Background: Glioma stem cells (GSCs) are glioma cells with stemness and are responsible for a variety of malignant behaviors of glioma. Evidence has shown that signals from tumor microenvironment (TME) enhance stemness of glioma cells. However, identification of the signaling molecules and underlying mechanisms has not been completely elucidated. Methods: Human samples and glioma cell lines were cultured in vitro to determine the effects of adenovirus (ADV) infection by sphere formation, RT-qPCR, western blotting, FACS and immunofluorescence. For in vivo analysis, mouse intracranial tumor model was applied. Bioinformatics analysis, gene knockdown by siRNA, RT-qPCR and western blotting were applied for further mechanistic studies. Results: Infection of patient-derived glioma cells with ADV increases the formation of tumor spheres. ADV infection upregulated stem cell markers and in turn promoted the capacities of self-renewal and multi-lineage differentiation of the infected tumor spheres. These ADV infected tumor spheres had stronger potential to form xenograft tumors in immune-compromised mice. GSCs formation could be promoted by ADV infection via TLR9, because TLR9 was upregulated after ADV infection, and knockdown of TLR9 reduced ADV-induced GSCs. Consistently, MYD88, as well as total STAT3 and phosphorylated (p-)STAT3, were also upregulated in ADV-induced GSCs. Knockdown of MYD88 or pharmaceutical inhibition of STAT3 attenuated stemness of ADV-induced GSCs. Moreover, we found that ADV infection upregulated lncRNA NEAT1. Knockdown of NEAT1 impaired stemness of ADV-induced GSCs. Lastly, HMGB1, a damage associated molecular pattern (DAMP) that triggers TLR signaling, also upregulated stemness markers in glioma cells. Conclusion: ADV, which has been developed as vectors for gene therapy and oncolytic virus, promotes the formation of GSCs via TLR9/NEAT1/STAT3 signaling.

Background: The aim of this study was to compare the long-term survival outcome and late toxicity in patients with FIGO (International Federation of Gynecology and Obstetrics) stage IIB cervical carcinoma after two treatment modalities, ie, concurrent chemoradiotherapy followed by radical surgery and concurrent chemoradiotherapy followed by high-dose-rate intracavitary brachytherapy. Methods: Between November 2004 and November 2011, 240 patients with FIGO stage IIB cervical carcinoma were analyzed, comprising 119 patients treated with concurrent chemoradiotherapy followed by radical surgery (group 1) and 121 patients treated with concurrent chemoradiotherapy followed by high-dose-rate intracavitary brachytherapy (group 2). Local control, overall survival, progression-free survival, and treatment-related complications were compared between the two groups. Results: The median follow-up duration was 36 months. Concurrent chemoradiotherapy followed by radical surgery showed a survival benefit when comparing group 1 and group 2 (3-year overall survival, 94.9% versus 84.6%, P=0.011; 3-year progression-free survival, 91.0% versus 81.8%, P=0.049, respectively). Three-year local pelvic control was 94.6% in group 1 and 93.3% in group 2 (P=0.325). Prognostic factors in group 1 were: age (≤35 years versus >35 years), 3-year progression-free survival (74.1% versus 90.9%, P=0.037); tumor diameter (≥6 cm versus <6 cm); and 3-year progression-free survival, (60.6% versus 92.9%, P=0.004). Prognostic factors in group 2 were: tumor diameter (≥4 cm versus <4 cm); 3-year overall survival (78.0% versus 94.8%, P=0.043); tumor diameter (≥6 cm versus <6 cm); 3-year progression-free survival (42.9% versus 84.2%, P=0.032); and 3-year overall survival (42.9% versus 87.1%, P=0.013). Further, 50 patients (42.02%) in group 1 and 46 patients (38.02%) in group 2 suffered from late complications. Analysis of the difference in composition of late complications showed that the rate of leg edema was higher in group 1 (35.29% versus 4.96%, P=0.000) while the rate of radiation enteritis was higher in group 2 (30.58% versus 5.04%, P=0.000). Conclusion: In patients with FIGO stage IIB cervical carcinoma, concurrent chemoradiotherapy followed by radical surgery achieved higher overall survival and progression-free survival rates in comparison with radical radiotherapy associated with concurrent chemotherapy. Tumor diameter could be a common prognostic factor in these two groups of patients.

The standard of care for locally advanced cervical cancer is concurrent chemoradiotherapy, which is associated with significant toxicity, especially hematologic toxicity. To evaluate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in preventing neutropenia during radical chemoradiotherapy for cervical cancer, 40 patients receiving prophylaxis from February 2018 to July 2019 were randomly divided into two arms in a 1:1 ratio. Patients in the study arm (N = 21) received PEG-rhG-CSF, while patients in the control arm (N = 19) received short-acting rhG-CSF. The primary endpoint was the incidence of grade 3–4 neutropenia, and the secondary endpoints were the incidence of febrile neutropenia, chemotherapy delay, and radiotherapy interruption. In addition, dynamic changes in absolute neutrophil count during radical chemoradiotherapy and adverse events were compared between the two groups. There were 0 and 4 cycles of grade 3–4 neutropenia in the PEG-rhG-CSF and rhG-CSF groups, respectively. The incidence of neutropenia of all grades was lower in patients on PEG-rhG-CSF than on rhG-CSF [24.05% (19/79) vs. 56.94% (41/72); p < 0.001]. No patient developed neutropenic fever. The lowest values of neutropenia during concurrent chemoradiotherapy cycles were 2.73 ± 1.02 and 1.91 ± 0.79 × 10 9/ml in the PEG-rhG-CSF and rhG-CSF groups, respectively (p < 0.001). In the PEG-rhG-CSF and rhG-CSF groups, 0 and 8 (11.11%) cycles of chemotherapy were delayed due to neutropenia, respectively (p = 0.01). There was no delay of radiotherapy by more than one week in either group. Prophylactic use of PEG-rhG-CSF during chemoradiotherapy for cervical cancer can effectively prevent neutropenia and associated adverse events. PEG-rhG-CSF may be an effective strategy to provide uninterrupted radical chemoradiotherapy for cervical cancer.

To clarify the effect of postmastectomy radiotherapy (PMRT) on pT_1-2N₁ breast cancer patients with different molecular subtypes. We retrospectively analyzed the data of 5442 patients with pT_1-2N₁ breast cancer treated using modified radical mastectomy in 11 hospitals in China. Univariate, multivariate, and propensity score matching (PSM) analyses were used to evaluate the effect of PMRT on locoregional recurrence (LRR). With a median follow-up duration of 63.8 months, the 5-year LRR rates were 4.0% and 7.7% among patients treated with and without PMRT, respectively (p < 0.001). PMRT was independently associated with reduced LRR after adjustments for confounders (p < 0.001). After grouping the patients according to the molecular subtype of cancer and conducting PSM, we found that the 5-year LRR rates among patients treated with and without PMRT (in that order) were as follows: luminal HER2-negative cancer, 1.9% and 6.5% (p < 0.001); luminal HER2-positive cancer, 3.8% and 13.7% (p = 0.041); HER2-overexpressing cancer, 10.2% and 15.5% (p = 0.236); and triple-negative cancer, 4.6% and 15.9% (p = 0.002). Among patients with HER2-overexpressing and triple-negative cancers, the LRR hazard rate displayed a dominant early peak, and was extremely low after 5 years. However, patients with luminal cancer continued to have a long-lasting high annual LRR hazard rate during follow-up. PMRT significantly reduced the LRR risk in patients with pT_1-2N₁ luminal and triple-negative breast cancers, but had no effect on the LRR risk in patients with HER2-overexpressing cancer. Patients with different molecular subtypes displayed different annual LRR patterns, and the late recurrence of the luminal subtype suggests the necessity of long-term follow-up to evaluate the efficacy of PMRT.