes (12.1%). The tumor staging, the total number of involved lymph nodes, vascular invasion, the number of lymph node metastases in the thorax, the number of lymph node metastasis in the abdomen, subcarinal node metastasis, and peri-esophageal lymph node metastasis were independent risk factors of right recurrent nerve node metastasis in esophageal carcinoma. CONCLUSION: Right recurrent nerve lymph nodes should be dissected in those patients with high risk factors of lymph node metastasis in thoracic esophageal carcinoma.