Acyl-CoA dehydrogenase long chain expression is associated with esophageal squamous cell carcinoma progression and poor prognosis.

BACKGROUND: Acyl-CoA dehydrogenase long chain (ACADL) was revealed to have a correlation with malignant progression of cancer. However, whether ACADL plays a role in clinical therapy remains unclear. The clinicopathological role of ACADL in esophageal squamous cell carcinoma (ESCC) will be discussed in this study. MATERIALS AND METHODS: The expression of ACADL was analyzed via real-time PCR and Western blotting to assess mRNA and protein levels in ESCC cell lines and normal esophageal epithelial cells (NEECs), in six paired ESCC tumors and relative normal tissues. Furthermore, immunohistochemical staining was performed on 135 paraffin-embedded ESCC specimens to assess ACADL expression. The clinicopathological significance of ACADL expression was further investigated via survival analysis and Cox regression analysis. RESULTS: ACADL was found to be markedly upregulated in ESCC cell lines when compared with NEECs. Moreover, various experiments such as quantitative real-time PCR, Western blot, and immunohistochemical analyses all revealed that ACADL expression was increased in all six paired ESCC tumors and matched normal tissues. Furthermore, immunohistochemical analysis revealed an increased level of ACADL protein expression in all 135 paraffin-embedded samples from ESCC patients, which increased with disease progression. CONCLUSION: We demonstrated that ACADL is overexpressed in ESCC, both in cell lines and clinical specimens. ACADL is found to be a vital regulator in ESCC progression and can predict a worse outcome for ESCC patients, suggesting that ACADL might be a valuable molecule to be targeted for clinical therapy of ESCC treatment.

Functional promoter rs189037 variant of ATM is associated with decrease in lung diffusing capacity after irradiation for non-small-cell lung cancer.

OBJECTIVE: Single-nucleotide polymorphisms (SNPs) in the ataxia telangiectasia-mutated gene ATM have been linked with pneumonitis after radiotherapy for lung cancer but have not been evaluated in terms of pulmonary function impairment. Here we investigated potential associations between SNPs in ATM and changes in diffusing capacity of the lung for carbon monoxide (DLCO) in patients with non-small-cell lung cancer (NSCLC) after radiotherapy. METHODS: From November 1998 through June 2009, 448 consecutive patients with inoperable primary NSCLC underwent definitive (≥60 Gy) radiotherapy, with or without chemotherapy. After excluding patients with a history of thoracic surgery, radiation, or lung cancer; without DNA samples available for analysis; or without pulmonary function testing within the 12 months before and the 12 months after radiotherapy, 100 patients were identified who are the subjects of this study. We genotyped two SNPs of ATM previously found to be associated with radiation-induced pneumonitis (rs189037 and rs228590) and evaluated potential correlations between these SNPs and impairment (decreases) in DLCO by using logistic regression analysis. RESULTS: Univariate and multivariate analyses showed that the AA genotype of ATM rs189037 was associated with decreased DLCO after definitive radiotherapy than the GG/AG genotypes [univariate coefficient, -0.122; 95% confidence interval (CI), -0.236 to -0.008; P = 0.037; and multivariate coefficient, -0.102; 95% CI, -0.198 to -0.005; P = 0.038]. No such correlations were found for rs228590 (univariate coefficient, -0.096; 95% CI, -0.208 to 0.017; P = 0.096). CONCLUSIONS: The AA genotype of ATM rs189037 was associated with higher risk of lung injury than were the GG/AG genotypes in patients with NSCLC treated with radiotherapy. This finding should be validated prospectively with other patient populations.

Efficacy and safety of late-course hypofractionated radiation therapy for muscle-invasive bladder carcinoma after bladder-conserving surgery.

AIM: To evaluate the efficacy and safety of late-course hypofractionated radiation treatment of muscle-invasive bladder carcinoma after bladder-conserving surgery. METHODS: Seventy-six patients with transitional cell bladder carcinoma, stage II (T2-4N0M0), after transurethral resection, were enrolled. Pirarubicin was given at 30 mg/m2 and 100 mL physiological saline once weekly (QW) for 12 weeks through and after intravesical instillation postoperatively. Radiation schedule delivered 46 Gy in 20 fractions for planning target volume, with an additional 20 Gy in five fractions for gross tumor volume as late-course radiation. Chemotherapy was stopped if Radiation Therapy Oncology Group grade 3 or higher bladder or bowel toxicity occurred. The primary end points were acute toxicity, local control and patients' survival. RESULTS: One-, three- and five-year overall survival rates were 98, 78 and 69.5%, respectively. Mean survival time was 58.4 months (95% CI: 52.6, 64.2). In addition, 1-, 3- and 5-year local control rates were 100, 80.5 and 76.1%, respectively. Mean local control time was 60.7 months (95% CI: 55.1, 66.3). The cumulative incidence of local/regional failure and distant failure was 28.9%. The rate of single local/regional failure was 13.2%, but distant failure rate was 21.1%. CONCLUSIONS: Concurrent pirarubicin-based late-course hypofractionated radiation therapy showed desirable local control rate and acceptable toxicity. It could be used after bladder-conserving surgery to allow patients to preserve their bladder.

Recent developments in sample preparation and data pre-treatment in metabonomics research.

Metabonomics is a powerful approach for biomarker discovery and an effective tool for pinpointing endpoint metabolic effects of external stimuli, such as pathogens and disease development. Due to its wide applications, metabonomics is required to deal with various biological samples of different properties. Hence sample preparation and corresponding data pre-treatment become important factors in ensuring validity of an investigation. In this review, we summarize some recent developments in metabonomics sample preparation and data-pretreatment procedures.

[Treatment of pyriform sinus carcinoma involving the lateral wall].

OBJECTIVE: To present and discuss the clinical features, treatment, and efficacy of pyriform sinus carcinoma involving the lateral wall. METHODS: Seventy-seven patients with pyriform sinus cancer involving the lateral wall (stage I 8, stage II 10, stage III 32, stage IV 27, according to UICC 2002 staging) were treated from Jun 1997 to Jun 2009 in the department of otorhinolaryngology head and neck surgery, Yuhuangding Hospital. The patients were divided into two groups: Group one 17 cases, simply underwent radiation therapy (R group); Group two 60 cases underwent surgery plus postoperative radiation (SR group). All patients underwent radiotherapy 50-75 Gy. In SR group, hyoid area and lateral pharyngeal approaches were taken according to the lesions for resection. To repair the defects and reconstruct the functions of larynx and pharynx, regional roping in suture, fascial flap/muscular- fascial of strap muscles, glosso-flap, musculocutaneous flap of major pectoral muscle, joint split graft or heterologous (bovine) acellular dermal matrix were used respectively. RESULTS: In group R, the primary tumor and neck lymph node metastasis disappeared at the end of radiotherapy in 15 cases. For one case, the N3 cervical lymph nodes shrank, but failed in local control and died of systemic metastases after 7 months. For another case, the N2 neck lymph nodes significantly reduced after the full course of radiation, PET-CT and biopsy did not find the cancer, but the tumor grew again after 6 months, and died of a neck bleeding 11 months later. All repairing materials used were alive in SR group. Two cases developed postoperative wound infection, and 2 cases suffered from pharyngeal fistula. All patients retained laryngeal functions, and all patients in SR group recovered diet 12 - 30 days, the mean time was 15.6 days. Three and 5 year survival rates for all 77 patients were 59.1% and 41.4%. For stage I + stage II cases in SR group and R group, 3 and 5 year survival rates were 63.6%, 53.0% and 66.7%, 50.0% respectively. There was no significant difference between the two groups (χ(2) = 0.021, P = 0.884). For cases of stage III + stage IV of the SR group and R group, 3 and 5 year survival rates were 63.9%, 43.7%, 16.4%, and 0. There was a very significant difference (χ(2) = 20.496, P = 0.000); all cases in SR group and in R group for 3, 5-year survival rates were 63.6%, 45.8%, 41.5%, and 24.9% respectively. There was also a significant stastical difference (χ(2) = 4.644, P = 0.031). CONCLUSIONS: Pyriform sinus carcinoma involving the lateral wall is characterized with scattered growth on the surface of mucous or submucously, tending to invade lamina cartilaginis thyroidea. Simple radiotherapy can get better therapeutic effect for early stage cases. The comprehensive therapy measures should be taken in advanced cases, especially those with surgical indications should be taken to surgery plus radiotherapy. For the purpose of excising the tumor thoroughly and preserving good laryngeal functions, proper operative approaches and ways of repairing should be selected.

Prognostic significance of 18F-fluorodeoxyglucose positron emission tomography (PET)-based parameters in neoadjuvant chemoradiation treatment of esophageal carcinoma.

AIMS AND BACKGROUND: The purpose of the research was to study the prognostic value of tumor 18F-FDG PET-based parameters in neoadjuvant chemoradiation for patients with squamous esophageal carcinoma. METHODS: Sixty patients received chemoradiation therapy followed by esophagectomy and two 18FDG-PET examinations at pre- and post-radiation therapy. PET-based metabolic-response parameters were calculated based on histopathologic response. Linear regression correlation and Cox proportional hazards models were used to determine prognostic value of all PET-based parameters with reference to overall survival. RESULTS: Sensitivity (88.2%) and specificity (86.5%) of a percentage decrease of SUVmax were better than other PET- based parameters for prediction of histopathologic response. Only percentage decrease of SUVmax and tumor length correlated with overall survival time (linear regression coefficient ß: 0.704 and 0.684, P<0.05). The Cox proportional hazards model indicated higher hazard ratio (HR=0.897, P=0.002) with decrease of SUVmax compared with decrease of tumor size (HR=0.813, P=0.009). CONCLUSION: Decrease of SUVmax and tumor size are significant prognostic factors in chemoradiation of esophageal carcinoma.

[Surgery and function reconstruction of laryngeal cancer involved supraglottic and glottis area].

OBJECTIVE: To investigate the surgery preserving epiglottis, the repair and the postoperative functions in laryngeal carcinoma involving supraglottic and glottic areas. METHODS: A total of 97 cases with laryngeal cancer involving both supraglottic and glottic areas with normal epiglottis underwent surgery between June 2005 and December 2010 was reviewed. Of them 37 cases were stage II, 41 cases were stage III, and 19 cases were stage IV. Vertical partial laryngectomy (VPL) or extended VPL with the repair and functional reconstruction was carried out in 86 cases and cricohyoidoepiglottopexy (CHEP) in 11 cases. Postoperative survival rate, laryngeal functions and quality of life were evaluated. RESULTS: The 3-year and 5-year total cumulative survival rate (Kaplan-Meire survival analysis) were 87.1% and 69.6% in the 97 cases; 86.6% and 68.3% in VPL/EVPL group; 90.0% and 78.8% in CHEP group, respectively, with no significant difference between VPL/EVPL and CHEP groups (P > 0.05). Of 97 cases, 86(88.7%) cases were decannulated postoperatively. The rates of decannulation were 87.2% (75/86) in VPL/EVPL group and 100% (11/11) in CHEP group, with no significant difference (P > 0.05). Average oral diet recovery time of VPL/EVPL group and CHEP group was (5.2 ± 1.3) and (15.7 ± 5.2) days, respectively, with a significant difference (P < 0.01). Voice evaluation showed the mean maximum phonation time of VPL/EVPL group was shorter than that of CHEP group (P < 0.01) and the S/Z ratio of VPL/EVPL group was higher than that of CHEP group (P < 0.01). Perceptual voice evaluation GRBAS ratings showed patients in VPL/EVPL group had higher G and B ratings compared to patients in CHEP group (P < 0.01), but no significant difference in R-rating between two groups (P > 0.05). Voice handicap index-10 (VHI-10) scores of VPL/EVPL and CHEP groups were 29.5 ± 4.7 and 31.6 ± 6.3, respectively, no significant difference (P > 0.05). CONCLUSIONS: For patients with the laryngeal carcinoma involving both supraglottic and glottic areas, VPL has better anatomical and functional outcomes than CHEP. The preservation of at least 2/3 of the lamina of thyroid cartilage on one side and shift-down of epiglottis were key to successful VPL and postoperative decannulation.

Moderately hypofractionated conformal radiation treatment of thoracic esophageal carcinoma.

AIMS: To prospectively assess the efficacy and safety of moderately hypofractionated conformal radiotherapy in patients with thoracic esophageal cancer. METHODS AND MATERIALS: From Sept. 2002 to Oct. 2005, 150 eligible patients with T2-4N0-1M0 stage thoracic esophageal squamous cell cancers were enrolled to receive either conventional fractionated radiation (CFR) or moderately hypofractionated radiation (MHR) with a three- dimensional conformal radiation technique. Of the total, 74 received moderately hypofractionated radiation with total dose of 54-60 Gy/18-20 fractions for 3.5-4 weeks in the MHR arm, and 76 received conventional radiation with total dose of 60 Gy/30 fractions for 6 weeks in the CFR arm. Concurrent chemotherapy comprised of paclitaxel and cisplatin. Safety was evaluated, and local control and overall survival rates were calculated. RESULTS: Statistically significant differences between the CFR versus MHR arms were observed in local/regional failure rate (47.3% v 27.0%, P=0.034) and the percentage of patients with persistent local disease (26.3% v 10.8%, P=0.012). But 3 and 5-year overall survival rates (43.2%, 38.8% v 38.2%, 28.0%, respectively) were not different between the two arms (P=0.268). There were no significant differences in the incidences of grade 3 or higher acute toxicities (66.3% v 50.0%) and late complications rates (27.0% v 22.4%) between the MHR and CFR arms. CONCLUSIONS: Moderately hypofractionated, three-dimensional radiation treatment could improve the local control rate of esophageal cancer and potentially increase patient survival.

Lysosomal membrane protein TMEM192 deficiency triggers crosstalk between autophagy and apoptosis in HepG2 hepatoma cells.

As constituents of lysosomes, lysosomal membrane proteins play important roles in lysosome-related autophagy and apoptosis. In a recent proteomic study of lysosomal proteins, we identified transmembrane protein 192 (TMEM192) as a novel lysosomal membrane protein candidate. Using specific anti-TMEM192 antibody and lysosomal markers, the lysosomal localization of TMEM192 was determined by immunofluorescence. TMEM192 shows a wide expression pattern in mouse tissues. Interestingly, TMEM192 was found to be highly expressed in tumor cell lines, while it was not expressed or was detected at low levels in normal cell lines. By knockdown of TMEM192 expression using specific siRNAs, we found that TMEM192-deficient HepG2 hepatoma cells show growth inhibition and increased apoptosis. Autophagy was shown to be activated through detection of LC3II expression. Increased apoptosis was inhibited by blocking the expression of the key autophagy gene Atg7 in TMEM192-deficient HepG2 cells. The results suggest that TMEM192 is important for tumor cell growth and proliferation. TMEM192 deficiency can induce autophagy in tumor cells, and can further activate apoptosis by the mitochondrial pathway through autophagy. TMEM192 promotion of autophagy may be a new route for tumor therapy.

Linear correlation between patient survival and decreased percentage of tumor [(18)F]fluorodeoxyglucose uptake for late-course accelerated hyperfractionated radiotherapy for esophageal cancer.

PURPOSE: The aims of this trial were to study whether a decreased percentage of tumor fluorodeoxyglucose (FDG) uptake (%DeltaSUVmax) correlated with overall survival and local control times for patients with esophageal cancer and which patients would benefit from a late-course accelerated hyperfractionated (LCHF) radiation scheme. METHODS AND MATERIALS: A total of 50 eligible patients with squamous esophageal cancer received positron-emission tomography examinations three times and were treated with the LCHF radiation scheme, with a dose of 68.4 Gy/41 fractions in 6.5 weeks. A %DeltaSUVmax value was calculated, and patients were stratified as highly radiosensitive (HR), moderately radiosensitive (MR), and low radiosensitivity (LR) according to %DeltaSUVmax values in the conventional fraction (CF) scheme. Then, a linear correlation was calculated between patients' survival time and %DeltaSUVmax. Local control and overall survival rates were compared after stratification. RESULTS: In the MR subgroup, there was no linear correlation between %DeltaSUVmax and the CF and LCHF schemes (correlation coefficient, R < 0.4; p > 0.05). In the other subgroups (HR and LR), %DeltaSUVmax values between the CF and LCHF schemes were correlated. Also, in the HR and LR subgroups, %DeltaSUVmax after radiation correlated with overall survival or local control rates (correlation coefficient, R ＞0.5, and p < 0.05). Three-year local control rates in the HR, MR, and LR subgroups were 100%, 81.5%, and 0%, respectively (p < 0.001). Also, 3-year overall survival rates were 92.4%, 58.8%, and 0% for HR, MR, and LR subgroups, respectively (p < 0.001). CONCLUSIONS: Postradiation %DeltaSUVmax was positively correlated with survival time for patients' with esophageal cancer. Patients who benefited from LCHF schedules were those with a decrease of 30% to 60% in tumor FDG uptake after the completion of CF radiation.

Feasibility of involved-field conformal radiotherapy for cervical and upper-thoracic esophageal cancer.

BACKGROUND: The aim of this study was to investigate the feasibility of involved-field irradiation (IFI) for the treatment of cervical and upper-thoracic esophageal cancer with concurrent chemoradiation. PATIENTS AND METHODS: 102 eligible patients with cervical or upper-thoracic esophageal cancer were treated with concurrent chemoradiation and randomized to either an IFI or elective nodal irradiation (ENI) group. RESULTS: Adverse events included infection (27.4 vs. 64.7%) and nausea (25.4 vs. 54.9%), with a statistically significant difference between the IFI and the ENI group (p = 0.008 and 0.028, respectively). No difference was seen for late radiation reaction. The cumulative incidence of local/regional failure (13.7 vs. 17.6%) and regional lymph failure (7.8 vs. 9.8%) showed no statistically significant difference between the IFI versus the ENI group (p = 0.837 and 0.837, respectively). A nodal out-field relapse rate of only 2% was seen in the IFI group. 3-year survival rates for the ENI and IFI group were 41.3 and 32.0%, respectively (p = 0.58), and 3-year local control rates were 85.7 and 80.1%, respectively (p = 0.34). CONCLUSION: IFI was acceptable for cervical and upper-thoracic esophageal cancer with a decrease in acute toxicities and no increase in lymph node failure.