Background The neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) are representative blood markers of systemic inflammatory responses. However, the clinical significance of the combination of these markers is unclear. This study aimed to investigate the NLR and PLR in patients with advanced gastric cancer treated with chemotherapy and assess the clinical utility of a new blood score combining the NLR and PLR (NLR-PLR score) as a predictor of tumor response and prognosis. Methods We retrospectively analyzed 175 patients with gastric cancer receiving chemotherapy or chemoradiotherapy. These patients were categorized into progressive disease (PD) and non-PD groups according to tumor response. The NLR and PLR before treatment were examined, and the cut-off values were determined. The NLR-PLR score ranged from 0 to 2 as follows: score of 2, high NLR (> 2.461) and high PLR (> 248.4); score of 1, either high NLR or high PLR; score of 0, neither high NLR nor high PLR. Results With regard to tumor response, 64 and 111 patients had PD and non-PD, respectively. The NLR-PLR score was significantly higher in patients with PD than in those with non-PD ( p = 0.0009). The prognosis was significantly poorer in patients with a higher NLR-PLR score than in those with a lower NLR-PLR score ( p <  0.0001). Multivariate analysis demonstrated that the NLR-PLR score was an independent prognostic factor for prediction of overall survival ( p = 0.0392). Conclusion Low-cost stratification according to the NLR-PLR score might be a promising approach for predicting tumor response and prognosis in patients with advanced gastric cancer.

BackgroundSince a phase I clinical trial using three HLA-A24-binding peptides from TTK protein kinase (TTK), lymphocyte antigen-6 complex locus K (LY6K), and insulin-like growth factor-II mRNA binding protein-3 (IMP3) had been shown to be promising for esophageal squamous cell carcinoma (ESCC), we further performed a multicenter, non-randomized phase II clinical trial.Patients and methodsSixty ESCC patients were enrolled to evaluate OS, PFS, immunological response employing ELISPOT and pentamer assays. Each of the three peptides was administered with IFA weekly. All patients received the vaccination without knowing an HLA-A type, and the HLA types were key-opened at the analysis point. Hence, the endpoints were set to evaluate differences between HLA-A*2402-positive (24(+)) and -negative (24(−)) groups.ResultsThe OS in the 24 (+) group (n = 35) tended to be better than that in the 24(−) group (n = 25) (MST 4.6 vs. 2.6 month, respectively, p = 0.121), although the difference was not statistically significant. However, the PFS in the 24(+) group was significantly better than that in the 24(−) group (p = 0.032). In the 24(+) group, ELISPOT assay indicated that the LY6K-, TTK-, and IMP3-specific CTL responses were observed after the vaccination in 63%, 45%, and 60% of the 24(+) group, respectively. The patients having LY6K-, TTK-, and IMP3-specific CTL responses revealed the better OS than those not having CTL induction, respectively. The patients showing the CTL induction for multiple peptides have better clinical responses.ConclusionsThe immune response induced by the vaccination could make the prognosis better for advanced ESCC patients.Trial registrationClinicalTrials.gov, number NCT00995358

Background & AimsOropharyngeal and esophageal squamous cell carcinomas, especially the latter, are a lethal disease, featuring intratumoral cancer cell heterogeneity and therapy resistance. To facilitate cancer therapy in personalized medicine, three-dimensional (3D) organoids may be useful for functional characterization of cancer cells ex vivo. We investigated the feasibility and the utility of patient-derived 3D organoids of esophageal and oropharyngeal squamous cell carcinomas.MethodsWe generated 3D organoids from paired biopsies representing tumors and adjacent normal mucosa from therapy-naïve patients and cell lines. We evaluated growth and structures of 3D organoids treated with 5-fluorouracil ex vivo.ResultsTumor-derived 3D organoids were grown successfully from 15 out of 21 patients (71.4%) and passaged with recapitulation of the histopathology of the original tumors. Successful formation of tumor-derived 3D organoids was associated significantly with poor response to presurgical neoadjuvant chemotherapy or chemoradiation therapy in informative patients (P = 0.0357, progressive and stable diseases, n = 10 vs. partial response, n = 6). The 3D organoid formation capability and 5-fluorouracil resistance were accounted for by cancer cells with high CD44 expression and autophagy, respectively. Such cancer cells were found to be enriched in patient-derived 3D organoids surviving 5-fluorouracil treatment.ConclusionsThe single cell-based 3D organoid system may serve as a highly efficient platform to explore cancer therapeutics and therapy resistance mechanisms in conjunction with morphological and functional assays with implications for translation in personalized medicine.

The purpose of the present study was to compare the clinical results between preoperative chemoradiotherapy followed by surgery (CRT group) and surgery alone (Surgery group) by a randomized controlled study. Twenty-two patients were assigned to the CRT group and 23 to the Surgery group. A total radiation dose of 40 Gy was applied and in the same period, intravenous chemotherapy was performed using cisplatin (7 mg over 2 h) and 5-fluorouracil (5-FU; 350 mg over 24 h). Surgical treatment was performed in 20 patients in the CRT group except for two patients with bone metastasis after CRT. According to histological effects of primary tumors, the number of patient with Grades 1, 2 and 3 was 11, 7 and 3, respectively. Frequency of lymphatic and venous invasion was significantly lower in the CRT group than in the Surgery group. The 5-year survival rate was 57% in the CRT group and 41% in the Surgery group (P = 0.58). According to the histological effect in the CRT group, 5-year survival was 30% for Grade 1, 83% for Grade 2 and 100% for Grade 3 (P = 0.0069). This randomized trial did not demonstrate a statistically significant survival difference between the CRT group and the Surgery group.

BackgroundInteractions of stromal hyaluronic acid (HA) with its binding protein RHAMM (receptor for HA-mediated motility) (CD168) have been reported to affect tumor extension and the migration of crucial molecules to promote tumor progression and metastases. Cancerous CD168 expression is correlated with aggressive biological features in several cancers. However, the clinical implications of CD168 positivity in gastric cancer have remained unclear.MethodsWe examined the CD168 expression of 196 consecutive gastric cancer patients by immunohistochemistry. According to CD168 positivity, the 196 gastric cancer patients were divided into two groups (57 CD168-positive and 139 CD168-negative patients). The correlation between CD168 expression and clinicopathological factors (age, sex, histology, tumor depth, lymph node status, and vessel invasion) was evaluated according to the Japanese Classification of Gastric Carcinoma.ResultsCancerous CD168 expression was detectable in 57 of the 196 tumors (29%). CD168 positivity was significantly correlated with the depth of invasion, nodal involvement, and vessel invasion (p < 0.01). Survival analysis of the 196 gastric cancer patients showed that the CD168-positive group had a significantly higher mortality than the CD168-negative group (p < 0.01). In terms of a correlation with CD168 positivity at separate clinical stages, a significance difference was only found in stages II and III. Multivariate analysis revealed that CD168 expression was a significant independent prognostic marker (p = 0.013) after depth of invasion (p < 0.005) and nodal involvement (p < 0.01).ConclusionOur results suggest that cancerous CD168 positivity is strongly related to the invasion and metastasis of gastric cancer tumors. These results suggest that cancerous CD168 expression can be used as a prognostic marker of gastric cancer owing to its interactions with stromal hyaluronic acid.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies in gastrointestinal tract cancers and even patients with early ESCC have a high metastatic potential. Difficulties are associated with clinically predicting tumor progression and prognosis based on conventional tumor markers determined from preoperative blood examinations. The aim of the present study was to measure plasma fibrinogen levels and the neutrophil–lymphocyte ratio (NLR) in blood and compare the clinical impacts of their combined values (fibrinogen and neutrophil–lymphocyte ratio score—F-NLR score) and the modified Glasgow Prognostic Score (mGPS) in patients with ESCC.We classified 238 patients with ESCC based on cut-off values for hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0) as F-NLR scores of 2 (both of these hematological abnormalities), 1 (one of these abnormalities), or 0 (neither abnormality). We also categorized patients based on cut-off values for high C-reactive protein (CRP) (>0.5 mg/dL) and hypoalbuminemia (<3.8 g/dL) as mGPS of 2 (elevated CRP and hypoalbuminemia), 1 (either elevated CRP or hypoalbuminemia), or 0 (neither elevated CRP nor hypoalbuminemia).The F-NLR score correlated with the depth of tumor invasion, lymph node metastasis, lymphovascular invasion, tumor size, and stage (all P < 0.05). Prognoses among the groups based on the F-NLR score and mGPS significantly differed (all P < 0.001). A multivariate analysis identified the depth of tumor invasion, lymph node metastasis, and F-NLR score as independent prognostic factors (P = 0.002, P = 0.007, and P = 0.037, respectively).The results of the present study showed that the F-NLR score is a promising blood predictor for tumor progression and outcomes in patients with ESCC.

Texture features IV and SZV, and volumetric parameters MTV and TLG can predict tumour response, but all of them have limited value in prediction of prognosis of patients with esophageal cancer treated by CRT.

Defects in mitochondrial oxidative phosphorylation complexes, altered bioenergetics and metabolic shift are often seen in cancers. Here we show a role for the dysfunction of electron transport chain component, cytochrome c oxidase (CcO) in cancer progression. We show that genetic silencing of the CcO complex by shRNA expression and loss of CcO activity in multiple cell types from the mouse and human sources resulted in metabolic shift to glycolysis, loss of anchorage dependent growth and acquired invasive phenotypes. Disruption of CcO complex caused loss of transmembrane potential and induction of Ca2+/Calcineurin-mediated retrograde signaling. Propagation of this signaling, includes activation of PI3-kinase, IGF1R and Akt, Ca2+ sensitive transcription factors and also, TGFβ1, MMP16, periostin that are involved in oncogenic progression. Whole genome expression analysis showed up regulation of genes involved in cell signaling, extracellular matrix interactions, cell morphogenesis, cell motility and migration. The transcription profiles reveal extensive similarity to retrograde signaling initiated by partial mtDNA depletion, though distinct differences are observed in signaling induced by CcO dysfunction. The possible CcO dysfunction as a biomarker for cancer progression was supported by data showing that esophageal tumors from human patients show reduced CcO subunits IVi1 and Vb in regions that were previously shown to be hypoxic core of the tumors. Our results show that mitochondrial electron transport chain defect initiates a retrograde signaling. These results suggest that a defect in CcO complex can potentially induce tumor progression.