Helicobacter pylori infection and Parkinson's Disease: etiology, pathogenesis and levodopa bioavailability.

Parkinson's disease (PD), a neurodegenerative disorder with an unknown etiology, is primarily characterized by the degeneration of dopamine (DA) neurons. The prevalence of PD has experienced a significant surge in recent years. The unidentified etiology poses limitations to the development of effective therapeutic interventions for this condition. Helicobacter pylori (H. pylori) infection has affected approximately half of the global population. Mounting evidences suggest that H. pylori infection plays an important role in PD through various mechanisms. The autotoxin produced by H. pylori induces pro-inflammatory cytokines release, thereby facilitating the occurrence of central inflammation that leads to neuronal damage. Simultaneously, H. pylori disrupts the equilibrium of gastrointestinal microbiota with an overgrowth of bacteria in the small intestinal known as small intestinal bacterial overgrowth (SIBO). This dysbiosis of the gut flora influences the central nervous system (CNS) through microbiome-gut-brain axis. Moreover, SIBO hampers levodopa absorption and affects its therapeutic efficacy in the treatment of PD. Also, H. pylori promotes the production of defensins to regulate the permeability of the blood-brain barrier, facilitating the entry of harmful factors into the CNS. In addition, H. pylori has been found to induce gastroparesis, resulting in a prolonged transit time for levodopa to reach the small intestine. H. pylori may exploit levodopa to facilitate its own growth and proliferation, or it can inflict damage to the gastrointestinal mucosa, leading to gastrointestinal ulcers and impeding levodopa absorption. Here, this review focused on the role of H. pylori infection in PD from etiology, pathogenesis to levodopa bioavailability.

Modified constraint-induced movement therapy enhances cortical plasticity in a rat model of traumatic brain injury: a resting-state functional MRI study.

Modified constraint-induced movement therapy (mCIMT) has shown beneficial effects on motor function improvement after brain injury, but the exact mechanism remains unclear. In this study, amplitude of low frequency fluctuation (ALFF) metrics measured by resting-state functional magnetic resonance imaging was obtained to investigate the efficacy and mechanism of mCIMT in a control cortical impact (CCI) rat model simulating traumatic brain injury. At 3 days after control cortical impact model establishment, we found that the mean ALFF (mALFF) signals were decreased in the left motor cortex, somatosensory cortex, insula cortex and the right motor cortex, and were increased in the right corpus callosum. After 3 weeks of an 8-hour daily mCIMT treatment, the mALFF values were significantly increased in the bilateral hemispheres compared with those at 3 days postoperatively. The mALFF signal values of left corpus callosum, left somatosensory cortex, right medial prefrontal cortex, right motor cortex, left postero dorsal hippocampus, left motor cortex, right corpus callosum, and right somatosensory cortex were increased in the mCIMT group compared with the control cortical impact group. Finally, we identified brain regions with significantly decreased mALFF values at 3 days postoperatively. Pearson correlation coefficients with the right forelimb sliding score indicated that the improvement in motor function of the affected upper limb was associated with an increase in mALFF values in these brain regions. Our findings suggest that functional cortical plasticity changes after brain injury, and that mCIMT is an effective method to improve affected upper limb motor function by promoting bilateral hemispheric cortical remodeling. mALFF values correlate with behavioral changes and can potentially be used as biomarkers to assess dynamic cortical plasticity after traumatic brain injury.

A multi-center, single-arm, phase II study of anlotinib plus paclitaxel and cisplatin as the first-line therapy of recurrent/advanced esophageal squamous cell carcinoma.

BACKGROUND: Anlotinib, a tyrosine kinase inhibitor, has shown encouraging anti-tumor activity in esophageal squamous cell carcinoma (ESCC). This study was designed to assess the efficacy and safety of anlotinib plus paclitaxel and cisplatin (TP) as first-line therapy for advanced ESCC. METHODS: In a multi-center, single-arm, phase II clinical trial, patients (aged > 18 years) with ESCC, which was judged to be locally advanced, recurrent, or metastatic, received 10 mg oral anlotinib once daily on days 1-14, 135 mg/m2 intravenous paclitaxel on day 1, and 60-75 mg/m2 intravenous cisplatin on days 1-3 every 3 weeks for a maximum of 4-6 cycles as the initial therapy in five centers in China. Subsequently, patients received anlotinib monotherapy (10 mg) as maintenance therapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-seven patients were enrolled in this study between October 2019 and March 2021. The median follow-up was 14.04 months (IQR, 9.30-19.38). Of 46 with assessable efficacy, the median PFS and median overall survival were 8.38 months (95% CI, 6.59-10.17) and 18.53 months (95% CI, 13.11-23.95), respectively. The objective response rate was 76.1% (95% CI, 61.2-87.4%), with 4 (8.7%) complete responses and 31 (67.4%) partial responses. The disease control rate was 91.3% (95% CI, 79.2-97.6%). The median duration of response was 6.80 months (95% CI, 4.52-9.08), and 1 patient had an ongoing response for 23 months. Subgroup analysis revealed no association between clinical factors and survival or response. Of the 47 patients with assessable safety, the main grade ≥ 3 treatment-emergent adverse events (TEAEs) were neutropenia (17.0%), bone marrow suppression (12.8%), and vomiting (10.6%). No treatment-related deaths or serious TEAEs were observed. Notably, higher c-Kit levels were an independent factor for superior PFS (HR = 0.032; 95% CI, 0.002-0.606; P = 0.022). CONCLUSIONS: The study demonstrated a manageable safety profile and durable clinical response of anlotinib plus TP as first-line therapy in advanced ESCC, which suggested a potential therapeutic option for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04063683. Registered 21 August 2019.

CircRNA-0008717 promotes cell proliferation, migration, and invasion by regulating miR-203/Slug in esophageal cancer cells.

BACKGROUND: Esophageal cancer (EC) is one of the deadliest cancers worldwide. Circular RNAs (circRNAs) have been implicated in the regulation of multiple human diseases, including cancer. In particular, the dysregulation of circRNA-0008717 has been linked to multiple types of cancer. However, the clinical significance and the molecular mechanisms of circRNA-0008717 in EC need to be further investigated. Therefore, this study aimed to prove the role of circRNA-0008717 in EC and its underlying molecular mechanism of action. METHODS: The expression of circRNA-0008717, miR-203, and the Slug was measured in two EC cell lines (EC109 and KYSE-150) by qRT-RCR. EC109 and KYSE-150 cells were first transfected with circRNA-0008717 siRNA (si-circRNA). After that, the proliferation, apoptosis, migration, and invasion of EC109 and KYSE-150 cells were measured. The western blot detected Slug, Vimentin, and E-cadherin protein levels. A dual-luciferase reporter gene assay was used to set up the interactions among circRNA-0008717, miR-203, and Slug. RESULTS: circRNA-0008717 expression was significantly upregulated in EC cells, and miR-2031 expression was decreased. Moreover, si-circRNA-0008717 or si-Slug inhibited the proliferation, migration, and invasion of EC cells. We found that circRNA-0008717 functioned as a sponge of miR-203, resulting in increased expression of Slug. We also reversed the effect of circRNA-0008717 knockdown on the EC progression by co-transfecting EC cells with a miR-203 inhibitor or Slug. CONCLUSIONS: The proliferation, invasion, and migration of EC cells were enhanced by circRNA-0008717 sponging the miR-203 to increase Slug expression.

Combination treatment with artemisinin and oxaliplatin inhibits tumorigenesis in esophageal cancer EC109 cell through Wnt/ß-catenin signaling pathway.

BACKGROUND: Esophageal cancer (EC) is a prevalent malignant cancer worldwide. Interestingly, the antimalaria compound artemisinin (ART) is also reported to have anticancer potential, although its underlying mechanism in EC is unclear. In this study, we explored the anticancer role of ART in EC109 and further explored the combination of ART and oxaliplatin (OXA) for their synergetic anticancer functions. METHODS: Human EC cell line EC109 was used. After ART or oxaliplatin (OXA) treatment, cell proliferation, migration, and invasion were measured by MTT, transwell, and scratch wound assays, respectively. Flow cytometry was performed to examine the cell cycle and apoptosis. The mRNA and protein levels were determined using qRT-PCR and western blotting. RESULTS: The migration and invasion abilities of EC109 were suppressed by ART. This was due to the inhibitory effect of ART on the Wnt/ß-catenin signaling pathway. The levels of ß-catenin, c-myc, and survivin were also downregulated by ART. ART inhibits the proliferation of EC109 cells by arresting the cells in the G1-phase of cell cycle. By using LiCl, an activator of the Wnt/ß-catenin pathway, we further verified that the inhibition of the Wnt/ß-catenin pathway was indeed due to ART. Remarkably, ART enhanced the anticancer effects of OXA in EC109 cells. OXA combined with ART was found to be more efficient in decreasing tumor growth compared to the individual drugs. CONCLUSIONS: ART could suppress tumor progression by inhibiting Wnt/ß-catenin signaling pathway, and it may also enhance the antitumor effect of OXA in EC. Thus, ART could be a novel anticancer drug for EC treatment. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: ART could be a novel anticancer drug for esophageal cancer (EC) treatment. WHAT THIS STUDY ADDS: Combination treatment with artemisinin and oxaliplatin inhibits tumorigenesis in esophageal cancer EC109 cells through the Wnt/ß-catenin signaling pathway.

LINC00657/miR-26a-5p/CKS2 ceRNA network promotes the growth of esophageal cancer cells via the MDM2/p53/Bcl2/Bax pathway.

LncRNA LINC00657 has oncogenic or anti-carcinoma roles in different cancers, and yet its detailed molecular mechanism in esophageal cancer (EC) remains unclear. In addition, competitive endogenous RNA (ceRNA) regulatory lncRNA-miRNA-mRNA networks are critical for tumorigenesis and progression. Hence, the present study explored the roles of LINC00657 in EC and identified its relevant ceRNA network. We first detected the expression of LINC00657 in EC. Then, we applied starBase and TargetScan websites to find miR-26a-5p binding to LINC00657 and obtain CKS2 as a target of miR-26a-5p. The roles of LINC00657, miR-26a-5p or CKS2 in the proliferation, migration, invasion, and apoptosis of EC cells were respectively assessed by CCK-8, wound healing assay, transwell invasion assay, and flow cytometry. The changes of the MDM2/p53/Bcl2/Bax pathway were measured via Western blot. The results revealed that LINC00657 showed an aberrant high expression in EC cells, which promoted the growth of EC cells. Additionally, LINC00657 functioned as a sponge of miR-26a-5p, and LINC00657 negatively mediated miR-26a-5p to regulate the growth of EC cells. Furthermore, CKS2 was observed as a direct target of miR-26a-5p, and CKS2 controlled the growth of EC cells via the MDM2/p53/Bcl2/Bax pathway. Moreover, there was a positive correlation between LINC00657 and CKS2. LINC00657 knockdown inhibited CKS2 expression to suppress the proliferation, migration, and invasion of EC cells and induced apoptosis via regulating the MDM2/p53/Bcl2/Bax pathway. Collectively, LINC00657/miR-26a-5p/CKS2 ceRNA network could promote the progression of EC, which is good for understanding the molecular mechanism of EC and offers novel biomarkers for EC diagnosis and therapy.

The Number of Negative Lymph Nodes is Positively Associated with Survival in Esophageal Squamous Cell Carcinoma Patients in China.

BACKGROUND: There is a controversial relationship between the negative lymph nodes (NLNs) and survival in patients with esophageal squamous cell carcinoma (ESCC). This study investigates the implications of total number of NLNs on thoracic ESCC patient prognosis. METHODS: 579 thoracic ESCC patients were categorized into four groups (0-9, 10-14, 15-19 and ≥20 NLNs). Univariate analysis was done by the log-rank tests while multivariate analysis was undertaken using Cox regression models. Survival analysis was determined employing the Kaplan-Meier method. RESULTS: When the numbers of NLNs were 9 or less, 10 to 14, 15 to 19 and 20 or more, patients of 3-year survival rates were 21.7%, 40.0%, 61.2% and 77.5%, respectively (P<0.001). In the node-negative and node-positive subgroups, 3-year survival rates were 34.9% and 14.3%, 50.9% and 19.3%, 65.6% and 51.8%, 81.4% and 68.9% respectively (P<0.001). Gender, tumor length, tumor differentiation, T and N stage as well as the total NLNs were found to be significantly linked to survival rates. Multivariate analysis showed tumor length, T stage, N stage and total NLNs were independent prognostic factors for ESCC patients. CONCLUSION: NLNs numbers is a significant independent prognostic indicator for thoracic ESCC patients' survival after curative esophagectomy.

SERPINB2 overexpression inhibited cell proliferation, invasion and migration, led to G2/M arrest, and increased radiosensitivity in nasopharyngeal carcinoma cells.

The aim of this study was to evaluate the effect of SERPINB2 on cell proliferation, cell cycle, epithelial-mesenchymal transition (EMT), invasion, migration, and radiosensitivity in nasopharyngeal carcinoma cells. Both CNE2R and CNE2 cells were transfected with pEGFP-N1-SERPINB2. Cell proliferation was measured by MTT assay, cell cycle by flow cytometry, and SERpINB2 expression by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was carried out to detect the protein expression. In addition, SERPINB2 and ß-catenin were located intracellularly using an immunofluorescent assay, and cell migration and invasion were measured by wound healing and Transwell assays, respectively. Radiosensitivity was assessed using colony formation and MTT assays. SERPINB2 expression was downregulated in CNE2R cells. After transfection with pEGFP-N1-SERPINB2, the OD values were decreased, and there was an increased fraction in the G2/M phase. Moreover, SERPINB2 overexpression could inhibit the invasion and migration capabilities of CNE2R and CNE2 cells, with downregulation of vimentin, N-cadherin, nuclear ß-catenin, matrix metalloproteinase (MMP)-2 and MMP-9, and upregulation of E-cadherin. Moreover, transfection with the SERPINB2 plasmid reduced the growth rate of CNE2R cells at doses of 2, 4 and 6 Gy, and also decreased the surviving fractions. Overexpression of SERPINB2 could reduce the proliferation, invasion and migration capabilities of CNE2R and CNE2 cells, and led to G2/M arrest via EMT inhibition, and this may be a potential strategy for enhancing the radiation sensitivity of nasopharyngeal carcinoma cells.

Meta-analysis on the association between xeroderma pigmentosum Group A A23G polymorphism and esophageal cancer in a Chinese population.

AIM OF THE STUDY: Several studies have evaluated the correlation between xeroderma pigmentosum Group A (XPA) A23G polymorphism (rs 1800975) and esophageal cancer in Chinese people. However, the results are inconsistent. To assess the effects of XPA A23G variants on the risk for development of esophageal cancer in the Chinese population, a meta-analysis was performed. MATERIALS AND METHODS: Studies were identified using PubMed and Chinese databases through December 2015. The associations were assessed with pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: This meta-analysis identified seven studies including 1514 esophageal cancer cases and 2120 controls. In the overall analysis, no significant association between XPA A23G polymorphism and esophageal cancer was found in the Chinese population. In the subgroup analyses by geographic area(s) and source of controls, significant results were only found in studies with hospital-based controls (GG vs. AA: OR = 0.42, 95% CI = 0.28-0.62; GG vs. AA + AG: OR = 0.55, 95% CI = 0.39-0.78; GG + AG vs. AA: OR = 0.54, 95% CI = 0.40-0.72; G vs. A: OR = 0.61, 95% CI = 0.50-0.75). CONCLUSIONS: This meta-analysis suggested that XPA A23G gene polymorphism may be one low-penetrant risk factor for esophageal cancer in Chinese individuals.

Low expression of BEX1 predicts poor prognosis in patients with esophageal squamous cell cancer.

The brain expressed x­linked gene 1 (BEX1) is a member of the BEX family and is aberrantly expressed in many cancers. However, the clinical significance of BEX1 expression level and its role in the pathology of esophageal squamous cell cancer (ESCC) remain unknown. In the present study, we determined BEX1 expression in the tumor and adjacent normal tissues from 118 ESCC patients by immunohistochemistry and determined the proliferation and growth of ESCC cells following ectopic overexpression of BEX1 in cultured cells and in mouse­ESCC xenografts. We observed that BEX1 was downregulated in ESCC tissues compared to adjacent normal tissues, and low BEX1 expression was significantly associated with larger ESCC tumor volume (P<0.001), advanced T stage (P=0.011) and advanced clinical stage (P=0.039). Additionally, survival analysis revealed that low expression of BEX1 significantly predicted poor prognosis in patients with ESCC (P<0.001). Multivariate analysis revealed that low BEX1 expression was an independent prognostic factor of poor survival (P=0.039). In vitro analysis revealed that overexpression of BEX1 inhibited ESCC cell proliferation and colony formation. Furthermore, in vivo tumorigenesis assays revealed that ectopic overexpression of BEX1 suppressed ESCC tumor growth in mice. Further immunoblotting analysis demonstrated that BEX1 upregulation led to reduced expression and phosphorylation of NF­κB p65, indicating inhibition of the NF­κB signaling pathway by BEX1. Our findings indicated that low BEX1 expression may be an independent prognostic marker for poor survival and may serve as a potential target for ESCC therapy.

Structural Characterization and Immunostimulatory Activity of Polysaccharides from Brassica rapa L. .

Two neutral polysaccharides (BRNP-1, 6.9 kDa; BRNP-2, 4.8 kDa) were purified from the common edible plant Brassica rapa L. via the combined techniques of ion-exchange chromatography and high-performance gel permeation chromatography. Monosaccharide composition analysis showed that BRNP-1 and BRNP-2 were composed of glucosyl residues. Methylation and 1D- and 2D-NMR analyses revealed that both BRNP-1 and BRNP-2 contained a backbone chain that was composed of α-D-(1 → 4)-linked Glcp residues and side chains that were composed of terminally linked Glcp residues attached at the O-6 position of backbone-glycosyl residues. BRNP-1 and BRNP-2, however, differed in branch degree and molecular weight. Bioassay results showed that treatment with the higher dosage (400 µg/mL) of BRNP-1 and BRNP-2 stimulated the proliferation, NO release, and cytokine secretion (IL-6 and TNF-α) of RAW264.7 macrophages. These results suggested that BRNP-1 and BRNP-2 may enhance macrophage-mediated immune responses.

Silencing of advanced glycosylation and glycosylation and product-specific receptor (RAGE) inhibits the metastasis and growth of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) constitutes the main cases of lung cancer and is the world's most common and lethal cancer owing to regional invasion or distant metastasis. Growing morbidity and lethality demonstrates that valid molecular target in management of NSCLC metastasis is still absence. The receptor of advanced glycation end-products (RAGE) has been identified as an oncogenic gene and appears to promote the growth and metastasis of various cancers. Here, we investigated if RAGE targeted by RNA interference (RNAi) might have certain effect on the restraint of the growth of NSCLC and tumor metastasis. Wound healing and Transwell invasion assays indicated that RAGE favored the metastatic capabilities of NSCLC H1975 cells. Besides, soft-agar colony assay revealed that silencing RAGE significantly blocked colony-forming capability of H1975 cells in vitro. Furthermore, we observed that RAGE participated in H1975 cells growth, metastasis and epithelial-mesenchymal transition (EMT) by regulating interdict crux intracellular signaling pathways, including phosphatidylinositol-3 kinase/serine-threonine kinase (PI3K/AKT) and V-Ki-ras2 kirsten rat sarcoma viral oncogene homolog/RAF proto-oncogene serine/threonine-protein kinase (KRAS/RAF-1). In xenograft model, significantly reduction intumor growth and Ki67 expression was demonstrated in nude mice inoculation with RAGE down-regulation H1975 cells. To conclude, our study demonstrated that RAGE played a crucial role in the metastasis and growth of NSCLC by regulating PI3K/AKT and KRAS/RAF-1 signaling pathways, thereby might be a promising therapeutic target for NSCLC.

Role of Nrf2 signaling pathway in the radiation tolerance of patients with head and neck squamous cell carcinoma: an in vivo and in vitro study.

We aimed to investigate the relationship between the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and the radiation tolerance of patients with head and neck squamous cell carcinoma (HNSCC). From January 2015 to January 2016, 117 patients with HNSCC were enrolled in our study and assigned into the sensitive and tolerance groups based on curative effect. Immunohistochemistry (IHC) was conducted to measure protein expressions of Nrf2, heme oxygenase-1 (HO1), NADPH quinine oxidoreductase 1 (NQO1) and glutathione S-transferase (GST). Human squamous cell carcinoma cell line, HSC-4, was induced by radiation to construct the HSC-4-radiation resistance (RR) cell line. HSC-4 and HSC-4-RR were also assigned into the blank, negative control (NC) and Nrf2 siRNA groups. Cell Counting Kit-8 (CCK-8), quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were employed to detect cell viability, mRNA expression and protein expression, respectively, of Nrf2, HO1, NQO1 and GST. A total of 40 nude mice were equally assigned into the untreated, Nrf2 siRNA, radiation therapy (RT) and RT + Nrf2 siRNA groups. Compared with the sensitive group, patients in the tolerance group had upregulated Nrf2, HO1, NQO1 and GST expressions. HSC-4-RR cell line had improved cell viability and higher protein and mRNA expressions of Nrf2, HO1, NQO1 and GST compared with HSC-4 cell line. Compared with the HSC-4-NC and HSC-4-blank groups, the HSC-4-Nrf2 siRNA group had downregulated cell viability. Compared with the HSC-4-RR-NC and HSC-4-RR-blank groups, the HSC-4-RR-Nrf2 siRNA group had lower cell viability. However, the HSC-4-RR-Nrf2 siRNA group had elevated cell viability than the HSC-4-Nrf2 siRNA group. Tumor volume and tumor weight in the RT and RT + Nrf2 siRNA groups decreased evidently. The RT + Nrf2 siRNA group exhibited decreased tumor volume and tumor weight in comparison with the RT group. Our data demonstrated that downregulation of HO1, NQO1 and GST via inhibiting Nrf2 signaling pathway reduces the radiation tolerance of patients with HNSCC.

Living donor liver transplantation with body-weight more or less than 10 kilograms.

AIM: To compare the outcomes of pediatric patients weighing less than or more than 10 kg who underwent liver transplantation. METHODS: Data for 196 pediatric patients who underwent living donor liver transplantation between June 1994 and February 2011 were reviewed retrospectively. The information for each patient was anonymized and de-identified before analysis. The data included information regarding the pre-transplant conditions, intraoperative fluid replacement and outcomes for each patient. The 196 patients were divided into two groups: those with body weights of less than 10 kg were included in group 1 (G1; n = 101), while those with body weights of more than 10 kg were included in group 2 (G2; n = 95). For each group, the patients' ages, body weights, heights, pediatric end stage liver disease scores, anesthesia times, and warm and cold ischemic times were analyzed. In addition, between-group comparisons were also made. Mann-Whitney U tests were used to compare all the variables except for complications and survival rates, which were analyzed using χ(2) tests and Kaplan-Meier tests, respectively. RESULTS: The general medical conditions of the G1 patients were worse than those of the G2 patients, as shown by the higher pediatric end stage liver disease scores and poorer Z-scores. In addition, the pre-operative Hb and serum albumin levels were all lower for the G1 patients than for the G2 patients. The G1 patients also had significantly more intraoperative blood loss than the G2 patients. In addition, the intraoperative fluid requirements for the G1 patients, including leukocyte poor red blood cell transfusions, 5% albumin infusions and crystalloid infusions, were significantly higher than those for the G2 patients. The risk of intraoperative portal vein thrombosis was higher for the patients in G1 than for those in G2. However, the one-year survival rates (95.9% and 96.8% for G1 and G2, respectively) and three-year survival rates (94.9% and 94.6% for G1 and G2, respectively) for both groups were similar. CONCLUSION: Patients weighing less than 10 kg typically have poorer conditions, but their survival rates are comparable to those of children weighing more than 10 kg.

Radiation dose is associated with prognosis of small cell lung cancer with superior vena cava syndrome.

Approximately 10% of small cell lung cancer (SCLC) cases develop superior vena cava syndrome (SVCS). Many SCLC patients with SVCS have relatively limited disease, requiring curative rather than palliative treatment. Besides chemotherapy, radiotherapy is important for treating SCLC with SVCS. We retrospectively evaluated the influence of radiotherapy dose on the prognosis of 57 patients with SCLC with SVCS treated with concurrent chemoradiotherapy. The mean biological equivalent radiation dose was 71.5 Gy. We administered etoposide/cisplatin as sequential and concurrent chemotherapy. All patients received at least one cycle of concurrent chemotherapy. All patients had partial or complete response; SVCS-associated symptoms were reduced in 87.7% (50/57) of patients within 3-10 days after treatment. Radiation dose did not affect 2-year local control (74.2% vs. 80.8%). Patients who received high-dose radiation had a lower 2-year overall survival rate than those who received low-dose radiation (11.6 vs. 33%; P = 0.024). The high dose group median survival was 15.0 months (95% confidence interval [CI]: 11.2-19.0) compared with 18.7 months (95% CI: 13.9-23.6) in the low dose group. Grade 3/4 neutropenia occurred in 22/26 high dose patients (84.6%) and 21/31 low dose patients (67.7%). In the high dose group, 30.8% of patients had grade 3/4 esophagitis compared with 19.4% of low dose patients. Only 29.0% of low dose patients received < 4 cycles of chemotherapy in the first 12 weeks after treatment began compared with 46.2% of high dose patients. Concurrent chemoradiotherapy is a tolerable modality for treating stage IIIA/IIIB SCLC with SVCS. Moderate-dose radiotherapy is preferable.

Prognostic significance of preoperative lymphocyte-monocyte ratio in patients with resectable esophageal squamous cell carcinoma.

BACKGROUND: The interaction between tumor cells and inflammatory cells has not been systematically investigated in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to evaluate whether preoperative the lymphocyte-monocyte ratio (LMR), the neutrophil-lymphocyte ratio (NLR), and the platelet-lymphocyte ratio (PLR) could predict the prognosis of ESCC patients undergoing esophagectomy. MATERIALS AND METHODS: Records from 218 patients with histologically diagnosed ESCC who underwent attempted curative surgery from January 2007 to December 2008 were retrospectively reviewed. Besides clinicopathological prognostic factors, we evaluated the prognostic value of the LMR, the NLR, and the PLR using Kaplan-Meier curves and Cox regression models. RESULTS: The median follow-up was 38.6 months (range 3-71 months). The cut-off values of 2.57 for the LMR, 2.60 for the NLR and 244 for the PLR were chosen as optimal to discriminate between survival and death by applying receiver operating curve (ROC) analysis. Kaplan-Meier survival analysis of patients with low preoperative LMR demonstrated a significant worse prognosis for DFS (p=0.004) and OS (p=0.002) than those with high preoperative LMR. The high NLR cohort had lower DFS (p=0.004) and OS (p=0.011). Marginally reduced DFS (p=0.068) and lower OS (p=0.039) were found in the high PLR cohort. On multivariate analysis, only preoperative LMR was an independent prognostic factor for both DFS (p=0.009, HR=1.639, 95% CI 1.129-2.381) and OS (p=0.004, HR=1.759, 95% CI 1.201-2.576) in ESCC patients. CONCLUSIONS: Preoperative LMR better predicts cancer survival compared with the cellular components of systemic inflammation in patients with ESCC undergoing esophagectomy.

Prognostic role of hepatoma-derived growth factor in solid tumors of Eastern Asia: a systematic review and meta- analysis.

Hepatoma-derived growth factor (HDGF) is a novel jack-of-all-trades in cancer. Here we quantify the prognostic impact of this biomarker and assess how consistent is its expression in solid tumors. A comprehensive search strategy was used to search relevant literature updated on October 3, 2014 in PubMed, EMBASE and WEB of Science. Correlations between HDGF expression and clinicopathological features or cancer prognosis was analyzed. All pooled HRs or ORs were derived from random-effects models. Twenty-six studies, primarily in Eastern Asia, covering 2,803 patients were included in the analysis, all of them published during the past decade. We found that HDGF overexpression was significantly associated with overall survival (OS) (HROS=2.35, 95%CI=2.04-2.71, p<0.001) and disease free survival (DFS) (HRDFS=2.25, 95%CI =1.81-2.79, p<0.001) in solid tumors, especially in non-small cell lung cancer, hepatocellular carcinoma and cholangiocarcinoma (CCA). Moreover, multivariate survival analysis showed that HDGF overexpression was an independent predictor of poor prognosis (HROS=2.41, 95%CI: 2.02-2.81, p<0.001; HRDFS=2.39, 95%CI: 1.77-3.24, p<0.001). In addition, HDGF overexpression was significantly associated with tumor category (T3-4 versus T1-2, OR=2.12, 95%CI: 1.17-3.83, p=0.013) and lymph node status (N+ versus N-, OR=2.37, 95%CI: 1.31-4.29, p=0.03) in CCA. This study provides a comprehensive examination of the literature available on the association of HDGF overexpression with OS, DFS and some clinicopathological features in solid tumors. Meta-analysis results provide evidence that HDGF may be a new indicator of poor cancer prognosis. Considering the limitations of the eligible studies, other large-scale prospective trials must be conducted to clarify the prognostic value of HDGF in predicting cancer survival.

Irradiated fibroblasts promote epithelial-mesenchymal transition and HDGF expression of esophageal squamous cell carcinoma.

Recent evidence suggested that nonirradiated cancer-associated fibroblasts (CAFs) promoted aggressive phenotypes of cancer cells through epithelial-mesenchymal transition (EMT). Hepatoma-derived growth factor (HDGF) is a radiosensitive gene of esophageal squamous cell carcinoma (ESCC). This study aimed to investigate the effect of irradiated fibroblasts on EMT and HDGF expression of ESCC. Our study demonstrated that coculture with nonirradiated fibroblasts significantly increased the invasive ability of ESCC cells and the increased invasiveness was further accelerated when they were cocultured with irradiated fibroblasts. Scattering of ESCC cells was also accelerated by the supernatant from irradiated fibroblasts. Exposure of ESCC cells to supernatant from irradiated fibroblasts resulted in decreased E-cadherin, increased vimentin in vitro and ß-catenin was demonstrated to localize to the nucleus in tumor cells with irradiated fibroblasts in vivo models. The expression of HDGF and ß-catenin were increased in both fibroblasts and ESCC cells of irradiated group in vitro and in vivo models. Interestingly, the tumor cells adjoining the stromal fibroblasts displayed strong nuclear HDGF immunoreactivity, which suggested the occurrence of a paracrine effect of fibroblasts on HDGF expression. These data suggested that irradiated fibroblasts promoted invasion, growth, EMT and HDGF expression of ESCC.

The tumor-stroma ratio is an independent predictor for survival in nasopharyngeal cancer.

BACKGROUND: The tumor-stroma ratio (TSR) has been identified as a new and practicable prognostic histological characteristic of solid tumors. The aim of this study was to evaluate the prognostic value of the TSR in nasopharyngeal cancer (NPC). PATIENTS AND METHODS: A total of 93 patients who presented with NPC from 2004 to 2007 were studied. Radiotherapy with or without chemotherapy was administered according to their Union for International Cancer Control (UICC) stages. The TSR was assessed visually on hematoxylin and eosin-stained tissue sections of biopsy specimens by 2 independent observers. RESULTS: The 5-year overall survival (OS) and disease-free survival (DFS) rates were 66.67% and 54.91%, respectively, in the stroma-poor group and 40.48% and 33.33%, respectively, in the stroma-rich group. Both the 5-year OS and DFS rates in the stroma-poor group were significantly better than those in the stroma-rich group (p < 0.05). In a multivariate analysis, the TSR was identified as a highly significant prognostic factor for the 5-year OS (hazard ratio (HR) 1.999; p = 0.030) and the 5-year DFS (HR 1.925; p = 0.042). CONCLUSION: Stroma-rich tumors were associated with poor prognosis and an increased risk of relapse, which may serve as a new prognostic histological characteristic in NPC.

BIIB021, a novel Hsp90 inhibitor, sensitizes esophageal squamous cell carcinoma to radiation.

BIIB021 is a novel, orally available inhibitor of heat shock protein 90 (Hsp90) that is currently in phase I/II clinical trials. BIIB021 induces the apoptosis of various types of tumor cells in vitro and in vivo. The aim of this study is to investigate the effect of BIIB021 on the radiosensitivity of esophageal squamous cell carcinoma (ESCC). The results indicated that BIIB021 exhibited strong antitumor activity in ESCC cell lines, either as a single agent or in combination with radiation. BIIB021 significantly downregulated radioresistant proteins including EGFR, Akt, Raf-1 of ESCC cell lines, increased apoptotic cells and enhanced G2 arrest that is more radiosensitive cell cycle phase. These results suggest that this synthetic Hsp90 inhibitor simultaneously affects multiple pathways involved in tumor development and progression in the ESCC setting and may represent a better strategy for the treatment of ESCC patients, either as a monotherapy or a radiosensitizer.