Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-ß1/Smad 3 signaling pathway.

To investigate the effect of adipose-derived stem cells (ASCs) transplantation on radiation-induced lung injury (RILI), Sprague-Dawley rats were divided into phosphate-buffered saline (PBS) group, ASCs group, Radiation + PBS group, and Radiation + ASCs group. Radiation + PBS and Radiation + ASCs groups received single dose of 30 Gy X-ray radiation to the right chest. The Radiation + PBS group received 1 mL PBS suspension and Radiation + ASCs group received 1 mL PBS suspension containing 1 × 107 CM-Dil-labeled ASCs. The right lung tissue was collected on Days 30, 90, and 180 after radiation. Hematoxylin-eosin and Masson staining were performed to observe the pathological changes and collagen fiber content in the lung tissue. Immunohistochemistry (IHC) and western blot (WB) were used to detect levels of fibrotic markers collagen I (Collal), fibronectin (FN), as well as transforming growth factor-ß1 (TGF-ß1), p-Smad 3, and Smad 3. Compared with the non-radiation groups, the radiation groups showed lymphocyte infiltration on Day 30 after irradiation and thickened incomplete alveolar walls, collagen deposition, and fibroplasia on Days 90 and 180. ASCs relieved these changes on Day 180 (Masson staining, P = 0.0022). Compared with Radiation + PBS group, on Day 180 after irradiation, the Radiation + ASCs group showed that ASCs could significantly decrease the expressions of fibrosis markers Collal (IHC: P = 0.0022; WB: P = 0.0087) and FN (IHC: P = 0.0152; WB: P = 0.026) and inhibit the expressions of TGF-ß1 (IHC: P = 0.026; WB: P = 0.0152) and p-Smad 3 (IHC: P = 0.0043; WB: P = 0.0087) in radiation-induced injured lung tissue. These indicated that ASCs could relieve RILI by inhibiting TGF-ß1/Smad 3 signaling pathway.

Multicenter phase I dose escalation and expansion study of pyrotinib in combination with camrelizumab and chemotherapy as first-line treatment for HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma.

Background: Pembrolizumab plus trastuzumab and chemotherapy showed remarkable efficacy as first-line therapy for advanced HER2-positive gastric cancer. Pyrotinib is an irreversible pan-HER inhibitor. This single-arm, open-label phase 1 dose-escalation (1a) and expansion (1b) study investigated camrelizumab, an anti-PD-1 antibody, plus pyrotinib and chemotherapy as first-line treatment for advanced HER2-positive gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. Methods: Between June 2020 and June 2022, 41 patients with previously untreated HER2-positive locally advanced unresectable or metastatic G/GEJ adenocarcinoma were enrolled. In phase 1a, patients underwent a 3 + 3 escalating dose design, receiving oral pyrotinib (240 mg, 320 mg, or 400 mg daily), intravenous camrelizumab (200 mg), and CapeOX (oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily for two weeks) every 3 weeks until progression, intolerable toxicity or consent withdrawal. The recommended phase 2 dose (RP2D) of pyrotinib was determined and used in the phase 1b. The primary endpoints were the safety, maximum tolerated dose (MTD), RP2D, and confirmed objective response rate (ORR). This trial was registered with chictr.org, number ChiCTR2000029717. Findings: Among 41 patients, 10 were in phase 1a (3 at 240 mg, 3 at 400 mg, and 4 at 320 mg due to one patient withdrawing consent), and 31 were in phase 1b. In phase 1a, the MTD of pyrotinib was 320 mg daily due to dose-limiting toxicities (diarrhea [n = 3] and vomiting [n = 1]) observed at 400 mg. Based on all available data, the RP2D of pyrotinib was set at 320 mg. Among 41 patients, 20 patients (48.8%) developed grade ≥3 treatment-emergent adverse events (TEAEs), and four patients (9.8%) had any grade serious adverse events. No deaths occurred due to TEAEs. Among 27 patients who received the RP2D of pyrotinib and had a post-baseline tumor assessment, two patients (7.4%) achieved a confirmed complete response, and 19 patients (70.4%) achieved a confirmed partial response, resulting in a confirmed ORR of 77.8% (95% CI: 57.7-91.4). Interpretation: Pyrotinib plus camrelizumab and chemotherapy showed promising efficacy in the first-line treatment of advanced HER2-positive G/GEJ cancer. The safety profile was consistent with known toxicities of the agents, and no new or unexpected safety signals were identified. Funding: This study was funded by the Beijing Xisike Clinical Oncology Research Foundation (Y-HR2019-0377).

Thalidomide combined with chemo-radiotherapy for treating esophageal cancer: A randomized controlled study.

The aim of the present study was to investigate the efficiency and safety of a combination of thalidomide and chemo-radiotherapy (CRT) for treating esophageal cancer (EC). Eligible patients received two cycles of chemotherapy using paclitaxel liposome and cisplatin concurrently with three-dimensional radiotherapy. Following radiotherapy, two cycles of maintenance chemotherapy were performed. Patients with elevation of vascular endothelial growth factor (VEGF) during radiotherapy were randomly divided into: i) a test group (n=31), who received a combination of CRT and thalidomide; and ii) a control group (n=30), who received CRT only. Patients with locally advanced EC in the test group demonstrated a significantly improved 3-year overall survival (OS) rate, progression-free survival (PFS) rate, local control and median PFS time compared with the control group (P<0.05). Multivariate analysis indicated that Tumor-Node-Metastasis (TNM) stage was associated with the OS time, while TNM stage and the residence of cancer cells following radiotherapy were associated with PFS time. The present data indicate that thalidomide contributes to an improvement of prognosis for patients with locally advanced EC with elevated serum VEGF levels during radiotherapy. In addition, the toxicities induced by thalidomide were demonstrated to be tolerable.

Pathological response and serum VEGF changes during chemoradiotherapy for esophageal carcinoma.

The aim of this study was to observe pathological response and change in serum vascular endothelial growth factor (VEGF) in esophageal carcinoma (EC) during chemoradiotherapy (CRT).Eighty-nine patients diagnosed with EC were treated with radiotherapy at the Department of Radiotherapy of the Second People's Hospital of Changzhou between May 2008 and December 2014, including 65 patients with CRT. Gastroscopy and pathological examination were conducted 4 weeks afterwards. The pathological responses were classified as complete response (CR) and non-CR. Serum samples were collected from the patients before radiotherapy, during week 4 of radiotherapy, and 1 week after radiotherapy. The VEGF changes were classified as increase, stable, and decrease.The median overall survival (OS) and median progression-free survival (PFS) in the pathological CR group was significantly longer than that of the non-CR group (P < .001). The 1-, 3-, and 5-year OS rates in the non-CR group were lower than that in the CR group (P < .05). Moreover, the 1-, 3-, and 5-year PFS rates in the non-CR group were lower than that in the CR group (P < .05). VEGF serum level was decreased during and after radiotherapy compared with pre-radiotherapy, and the differences were statistically significant (P < .05). The 1-, 3-, and 5-year OS rates in the increased group were lower than that in the decreasing group (P < .05). Moreover, the 1-, 3-, and 5-year PFS rates in the increasing group were lower than that in the decreasing group (P < .05). Pathological response (P < .05), serum VEGF trend (P < .05), and tumor-node-metastasis stage (P < .05) in response to CRT were factors that influenced patient prognosis.Pathological response and serum VEGF change during CRT can predict prognosis of nonsurgical patients with EC. Monitoring these changes is of significance in individualized treatment.

Apatinib enhances the radiosensitivity of the esophageal cancer cell line KYSE-150 by inducing apoptosis and cell cycle redistribution.

To determine the radiosensitizing effect of apatinib on esophageal cancer cells, and to preliminarily investigate the underlying mechanism, KYSE-150 cells were treated with apatinib, x-ray or apatinib combined with x-ray, and compared with a blank control. It was observed that apatinib significantly inhibited vascular endothelial growth factor (VEGF) secretion and the proliferation of KYSE-150 cells in a dose-dependent manner. As the concentration of apatinib increased, the radiobiological parameters inactivation dose (D0), quasi domain does (Dq) and survival fraction (SF2) of KYSE-150 cells decreased, while the sensitization enhancement ratio SERD0 increased. The rate of apoptosis in cells treated with apatinib and x-ray was markedly higher compared with those of the blank control, x-ray and apatinib alone groups (P<0.05). The proportion of cells in the G2/M phase was significantly increased in the apatinib, x-ray and combination groups compared with the blank control group (P<0.05). Compared with the control and x-ray groups, combination treatment did not significantly alter the expression level of polyADP-ribose polymerase (PARP), although it significantly increased the expression of cleaved-PARP (P<0.05). Moreover, the expression of cell serine/threonine-protein kinase-2 (CHK2) was downregulated (P<0.05), whilst expression of the phosphorylated form, pCHK2, was significantly increased (P<0.05) in the combination group when compared with the control and x-ray groups. In conclusion, the present study suggested that apatinib increases the radiosensitivity of KYSE-150 esophageal cancer cells by inhibiting VEGF secretion and cell proliferation, and promoting apoptosis and cell cycle redistribution.

Lower limb immobilization device induced small setup errors in the radiotherapy.

The aim of this study was to design a lower limb immobilization device and investigate its clinical application in the radiotherapy of the lower limbs.Around 38 patients who underwent lower limb radiotherapy using the designed immobilization device were included in this study. The setup errors were calculated by comparison of the portal images and the simulator films or digital reconstructed radiographs (DRRs).From all 38 patients accomplished the radiotherapy using this device, 178 anteroposterior portal images and 178 lateral portal images were used for the analysis of the positional accuracy. Significant differences were observed in the setup error of the head-foot direction compared with the left-right direction (t = 3.404, P = .002) and the anterior-posterior directions (t = 3.188, P = .003). No statistical differences were identified in the setup error in the left-right direction and anterior-posterior direction (t = 0.497, P = .622).The use of the in-house designed lower limb immobilization device allowed for relatively small setup errors. Furthermore, it showed satisfactory accuracy and repeatability.

Adipose-Derived Stem Cells Alleviate Radiation-Induced Muscular Fibrosis by Suppressing the Expression of TGF-ß1.

We aim to investigate the effects of adipose-derived stem cells (ASCs) transplantation on irradiation-induced skeletal muscle fibrosis. Sixty-four rabbits were randomly divided into ASCs group and PBS group followed by irradiation at unilateral hip with a single dose of 80 Gy. Nonirradiated side with normal skeletal muscle served as normal control. Skeletal muscle tissues were collected from eight rabbits in each group at 1 w, 4 w, 8 w, and 26 w after irradiation. Migration of ASCs was observed in the peripheral tissues along the needle passage in the injured muscle. The proportion of the area of collagen fibers to the total area in sections of ASCs group was lower than those of PBS groups at 4 w, 8 w, and 26 w after irradiation. Significant decrease was noted in the integrated optimal density of the transforming growth factor ß1 (TGF-ß1) in the ASCs group compared with those of PBS group at 4 w, 8 w, and 26 w after irradiation. Moreover, the expression of TGF-ß1 was lower in the ASCs group compared to those of the PBS group at each time point determined by Western blot analysis. ASCs transplantation could alleviate irradiation fibrosis by suppressing the level of TGF-ß1 in the irradiated skeletal muscle.

Pathologic response during chemo-radiotherapy and variation of serum VEGF levels could predict effects of chemo-radiotherapy in patients with esophageal cancer.

BACKGROUND: To investigate the relationship between pathologic tumor response to concurrent chemo- radiotherapy and variation of serum VEGF in patients with esophageal cancer. MATERIALS AND METHODS: Forty six patients with esophageal cancer who were treated with concurrent chemo-radiotherapy were enrolled. Endoscopic and pathologic examination was conducted before and four weeks afterwards. Serum level of VEGF was documented before, four weeks later and after chemo-radiotherapy. The relationship between pathologic response and the variation of serum level of VEGF and its influence on the prognosis were investigated. RESULTS: Serum level of VEGF decreased remarkably during and after chemo-radiotherapy in patients whose pathologic response was severe (F=5.393, 4.587, P(0.05). There were no statistical differences of serum VEGF level before, during and after chemo-radiotherapy for patients whose pathologic response was moderate or mild. There were 18 (85.7%), 7 (53.8%) and 6 patients (50.0%) whose serum VEGF level dropped in the severe, moderate and mild group, respectively, with significant differences among these groups (p=0.046). Two year survival rates of patients with severe, moderate and mild pathologic response were 61.9%, 53.8% and 33.3% respectively, and no statistically difference between severe and mild group regarding OS (p=0.245) was tested. CONCLUSIONS: Tumor pathologic response during chemo-radiotherapy and the changes of serum VEGF lever could predict curative effects of chemo-radiotherapy in patients with esophageal cancer.

Clinical trial of thalidomide combined with radiotherapy in patients with esophageal cancer.

AIM: To investigate the short-term efficacy and tolerability of radiotherapy plus thalidomide in patients with esophageal cancer (EC). METHODS: Serum samples from 86 EC patients were collected before, during, and after radiotherapy, and the vascular endothelial growth factor (VEGF) level was examined by ELISA. According to the change in serum VEGF level during radiotherapy, the patients were divided into two groups: in the drug group, VEGF level was increased or remained unchanged, and thalidomide was administered up to the end of radiotherapy; in the non-drug group, VEGF level was decreased and radiotherapy was given alone. Thirty healthy volunteers served as controls. The efficacy and safety of radiotherapy plus thalidomide therapy were investigated. RESULTS: The 86 EC patients had a significantly higher level of VEGF compared with the 30 healthy controls before radiotherapy (P < 0.01), and the VEGF level was significantly correlated with primary tumor size, lymph node metastasis, histopathologic type, and clinical stage (P < 0.01). Of 83 evaluable cases, VEGF level was significantly decreased after radiotherapy in 32 patients in the drug group (P < 0.05), with an effective rate of 71.88%. The incidence of dizziness and/or burnout in the drug group and non-drug group was 62.50% and 15.69%, respectively (P = 0.000), and the incidence of somnolence was 12.50% and 0%, respectively (P = 0.019). No significant differences were observed. CONCLUSION: Thalidomide can down-regulate serum VEGF level in EC patients, and combined with radiotherapy may improve treatment outcome. Thalidomide was well tolerated by EC patients.

Therapeutic potential of adipose stem cells in tissue repair of irradiated skeletal muscle in a rabbit model.

The repairing function and differentiation potency of adipose stem cells (ASCs) transplantation following skeletal muscle injury induced by radiotherapy are still not well defined. In this study, one side of the buttocks of 64 New Zealand white rabbits underwent irradiation and were randomly divided into an ASCs group [5×10(7) ASCs labeled with CM-Dil and suspended in 1 mL of phosphate-buffered saline (PBS), via intramuscular injection] and a PBS group (1 mL of PBS, via intramuascular injection). ASCs were isolated in New Zealand white rabbits in vitro, and migration of ASCs labeled with CM-Dil was observed after transplantation in vivo. A significant decrease of histological severity scoring was found in irradiated tissue obtained in the ASCs group compared with that in PBS group. Additionally, compensatory hyperplasia was noted after ASCs transplantation in the injured tissues. Moreover, ASCs could upregulate the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and promote the angiogenesis of the injured tissues. Interestingly, myofilament-like structures were identified in irradiated muscle cells after ASCs transplantation. We concluded that ASCs transplantation could repair the radiation-induced skeletal muscle injury. Its mechanism may be, at least partly, associated with the upregulation of VEGF and bFGF, angiogenesis, promoting the compensatory hyperplasia of muscle satellite cells, as well as the myogenic differentiation.