Association of survivin positive circulating tumor cell levels with immune escape and prognosis of osteosarcoma.

PURPOSE: Function of survivin protein (encoded by BIRC5) in circulating tumor cells (CTCs) of osteosarcoma (OS) has not been investigated. The goal of this study is to determine whether the expression of survivin protein of CTCs is associated with circulating immune cell infiltration and disease prognosis of OS. METHODS: Blood samples of 20 patients with OS were collected. CanPatrol™ CTC enrichment technology combined with in situ hybridization (ISH) was applied to enrich and test CTCs and survivin protein. Bioinformation analysis combined with data of routine blood test was used to verify the association between survivin and immune cell infiltration in circulatory system. To screen independent prognostic factors, Kaplan-Meier survival curve, univariate and multivariable Cox regression analyses were performed. RESULTS: Bioinformatics analysis showed that BIRC5 was strongly negatively related to lymphocyte, including T cell, NK cell and B cell, which released that BIRC5 played a key role in immune escape via reducing immune cell infiltration in circulatory system. Meanwhile, the number of survivin+ CTCs was significantly negatively connection with lymphocyte count (R = -0.56, p = 0.011), which was consistent with bioinformatics analysis. Kaplan-Meier curve showed that the overall survival rate in high survivin+ CTCs group was significantly lower than low group (88.9% vs 36.4%, p = 0.04). Multivariable Cox regression analyses showed that survivin+ CTCs were an independent prognostic factor (p = 0.019). CONCLUSION: These findings suggested that survivin protein played a key role in immune escape of CTCs and the presence of survivin+ CTCs might be a promising prognostic factor in OS patients.

Constructing a competing endogenous RNA network for osteoarthritis.

Background: Osteoarthritis (OA) is one of the most common diseases in elderly people; however, the correlation between molecular alterations and the occurrence and progression of OA are still not well understood. We conducted this study to investigate the molecular changes in OA via the competing endogenous ribonucleic acid (ceRNA) network. Methods: We downloaded the messenger RNA (mRNA) data set, GSE48556, the microRNA (miRNA) data set, GSE105027, and the long non-coding (lncRNA) data set, GSE126963 from the Gene Expression Omnibus (GEO) database, and examined the differentially expressed genes (DEGs) in these data sets. Further, we constructed a ceRNA network of the differentially expressed miRNAs, mRNAs, and lncRNAs. To determine the biological functions of the ceRNA network, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Finally, we conducted an immune cell infiltration analysisusing single-sample gene set enrichment analysis to examine the abundance of immune cells in healthy and OA patients, and compared the infiltration of 28 immune cells between the healthy and OA samples. We also analyzed the relationship between the abundance of immune cells and mRNA expression levels in the ceRNA network. Results: Ultimately hsa-mir-425-3p, dual specificity phosphatase 1, and 24 lncRNAs were identified in the ceRNA network. The functional enrichment analyses showed that these lncRNAs, miRNAs, and mRNAs are involved in various significant biological process, such as the regulation of leukocyte migration, Mitogen-Activated Protein (MAP) kinase tyrosine/serine/threonine phosphatase activity, the interleukin-17 signaling pathway, the tumor necrosis factor signaling pathway, and osteoclast differentiation, and can also have a strong effect on immune cell infiltration. Conclusions: The dual-specificity phosphatase 1-specific ceRNA network can be used as a diagnostic tool to assess the progression of OA patients.

Comparison of FOLFOX and DOF regimens as first-line treatment in East Asian patients with advanced gastric cancer.

BACKGROUND: Our study retrospectively assesses the safety and efficacy of the FOLFOX (oxaliplatin, fluorouracil, and leucovorin) versus DOF (docetaxel, oxaliplatin, and fluorouracil) regimens in untreated locally advanced gastric cancer (AGC). PATIENTS AND METHODS: A total of 108 patients underwent DOF (N=58) and FOLFOX (N=50) regimens. The end points were overall response rate (ORR), survival, and toxicity. Kaplan-Meier curve was used to estimate overall survival (OS) and progression-free survival (PFS) and Cox regression for multivariate analysis. RESULTS: The ORRs were 50% for DOF and 30% for FOLFOX groups (P<0.05), and disease control rates were 91.4% and 72%, respectively. The median PFS and OS in DOF group were significantly better than FOLFOX group (8.2 versus 6.4 months, P<0.05; 16.3 versus 11.2 months, P<0.001). Both groups showed acceptable toxicity; all grades and grade 3-4 toxicity had no significant differences (P=0.071; P=0.247). However, the incidence of grade 3-4 peripheral neuropathy was significantly higher in DOF group (10.3% versus 2%, P<0.05). In the subgroup analysis for elderly AGC patients (≥65 years), administration of DOF also resulted in a superior PFS (8.5 versus 5.9 months; P=0.038) and OS (15.3 versus 9.8 months; P=0.004) compared with FOLFOX. However, DOF regimen was associated with more neutropenia (67% versus 30%; P<0.05), thrombocytopenia (61% versus 52%; P<0.05), and peripheral neuropathy (49% versus 22%; P<0.05). CONCLUSION: DOF regimen was more effective than FOLFOX for AGC, both in younger and older patients. The adverse effects of the two regimens were manageable. The combination of docetaxel/oxaliplatin/fluorouracil was active and well tolerated in AGC patients and deserves further evaluation. However, for elderly patients with AGC, the DOF regimen was associated with worse toxicities; therefore, the FOLFOX regimen might be a more suitable option.

Comparison of definitive chemoradiotherapy and radiotherapy alone in patients older than 75 years with locally advanced esophageal carcinoma: A retrospective cohort study.

The aim of this study was to evaluate the efficacy and acute toxicity of definitive chemoradiotherapy (CRT) and radiotherapy (RT) alone as initial treatment in patients aged 75 years and older with locally advanced esophageal squamous cell carcinoma (ESCC) who are not eligible for surgery.Between February 2009 and February 2015, 122 patients older than 75 years with locally advanced ESCC were retrospectively reviewed, in whom 52 patients allocated to the CRT group were treated with at least 2 cycles of platinum and 5-fluorouracil, 70 patients allocated to the RT group were treated with RT alone, all patients were received a total radiation dose of 54-66 Gy, with 1.8 or 2-Gy/fraction. Response rate (RR), progression-free survival (PFS), overall survival (OS), and acute toxicities were compared between the 2 different treatment groups.In the CRT group, the median PFS and OS were 15.3 and 24.6 months, while 10.6 and 19.4 months in the RT group (P = .008 and P = .018). The 1-year survival rates of the 2 groups were 78.8% versus 64.3% (P = .081), and the 2-year survival rates were 48.1% and 30.0% (P = .042), respectively. The objective RR was 55.8% in the CRT group with 18 complete response (CR) and 18.6% in the RT group with 13 CR. Acute toxicity in the CRT group was higher than in the RT group, especially the grade 3 to 4 acute toxicities.Compared with RT alone, definitive CRT in the treatment of locally advanced ESCC can prolong the survival time in elderly patients. Definitive CRT should be considered the first-treatment choice for elderly patients like the younger patients who are not eligible for surgery.

The status of immunosuppression in patients with stage IIIB or IV non-small-cell lung cancer correlates with the clinical characteristics and response to chemotherapy.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step of tryptophan (Trp) degradation via the kynurenine (Kyn) pathway, which inhibits the proliferation of T cells and induces the apoptosis of T cells, leading to immune tolerance. Therefore, IDO has been considered as the most important mechanism for tumor cells to escape from immune response. Previous studies suggested that IDO might be involved in the progression of tumor and resistance to chemotherapy. Several preclinical and clinical studies have proven that IDO inhibitors can regulate IDO-mediated tumor immune escape and potentiate the effect of chemotherapy. Thus, the present study investigated the correlation between the clinical parameters, responses to chemotherapy, and IDO activity to provide a theoretical basis for the clinical application of IDO inhibitors to improve the suppression status and poor prognosis in cancer patients. METHODS: The serum concentrations of Trp and Kyn were measured by high-performance liquid chromatography in 252 patients with stage IIIB or IV non-small-cell lung cancer, and 55 healthy controls. The IDO activity was determined by calculating the serum Kyn-to-Trp (Kyn/Trp) ratio. RESULTS: The IDO activity was significantly higher in the lung cancer patients than in the controls (median 0.0389 interquartile range [0.0178-0.0741] vs 0.0111 [0.0091-0.0133], respectively; P<0.0001). In addition, patients with adenocarcinoma had higher IDO activity than patients with nonadenocarcinoma (0.0449 [0.0189-0.0779] vs 0.0245 [0.0155-0.0563], respectively; P=0.006). Furthermore, patients with stage IIIB disease had higher IDO activity than patients with stage IV disease (0.0225 [0.0158-0.0595] vs 0.0445 [0.0190-0.0757], respectively; P=0.012). The most meaningful discovery was that there was a significant difference between the partial response (PR) patients and the stable disease (SD) and progressive disease (PD) patients (0.0240 [0.0155-0.0381] vs 0.0652 [0.0390-0.0831] vs 0.0868 [0.0209-0.0993], respectively, P<0.0001). CONCLUSION: IDO activity was increased in lung cancer patients. Higher IDO activity correlated with histological types and disease stages of lung cancer patients, induced the cancer cells' resistance to chemotherapy, and decreased the efficacy of chemotherapy.

Comparison of cisplatinum/paclitaxel with cisplatinum/5-fluorouracil as first-line therapy for nonsurgical locally advanced esophageal squamous cell carcinoma patients.

BACKGROUND: To retrospectively evaluate the efficacy and toxicity of definitive concurrent chemoradiotherapy (dCRT) with cisplatinum/paclitaxel versus cisplatinum/5-fluorouracil in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who received nonsurgical treatment. METHODS: This study retrospectively evaluated 202 patients with locally advanced ESCC treated at Shandong Cancer Hospital between January 2009 and December 2013. All the patients initially received dCRT, including platinum and paclitaxel or 5-fluorouracil, with concurrent 1.8 or 2 Gy/fraction radiation (total dose, 54-60 Gy). The patient population was divided into two treatment groups: 105 patients who received the cisplatinum/paclitaxel regimen were allocated to group A, and 97 patients who received the cisplatinum/5-fluorouracil regimen were allocated to group B. We compared the progression-free survival (PFS) and overall survival (OS) by various clinical variables, including prior treatment characteristics, major toxicities (mainly in grade 3 and 4 hematological), and response to dCRT. We used the receiver operating curve analysis to determine the optimal cutoff value of clinical stage and radiation dose. The Kaplan-Meier method was used for survival comparison and Cox regression for multivariate analysis. RESULTS: Median PFS and OS in group A were significantly better compared with group B (median PFS, 15.9 versus 13.0 months, P=0.016 and median OS, 33.9 versus 23.1 months, P=0.014, respectively). The 1- and 2-year survival rates of the two groups were 82.9% versus 76.3%, and 61.9% versus 47.6%, respectively. The complete response and response rate were 17.1% versus 7.2% (P=0.032) and 52.4% versus 30.9% (P=0.042) in group A and B, respectively. Meanwhile, group B was associated with a significantly lower rate of grade 3/4 overall toxicity than group A (P=0.039). CONCLUSION: Our data showed that patients with locally advanced ESCC in group A had longer PFS and OS compared with group B. Cisplatinum/paclitaxel can be considered a good candidate chemotherapy regimen for patients with locally advanced ESCC who are being treated with nonsurgical therapy.

Efficacy and safety of gemcitabine plus erlotinib for locally advanced or metastatic pancreatic cancer: a systematic review and meta-analysis.

BACKGROUND: Pancreatic cancer is considered as a chemoresistant neoplasm with extremely dismal prognosis. Gemcitabine is recommended as the standard agent for locally advanced or metastatic pancreatic cancer. A series of trials have been conducted to improve the outcome of advanced pancreatic cancer with other anticancer drugs in combination with gemcitabine. Unfortunately, the designers of the clinical trials failed to improve the poor prognosis of patients with advanced pancreatic cancer. Erlotinib was the first additional drug that improved the overall survival of patients with advanced pancreatic cancer with gemcitabine. We performed this systematic review and meta-analysis to explore the efficacy and safety of the combination of gemcitabine with erlotinib (GemErlo) for patients with advanced pancreatic cancer using the currently available evidence. METHODS: PubMed/MEDLINE, EMBASE, the Cochrane Library, and relevant abstracts of major conferences were comprehensively searched. Data results on objective response rate, disease control rate, and 1-year survival were pooled by using MetaAnalyst with a random-effects model. Results on progression-free survival and overall survival were only summarized descriptively. RESULTS: A total of 24 studies with 1,742 patients with locally advanced or metastatic pancreatic cancer treated with GemErlo were included. Combined objective response rate was 14.4% (95% CI: 11.6%-17.7%), disease control rate was 55.0% (95% CI: 51.5%-58.5%), and 1-year survival rate was 28.5% (95% CI: 24.0%-33.4%). Progression-free survival ranged from 2.63 to 9.6 months, and overall survival varied from 6 to 10 months. As for the toxicity profile, the most common adverse events (AEs) were hematologic reactions, skin rash, and gastrointestinal reactions. Other severe AEs, which had low incidence, included treatment-induced death and interstitial lung disease. CONCLUSION: Our study showed that GemErlo is associated with reasonable activity in treating patients with locally advanced or metastatic pancreatic cancer. Most of the AEs were tolerable, while some severe AEs needed careful detection.

A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome.

Brooke-Spiegler syndrome (BSS, familial cylindromatosis or turban tumor syndrome) is an inherited disease characterized by neoplasms of the skin appendages such as cylindroma, trichoepithelioma, and spiradenoma. The disease has been mapped to 16q12-13, and mutations in the CYLD gene have been identified in families with this disorder. Of interest, multiple familial trichoepithelioma (MFT) has been described as a distinct disorder characterized by the familial occurrence of trichoepitheliomas. MFT has been mapped to 9p21; however, to date a candidate gene has not been identified. In this report, we describe a four-generation family with BSS presenting predominantly with trichoepitheliomas (resembling MFT phenotype). We identified a novel missense mutation in the CYLD gene, designated E474G, in the affected individuals of this family. Our findings exemplify clinical heterogeneity within BSS and extend the body of evidence that mutations in CYLD are implicated in this disease. Although not conclusive, these findings suggest that BSS and MFT may represent a single entity.

A recurrent mutation in the ARS (component B) gene encoding SLURP-1 in Turkish families with mal de Meleda: evidence of a founder effect.

Mal de Meleda is a rare form of palmoplantar keratoderma, and recently mutations in the ARS (component) B gene have been identified in families with this disease. We identified a recurrent nonsense mutation, R96X, in four families of Turkish descent. In this report, we demonstrate that these families share a common ancestral haplotype at the mal de Meleda locus, suggesting a founder effect.