Accumulating evidence supports the existence of cancer stem cells (CSCs) in human tumors, and the successful certification of CSCs may lead to the identification of therapeutic targets, which are more effective for the treatment of cancer. The use of spherical cancer models has increased in popularity in cancer stem cell investigations. Tumorospheres, which are used as a model of CSCs and are established in serum-free medium supplemented with growth factors under non-adherent conditions, are one of the most commonly used cancer spherical models and are a valuable method for enriching the CSC fraction. To investigate whether this model is applicable in lung cancer (LC), the identification of lung CSCs and their capacities is essential. In the present study, lung CSCs were enriched by sphere-forming culturing and their stem-like properties were assessed. The results indicated that the lung tumorospheres had enhanced proliferation, clonality, invasion and cisplatin-resistance, and showed significantly increased expression levels of CD133 and breast cancer resistance protein (ABCG2). These results, together with findings previously reported in literature, indicated that the sphere-forming culturing of LC cells induced the enrichment of CSCs and that the tumorospheres exhibited stem cell characteristics. In addition, the higher expression levels of CD133 and ABCG2 in the tumorospheres may provide a rationale for therapeutic targets for LC.
Radiotherapy is one of the primary methods of treatment of malignant tumors, however, resistance to radiation is a major problem. The reasons for the radioresistance are still poorly understood. However, it is generally accepted that microRNAs (miRNAs or miRs) can regulate the radiosensitivity of tumors. The present study therefore aimed to identify specific miRNAs and their effects on radioresistant cells. More specifically, the aim was to investigate specific miRNAs and their effects on radioresistant tumor cells. The radioresistant tumor cells (CNE‑2R) were established using a dose gradient method, and the miRNA expression profiles of CNE‑2R cells and the parental cells (CNE‑2) were determined. The expression of miR‑210 in CNE‑2R cells was significantly higher than in CNE‑2 cells. CNE‑2R cells were transfected with LV‑hsa‑miR‑210‑inhibitor, and CNE‑2 cells were transfected with LV‑hsa‑miR‑210. The expression of miR‑210 was confirmed by reverse transcription quantitative‑polymerase chain reaction. The percentages of CNE‑2R‑miR‑210‑inhibitor and CNE‑2 cells in the G2/M phase were higher than in the CNE‑2R and CNE‑2‑miR‑210 cells, and the percentages of cells in S phase were lower than in the CNE‑2R and CNE‑2‑miR‑210 cells. Following 4 Gy of radiation, CNE‑2R‑miR‑210‑inhibitor and CNE‑2 cells, which express low levels of miR‑210, had a higher apoptosis rate than CNE‑2R and CNE‑2‑miR‑210 cells. Following 4, 8 and 12 Gy of radiation, cell viability and survival fraction of CNE‑2R‑miR‑210‑inhibitor cells were lower than those of CNE‑2R and CNE‑2‑miR‑210 cells, and similar to those of CNE‑2 cells. Together, these findings strongly suggest that miR‑210 negatively regulates the radiosensitivity of tumor cells, and may therefore have therapeutic potential for the treatment of radiation resistance.
To the Editor: The outbreak of the coronavirus disease 2019 (COVID-19) has brought great challenges to the routine diagnosis and treatment of patients. 1 It has been proved in our clinical practice that the buffer ward, as the intermediate platform of pre-examination and risk screening for patients requiring hospitalization, was an effective way to control the COVID-19 transmission in hospitals. 2 However, limited literatures reported the operation and efficiency of the buffer ward. We therefore summarized the admission, characteristics, and outcomes of the patients in buffer wards in our hospital. A total of 1003 patients were included (median age 57 years [interquartile range, IQR, 48-65; range 2-95 years]; 49.5% female; 36.0% cancer) between March 11 and April 23, 2020 (Table 1). Cancer patients, who were vulnerable to COVID-19, were also the focus of this study. Subgroup analyses were performed between cancer and noncancer patients. The demographic distribution between two groups was well balanced (median age 57 years [IQR 50-64; range 3-88 years] and 51.3% female vs median age 57 years [IQR 47-67; range 2-95 years] and 48.4% female; P = .68 for age and P = .39 for gender). Among all the 361 cancer patients, those with thoracic tumors (98, 27.2%), mainly lung cancer, have the most urgent need for hospitalization, followed by gastrointestinal tumors (67, 18.6%) and breast cancer (56, 15.5%) (Table 1). Among the 642 noncancer patients, those with chronic cardio-cerebrovascular diseases (115, 31.2%) were the most affected population, which mirrors findings of other literatures. 3,4 In addition, 19 (3.0%) patients were admitted for thrombotic disease, reflecting the inevitable reality of limited social activities under the epidemic. 5 The process of hospitalization and risk stratification of COVID-19 is shown in Figure 1. All patients would undergo two rounds of risk screening in outpatient and emergency department and buffer ward, respectively. Patients with confirmed infection would be reported immediately and sent to designated hospitals, meanwhile the suspicious This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Objective Definitive chemoradiotherapy (dCRT) is one of the standard treatments for esophageal squamous cell carcinoma (ESCC), but local recurrence is the main cause of treatment failure. The changes in apoptosis and autophagy in recurrent tumors of patients with ESCC following dCRT have been poorly estimated. Thus, this study aimed to investigate the expressions of key regulators of apoptosis and autophagy in matched paired samples of primary and recurrent ESCC. Methods The medical records of patients with locally advanced ESCC who developed local recurrence after dCRT were reviewed, and the expression profiling of apoptosis-related genes, cell apoptosis, autophagy and autophagy-related proteins were detected in normal esophageal squamous epithelium and paired samples of primary and recurrent ESCC. Results A total of 126 patients were enrolled, and 52.4% of them had stage III disease. The 1-, 3- and 5-year local recurrence-free survival (LRFS) rates were 54.8, 19.8 and 14.3%, respectively, with a median LRFS of 13.0 months. Patients with T2 tumor or stage II disease showed a significantly prolonged LRFS compared with that of patients with T3-4 tumor or stage III disease. The Apoptotic Machinery key genes expression profiling identified 5 upregulated and 7 downregulated apoptosis-related genes in recurrent tumors compared with their expression levels in the matched primary ESCC tumors. High expression of CD40, TRAF4 and BCL2A1, and low expression of CARD6 and TNFRSF21 were associated with increased risk of early local recurrence after dCRT. No differences in apoptotic index between primary and recurrent samples were detected. However, typical morphological features of autophagosomes and elevated LC3-II protein expression were detected in recurrent tumor samples, and positive LC3-II expression was correlated with increased risk of early local recurrence. Conclusion Our findings indicated that apoptosis and autophagy dysfunction correlated with early local recurrence in patients with locally advanced ESCC receiving dCRT. Further studies are necessary to understand the biology of tumor recurrence in esophageal cancer.
326 Background: Patients with metastatic esophageal squamous cell carcinoma (mESCC) have dismal prognosis, immune checkpoint inhibitors (ICIs) have been reported to offer objective response rate (ORR) of approximately 30% with a median progression-free survival (PFS) of 3.6 months for mESCC. Emerging evidence suggests that radiation might be a potent immunomodulator in multiple malignancies. In this trial, we aimed to assess the efficacy and safety of the combination of camrelizumab with radiotherapy and chemotherapy in mESCC. Methods: Patients with ECOG performance status of 0-1 and normal renal, liver and bone marrow function who initially diagnosed with mESCC or progressed after prior systemic treatments were received camrelizumab 200 mg of 21-day cycles plus radiotherapy (30-50Gy/10-25f) and platinum-based combination chemotherapy. The primary endpoint was disease control rate (DCR); secondary endpoints were PFS, overall survival (OS), objective response rate (ORR) and safety. Chinese Clinical Trial Registry identifier: ChiCTR2000040533. Results: From September 2018 to March 2021, 34 patients (85.3% men; median age, 60 years; 85.3% ECOG PS=1; 61.8% ≥2 organ metastases) were recruited. At a median follow-up of 14.3 months, the DCR was 70.6% (24 of 34; 95%CI, 52.3 to 84.3); ORR was 38.2% (13 of 34; 95%CI, 22.7 to 56.4); 44.1% had decrease in measurable disease; ≥6 months clinical benefit rate (CBR) was 41.2% (14 of 34; 95%CI, 25.1 to 59.2). Median PFS and OS of 9.5 months (95% CI, 7.1 to NR) and 19.5 months (95% CI, 13.9 to NR), respectively. Of the 34 patients, 32 (94.1%) had treatment-related adverse events (TRAEs) of any grade and 13 (38.3%) had grade 3-4 TRAEs that including reactive cutaneous capillary endothelial proliferation (17.6%), myelotoxicity (23.5%) and interstitial pneumonia (2.9%). No treatment-related death occurred. To the cut-off date of observation, 15 (44.1%) patients died and 12 (35.3%) are still receiving the treatment without events. Conclusions: The combination of camrelizumab with radiotherapy and chemotherapy has notable efficacy compared with historical controls in mESCC with manageable safety. This combination therapy strategy should be validated in a larger trial in the future. Variable N=34 Clinical trial information: ChiCTR2000040533. [Table: see text]
e16136 Background: To estimate the clinical outcomes and safety for patients with unresectable advanced hepatocelluar carcinoma (HCC) treated with apatinib in combination with intensity modulated radiation therapy (IMRT). Methods: This study was an open-label, single-arm, phase 2 clinical trial of apatinib combined with IMRT for treatment of patients with unresectable advanced HCC. Patients aged between 18 and 75 years with adequate hematologic, liver, and renal functions, and ECOG performance status of 1 or less were included in the study between March 2017 and September 2020. Patients received IMRT (biologically effective dose(BED): 46-60Gy), and continuous apatinib (250-500 mg/d) orally until disease progression or unacceptable toxic effects. The primary end point was progression-free survival(PFS), the secondary end points included overall survival(OS), disease control rate (DCR), objective response rate(ORR) and safety. The data were analyzed for this report with cutoff on February 1, 2021. Results: A total of 46 patients were screened and 33 were enrolled in this study. The cohort had a median age of 56.7 years (range 21-77), 28(84.85%) were men. 25(75.76%) patients had hepatitis B, 32(96.7%) were BCLC stage B-C, 31(93.9%) were Child-Pugh A-B,and 8(24.2%) had portal vein involvement. Receiving first-line and second- or later-line treatment were 21(63.6%) and 12(36.4%), respectively. At a median follow-up of 11.6 months, the median PFS was 7.68 months(95% confidence interval:5.39-9.76) .The 6-month and 12-month overall survival rates were 100% and 96.2%, respectively. According to Response Evaluation Criteria in Solid Tumors Version 1.1, the ORR and DCR were 15% and 82%, respectively. There were 15 (15.2%) grade 3-4 treatment-related adverse events including neutropenia, thrombocytopenia, hypertension, proteinuria and hand and foot syndrome. There were no treatment-related deaths. Conclusions: Apatinib in combination with IMRT was safe and effective in improving PFS and DCR, and suggested an encouraging anti-tumor activity in patients with unresectable advanced HCC. Clinical trial information: ChiCTR-OPC-17011890.
3582 Background: Emerging evidence suggested that chemotherapy in combination with anti-angiogenic targeted agents can achieve higher response in multiple solid tumors. Fruquintinib is a highly selective small-molecule VEGFR inhibitor that has been approved for the third-line treatment in metastatic colorectal cancer (mCRC) patients in China. Here, we assessed the efficacy and safety of fruquintinib plus investigator's choice of chemotherapy as second-line therapy in pretreated advanced mCRC patients. Methods: In this prospective, open-label, multicenter, single-arm phase 2 trial (ChiCTR2200059280), patients with mCRC progressed after first-line prior systemic treatment were administered fruquintinib (5~3mg, D1-21, Q4w) and investigator's choice of chemotherapy (fluorouracil ± irinotecan ± oxaliplatin, Q3w) for up to 8 cycles. Patients without disease progression (PD) were followed by fruquintinib maintenance until PD or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety. Results: As the data cutoff on February 10, 2023, 37 patients have been enrolled and treated, with 31 evaluable for efficacy. Median age was 63 years (range, 44-76) and 22 (59.5%) were male. The left colon cancer involved in 28 patients (75.7%). All patients were microsatellite-stable phenotype and 11 (29.7%) had mutations in KRAS gene. 16 (43.2%) patients received prior anti-VEGF therapy. 20 (54.1%) and 11 (29.7%) patients had liver and lung metastases respectively. At a median follow-up of 8.4 months, 28 patients are still on treatment. The ORR is 48.4%, with 15 partial response. The DCR is 90.3%. At data cutoff, median PFS has not yet reached. 23 patients (74.2%) remained progression free at 6 months. In terms of safety, the regimen was well tolerated, mainly grade 1/2 adverse events (AEs). Grade 3/4 AEs were neutropenia (21.6%), leukopenia (10.8%), thrombocytopenia (5.4%), proteinuria, diarrhea, hand-foot syndrome and hypertension accounted for 2.7% respectively. 5 pts received reduced doses of fruquintinib. No treatment-related deaths occurred. Conclusions: Fruquintinib combined with chemotherapy followed by fruquintinib maintenance shows promising efficacy and manageable safety profile for mCRC patients in second-line setting. Updated follow up data will be presented in the future. Clinical trial information: ChiCTR2200059280 .
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