For metastatic non-small cell lung cancer (NSCLC) patients with controlled extrathoracic disease ... more For metastatic non-small cell lung cancer (NSCLC) patients with controlled extrathoracic disease after systemic treatment, stable or progressive primary lung lesions may cause respiratory symptoms and increase comorbidities. In the present study, we sought to investigate whether aggressive palliative thoracic radiotherapy (RT) can enhance local control and improve the survival for this subgroup of patients. Between March 2006 and December 2014, 56 patients with metastatic NSCLC who had responsive or stable extrathoracic diseases after chemotherapy and/or molecular targets, and received thoracic RT for stable and progressive primary lung lesions were included. RT with a median dose of 55 Gy (range, 40-62 Gy) was administered in 1.8-2.5 Gy fractions to primary lung tumor and regional mediastinal lymph nodes using modern RT technique. Overall survival (OS) from diagnosis, and locoregional progression-free survival (LRPFS), and survival calculated from radiotherapy (OS-RT) were estimated using the Kaplan-Meier method. There were 37 men and 19 women with a median age of 60 years at diagnosis. The median interval from the diagnosis of metastatic disease to thoracic RT was 8 months. Following thoracic RT, 26 patients (46%) achieved complete or partial response (overall response rate, ORR). Patients with squamous cell carcinoma or poorly-differentiated carcinoma had a higher ORR than those with adenocarcinoma (63% vs. 34%, P = 0.034). EGFR mutations was closely associated with a better ORR (45% vs. 29%, P = 0.284). At a median follow-up time of 44 months, the median OS, LRPFS after RT, and OS-RT were 50 months, 15 months, and 18 months. Radical palliative throractic RT is safe and might be beneficial for primary lung lesions of metastatic NSCLC patients with controlled extrathoracic diseases.
This retrospective study tested the hypothesis that disease control and treatment-related toxicit... more This retrospective study tested the hypothesis that disease control and treatment-related toxicity in patients undergoing high-dose radiotherapy (HDRT) for prostate cancer varies in a circadian manner. Patients with localized prostate adenocarcinoma receiving HDRT (median 78 Gy) to the prostate and involved seminal vesicle(s) without elective pelvic irradiation were divided into a daytime treatment (before 5 PM) group (n = 267) and evening treatment (after 5 PM) group (n = 142). Biochemical failure (Phoenix definition), acute and late gastrointestinal (GI) and genitourinary toxicities (Common Terminology Criteria for Adverse Events version 4), biochemical failure-free survival (BFFS) and freedom from late toxicity were assessed. Analyses were performed by binary logistic regression and Cox proportional hazard regression. The median follow-up was 68 months, and 75% of patients were ≥70 years old. Evening HDRT was significantly associated with worse freedom from ≥grade 2 late GI complications (hazard ratio = 2.96; p < 0.001). The detrimental effect of evening HDRT was significant in patients older than 70 years old (p < 0.001) but not in younger patients (p = 0.63). In a subgroup of propensity score-matched cohort with T2b-T3 disease (n = 154), the 5-year BFFS was worse in the evening group than the daytime group (72% vs. 85%, hazard ratio = 1.95, p = 0.05). Our study indicates that evening HDRT may lead to more GI complications, especially in older patients, and worse BFFS in patients with T2b-T3 disease.
This study analyzed the difference in reconstructing volume by using phantom model between variou... more This study analyzed the difference in reconstructing volume by using phantom model between various settings of axial-mode and spiral-mode computed tomography (CT) simulator for three-dimensional conformal radiotherapy. Three phantom balls with different diameters (5.1, 9.9, 12.2 cm) were scanned by a single-row detector CT simulator. The volumes of all phantom balls were reconstructed in the same system. The exactly calculated phantom ball volumes were the baselines as compared to the volumes by the conventional axial-mode CT reconstruction. The reconstructed volumes from the axial scanning mode were compared with the corresponding settings of the spiral scanning mode in CT simulation, with four different Hounsfield (HU) thresholds, three different pitches (1, 1.5 and 2), and four different slice widths (1, 2, 3 and 5 mm). The reconstructed volumes were less than the exactly calculated volumes in all phantom balls using the conventional axial-mode CT simulation. Larger slice width and HU threshold were associated with larger difference between the exactly calculated volumes and reconstructed volumes in axial CT mode. For the small phantom ball at slice width of no more than 3 mm, there were less than 5% of volume losses compared with axial-mode CT settings. The lowest HU threshold and slice width of less than 5 mm were needed to maintain volume loss of less than 5% in medium and large balls. As compared to axial-mode scanning, spiral-mode scanning offered volume reconstruction loss of less than 5% at almost all settings. The exceptions existed in the small phantom ball with slice width of 5 mm, spiral pitch of 1.5 and 2 at 50 HU, and slice width of 5 mm, spiral pitch of 2 at 0 HU. Slice interval, spiral scanning pitch and HU threshold were the factors with impact on the accurate estimation of volume reconstruction by spiral CT simulator. Spiral CT mode was feasible in most scanning settings, with acceptable volume reconstruction accuracy threshold of more than 95%.
International Journal of Radiation Oncology*Biology*Physics, 2015
Our aim was to investigate the association of clinical factors, dosimetric parameters, and biomar... more Our aim was to investigate the association of clinical factors, dosimetric parameters, and biomarkers with postoperative pulmonary complications (PPCs) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated by neoadjuvant concurrent chemoradiation therapy (CCRT) under strict pulmonary dose constraints and esophagectomy. We prospectively enrolled 112 patients undergoing trimodality treatment (including radiation therapy [40 Gy], concurrent taxane-/5-fluorouracil-based regimens, and radical esophagectomy) for ESCC. A PPC was defined as pneumonia or acute respiratory distress syndrome within 30 days after surgery. Serum samples were collected before and within 1 month after CCRT. The association of serum biomarkers with PPCs was detected by proximity ligation assay (PLA) and verified by enzyme-linked immunosorbent assay. Associations of clinical factors, lung dosimetric parameters, and biomarkers with PPC were tested statistically. Thirty-three patients (29.5%) had PPCs. None of the dosimetric parameters was associated with PPCs. Preoperative functional vital capacity (FVC) was significantly associated with PPCs (P=.004). Of the 15 PLA-screened biomarkers, posttreatment transforming growth factor-β1 (TGF-β1) was borderline significantly associated with PPCs (P=.087). Patients with PPCs had significantly larger pre-CCRT to post-CCRT decrease in serum TGF-β1 concentration (-11,310 vs -5332 pg/mL, P=.005) and higher pre-CCRT to post-CCRT percent decline in serum TGF-β1 concentration (-37.4% vs -25.0%, P=.009) than patients without PPCs. On multivariate analysis, preoperative FVC (P=.003) and decrease in TGF-β1 >7040 pg/mL (P=.014) were independent factors associated with PPCs. Preoperative FVC and decrease in serum TGF-β1 level after dose-limited CCRT to the lung are associated with the development of PPCs.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, Jan 24, 2015
To determine whether the postchemoradiotherapy (post-CRT) pathologic stage predicts the outcomes ... more To determine whether the postchemoradiotherapy (post-CRT) pathologic stage predicts the outcomes of patients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing preoperative chemoradiotherapy followed by surgery. From 3 phase II trials of preoperative CRT for locally advanced ESCC, 140 patients were included. Preoperative CRT comprised twice weekly paclitaxel and cisplatin-based regimens and 40-Gy radiotherapy in 20 fractions. The post-CRT pathologic stage was classified according to the American Joint Committee on Cancer, 7th edition staging system (AJCC-7). The prognostic effects of clinicopathologic factors were analyzed using Cox regression. With a median follow-up of 61.9 months, the median progression-free survival (PFS) and overall survival (OS) of the entire cohort were 24.5 and 30.9 months, respectively. The post-CRT pathologic stage was 0 in 34.5%, I in 12.9%, II in 29.3%, III in 13.6%, and ypT0N1-2 in 6.4% of the patients. The median PFS was 47.2 mo...
Esophageal cancer patients with pathological complete response (pCR) to neoadjuvant chemoradiatio... more Esophageal cancer patients with pathological complete response (pCR) to neoadjuvant chemoradiation (CRT) have favorable outcomes. Currently, there was no reliable biomarker predicting the response to CRT. Perioperative circulating mRNA may be associated with prognosis, but its application for predicting treatment response is unclear. We prospectively assessed the value of circulating messenger RNA (mRNA) profiling in predicting pCR for esophageal squamous cell carcinoma (ESCC). Patients with ESCC completing CRT followed by surgery were enrolled for analysis. Venous peripheral blood was obtained before and after CRT, and total RNA was extracted for hybridization-based whole genome expression analysis and quantitative RT-PCR. We found circulating expression profiling was significantly altered after CRT. Altered FAM84B expression was significantly predictive of pCR. The decrease of serum FAM84B protein level after CRT was also associated with pCR. Immunohistochemistry and western blot confirmed that FAM84B protein was overexpressed in the majority of patients and ESCC cell lines. Furthermore, knockdown of FAM84B delayed tumor growth in ectopic xenografts. We demonstrated the decreased of circulating FAM84B mRNA and protein after neoadjuvant CRT may predict pCR, and FAM84B protein is overexpressed in ESCC. The potential of FAM84B as a novel predictive biomarker, and its biological functions deserve further investigation.
Cytolethal distending toxin (CDT) produced by Campylobacter jejuni is a genotoxin that induces ce... more Cytolethal distending toxin (CDT) produced by Campylobacter jejuni is a genotoxin that induces cell-cycle arrest and apoptosis in mammalian cells. Recent studies have demonstrated that prostate cancer (PCa) cells can acquire radio-resistance when DOC-2/DAB2 interactive protein (DAB2IP) is downregulated. In this study, we showed that CDT could induce cell death in DAB2IP-deficient PCa cells. A combination of CDT and radiotherapy significantly elicited cell death in DAB2IP-deficient PCa cells by inhibiting the repair of ionizing radiation (IR)-induced DNA double-strand break (DSB) during G2/M arrest, which is triggered by ataxia telangiectasia mutated (ATM)-dependent DNA damage checkpoint responses. We also found that CDT administration significantly increased the efficacy of radiotherapy in a xenograft mouse model. These results indicate that CDT can be a potent therapeutic agent for radio-resistant PCa.
DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key component of the non-homologous ... more DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key component of the non-homologous end-joining (NHEJ) pathway, is involved in DNA double-strand break repair, immunocompetence, genomic integrity, and epidermal growth factor receptor signaling. Clinical studies indicate that expression and activity of DNA-PKcs is correlated with cancer progression and response to treatment. Various anti-DNA-PKcs strategies have been developed and tested in preclinical studies to exploit the benefit of DNA-PKcs inhibition in sensitization of radiotherapy and in combined modality therapy with other antitumor agents. In this article, we review the association between DNA-PKcs and cancer development and discuss current approaches and mechanisms for inhibition of DNA-PKcs. The future challenges are to understand how DNA-PKcs activity is correlated with cancer susceptibility and to identify those patients who would most benefit from DNA-PKcs inhibition.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, Jan 26, 2015
To assess the usefulness of pathological stage according to the 7th edition of the Union for Inte... more To assess the usefulness of pathological stage according to the 7th edition of the Union for International Cancer Control-American Joint Committee on Cancer (UICC-AJCC) as a prognostic tool in patients undergoing neoadjuvant chemoradiation followed by esophagectomy (trimodality therapy, TMT) for locally advanced esophageal squamous cell carcinoma. One hundred twenty-five eligible patients completing TMT were enrolled for analysis. The clinical (cTNM7) and pathological (ypTNM7) stage groups of their tumors were prospectively classified, and re-grouped by the 6th edition (ypTNM6). Survival was analyzed using the Kaplan-Meier method. The Cox proportional hazard model and the Akaike information criterion (AIC) were used to compare the performance of staging systems. With a median follow-up of 24.6months, 54 patients (43.2%) died. Forty patients (32%) achieved pathological complete remission (pCR). The median survival was 31.8months. On multivariate analysis, ypTNM7 (but not pCR or pN) w...
The current standard of care for lung cancer consists of concurrent chemotherapy and radiation. S... more The current standard of care for lung cancer consists of concurrent chemotherapy and radiation. Several studies have shown that the DNA-PKcs inhibitor NU7441 is a highly potent radiosensitizer, however, the mechanism of NU7441's anti-proliferation effect has not been fully elucidated. In this study, the combined effect of NU7441 and ionizing radiation (IR) in a panel of non-small cell lung cancer cell lines (A549, H460 and H1299) has been investigated. We found that NU7441 significantly enhances the effect of IR in all cell lines. The notable findings in response to this combined treatment are (i) prolonged delay in IR-induced DNA DSB repair, (ii) induced robust G2/M checkpoint, (iii) increased aberrant mitosis followed by mitotic catastrophe specifically in H1299, (iv) dramatically induced autophagy in A549 and (v) IR-induced senescence specifically in H460. H1299 cells show greater G2 checkpoint adaptation after combined treatment, which can be attributed to higher expression ...
Radiation therapy (RT) is an effective strategy for the treatment of localized prostate cancer (P... more Radiation therapy (RT) is an effective strategy for the treatment of localized prostate cancer (PCa) as well as local invasion. However, some locally advanced cancers develop radiation resistance and recur after therapy; therefore, the development of radiation-sensitizing compounds is essential for treatment of these tumors. DOC-2/DAB2 interactive protein (DAB2IP), which is a novel member of the Ras-GTPase activating protein family and a regulator of phosphatidylinositol 3-kinase-Akt activity, is often downregulated in aggressive PCa. Our previous studies have shown that loss of DAB2IP results in radioresistance in PCa cells primarily because of accelerated DNA double-strand break (DSB) repair kinetics, robust G(2)/M checkpoint control, and evasion of apoptosis. A novel DNA-PKcs inhibitor NU7441 can significantly enhance the effect of radiation in DAB2IP-deficient PCa cells. This enhanced radiation sensitivity after NU7441 treatment is primarily due to delayed DNA DSB repair. More s...
Tumor control of hepatocellular carcinoma by radiotherapy remains unsatisfactory. The phosphatidy... more Tumor control of hepatocellular carcinoma by radiotherapy remains unsatisfactory. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a critical role in inhibiting cancer cell death. Elevated PI3K/Akt activity is associated with increased cellular resistance to irradiation. Our aim was to determine whether the inhibition of PI3K/Akt activity by a PI3K inhibitor, BKM120, contributes to the increased sensitivity of liver cancer cells to irradiation. The hepatocellular carcinoma cell lines (Huh7 and BNL) were used to evaluate the in vitro synergism between BKM120 and irradiation. Balb/c mice bearing ectopic BNL xenografts were treated with BKM120 and/or radiotherapy to assess the in vivo response. BKM120 increased cell killing by radiation, increased the expression of apoptotic markers, and suppressed the repair of radiation-induced DNA double-strand breaks. BKM120 pretreatment inhibited radiation-induced Akt phosphorylation and enhanced the tumor-suppressive effect and radiatio...
Journal of gastroenterology and hepatology, Jan 13, 2015
Sonic Hedgehog (SHH) is a regulator in tumorigenesis of hepatocellular carcinoma (HCC). This stud... more Sonic Hedgehog (SHH) is a regulator in tumorigenesis of hepatocellular carcinoma (HCC). This study aimed to determine whether radiation-induced SHH signaling occurs in HCC, and whether SHH inhibitor acts as a radiosensitizer. The in vitro effects of combining SHH ligand (recombinant human SHH) or inhibitor (cyclopamine) with irradiation were evaluated in the human HCC cell lines, Huh-7 and PLC/PRF/5, and murine cell line BNL. Cell survival and apoptosis were measured using a colony formation assay, annexin-V staining, and poly (ADP-ribose) polymerase activation. Western blotting and immunofluorescence staining were used to detect protein expression. The in vivo response to radiotherapy and/or cyclopamine was tested in BALB/c mice bearing an orthotopic allogeneic tumor. Treatment of HCC cells with irradiation and SHH ligand had a protective effect on clonogenic cell survival. Treatment with irradiation and cyclopamine was a more potent inhibitor of cell proliferation than either moda...
Purpose: To assess bladder filling status and its impact on target position during daily intensit... more Purpose: To assess bladder filling status and its impact on target position during daily intensity-modulated radiation therapy (IMRT) using cone-beam computed tomography (CBCT) in prostate cancer patients. Patients and Methods: 23 patients with prostate cancer undergoing image-guided IMRT (78 Gy in 39 fractions) were included. On-board CBCT images were acquired daily and an endorectal balloon was placed daily. All patients were instructed to have a full bladder. The interfraction changes in bladder dimensions in left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions were measured from CBCT images. Distances from the uppermost part of prostate to pubic bone (PP) and from the uppermost part of prostate to treatment isocenter (PI) were measured to determine changes in target position. Standard deviation (SD) in all fractions of each patient was used to compare the variations between patients. Bladder dimension change ratio and Z-score were used to normalize data between patients. Results: A total of 867 CBCT images were evaluated. The average LR, AP, and SI bladder dimensions were 7.8 ± 1.5 cm, 6.7 ± 1.4 cm, and 5.6 ± 1.7 cm, respectively. The average LR, AP, and SI bladder dimension change ratios were 0.88 ± 0.17, 0.90 ± 0.15, and 0.86 ± 0.32, respectively. The SD was significantly greater in SI dimension than in LR (p < 0.001) and AP (p < 0.001) dimensions. The interfraction changes in the three bladder dimensions were significantly larger than those of target position, and did not correlate with target position changes. Conclusion: Though they were not negligible, changes in bladder filling status did not have a significant impact on target position.
Radiotherapy (RT) has been gradually integrated into the multimodality treatment for hepatocellul... more Radiotherapy (RT) has been gradually integrated into the multimodality treatment for hepatocellular carcinoma (HCC). The various patterns of failure in HCC patients undergoing RT drive the need of effective biomarkers to guide treatment decisions. Limited numbers of biomarkers have been investigated in HCC, with even fewer of them for patients treated by RT. Serum or plasma biomarkers measured by enzyme-linked immunosorbent assay were the most common practice. Of particular interest are those biomarkers that are detectable early in the course of radiotherapy which correlated with ultimate clinical outcome. Functional magnetic resonance imaging (MRI) is increasingly used to evaluate the imaging pattern indicative of disease control following RT. Positron emission tomography shows that pre-RT standard uptake values associate with various types of recurrence after treatment. Proximity ligation assay (PLA) is evolving with the unique features of dual-probe identification, ligation and amplification to allow the small volume of serum/plasma samples for evaluating multiple biomarkers. We demonstrate the screening work of biomarkers by PLA with pre- and post-RT serum samples from HCC patients undergoing RT. Efforts are being made to search for the potential biomarkers for HCC patients treated by RT.
Compared with step-and-shoot intensity-modulated radiotherapy (sIMRT) and tomotherapy, volumetric... more Compared with step-and-shoot intensity-modulated radiotherapy (sIMRT) and tomotherapy, volumetric-modulated arc therapy (VMAT) allows additional arc configurations in treatment planning and noncoplanar (NC) delivery. This study was first to compare VMAT planning with sIMRT planning, and the second to evaluate the toxicity of coplanar (C)/NC-VMAT treatment in patients with hepatocellular carcinoma (HCC). Fifteen patients with HCC (7 with left-lobe and 8 with right-lobe tumors) were planned with C-VMAT, C/NC-VMAT, and sIMRT. The median total dose was 49Gy (range: 40 to 56Gy), whereas the median fractional dose was 3.5Gy (range: 3 to 8Gy). Different doses/fractionations were converted to normalized doses of 2Gy per fraction using an α/β ratio of 2.5. The mean liver dose, volume fraction receiving more than 10Gy (V10), 20Gy (V20), 30Gy (V30), effective volume (Veff), and equivalent uniform dose (EUD) were compared. C/NC-VMAT in 6 patients was evaluated for delivery accuracy and treatment-related toxicity. Compared with sIMRT, both C-VMAT (p = 0.001) and C/NC-VMAT (p = 0.03) had significantly improved target conformity index. Compared with C-VMAT and sIMRT, C/NC-VMAT for treating left-lobe tumors provided significantly better liver sparing as evidenced by differences in mean liver dose (p = 0.03 and p = 0.007), V10 (p = 0.003 and p = 0.009), V20 (p = 0.006 and p = 0.01), V30 (p = 0.02 and p = 0.002), Veff (p = 0.006 and p = 0.001), and EUD (p = 0.04 and p = 0.003), respectively. For right-lobe tumors, there was no difference in liver sparing between C/NC-VMAT, C-VMAT, and sIMRT. In all patients, dose to more than 95% of target points met the 3%/3mm criteria. All 6 patients tolerated C/NC-VMAT and none of them had treatment-related ≥ grade 2 toxicity. The C/NC-VMAT can be used clinically for HCC and provides significantly better liver sparing in patients with left-lobe tumors.
Background and Objectives: To investigate the impact of using paclitaxel in chemoradiation on loc... more Background and Objectives: To investigate the impact of using paclitaxel in chemoradiation on locally advanced esophageal squamous cell carcinoma (SCC) treated with or without surgery. Methods: Of 127 patients with AJCC stages II-III esophageal SCC undergoing definitive chemoradiation (DefCRT, n ¼ 44) or neoadjuvant chemoradiation plus surgery (NeoCRT þ S, n ¼ 83), 57 received chemotherapy with paclitaxel and cisplatin (TP), and 70 received 5-fluorouracil and cisplatin (PF). Three-year local progression-free survival (LPFS), distant metastasis-free survival, overall survival, and prognostic factors were retrospectively analyzed. Results: The median survival was 30 months. Pathological complete response rate was 41% and 27% with TP and PF, respectively (P ¼ 0.19). NeoCRT þ S achieved significantly higher LPFS than DefCRT (71% vs. 39%, P < 0.001). Patients receiving TP had significantly higher LPFS than PF (74% vs. 48%, P ¼ 0.04). Local control was similar between DefCRT with TP and NeoCRT þ S. Distant metastasis-free survival and overall survival were not different between treatment modalities or chemotherapy regimens. In multivariate analysis, surgery (HR 0.30, P < 0.001), TP regimen (HR 0.38, P ¼ 0.007), and mediastinal lymphadenopathy (HR 2.37, P ¼ 0.008) were independent factors for LPFS. Conclusions: Both surgery and the use of paclitaxel-based chemoradiation may improve local disease control. Future randomized trials should integrate paclitaxel into definitive chemoradiation.
This work investigated the role of structure in the binding of polysaccharides from 10 regionally... more This work investigated the role of structure in the binding of polysaccharides from 10 regionally different strains of Lentinula edodes to Toll-like receptor 4 (TLR-4) on monocytes (THP-1) and the potential effect of this interaction on tumor cell viability. Principal component analysis and multiple linear regression identified arabinose, glucose 1 → 4 linkage, and molecular weights about 2700 and 534 kDa as the significant determinant factors associated with TLR-4 binding activity. The branched α-(1,4)-glucan (L10) had the strongest ability to bind to TLR-4 and induce THP-1 cell differentiation. L10 induction of the THP-1 cell differentiation, superoxide production, and cytokine production followed the TLR-4/MyD88/IKK/NFκB pathway. Coculture of irradiated human lung adenocarcinoma A549 cells with L10-activated THP-1 cells resulted in significantly decreased percentage of viable A549 cells from 66 to 37% (p = 0.018), increased levels of superoxide, interleukin-8, and RANTES, and decreased levels of angiogenin and vascular endothelial growth factor. The results indicate that L10-activated monocytes have the potential to boost the antitumor immune response and antitumor activity of radiotherapy.
International Journal of Radiation Oncology*Biology*Physics, 2011
Purpose: To evaluate the efficacy and patterns of failure of elective nodal irradiation (ENI) in ... more Purpose: To evaluate the efficacy and patterns of failure of elective nodal irradiation (ENI) in patients with esophageal squamous cell carcinoma (SCC) undergoing preoperative concurrent chemoradiation (CCRT) followed by radical surgery. Methods and Materials: We retrospectively studied 118 patients with AJCC Stage II to III esophageal SCC undergoing preoperative CCRT (median, 36 Gy), followed by radical esophagectomy. Of them, 73 patients (62%) had ENI and 45 patients (38%) had no ENI. Patients with ENI received radiotherapy to either supraclavicular (n = 54) or celiac (n = 19) lymphatics. Fifty-six patients (57%) received chemotherapy with paclitaxel plus cisplatin. The 3-year progression-free survival, overall survival, and patterns of failure were analyzed. Distant nodal recurrence was classified into M1a and M1b regions. A separate analysis using matched cases was conducted. Results: The median follow-up was 38 months. There were no differences in pathological complete response rate (p = 0.12), perioperative mortality rate (p = 0.48), or delayed Grade 3 or greater cardiopulmonary toxicities (p = 0.44), between the groups. More patients in the non-ENI group had M1a failure than in the ENI group, with 3-year rates of 11% and 3%, respectively (p = 0.05). However, the 3-year isolated distant nodal (M1a + M1b) failure rates were not different (ENI, 10%; non-ENI, 14%; p = 0.29). In multivariate analysis, pathological nodal status was the only independent prognostic factor associated with overall survival (hazard ratio = 1.78, p = 0.045). The 3-year overall survival and progression-free survival were 45% and 45%, respectively, in the ENI group, and 52% and 43%, respectively, in the non-ENI group (p = 0.31 and 0.89, respectively). Matched cases analysis did not show a statistical difference in outcomes between the groups. Conclusions: ENI reduced the M1a failure rate but was not associated with improved outcomes in patients undergoing preoperative CCRT for esophageal SCC. Pathological nodal metastasis predicted poor outcome. Ó 2011 Elsevier Inc.
For metastatic non-small cell lung cancer (NSCLC) patients with controlled extrathoracic disease ... more For metastatic non-small cell lung cancer (NSCLC) patients with controlled extrathoracic disease after systemic treatment, stable or progressive primary lung lesions may cause respiratory symptoms and increase comorbidities. In the present study, we sought to investigate whether aggressive palliative thoracic radiotherapy (RT) can enhance local control and improve the survival for this subgroup of patients. Between March 2006 and December 2014, 56 patients with metastatic NSCLC who had responsive or stable extrathoracic diseases after chemotherapy and/or molecular targets, and received thoracic RT for stable and progressive primary lung lesions were included. RT with a median dose of 55 Gy (range, 40-62 Gy) was administered in 1.8-2.5 Gy fractions to primary lung tumor and regional mediastinal lymph nodes using modern RT technique. Overall survival (OS) from diagnosis, and locoregional progression-free survival (LRPFS), and survival calculated from radiotherapy (OS-RT) were estimated using the Kaplan-Meier method. There were 37 men and 19 women with a median age of 60 years at diagnosis. The median interval from the diagnosis of metastatic disease to thoracic RT was 8 months. Following thoracic RT, 26 patients (46%) achieved complete or partial response (overall response rate, ORR). Patients with squamous cell carcinoma or poorly-differentiated carcinoma had a higher ORR than those with adenocarcinoma (63% vs. 34%, P = 0.034). EGFR mutations was closely associated with a better ORR (45% vs. 29%, P = 0.284). At a median follow-up time of 44 months, the median OS, LRPFS after RT, and OS-RT were 50 months, 15 months, and 18 months. Radical palliative throractic RT is safe and might be beneficial for primary lung lesions of metastatic NSCLC patients with controlled extrathoracic diseases.
This retrospective study tested the hypothesis that disease control and treatment-related toxicit... more This retrospective study tested the hypothesis that disease control and treatment-related toxicity in patients undergoing high-dose radiotherapy (HDRT) for prostate cancer varies in a circadian manner. Patients with localized prostate adenocarcinoma receiving HDRT (median 78 Gy) to the prostate and involved seminal vesicle(s) without elective pelvic irradiation were divided into a daytime treatment (before 5 PM) group (n = 267) and evening treatment (after 5 PM) group (n = 142). Biochemical failure (Phoenix definition), acute and late gastrointestinal (GI) and genitourinary toxicities (Common Terminology Criteria for Adverse Events version 4), biochemical failure-free survival (BFFS) and freedom from late toxicity were assessed. Analyses were performed by binary logistic regression and Cox proportional hazard regression. The median follow-up was 68 months, and 75% of patients were ≥70 years old. Evening HDRT was significantly associated with worse freedom from ≥grade 2 late GI complications (hazard ratio = 2.96; p &amp;amp;amp;amp;lt; 0.001). The detrimental effect of evening HDRT was significant in patients older than 70 years old (p &amp;amp;amp;amp;lt; 0.001) but not in younger patients (p = 0.63). In a subgroup of propensity score-matched cohort with T2b-T3 disease (n = 154), the 5-year BFFS was worse in the evening group than the daytime group (72% vs. 85%, hazard ratio = 1.95, p = 0.05). Our study indicates that evening HDRT may lead to more GI complications, especially in older patients, and worse BFFS in patients with T2b-T3 disease.
This study analyzed the difference in reconstructing volume by using phantom model between variou... more This study analyzed the difference in reconstructing volume by using phantom model between various settings of axial-mode and spiral-mode computed tomography (CT) simulator for three-dimensional conformal radiotherapy. Three phantom balls with different diameters (5.1, 9.9, 12.2 cm) were scanned by a single-row detector CT simulator. The volumes of all phantom balls were reconstructed in the same system. The exactly calculated phantom ball volumes were the baselines as compared to the volumes by the conventional axial-mode CT reconstruction. The reconstructed volumes from the axial scanning mode were compared with the corresponding settings of the spiral scanning mode in CT simulation, with four different Hounsfield (HU) thresholds, three different pitches (1, 1.5 and 2), and four different slice widths (1, 2, 3 and 5 mm). The reconstructed volumes were less than the exactly calculated volumes in all phantom balls using the conventional axial-mode CT simulation. Larger slice width and HU threshold were associated with larger difference between the exactly calculated volumes and reconstructed volumes in axial CT mode. For the small phantom ball at slice width of no more than 3 mm, there were less than 5% of volume losses compared with axial-mode CT settings. The lowest HU threshold and slice width of less than 5 mm were needed to maintain volume loss of less than 5% in medium and large balls. As compared to axial-mode scanning, spiral-mode scanning offered volume reconstruction loss of less than 5% at almost all settings. The exceptions existed in the small phantom ball with slice width of 5 mm, spiral pitch of 1.5 and 2 at 50 HU, and slice width of 5 mm, spiral pitch of 2 at 0 HU. Slice interval, spiral scanning pitch and HU threshold were the factors with impact on the accurate estimation of volume reconstruction by spiral CT simulator. Spiral CT mode was feasible in most scanning settings, with acceptable volume reconstruction accuracy threshold of more than 95%.
International Journal of Radiation Oncology*Biology*Physics, 2015
Our aim was to investigate the association of clinical factors, dosimetric parameters, and biomar... more Our aim was to investigate the association of clinical factors, dosimetric parameters, and biomarkers with postoperative pulmonary complications (PPCs) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated by neoadjuvant concurrent chemoradiation therapy (CCRT) under strict pulmonary dose constraints and esophagectomy. We prospectively enrolled 112 patients undergoing trimodality treatment (including radiation therapy [40 Gy], concurrent taxane-/5-fluorouracil-based regimens, and radical esophagectomy) for ESCC. A PPC was defined as pneumonia or acute respiratory distress syndrome within 30 days after surgery. Serum samples were collected before and within 1 month after CCRT. The association of serum biomarkers with PPCs was detected by proximity ligation assay (PLA) and verified by enzyme-linked immunosorbent assay. Associations of clinical factors, lung dosimetric parameters, and biomarkers with PPC were tested statistically. Thirty-three patients (29.5%) had PPCs. None of the dosimetric parameters was associated with PPCs. Preoperative functional vital capacity (FVC) was significantly associated with PPCs (P=.004). Of the 15 PLA-screened biomarkers, posttreatment transforming growth factor-β1 (TGF-β1) was borderline significantly associated with PPCs (P=.087). Patients with PPCs had significantly larger pre-CCRT to post-CCRT decrease in serum TGF-β1 concentration (-11,310 vs -5332 pg/mL, P=.005) and higher pre-CCRT to post-CCRT percent decline in serum TGF-β1 concentration (-37.4% vs -25.0%, P=.009) than patients without PPCs. On multivariate analysis, preoperative FVC (P=.003) and decrease in TGF-β1 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;7040 pg/mL (P=.014) were independent factors associated with PPCs. Preoperative FVC and decrease in serum TGF-β1 level after dose-limited CCRT to the lung are associated with the development of PPCs.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, Jan 24, 2015
To determine whether the postchemoradiotherapy (post-CRT) pathologic stage predicts the outcomes ... more To determine whether the postchemoradiotherapy (post-CRT) pathologic stage predicts the outcomes of patients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing preoperative chemoradiotherapy followed by surgery. From 3 phase II trials of preoperative CRT for locally advanced ESCC, 140 patients were included. Preoperative CRT comprised twice weekly paclitaxel and cisplatin-based regimens and 40-Gy radiotherapy in 20 fractions. The post-CRT pathologic stage was classified according to the American Joint Committee on Cancer, 7th edition staging system (AJCC-7). The prognostic effects of clinicopathologic factors were analyzed using Cox regression. With a median follow-up of 61.9 months, the median progression-free survival (PFS) and overall survival (OS) of the entire cohort were 24.5 and 30.9 months, respectively. The post-CRT pathologic stage was 0 in 34.5%, I in 12.9%, II in 29.3%, III in 13.6%, and ypT0N1-2 in 6.4% of the patients. The median PFS was 47.2 mo...
Esophageal cancer patients with pathological complete response (pCR) to neoadjuvant chemoradiatio... more Esophageal cancer patients with pathological complete response (pCR) to neoadjuvant chemoradiation (CRT) have favorable outcomes. Currently, there was no reliable biomarker predicting the response to CRT. Perioperative circulating mRNA may be associated with prognosis, but its application for predicting treatment response is unclear. We prospectively assessed the value of circulating messenger RNA (mRNA) profiling in predicting pCR for esophageal squamous cell carcinoma (ESCC). Patients with ESCC completing CRT followed by surgery were enrolled for analysis. Venous peripheral blood was obtained before and after CRT, and total RNA was extracted for hybridization-based whole genome expression analysis and quantitative RT-PCR. We found circulating expression profiling was significantly altered after CRT. Altered FAM84B expression was significantly predictive of pCR. The decrease of serum FAM84B protein level after CRT was also associated with pCR. Immunohistochemistry and western blot confirmed that FAM84B protein was overexpressed in the majority of patients and ESCC cell lines. Furthermore, knockdown of FAM84B delayed tumor growth in ectopic xenografts. We demonstrated the decreased of circulating FAM84B mRNA and protein after neoadjuvant CRT may predict pCR, and FAM84B protein is overexpressed in ESCC. The potential of FAM84B as a novel predictive biomarker, and its biological functions deserve further investigation.
Cytolethal distending toxin (CDT) produced by Campylobacter jejuni is a genotoxin that induces ce... more Cytolethal distending toxin (CDT) produced by Campylobacter jejuni is a genotoxin that induces cell-cycle arrest and apoptosis in mammalian cells. Recent studies have demonstrated that prostate cancer (PCa) cells can acquire radio-resistance when DOC-2/DAB2 interactive protein (DAB2IP) is downregulated. In this study, we showed that CDT could induce cell death in DAB2IP-deficient PCa cells. A combination of CDT and radiotherapy significantly elicited cell death in DAB2IP-deficient PCa cells by inhibiting the repair of ionizing radiation (IR)-induced DNA double-strand break (DSB) during G2/M arrest, which is triggered by ataxia telangiectasia mutated (ATM)-dependent DNA damage checkpoint responses. We also found that CDT administration significantly increased the efficacy of radiotherapy in a xenograft mouse model. These results indicate that CDT can be a potent therapeutic agent for radio-resistant PCa.
DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key component of the non-homologous ... more DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key component of the non-homologous end-joining (NHEJ) pathway, is involved in DNA double-strand break repair, immunocompetence, genomic integrity, and epidermal growth factor receptor signaling. Clinical studies indicate that expression and activity of DNA-PKcs is correlated with cancer progression and response to treatment. Various anti-DNA-PKcs strategies have been developed and tested in preclinical studies to exploit the benefit of DNA-PKcs inhibition in sensitization of radiotherapy and in combined modality therapy with other antitumor agents. In this article, we review the association between DNA-PKcs and cancer development and discuss current approaches and mechanisms for inhibition of DNA-PKcs. The future challenges are to understand how DNA-PKcs activity is correlated with cancer susceptibility and to identify those patients who would most benefit from DNA-PKcs inhibition.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, Jan 26, 2015
To assess the usefulness of pathological stage according to the 7th edition of the Union for Inte... more To assess the usefulness of pathological stage according to the 7th edition of the Union for International Cancer Control-American Joint Committee on Cancer (UICC-AJCC) as a prognostic tool in patients undergoing neoadjuvant chemoradiation followed by esophagectomy (trimodality therapy, TMT) for locally advanced esophageal squamous cell carcinoma. One hundred twenty-five eligible patients completing TMT were enrolled for analysis. The clinical (cTNM7) and pathological (ypTNM7) stage groups of their tumors were prospectively classified, and re-grouped by the 6th edition (ypTNM6). Survival was analyzed using the Kaplan-Meier method. The Cox proportional hazard model and the Akaike information criterion (AIC) were used to compare the performance of staging systems. With a median follow-up of 24.6months, 54 patients (43.2%) died. Forty patients (32%) achieved pathological complete remission (pCR). The median survival was 31.8months. On multivariate analysis, ypTNM7 (but not pCR or pN) w...
The current standard of care for lung cancer consists of concurrent chemotherapy and radiation. S... more The current standard of care for lung cancer consists of concurrent chemotherapy and radiation. Several studies have shown that the DNA-PKcs inhibitor NU7441 is a highly potent radiosensitizer, however, the mechanism of NU7441's anti-proliferation effect has not been fully elucidated. In this study, the combined effect of NU7441 and ionizing radiation (IR) in a panel of non-small cell lung cancer cell lines (A549, H460 and H1299) has been investigated. We found that NU7441 significantly enhances the effect of IR in all cell lines. The notable findings in response to this combined treatment are (i) prolonged delay in IR-induced DNA DSB repair, (ii) induced robust G2/M checkpoint, (iii) increased aberrant mitosis followed by mitotic catastrophe specifically in H1299, (iv) dramatically induced autophagy in A549 and (v) IR-induced senescence specifically in H460. H1299 cells show greater G2 checkpoint adaptation after combined treatment, which can be attributed to higher expression ...
Radiation therapy (RT) is an effective strategy for the treatment of localized prostate cancer (P... more Radiation therapy (RT) is an effective strategy for the treatment of localized prostate cancer (PCa) as well as local invasion. However, some locally advanced cancers develop radiation resistance and recur after therapy; therefore, the development of radiation-sensitizing compounds is essential for treatment of these tumors. DOC-2/DAB2 interactive protein (DAB2IP), which is a novel member of the Ras-GTPase activating protein family and a regulator of phosphatidylinositol 3-kinase-Akt activity, is often downregulated in aggressive PCa. Our previous studies have shown that loss of DAB2IP results in radioresistance in PCa cells primarily because of accelerated DNA double-strand break (DSB) repair kinetics, robust G(2)/M checkpoint control, and evasion of apoptosis. A novel DNA-PKcs inhibitor NU7441 can significantly enhance the effect of radiation in DAB2IP-deficient PCa cells. This enhanced radiation sensitivity after NU7441 treatment is primarily due to delayed DNA DSB repair. More s...
Tumor control of hepatocellular carcinoma by radiotherapy remains unsatisfactory. The phosphatidy... more Tumor control of hepatocellular carcinoma by radiotherapy remains unsatisfactory. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a critical role in inhibiting cancer cell death. Elevated PI3K/Akt activity is associated with increased cellular resistance to irradiation. Our aim was to determine whether the inhibition of PI3K/Akt activity by a PI3K inhibitor, BKM120, contributes to the increased sensitivity of liver cancer cells to irradiation. The hepatocellular carcinoma cell lines (Huh7 and BNL) were used to evaluate the in vitro synergism between BKM120 and irradiation. Balb/c mice bearing ectopic BNL xenografts were treated with BKM120 and/or radiotherapy to assess the in vivo response. BKM120 increased cell killing by radiation, increased the expression of apoptotic markers, and suppressed the repair of radiation-induced DNA double-strand breaks. BKM120 pretreatment inhibited radiation-induced Akt phosphorylation and enhanced the tumor-suppressive effect and radiatio...
Journal of gastroenterology and hepatology, Jan 13, 2015
Sonic Hedgehog (SHH) is a regulator in tumorigenesis of hepatocellular carcinoma (HCC). This stud... more Sonic Hedgehog (SHH) is a regulator in tumorigenesis of hepatocellular carcinoma (HCC). This study aimed to determine whether radiation-induced SHH signaling occurs in HCC, and whether SHH inhibitor acts as a radiosensitizer. The in vitro effects of combining SHH ligand (recombinant human SHH) or inhibitor (cyclopamine) with irradiation were evaluated in the human HCC cell lines, Huh-7 and PLC/PRF/5, and murine cell line BNL. Cell survival and apoptosis were measured using a colony formation assay, annexin-V staining, and poly (ADP-ribose) polymerase activation. Western blotting and immunofluorescence staining were used to detect protein expression. The in vivo response to radiotherapy and/or cyclopamine was tested in BALB/c mice bearing an orthotopic allogeneic tumor. Treatment of HCC cells with irradiation and SHH ligand had a protective effect on clonogenic cell survival. Treatment with irradiation and cyclopamine was a more potent inhibitor of cell proliferation than either moda...
Purpose: To assess bladder filling status and its impact on target position during daily intensit... more Purpose: To assess bladder filling status and its impact on target position during daily intensity-modulated radiation therapy (IMRT) using cone-beam computed tomography (CBCT) in prostate cancer patients. Patients and Methods: 23 patients with prostate cancer undergoing image-guided IMRT (78 Gy in 39 fractions) were included. On-board CBCT images were acquired daily and an endorectal balloon was placed daily. All patients were instructed to have a full bladder. The interfraction changes in bladder dimensions in left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions were measured from CBCT images. Distances from the uppermost part of prostate to pubic bone (PP) and from the uppermost part of prostate to treatment isocenter (PI) were measured to determine changes in target position. Standard deviation (SD) in all fractions of each patient was used to compare the variations between patients. Bladder dimension change ratio and Z-score were used to normalize data between patients. Results: A total of 867 CBCT images were evaluated. The average LR, AP, and SI bladder dimensions were 7.8 ± 1.5 cm, 6.7 ± 1.4 cm, and 5.6 ± 1.7 cm, respectively. The average LR, AP, and SI bladder dimension change ratios were 0.88 ± 0.17, 0.90 ± 0.15, and 0.86 ± 0.32, respectively. The SD was significantly greater in SI dimension than in LR (p < 0.001) and AP (p < 0.001) dimensions. The interfraction changes in the three bladder dimensions were significantly larger than those of target position, and did not correlate with target position changes. Conclusion: Though they were not negligible, changes in bladder filling status did not have a significant impact on target position.
Radiotherapy (RT) has been gradually integrated into the multimodality treatment for hepatocellul... more Radiotherapy (RT) has been gradually integrated into the multimodality treatment for hepatocellular carcinoma (HCC). The various patterns of failure in HCC patients undergoing RT drive the need of effective biomarkers to guide treatment decisions. Limited numbers of biomarkers have been investigated in HCC, with even fewer of them for patients treated by RT. Serum or plasma biomarkers measured by enzyme-linked immunosorbent assay were the most common practice. Of particular interest are those biomarkers that are detectable early in the course of radiotherapy which correlated with ultimate clinical outcome. Functional magnetic resonance imaging (MRI) is increasingly used to evaluate the imaging pattern indicative of disease control following RT. Positron emission tomography shows that pre-RT standard uptake values associate with various types of recurrence after treatment. Proximity ligation assay (PLA) is evolving with the unique features of dual-probe identification, ligation and amplification to allow the small volume of serum/plasma samples for evaluating multiple biomarkers. We demonstrate the screening work of biomarkers by PLA with pre- and post-RT serum samples from HCC patients undergoing RT. Efforts are being made to search for the potential biomarkers for HCC patients treated by RT.
Compared with step-and-shoot intensity-modulated radiotherapy (sIMRT) and tomotherapy, volumetric... more Compared with step-and-shoot intensity-modulated radiotherapy (sIMRT) and tomotherapy, volumetric-modulated arc therapy (VMAT) allows additional arc configurations in treatment planning and noncoplanar (NC) delivery. This study was first to compare VMAT planning with sIMRT planning, and the second to evaluate the toxicity of coplanar (C)/NC-VMAT treatment in patients with hepatocellular carcinoma (HCC). Fifteen patients with HCC (7 with left-lobe and 8 with right-lobe tumors) were planned with C-VMAT, C/NC-VMAT, and sIMRT. The median total dose was 49Gy (range: 40 to 56Gy), whereas the median fractional dose was 3.5Gy (range: 3 to 8Gy). Different doses/fractionations were converted to normalized doses of 2Gy per fraction using an α/β ratio of 2.5. The mean liver dose, volume fraction receiving more than 10Gy (V10), 20Gy (V20), 30Gy (V30), effective volume (Veff), and equivalent uniform dose (EUD) were compared. C/NC-VMAT in 6 patients was evaluated for delivery accuracy and treatment-related toxicity. Compared with sIMRT, both C-VMAT (p = 0.001) and C/NC-VMAT (p = 0.03) had significantly improved target conformity index. Compared with C-VMAT and sIMRT, C/NC-VMAT for treating left-lobe tumors provided significantly better liver sparing as evidenced by differences in mean liver dose (p = 0.03 and p = 0.007), V10 (p = 0.003 and p = 0.009), V20 (p = 0.006 and p = 0.01), V30 (p = 0.02 and p = 0.002), Veff (p = 0.006 and p = 0.001), and EUD (p = 0.04 and p = 0.003), respectively. For right-lobe tumors, there was no difference in liver sparing between C/NC-VMAT, C-VMAT, and sIMRT. In all patients, dose to more than 95% of target points met the 3%/3mm criteria. All 6 patients tolerated C/NC-VMAT and none of them had treatment-related ≥ grade 2 toxicity. The C/NC-VMAT can be used clinically for HCC and provides significantly better liver sparing in patients with left-lobe tumors.
Background and Objectives: To investigate the impact of using paclitaxel in chemoradiation on loc... more Background and Objectives: To investigate the impact of using paclitaxel in chemoradiation on locally advanced esophageal squamous cell carcinoma (SCC) treated with or without surgery. Methods: Of 127 patients with AJCC stages II-III esophageal SCC undergoing definitive chemoradiation (DefCRT, n ¼ 44) or neoadjuvant chemoradiation plus surgery (NeoCRT þ S, n ¼ 83), 57 received chemotherapy with paclitaxel and cisplatin (TP), and 70 received 5-fluorouracil and cisplatin (PF). Three-year local progression-free survival (LPFS), distant metastasis-free survival, overall survival, and prognostic factors were retrospectively analyzed. Results: The median survival was 30 months. Pathological complete response rate was 41% and 27% with TP and PF, respectively (P ¼ 0.19). NeoCRT þ S achieved significantly higher LPFS than DefCRT (71% vs. 39%, P < 0.001). Patients receiving TP had significantly higher LPFS than PF (74% vs. 48%, P ¼ 0.04). Local control was similar between DefCRT with TP and NeoCRT þ S. Distant metastasis-free survival and overall survival were not different between treatment modalities or chemotherapy regimens. In multivariate analysis, surgery (HR 0.30, P < 0.001), TP regimen (HR 0.38, P ¼ 0.007), and mediastinal lymphadenopathy (HR 2.37, P ¼ 0.008) were independent factors for LPFS. Conclusions: Both surgery and the use of paclitaxel-based chemoradiation may improve local disease control. Future randomized trials should integrate paclitaxel into definitive chemoradiation.
This work investigated the role of structure in the binding of polysaccharides from 10 regionally... more This work investigated the role of structure in the binding of polysaccharides from 10 regionally different strains of Lentinula edodes to Toll-like receptor 4 (TLR-4) on monocytes (THP-1) and the potential effect of this interaction on tumor cell viability. Principal component analysis and multiple linear regression identified arabinose, glucose 1 → 4 linkage, and molecular weights about 2700 and 534 kDa as the significant determinant factors associated with TLR-4 binding activity. The branched α-(1,4)-glucan (L10) had the strongest ability to bind to TLR-4 and induce THP-1 cell differentiation. L10 induction of the THP-1 cell differentiation, superoxide production, and cytokine production followed the TLR-4/MyD88/IKK/NFκB pathway. Coculture of irradiated human lung adenocarcinoma A549 cells with L10-activated THP-1 cells resulted in significantly decreased percentage of viable A549 cells from 66 to 37% (p = 0.018), increased levels of superoxide, interleukin-8, and RANTES, and decreased levels of angiogenin and vascular endothelial growth factor. The results indicate that L10-activated monocytes have the potential to boost the antitumor immune response and antitumor activity of radiotherapy.
International Journal of Radiation Oncology*Biology*Physics, 2011
Purpose: To evaluate the efficacy and patterns of failure of elective nodal irradiation (ENI) in ... more Purpose: To evaluate the efficacy and patterns of failure of elective nodal irradiation (ENI) in patients with esophageal squamous cell carcinoma (SCC) undergoing preoperative concurrent chemoradiation (CCRT) followed by radical surgery. Methods and Materials: We retrospectively studied 118 patients with AJCC Stage II to III esophageal SCC undergoing preoperative CCRT (median, 36 Gy), followed by radical esophagectomy. Of them, 73 patients (62%) had ENI and 45 patients (38%) had no ENI. Patients with ENI received radiotherapy to either supraclavicular (n = 54) or celiac (n = 19) lymphatics. Fifty-six patients (57%) received chemotherapy with paclitaxel plus cisplatin. The 3-year progression-free survival, overall survival, and patterns of failure were analyzed. Distant nodal recurrence was classified into M1a and M1b regions. A separate analysis using matched cases was conducted. Results: The median follow-up was 38 months. There were no differences in pathological complete response rate (p = 0.12), perioperative mortality rate (p = 0.48), or delayed Grade 3 or greater cardiopulmonary toxicities (p = 0.44), between the groups. More patients in the non-ENI group had M1a failure than in the ENI group, with 3-year rates of 11% and 3%, respectively (p = 0.05). However, the 3-year isolated distant nodal (M1a + M1b) failure rates were not different (ENI, 10%; non-ENI, 14%; p = 0.29). In multivariate analysis, pathological nodal status was the only independent prognostic factor associated with overall survival (hazard ratio = 1.78, p = 0.045). The 3-year overall survival and progression-free survival were 45% and 45%, respectively, in the ENI group, and 52% and 43%, respectively, in the non-ENI group (p = 0.31 and 0.89, respectively). Matched cases analysis did not show a statistical difference in outcomes between the groups. Conclusions: ENI reduced the M1a failure rate but was not associated with improved outcomes in patients undergoing preoperative CCRT for esophageal SCC. Pathological nodal metastasis predicted poor outcome. Ó 2011 Elsevier Inc.
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Papers by Feng-ming Hsu