Pericytes: a double-edged sword in cancer therapy.

Pericytes, which envelope the vascular endothelium throughout the body, are often targeted to promote vascular normalization and restore normal function of blood vessels in cancer treatment. The goals of pericyte-targeted therapy tend to promote proper vascular normalization of the tumor. Tumor vascular normalization prevents metastasis, increases tumor oxygenation (making radiation more effective in killing tumor cells), optimizes Starling forces to increase delivery of cancer cell-directed therapies (e.g., chemotherapy or targeted agents), increases the efficacy of focal therapies (e.g., surgery or radiation), and increases recognition by the host immune system. We review how approaches in pericyte-targeted therapy aim to reach a balance between pro-angiogenic and anti-angiogenic function (i.e., by targeting platelet-derived growth factor beta receptors, vascular endothelial growth factor receptors and Tie-2) for tumor vascular normalization.

Similar Outcomes of Standard Radiotherapy and Hypofractionated Radiotherapy Following Breast-Conserving Surgery.

BACKGROUND: Adjuvant radiation therapy is commonly administered to breast cancer patients who received breast-conserving surgery. However, lengthy treatment times of standard radiotherapy pose certain challenges. Here, we performed a prospective controlled study comparing standard radiation to hypofractionated radiotherapy in terms of efficacy and outcome. MATERIAL AND METHODS: Eighty breast cancer patients (tumor stage pT1-2N0-1M0) who had undergone breast-conservation surgery were randomly divided into 2 groups (40 patients/group). The experimental group received 43.2 Gy to the whole breast in 18 fractions for 24 days with a concomitant boost (50.4 Gy) to the tumor bed. The control group received 45 Gy to the whole breast in 25 fractions for 44 days with a boost to the tumor bed of 59 Gy. Survival, locoregional recurrence, adverse effects, and aesthetic results were all considered for analysis. RESULTS: The following criteria were included as part of study follow-up: local control, survival, adverse skin reactions, cosmetic outcome, and hematological toxicity. At a median follow-up of 27 months (follow-up rate 100%), there were no statistical differences in any of the categories between the 2 groups. The 2-year survival rate of both groups was 100% without any locoregional recurrence. Although there was some skin toxicity, these instances were not severe and they cleared on their own within 6 weeks. The most common problems encountered by patients were breast fibrosis and altered pigmentation. CONCLUSIONS: A shortened whole-breast hypofractionated irradiation schedule with a concomitant boost is as effective as standard radiation and may be a reasonable alternative following breast conservation surgery.

Experimental study on the regulation of erlotinib-induced radiosensitization with an anti-c-MET monoclonal antibody.

PURPOSE: Erlotinib is a novel therapeutic agent for cancer treatment. This study was performed to investigate the role of c-MET-PI3K-AKT pathway in the regulation of erlotinib-induced radiosensitization. METHODS: A973 lung adenocarcinoma cells treated with 6 Gy of radiation were incubated in the presence of erlotinib. The apoptotic rate after 24 hours, the colony-formating rate after 14 days, and changes in the c-MET expression levels after 14 days of irradiation were examined. Surviving fractions in different treatment groups (blank control, radiation alone, erlotinib alone, anti-c-MET monoclonal antibody alone, combined erlotinib and radiation, and combined erlotinib and radiation with anti-c-MET monoclonal antibody groups) were determined, the survival curves were plotted, and the sensitizer enhancement ratio was calculated using colony formation assays. Expressions of c-MET, p-c-MET, PI3K, AKT, and p-AKT in cells in different treatment groups were examined by Western blot analysis. RESULTS: The apoptotic rate in the combined erlotinib and radiation group was higher than those in single treatment groups; however, the colony-forming rate remained approximately 2.04 ± 1.02%. The expression of c-MET in colony-forming cells in the combined group significantly increased, and the blockade of c-MET activity significantly enhanced the radiosensitizing effect of erlotinib. The expression of c-Met, p-c-MET, PI3K, AKT, and p-AKT among colony-forming cells significantly decreased upon the inhibition of c-MET. CONCLUSIONS: Upregulated activity of the c-MET-PI3K-AKT pathway was found to be important for cell survival under combined the treatment with erlotinib and radiation. The blockade of the c-MET-PI3K-AKT signaling pathway enhanced the radiosensitizing effect of erlotinib.

Dosimetric analysis of brachial plexopathy after stereotactic body radiotherapy: Significance of organ delineation.

OBJECTIVES: Examine the significance of contouring the brachial plexus (BP) for toxicity estimation and select metrics for predicting radiation-induced brachial plexopathy (RIBP) after stereotactic body radiotherapy. MATERIALS AND METHODS: Patients with planning target volume (PTV) ≤ 2 cm from the BP were eligible. The BP was contoured primarily according to the RTOG 1106 atlas, while subclavian-axillary veins (SAV) were contoured according to RTOG 0236. Apical PTVs were classified as anterior (PTV-A) or posterior (PTV-B) PTVs. Variables predicting grade 2 or higher RIBP (RIBP2) were selected through least absolute shrinkage and selection operator regression and logistic regression. RESULTS: Among 137 patients with 140 BPs (median follow-up, 32.1 months), 11 experienced RIBP2. For patients with RIBP2, the maximum physical dose to the BP (BP-Dmax) was 46.5 Gy (median; range, 35.7 to 60.7 Gy). Of these patients, 54.5 % (6/11) satisfied the RTOG limits when using SAV delineation; among them, 83.3 % (5/6) had PTV-B. For patients with PTV-B, the maximum physical dose to SAV (SAV-Dmax) was 11.2 Gy (median) lower than BP-Dmax. Maximum and 0.3 cc biologically effective doses to the BP based on the linear-quadratic-linear model (BP-BEDmax LQL and BP-BED0.3cc LQL, α/ß = 3) were selected as predictive variables with thresholds of 118 and 73 Gy, respectively. CONCLUSION: Contouring SAV may significantly underestimate the RIBP2 risk in dosimetry, especially for patients with PTV-B. BP contouring indicated BP-BED0.3cc LQL and BP-BEDmax LQL as potential predictors of RIBP2.

[Metastatic characteristics of lymph node in supraclavicular zone and radiotherapy target volume for limited-stage small cell lung cancer].

OBJECTIVE: To explore the reasonable radiotherapy range by analyzing the characteristics of supraclavicular lymph node metastasis in limited-stage small cell lung cancer (LS-SCLC). METHODS: From January 2005 to December 2011, patients of LS-SCLC were reviewed. Supraclavicular zone was further divided into five subgroups including para-recurrent laryngeal nerve (region I and region II ), para-internal jugular vein (region III ), supraclavicular region (region IV), as well as the other regions except for the mentioned above (region V). The characteristics of the lymph nodes in each region were analyzed. RESULTS: The supraclavicular lymph node metastasis was found in 60 patients, with a positive rate of 34.5%. In multivariate Logistic regression analysis,intra-thoracic lymph node metastasis in the lymph node stations of level 2 and 3 were found to be the risk factors of supraclavicular lymph node metastasis (P = 0.006,P = 0.000). Our data suggests that the frequencies of metastasis in region I and III were much higher than those in the other areas.Among the sixty patients with supraclavicular lymph node metastasis, 95.0% were found at region I or III while the incidence of skip metastasis was only 5.0%. CONCLUSIONS: It is advisable to contain the bilateral supraclavicular nodes in patients with mediastinal lymph nodes metastasis to the level 2 or 3 for elective radiation target volume.The clinical target volume (CTV) exterior margin containing the outer margin of internal jugular vein may be suitable.

Development and validation of a nomogram for prediction of recovery from moderate-severe xerostomia post-radiotherapy in nasopharyngeal carcinoma patients.

PURPOSE: Aim to create and validate a comprehensive nomogram capable of accurately predicting the transition from moderate-severe to normal-mild xerostomia post-radiotherapy (postRT) in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: We constructed and internally verified a prediction model using a primary cohort comprising 223 patients who were pathologically diagnosed with NPC from February 2016 to December 2019. LASSO regression model was used to identify the clinical factors and relevant variables (the pre-radiotherapy (XQ-preRT) and immediate post-radiotherapy (XQ-postRT) xerostomia questionnaire scores, as well as the mean dose (Dmean) delivered to the parotid gland (PG), submandibular gland (SMG), sublingual gland (SLG), tubarial gland (TG), and oral cavity). Cox proportional hazards regression analysis was performed to develop the prediction model, which was presented as a nomogram. The models' performance with regard to calibration, discrimination, and clinical usefulness was evaluated. The external validation cohort comprised 78 patients. RESULTS: Due to better discrimination and calibration in the training cohort, age, gender, XQ-postRT, and Dmean of PG, SMG, and TG were included in the individualized prediction model (C-index of 0.741 (95% CI:0.717 to 0.765). Verification of the nomogram's performance in internal and external validation cohorts revealed good discrimination (C-index of 0.729 (0.692 to 0.766) and 0.736 (0.702 to 0.770), respectively) and calibration. Decision curve analysis revealed that the nomogram was clinically useful. The 12-month and 24-month moderate-severe xerostomia rate was statistically lower in the SMG-spared arm (28.4% (0.230 to 35.2) and 5.2% (0.029 to 0.093), respectively) than that in SMG-unspared arm (56.8% (0.474 to 0.672) and 12.5% (0.070 to 0.223), respectively), with an HR of 1.84 (95%CI: 1.412 to 2.397, p = 0.000). The difference in restricted mean survival time for remaining moderate-severe xerostomia between the two arms at 24 months was 5.757 months (95% CI, 3.863 to 7.651; p = 0.000). CONCLUSION: The developed nomogram, incorporating age, gender, XQ-postRT, and Dmean to PG, SMG, and TG, can be used for predicting recovery from moderate-severe xerostomia post-radiotherapy in NPC patients. Sparing SMG is highly important for the patient's recovery.

[Significance of expression of chemokine receptor and matrix metalloproteinase in small cell lung cancer].

OBJECTIVE: To explore the expressions of CXC chemokine receptor 4 (CXCR4) and matrix metalloproteinase-9 (MMP-9) and examine their correlations with metastasis and prognosis in small cell lung cancer (SCLC). METHODS: Immunohistochemistry was employed to detect the expressions of CXCR4 and MMP-9 in the tissue samples from 65 SCLC patients treated in Cancer Institute and Hospital Attached to Tianjin Medical University from January 2003 to October 2009. And their correlations with metastasis and prognosis were analyzed by Chi-square test and Kaplan-Meier method and Cox regression. RESULTS: The positive expression rates of CXCR4 and MMP-9 were 100.0% (65/65) and 87.7% (57/65) in SCLC tissues respectively. Significant difference of the expression rate of CXCR4 was found between patients undergoing bone metastasis or not (P = 0.004). But the differences were not significant between brain metastasis or not (P = 0.068) and lymph node metastasis or not (P = 0.085). A high expression rate of MMP-9 was significantly associated with pathological staging (P = 0.048). But the difference between lymph node metastasis or not was not significant (P = 0.085). Univariate analysis suggested that a high expression rate of CXCR4 was significantly correlated with the disease-free survival (DFS) of SCLC patients (P = 0.005). But a high expression rate of MMP-9 was not associated with DFS (P = 0.341). Multivariate analysis suggested that a high expression rate of CXCR4 was an independent prognostic factor for DFS in SCLC. CONCLUSIONS: The elevated levels of CXCR4 and MMP-9 are found in SCLC tissues. And the expression rate of CXCR4 may be correlated with bone metastasis, but the correlation is not notable for MMP-9. The expression rate of CXCR4 is an independent prognostic factor for DFS in SCLC.

Survival Outcomes of Local Compared With Systemic First Treatment of Non-Small Cell Lung Cancer Brain Metastases.

OBJECTIVE: This retrospective study evaluated the survival advantage of local treatment targeted to brain metastases, relative to systemic therapy, as the first option for brain metastases of non-small cell lung cancer (NSCLC). METHODS: First reviewed were 291 cases of NSCLC brain metastases from two centers. All patients were at least 18 years old, with histologically confirmed NSCLC, and required and underwent both local (radiotherapy or brain surgery) and systemic treatment (chemotherapy and tyrosine kinase inhibitor [TKI] medication). Demographics, clinical characteristics, and treatment-related variables were collected. RESULTS: The final population comprised 160 patients. Overall, the multivariate analysis suggested that the following were associated with better survival: >3 cycles of chemotherapy; stereotactic radiosurgery; and TKI medication (all, P = 0.000). Local treatment that began within 1 week of the diagnosis of brain metastases was associated with poorer survival (P = 0.006). Among the 111 patients with symptomatic brain metastases, the multivariate analysis indicated that better survival was associated with >3 cycles of chemotherapy (P = 0.000), radiation dose >40 Gy (P = 0.001), stereotactic radiosurgery (P = 0.000), and TKI medication (P = 0.000), while local treatment that began within 1 week after the diagnosis of brain metastases was associated with poorer survival (P = 0.015). CONCLUSIONS: For patients with NSCLC brain metastases, regardless of the presence of clinical symptoms associated with brain metastases, systemic treatment before local may be better for survival. Even when used to relieve clinical symptoms, local treatment should be within a setting of sufficient systemic treatment.

Overcoming of Radioresistance in Non-small Cell Lung Cancer by microRNA-320a Through HIF1α-Suppression Mediated Methylation of PTEN.

BACKGROUND: Radioresistance is a major challenge in the use of radiotherapy for the treatment of lung cancer while microRNAs (miRs) have been reported to participate in multiple essential cellular processes including radiosensitization. This study was conducted with the main objective of investigating the potential role of miR-320a in radioresistance of non-small cell lung cancer (NSCLC) via the possible mechanism related to HIF1α, KDM5B, and PTEN. METHODS: Firstly, NSCLC radiosensitivity-related microarray dataset GSE112374 was obtained. Then, the expression of miR-320a, HIF1α, KDM5B, and PTEN was detected in the collected clinical NSCLC samples, followed by Pearson's correlation analysis. Subsequently, ChIP assay was conducted to determine the content of the PTEN promoter fragment enriched by the IgG antibody and H3K4me3 antibody. Finally, a series of in vitro and in vivo assays were performed in order to evaluate the effects of miR-320a on radioresistance of NSCLC with the involvement of HIF1α, KDM5B, and PTEN. RESULTS: The microarray dataset GSE112374 presented with a high expression of miR-320a in NSCLC radiosensitivity samples, which was further confirmed in our clinical samples with the use of reverse transcription-quantitative polymerase chain reaction. Moreover, miR-320a negatively targeted HIF1α, inhibiting radioresistance of NSCLC. Interestingly, miR-320a suppressed the expression of KDM5B, and KDM5B was found to enhance the radioresistance of NSCLC through the downregulation of PTEN expression. The inhibition of miR-320a in radioresistance of NSCLC was also reproduced by in vivo assay. CONCLUSION: Taken together, our findings were suggestive of the inhibitory effect of miR-320a on radioresistance of NSCLC through HIF1α-suppression mediated methylation of PTEN.

Radiosensitizing effects of gefitinib at different administration times in vitro.

The optimal administration time for applying epidermal growth factor receptor inhibitors combined with radiotherapy has been unclear. We investigated the efficacy of combining gefitinib with radiation in different treatment schedules. We demonstrated that gefitinib was administered to A549 lung cancer cells in three ways (administration before irradiation, administration upon irradiation, administration after irradiation) to establish the radiosensitizing effect. Cell-survival rates were evaluated by colony-forming assays. Cell apoptosis and cell-cycle distribution were investigated using flow cytometry; meanwhile, the expression of P21, Cdc25c, Bcl-2, Bax, Rad51 and phosphorylated DNA-PKcs (phospho-DNA-PK) after 6 Gy irradiation and/or gefitinib were determined by Western blot analysis. The sensitizer enhancement ratios of the gefitinib administration before irradiation, administration upon irradiation, and administration after irradiation groups were 2.23, 1.51 and 1.30, respectively. A higher apoptosis rate and G(2)/M phase arrest were observed in cells at 48 h after exposure to 6 Gy irradiation when gefitinib was administrated before irradiation. Increased cell apoptosis and cell cycle arrest were further supported by the expression changes of Bcl-2, Bax, P21, Cdc25c, Rad51 and phospho-DNA-PK at the same time. The best radiosensitizing effect was obtained when gefitinib was delivered before irradiation. Apoptosis might be an important way of cell killing and G(2)/M phase arrest might be an important mechanism of apoptosis. The expression proportion changes of P21/Cdc25c proteins may play an important role in G(2)/M cell cycle arrest. Moreover, the pro-apoptotic/antiapoptotic and DNA repair factors may be important modulators taking part in the molecular events of the radiosensitizing effect of gefitinib combined with irradiation.

Thoracic radiotherapy (TRT) improved survival in both oligo- and polymetastatic extensive stage small cell lung cancer.

There has been no previous study on the efficacy of the thoracic radiotherapy (TRT) in oligometastatic or polymetastatic extensive stage small-cell lung cancer (ES-SCLC) to the overall survival (OS). In a group of 270 ES-SCLC cases retrospective study, 78 patients (28.9%) had oligometastases and 192 (71.1%) had polymetastases, among which 51 oligometastatic patients (65.4%) and 93 polymetastatic patients (51.6%) received TRT. Propensity score matching (PSM) was utilized. The 2-year OS, progression free survival (PFS) and local control (LC) in oligometastatic and polymetastatic patients were 22.8% and 4.5% (p < 0.001), 12.0% and 3.8% (p < 0.001), and 36.7% and 6.1% (p < 0.001), respectively. The 2-year OS in oligometastatic patients with the chemotherapy + radiotherapy and chemotherapy alone were 25.2% and 12.7% (p = 0.002), in contrast to 10.0% and 6.8% (p = 0.030) in polymetastatic patients. The estimated hazard ratios for survival were 2.9 and 1.7 for both oligometastatic and polymetastatic patients with radiotherapy. The polymetastatic group has a lower LC (6.1% v.s. 36.7%, (p < 0.001)), due to polymetastases patients receiving involved-sites radiotherapy with low dose schemas. TRT improved OS of patients with oligometastases and polymetastases. Our study demonstrated that aggressive TRT might be a suitable addition of chemotherapy when treating ES-SCLC patients with oligometastases and polymetastases.

Receipt of thoracic radiation therapy and radiotherapy dose are correlated with outcomes in a retrospective study of three hundred and six patients with extensive stage small-cell lung cancer.

BACKGROUND: The importance of the thoracic radiation therapy (TRT) dose has not been clearly defined in extensive stage small-cell lung cancer (ES-SCLC) and it is unclear whether improved TRT dose translates into a survival benefit. METHODS: 306 patients with ES-SCLC were retrospectively reviewed, of which 170 received IMRT/CRT fractionation RT after ChT, and 136 received chemotherapy (ChT) alone. We adopted the time-adjusted BED (tBED) for effective dose fractionation calculation. Due to the nonrandomized nature of this study, we compared the ChT+RT with ChT groups that matched on possible confounding variables. RESULTS: Patients achieved 2-year OS, PFS and LC rates of 19.7%, 10.7% and 28.4%, respectively. After propensity score matching, (113 cases for each group), the rates of OS, PFS and LC at 2 years were 21.4%, 7.7% and 34.5% for ChT+TRT, and 10.3% (p<0.001), 4.6% (p<0.001) and 6.3% for ChT only (p<0.001), respectively. Among propensity score matching patients, 56 cases for each group received the high dose (tBED>50 Gy) TRT and received low dose (tBED≤50 Gy) TRT. Two-year OS, PFS and LC rates were 32.3%, 15.3% and 47.1% for the high dose compared with 17.0% (p<0.001), 12.9% (p=0.097) and 34.7% (p=0.029) for low dose radiotherapy. CONCLUSIONS: TRT added to ChT improved ES-SCLC patient OS. High dose TRT improved OS over lower doses. Our results suggest that high-dose thoracic radiation therapy may be a reasonable consideration in select patients with ES-SCLC.

Early postoperative radiotherapy is associated with improved outcomes over late postoperative radiotherapy in the management of completely resected (R0) Stage IIIA-N2 non-small cell lung cancer.

AIMS: The aim of this study was to evaluate the ideal timing of PORT in the management of completely resected (R0) Stage IIIA-N2 NSCLC. PATIENTS AND METHODS: Between January 2008 and December 2015, patients with known histologies of pathologic Stage IIIA-N2 NSCLC who underwent R0 resection and received PORT concurrent with or prior to two sequential cycles of chemotherapy ("early PORT") or with PORT administered after two cycles of chemotherapy ("late PORT") at multiple hospitals. The primary endpoint was OS; secondary end points included pattern of the first failure, LRRFS, and DMFS. Kaplan-Meier OS, LRRFS, and DMFS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS, LRRFS, and DMFS. RESULTS: Of 112 included patients, 41 (36.6%) and 71 (63.4%) patients received early PORT and late PORT, respectively. The median OS, LRRFS, and DMFS were longer for those who received early PORT than for those who received late PORT at the median follow-up of 29.6 months (all p < 0.05). Uni- and multi-variate analyses showed that number of POCT cycles and the combination schedule of PORT and POCT were independent prognostic factors for OS, LRRFS, and DMFS. CONCLUSIONS: Early PORT is associated with improved outcomes in pathologic Stage IIIA-N2 R0 NSCLC patients.

[Three-dimensional conformal radiotherapy for locoregionally recurrent non-small cell lung cancer after initial radiotherapy].

OBJECTIVE: To evaluate the feasibility, therapeutic effects and normal tissue complications of three-dimensional conformal radiotherapy (3DCRT) for locoregionally recurrent non-small cell lung cancer after initial radiotherapy. METHODS: Between August 1999 and August 2003, 27 such patients were treated with 3DCRT after initial radiotherapy. This series consisted of 25 men and 2 women with a median age of 64 years. Radiotherapy was delivered at 2 Gy per fraction, 5 fractions per week, to a median dose of 50 Gy. Treatment results and normal tissue complications were assessed with WHO and RTOG/EORTC criteria. RESULTS: Based upon a median follow-up time of 20.6 months, 25 patients (92.6%) completed the planned 3DCRT treatment. Their clinical symptom relief rate was 79.1%, and the response rate was 59.3% with a complete remission rate of 14.8% (4/27), partial remission rate of 44.4% (12/27). The overall 1- and 2-year survival (OS) rates were 73.8% and 25.4% with a median survival time (MST) of 20 months. The 1- and 2-year local progression free survival (LPFS) rates were both 88.8%. Grade 2 and grade 3 acute radiation pneumonitis developed in 7.4% (2/27) and 11.1% (3/27). Grade 2 late radiation pneumonitis developed in 11.1% (3/27). CONCLUSION: 3DCRT is feasible and advisable for locoregionally recurrent non-small-cell lung cancer, giving a good immediate tumor response and acceptable normal tissue complications.

[SPECT lung perfusion scans in predicting radiation pneumonitis in lung cancer patients].

OBJECTIVE: To evaluate single photon emission computed tomography (SPECT) lung perfusion in predicting radiation pneumonitis in lung cancer patients. METHODS: From April 2003 to March 2004, 31 lung cancer patients treated with radical radiotherapy received SPECT lung perfusion scans, among whom, 23 had had perfusion scans both before and at the time of 40 Gy irradiation. The perfusion changes in the region of interest (ROI) after irradiation were obtained through comparing post-radiotherapy with pre-radiotherapy average proportion of SPECT counts within the ROI relative to average counts of the whole lung. Endpoint was defined as grade 2 and above radiation pneumonitis according to RTOG criteria. RESULTS: Lung perfusion defect was observed in all the patients at baseline. > or = grade 2 lung perfusion defect was found in 68.2% (15/22) of patients with central lesion and in 22.2% (2/9) of patients with peripheral lesions (P = 0.04). Seventy percent of the patients (16/23) experienced improved perfusion at 40 - 50 Gy. > or = grade 2 radiation pneumonitis was observed in 12 patients (38.7%) in the whole group, with 6 in those with grade 1 perfusion defects and another 6 in > or = grade 2 group, respectively; Of the 23 patients who had had both pre- and post-radiotherapy SPECT perfusion scan, 5 > or = grade 2 radiation pneumonitis occurred in the 16 perfusion-improved patients and 3 in the 7 unimproved patients. CONCLUSION: There is no significant correlation between radiation pneumonitis and the extent of perfusion defect either before or after 40 - 50 Gy irradiation based on our limited data analysis in this series.

Stereotactic radiation therapy for oligometastases or oligorecurrence within mediastinal lymph nodes.

AIMS: This study evaluated the safety and efficacy of stereotactic radiation therapy (SRT) for the treatment of patients with oligometastases or oligorecurrence within mediastinal lymph nodes (MLNs) originating from different tumors. METHODS: Between October 2006 and May 2015, patients with MLN oligometastases or oligorecurrence were enrolled and treated with SRT at our hospital. The primary endpoint was MLN local control (LC). Secondary endpoints were time to symptom alleviation, overall survival (OS) after SRT, and toxicity using the Common Terminology Criteria for Adverse Events (CTCAE v4.0). RESULTS: Eighty-five patients with 98 MLN oligometastases or oligorecurrences were treated with SRT. For the entire cohort, the 1-year and 5-year actuarial LC rates were 97% and 77%, respectively. Of 53 symptomatic patients, symptom alleviation was observed in 47 (89%) after a median of 5 days (range, 3-30 days). The median OS was 27.2 months for all patients. For patients with non-small cell lung cancer, univariate and multivariate analyses revealed that a shorter interval between diagnosis of primary tumors and SRT and larger MLN SRT volume were associated with worse OS. CTCAE v4.0 ≥ Grade 3 toxicities occurred in six patients (7%), with Grade 5 in three patients (all with RT history to MLN station 7). CONCLUSIONS: SRT is a safe and efficacious treatment modality for patients with oligometastases or oligorecurrence to MLNs originating from different tumors, except for patients who received radiotherapy to MLN station 7. Further investigation is warranted to identify the patients who benefit most from this treatment modality.

Stereotactic body radiation therapy for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph nodes or postoperative stump including pancreatic stump and other stump.

BACKGROUND AND AIM: The aim of this study is to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) using CyberKnife in the treatment of patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. PATIENTS AND METHODS: Between October 1, 2006 and May 1, 2015, patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery were enrolled and treated with SBRT at our hospital. The primary end point was local control rate after SBRT. Secondary end points were overall survival, time to symptom alleviation, and toxicity, assessed using the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Twenty-four patients with 24 lesions (17 abdominal lymph nodes and seven stumps) were treated with SBRT, of which five patients presented with abdominal lymph nodes and synchronous metastases in the liver and lung. The 6-, 12-, and 24-month actuarial local control rates were 95.2%, 83.8%, and 62.1%, respectively. For the entire cohort, the median overall survival from diagnosis and SBRT was 28.9 and 12.2 months, respectively. Symptom alleviation was observed in eleven of 14 patients (78.6%) within a median of 8 days (range, 1-14 days) after SBRT. Nine patients (37.5%) experienced Common Terminology Criteria for Adverse Events version 4.0 grade 1-2 acute toxicities; one patient experienced grade 3 acute toxicity due to thrombocytopenia. CONCLUSION: SBRT is a safe and effective treatment for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Further studies are needed before SBRT can be recommended routinely.

Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is postulated to enhance the recruitment of mesenchymal stem cells (MSCs) into the tumor microenvironment, which promote tumor recurrence. The aim of this study is to determine the molecular mechanisms behind SBRT stimulating MSC migration and differentiation. METHODS: In vitro, mediated factors and migrated MSCs (post-SBRT) were generated. In vivo, bone-marrow derived MSCs were identified and harvested from green fluorescent protein (GFP)-expressing transgenic male mice and transplanted into sub-lethally irradiated recipient female mice to establish a model of bone marrow transplantation. Lewis lung carcinoma and malignant melanoma-bearing recipient mice were treated with SBRT, 14 Gy/1 fraction. The migration and differentiation potential of MSCs were characterized. RESULTS: SBRT increased the release of stromal cell derived factor-1α (SDF-1α) and platelet-derived growth factor-B (PDGF-B) by tumor cells; these ligands bound to chemokine (C-X-C motif) receptor 4 (CXCR4) and platelet-derived growth factor receptor-ß (PDGFR-ß), respectively, on circulating bone marrow-derived MSCs, resulting in engraftment of the MSCs into the tumor parenchyma. The newly-homed MSCs differentiated into pericytes, which induced the tumor vasculogenesis, and promoted tumor regrowth. Targeted therapies, AMD3100 and imatinib abrogated MSC homing, vasculogenesis, and tumor regrowth. CONCLUSION: Bone-marrow derived MSCs migrate to the tumor parenchyma and differentiate into pericytes, inducing tumor vasculogenesis after SBRT, and promoting tumor recurrence. MSC migration and maturation may be abrogated with AMD3100 and imatinib. This novel treatment strategy warrants clinical investigation.

[Prognostic factors and outcome of esthesioneuroblastoma].

OBJECTIVE: To investigate the clinical feature, prognostic factors and the appropriate treatment modality of esthesioneuroblastoma (ENB). METHODS: The data of 49 patients with ENB treated from Dec. 1978 to Dec. 2001 were retrospectively reviewed and analyzed. In this series, 3 patients had modified Kadish stage A disease, 15 stage B, 22 stage C, and 9 stage D lesion. The treatment modalities included surgery alone in 4 patients, and radiotherapy alone in 11, surgery plus radiotherapy in 19, radiotherapy plus chemotherapy in 8, surgery plus radiotherapy plus chemotherapy in 7. Statistic analysis was performed using software SPSS 10.0. Overall survival (OS) and disease free survival (DFS) were calculated using Kaplan-Meier method. Differences between survival curves were tested by Log rank method. RESULTS: The 5-year OS and DFS of the whole group was 60.5% and 41.9%, respectively. The 5-year OS of patients with modified Kadish stage A or B disease and those with stage C or D was 78.4% and 49.7% (chi(2) = 2.10, P = 0.15), and the 5-year DFS was 47.1% and 38.4% (chi(2) = 0.08, P = 0.78), respectively. The 5-year OS of patients with or without neck lymph nodal metastasis was 17.8% and 70.8% (chi(2) = 2.32, P = 0.13), and the 5-year DFS was 0 and 53.4% (chi(2) = 11.67, P < 0.01), respectively. For patients with kfs > or = 80 and those with kfs < 80, the 5-year OS was 69.0% and 30.1% (chi(2) = 7.01, P < 0.01), and 5-year DFS was 46.7% and 24.9% (chi(2) = 6.37, P = 0.01), respectively. As regard to the treatment modality, The 5-year OS was 69.7% for the patients treated with combined modalities and 46.3% for those with surgery alone or radiotherapy alone (chi(2) = 3.49, P = 0.06), and the 5-year DFS were 52.2% and 21.8% (chi(2) = 7.03, P < 0.01), respectively. The 5-year OS was 71.1% for patients who received surgical treatment and 44.6% for those without it (chi(2) = 7.99, P < 0.01), and 5-year DFS was 54.0% and 24.1% (chi(2) = 6.41, P = 0.01), respectively. The 5-year OS and DFS of 11 patients who received radiotherapy alone were 47.7% and 30.7%, respectively. For 19 patients treated by radiotherapy with radical purpose (including patients who received combined modality with radiotherapy plus chemotherapy), the 5-year OS were 33.9% for < 70 Gy patients and 48.0% for > or = 70 Gy (chi(2) = 0.89, P = 0.35), and the 5-year DFS was 13.3% and 33.3% (chi (2) = 4.48, P = 0.03), respectively. For those who received chemotherapy or not, the 5-year OS was 50.0% and 64.9% (chi(2) = 0.91, P = 0.34), and the 5-year DFS was 38.9% and 43.1% (chi(2) = 0.01, P = 0.91), respectively. CONCLUSION: Esthesioneuroblastoma is more prevalent in the young male adults than female, usually with locally advanced stage lesion when first diagnosed. Performance status and neck lymph node metastasis are significantly correlated with the prognosis. Combined treatment modality consisting of surgery may help to gain more favorable result. Radiotherapy plays an important role in the management of the disease.