Mian Xi

Effectiveness of stereotactic body radiotherapy for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombosis.

Background To report the feasibility, efficacy, and toxicity of stereotactic body radiotherapy (SBRT) for the treatment of portal vein tumor thrombosis (PVTT) and/or inferior vena cava tumor thrombosis (IVCTT) in patients with advanced hepatocellular carcinoma (HCC). Materials and methods Forty-one patients treated with SBRT using volumetric modulated arc therapy (VMAT) for HCC with PVTT/IVCTT between July 2010 and May 2012 were analyzed. Of these, 33 had PVTT and 8 had IVCTT. SBRT was designed to target the tumor thrombosis and deliver a median total dose of 36 Gy (range, 30–48 Gy) in six fractions during two weeks. Results The median follow-up was 10.0 months. At the time of analysis, 15 (36.6%) achieved complete response, 16 (39.0%) achieved partial response, 7 (17.1%) patients were stable, and three (7.3%) patients showed progressive disease. No treatment-related Grade 4/5 toxicity was seen within three months after SBRT. One patient had Grade 3 elevation of bilirubin. The one-year overall survival rate was 50.3%, with a median survival of 13.0 months. The only independent predictive factor associated with better survival was response to radiotherapy. Conclusions VMAT-based SBRT is a safe and effective treatment option for PVTT/IVCTT in HCC. Prospective randomized controlled trials are warranted to validate the role of SBRT in these patients.

How many sets of 4DCT images are sufficient to determine internal target volume for liver radiotherapy

BACKGROUND AND PURPOSE To determine the feasibility of using limited four-dimensional computed tomography (4DCT) images for treatment planning. MATERIALS AND METHODS The 4DCT scans of 16 patients with hepatocellular carcinoma (HCC) were analyzed. Gross tumor volumes (GTVs) were manually contoured on all 10 respiratory phases, and different internal clinical target volumes (ICTVs) were derived by encompassing volumes of the respective CTVs. Volume, position, and shape of ICTVs were calculated and compared. RESULTS The ICTV(2 phases), ICTV(3 phases), ICTV(4 phases), and ICTV(6 phases) all showed excellent agreement with ICTV(10 phases), and the ICTV(2 phases) encompassed ICTV(10 phases) by 94.1+/-1.8% on average. The 3D shift between the centers of mass of the ICTVs was only 0.6mm. The surface distance between ICTV(10 phases) and ICTV(2 phases) was 1.7+/-0.8mm in the left-right (LR) and anteroposterior (AP) directions. CONCLUSIONS Contouring two extreme phases at end-inhalation and end-exhalation is a reasonably safe and labor-saving method of deriving ITV for liver radiotherapy with low and medium tumor motion amplitude (1.6 cm). Whether the larger tumor movement affects the results is the subject of ongoing research.

Radiation-induced sarcoma in patients with nasopharyngeal carcinoma: a single-institution study.

The increasing incidence of radiation‐induced sarcoma (RIS) has become a significant problem that can limit long‐term survival. The objective of the current study was to analyze the clinicopathologic characteristics, treatment outcomes, and prognostic factors of RIS after radiotherapy for nasopharyngeal carcinoma (NPC).

Long non-coding RNA HOTTIP is correlated with progression and prognosis in tongue squamous cell carcinoma

Long non-coding RNAs (lncRNAs) have been demonstrated to be a critical role in cancer progression and prognosis. However, little is known about the pathological role of lncRNA HOXA transcript at the distal tip (HOTTIP) in tongue squamous cell carcinoma (TSCC) patients. The aim of this study is to measure the expression of lncRNA HOTTIP in TSCC patients and to explore the clinical significance of the lncRNA HOTTIP. The expression of lncRNA HOTTIP was measured in 86 TSCC tissues and 14 adjacent non-malignant tissues using qRT-PCR. In our study, results indicated that lncRNA HOTTIP was highly expressed in TSCC compared with adjacent non-malignant tissues (P < 0.001) and positively correlated with T stage (T1–2 vs. T3–4, P = 0.023), clinical stage (I–II stages vs. III–IV stages, P = 0.018), and distant metastasis (absent vs. present, P = 0.031) in TSCC patients. Furthermore, we also found that lncRNA HOTTIP overexpression was an unfavorable prognostic factor in TSCC patients (P < 0.001), regardless of T stage, distant metastasis, and clinical stage. Finally, overexpression of lncRNA HOTTIP was supposed to be an independent poor prognostic factor for TSCC patients through multivariate analysis (P = 0.023). In conclusion, increased lncRNA HOTTIP expression may be serve as an unfavorable prognosis predictor for TSCC patients. Nevertheless, further investigation with a larger sample size is needed to support our results.

Clinical efficacy and failure pattern in patients with cervical esophageal cancer treated with definitive chemoradiotherapy

BACKGROUND Data on cervical esophageal cancer (CEC) based on modern radiotherapy technique are rare. We aimed to analyze the clinical efficacy and failure pattern of patients with CEC who underwent definitive chemoradiotherapy. METHODS Between February 2002 and October 2013, 102 patients with CEC treated with definitive chemoradiotherapy were retrospectively analyzed. All patients received concurrent platinum-based chemotherapy with conformal radiotherapy (50-70 Gy in 25-35 fractions, 5 fractions per week over 5-7 weeks). Overall survival (OS), progression-free survival (PFS) and loco-regional failure-free survival (LRFFS) were calculated. RESULTS The 3-year OS, PFS and LRFFS rates for the entire sample were 39.3%, 33.6% and 35.3%, respectively. During follow-up, 32, 26, and 41 patients had developed local, regional, and distant failure, respectively. Sex and hoarseness were independent prognostic indicators for OS (P=0.011, P<0.001; respectively) and PFS (P=0.008, P=0.001; respectively). Hoarseness was the only independent prognostic factor for LRFFS (P=0.002). CONCLUSIONS Distant metastasis was the most common failure pattern in CEC patients undergoing definitive chemoradiotherapy. Hoarseness was an independent prognostic factor for OS, PFS, and LRFFS.

Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous cell carcinoma cells by upregulating IGFBP-3

BackgroundEpidermal growth factor receptor (EGFR) is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC). The objective of this study was to investigate the efficacy of Nimotuzumab (an anti-EGFR monoclonal antibody) on ESCC radiotherapy (RT) and underlying mechanisms.MethodsNimotuzumab was administrated to 2 ESCC cell lines KYSE30 and TE-1 treated with RT. Cell growth, colony formation and apoptosis were used to measure anti-proliferation effects. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3) in ESCC cells radiosensitivity treated with Nimotuzumab. In vivo effect of Nimotuzumab on ESCC radiotherapy was done using a mouse xenograft model.ResultsNimotuzumab enhanced radiation response of KYSE30 cells (with high EGFR expression) in vitro, as evidenced by increased radiation-inhibited cell growth and colony formation and radiation-mediated apoptosis. Mechanism study revealed that Nimotuzumab inhibited phosphorylated EGFR (p-EGFR) induced by EGF in KYSE30 cells. In addition, knockdown of IGFBP-3 by short hairpin RNA significantly reduced KYSE30 cells radiosensitivity (P<0.05), and even after the administration of Nimotuzumab, the RT response of IGFBP-3 silenced KYSE30 cells was not enhanced (P>0.05). In KYSE30 cell xenografts, Nimotuzumab combined with radiation led to significant tumor growth delay, compared with that of radiation alone (P=0.029), and also with IGFBP-3 up-regulation in tumor tissue.ConclusionsNimotuzumab could enhance the RT effect of ESCC cells with a functional active EGFR pathway. In particular, the increased ESCC radiosensitivity by Nimotuzumab might be dependent on the up-regulation of IGFBP-3 through EGFR-dependent pathway.

The modified glasgow prognostic score is an independent prognostic factor in patients with inoperable thoracic esophageal squamous cell carcinoma undergoing chemoradiotherapy.

Background and purpose: There is increasing evidence that the presence of an inflammation-based prognostic score (modified Glasgow prognostic score, mGPS) is associated with survival in patients with advanced cancer. This study aimed to assess whether the mGPS has prognostic value in patients with thoracic esophageal squamous cell carcinoma undergoing chemoradiotherapy. Materials and methods: A total of 212 patients undergoing chemoradiotherapy for newly-diagnosed esophageal squamous cell carcinoma between October, 2006 and December, 2011 were retrospectively analyzed. Serum C-reactive protein (CRP) and albumin were measured before initiation of treatment. The relationships between the mGPS and other relevant variables including white blood cell count, neutrophilic granulocyte count, platelet count, hemoglobin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were analyzed. Overall survival (OS) and progression-free survival (PFS) were calculated. Significant prognostic factors were identified using univariate and multivariate analyses. Results: Three-year OS for all patients was 24.6%; 3-year PFS was 21.3%. Patients with a mGPS of 0, 1 and 2 were 90, 78, 44, respectively. Higher mGPS was related to higher white blood cell, neutrophilic granulocyte and platelet counts, and lower total bilirubin. T stage, M stage and mGPS were independent prognostic indicators for OS; T stage, M stage, mGPS and platelet count were independent prognostic indicators for PFS. Conclusions: Pretreatment mGPS is an easily measurable significant prognostic factor and can be used in combination with conventional TNM staging to predict survival in patients with squamous cell carcinoma undergoing chemoradiotherapy.

Dosimetric Analysis of Respiratory-Gated Radiotherapy for Hepatocellular Carcinoma

The purpose of this study was to define individualized internal target volume (ITV) for hepatocellular carcinoma (HCC) using 4D computed tomography (4DCT), and to determine the geometric and dosimetric benefits of respiratory gating. Gross tumor volumes (GTVs) were contoured on 10 respiratory phases of 4DCT images for 12 patients with HCC. Three treatment plans were prepared using different planning target volumes (PTVs): (1) PTV(3D), derived from a single helical clinical target volume (CTV) plus conventional margins; (2) PTV(10 phases), derived from ITV(10 phases), which encompassed all 10 CTVs plus an isotropic margin of 0.8 cm; (3) PTV(gating), derived from ITV(gating), which encompassed three CTVs within gating-window at end-expiration plus an isotropic margin of 0.8 cm. The PTV(3D) was the largest volume for all patients. The ITV-based plans and gating plans spared more normal tissues than 3D plans, especially the liver. Without increasing normal tissue complication probability of the 3D plans, the ITV-based plans allowed for increasing the calculated dose from 50.8 Gy to 54.7 Gy on average, and the gating plans could further escalate the dose to 58.5 Gy. Compared with ITV-based plans, the dosimetric gains with gating plan strongly correlated with GTV mobility in the craniocaudal direction. The ITV-based plans can ensure target coverage with less irradiation of normal tissues compared with 3D plans. Respiratory-gated radiotherapy can further reduce the target volumes to spare more surrounding tissues and allow dose escalation, especially for patients with tumor mobility >1 cm.

The overexpression of IGFBP-3 is involved in the chemosensitivity of esophageal squamous cell carcinoma cells to nimotuzumab combined with cisplatin

Nimotuzumab is an antibody against epidermal growth factor receptor (EGFR). The objective of this study was to examine the capacity and specific underlying mechanisms of nimotuzumab to modulate cytotoxicity of cisplatin (DDP) in esophageal squamous cell carcinoma (ESCC) cell lines with different EGFR expression levels. Nimotuzumab was administrated to two ESCC cell lines KYSE30 and TE-1 treated with DDP. Cell growth, colony formation, and apoptosis were analyzed by MTT and flow cytometry assays. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3) in ESCC cells chemosensitivity treated with nimotuzumab. Combination of nimotuzumab and DDP resulted in a DDP cytotoxicity increase in overexpressing EGFR cells (KYSE30) but not in low-expressing EGFR cells (TE-1). Meantime, DDP activated the EGFR pathway in the two cell lines in a ligand-independent fashion. Furthermore, DDP-induced EGFR activation was inhibited by nimotuzumab in KYSE30 cells, and this result was not observed in TE-1 cells. EGF reduced the expression of IGFBP-3 in KYSE30 cells; however, nimotuzumab could reverse the downregulation of IGFBP-3, and this result was also not observed in TE-1 cells. After IGFBP-3 was silenced by small interfering RNA, the potential of nimotuzumab to enhance DDP-mediated cytotoxicity was inhibited in KYSE30 cells. The results indicated that the increased ESCC chemosensitivity to DDP by nimotuzumab might be dependent on IGFBP-3 upregulation through EGFR-dependent pathway, which would facilitate preselection of ESCC patients for treatment of nimotuzumab combined with DDP.

Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner

BackgroundHepatocellular carcinoma (HCC) has a high incidence and mortality. Radiotherapy and sorafenib have proven effective for HCC. Here, we investigated whether sorafenib modulated the response of HCC cells to irradiation in vitro, effect of timing of sorafenib, and the underlying mechanisms.MethodsCell viability of the HCC cell lines, SMMC-7721 and Bel-7402, was examined by the 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2(4-sulfophenyl)-2 H-terazolium (MTT) assays. Clonogenic growth assays of SMMC-7721 and Bel-7402 were determined by colony formation assays. DNA damage was assessed by monitoring γ-HAX foci in irradiated cells with immunofluorescence microscopy, and cell cycle distribution changes were examined by flow cytometry. Effects of sorafenib (15 μM) added 30 min prior to radiation (pre-irradiation sorafenib) of SMMC-7721 and BEL-7402 or 24 h post-irradiation (post-irradiation sorafenib) on irradiated SMMC-7721 and BEL-7402 cells were compared to those of radiation alone or no treatment.ResultsThe effect of sorafenib was dependent on its time of addition in relationship to irradiation of cells. Pre-irradiation sorafenib did not significantly affect the viability of SMMC-7221 and BEL-7402 cells compared with irradiation treatment alone. In contrast, post-irradiation sorafenib increased the sensitivity of irradiated SMMC-7221 and BEL-7402 cells significantly in a time-dependent manner. Pre-irradiation sorafenib significantly increased the surviving fraction of SMMC-7221 and BEL-7402 cells in clonogenic assays whereas post-irradiation sorafenib significantly reduced the surviving fractions of SMMC-7221 and BEL-7402 cells. SMMC-7721 cells treated with sorafenib 30 min before irradiation had significantly fewer cells with γ-H2AX foci (23.8 ± 2.9%) than SMMC-7721 cells receiving radiation alone (59.9 ± 2.4; P < 0.001). Similarly, BEL-7402 cells receiving sorafenib prior to irradiation had significantly fewer cells with γ-H2AX foci (46.4 ± 3.8%) than those receiving radiation alone (25.0 ± 3.0%; P < 0.001). In addition, irradiation (6 Gy) caused a significant increase in the percentage of both SMMC-7721 and BEL-7402 cells in G2/M at 12 to 16 h post irradiation, which was markedly delayed by pre-irradiation sorafenib.ConclusionsSorafenib combined with irradiation exerted a schedule-dependent effect in HCC cells in vitro, which has significant implications for the combined use of sorafenib and radiotherapy for HCC patients.