Postoperative Adjuvant Therapy for Resectable Pancreatic Cancer With Gemcitabine and Adoptive Immunotherapy.

OBJECTIVES: We previously described adoptive immunotherapy (AIT) with cytotoxic T lymphocytes (CTLs) stimulated by the mucin 1 (MUC1)-expressing human pancreatic cancer cell line YPK-1 (MUC1-CTLs) and demonstrated that MUC1-CTLs might prevent liver metastasis. In the present study, we combined gemcitabine (GEM) and AIT for the treatment of pancreatic cancer. METHODS: A total of 43 patients who underwent radical pancreatectomy received treatment with MUC1-CTLs and GEM. After surgery, MUC1-CTLs were induced and administered intravenously 3 times, and GEM administered according to the standard regimen for 6 months. The patients whose relative dose intensity of GEM was 50% or more and who received 2 or more MUC1-CTL treatments were used as the adequate treatment group (n = 21). RESULTS: In the adequate treatment group, disease-free survival was 15.8 months, and overall survival was 24.7 months. Liver metastasis was found only in 7 patients (33%), and local recurrence occurred in 4 patients (19%). The independent prognostic factor of long-term disease-free survival on multivariate analysis was the average number of CTLs administered (P = 0.0133). CONCLUSIONS: The combination therapy with AIT and GEM prevented liver metastasis and local recurrence. Moreover, the disease free-survival was improved in patients who received sufficient CTLs.

MicroRNA-6826 and -6875 in plasma are valuable non­invasive biomarkers that predict the efficacy of vaccine treatment against metastatic colorectal cancer.

Various vaccine treatments against metastatic colorectal cancer have been developed and applied. However, to improve the efficacy of immunotherapy, biomarkers that can predict the effects are needed. It has been reported that various microRNAs (miRNAs) in peripheral blood may be useful as non-invasive biomarkers. In this study, miRNAs influencing the efficacy of vaccine treatment were screened for in a microarray analysis of 13 plasma samples that were obtained from patients prior to vaccine treatment. To validate the screening results, real-time RT-PCR was performed using 93 plasma samples obtained from patients prior to vaccine treatment. Four candidate miRNAs were selected according to the results of the comprehensive analysis of miRNA expression, which were ranked using the Fisher criterion and the absolute value of the log2 ratio in the screening analysis. The validation analysis showed that in the HLA-A*2402­matched patient group (vaccine-treated group), patients with a high expression of plasma miR-6826 had a poorer prognosis than those with a low expression (P=0.048). In contrast, in the HLA-A*2402-unmatched patient group (control group), there was no difference between the patients with high or low plasma miR-6826 expression (P=0.168). Similar results were obtained in the analysis of miR-6875 (P=0.029 and P=0.754, respectively). Moreover, multivariate analysis of the Cox regression model indicated that the expression of miR-6826 was the most significant predictor for overall survival (P=0.003, hazard ratio, 3.670). In conclusion, plasma miR-6826 and miR-6875 may be predictive biomarkers for a poor response to vaccine treatment. Although further clarification is needed regarding the functions of miR-6826 and miR-6875 and their relationship to immune­related molecules, plasma miR-6826 and miR-6875 may be useful negative biomarkers for predicting the efficacy of vaccine treatment.

New diagnostic criteria and operative strategy for cesarean scar syndrome: Endoscopic repair for secondary infertility caused by cesarean scar defect.

AIM: The aim of the present study was to assess the efficacy of endoscopic repair for secondary infertility caused by post-cesarean scar defect (PCSD). Our investigation focused on the validity of new diagnostic criteria and selection methods. MATERIAL AND METHODS: The subjects were 22 women with secondary infertility due to PCSD with retention of bloody fluid in the uterine cavity. Women with a residual myometrial thickness of ≥ 2.5 mm and an anteflexed or straight uterus underwent hysteroscopic surgery, while all others underwent laparoscopic repair. Hysteroscopic surgery involved resection and coagulation of scarred areas, whereas laparoscopic surgery involved removal of scarred areas combined with hysteroscopy, followed by resuturing. RESULTS: Fourteen of the 22 women (63.6%) who were followed up for ≥ 1 year after surgery achieved pregnancy. Pregnancies occurred in all four women (100%) who underwent hysteroscopic surgery and in 10 of the 18 women (55.6%) who underwent laparoscopic surgery. Three out of four women who underwent hysteroscopic surgery had term deliveries. Among the women who underwent laparoscopic surgery, five had term deliveries. No cases of uterine rupture were experienced, and the delivery method was cesarean section in all cases. CONCLUSION: We propose that infertility associated with PCSD, cesarean scar syndrome, is caused by the retention of bloody fluid in the uterine cavity and scarring. Endoscopic treatment, such as hysteroscopy or laparoscopy, was effective for cesarean scar syndrome.

Apoptosis induced by an alkylated purine, 6-dimethylaminopurine, and changes in gene expression in human lymphoma U937 cells.

Apoptosis induced by an alkylated purine, 6-dimethylaminopurine (6-DMAP), was investigated to explore the p53-independent pathway in a human lymphoma U937 cell line. Here, it was discovered that the apoptosis was induced by 6-DMAP in a dose- and time-dependent manner and treatment for 16 h at a concentration of 5 mM induced apparent DNA fragmentation, phosphatidylserine externalization and lowering of the mitochondrial membrane potential, which are typical markers of apoptosis. Western blotting revealed reduced expression in Bcl-XL, increased expression in Bax and release of cytochrome c. These were associated with activation of caspase-3. The 6-DMAP-induced apoptosis was preceded by an increase in the intracellular calcium ion concentration ([Ca2+]i), indicating the involvement of intracellular Ca2+ ions in apoptosis. Two independent sets of cDNA microarray systems were used to examine changes in gene expression. Of the 3,893 and 886 genes analyzed, 32 and 13 genes were identified as down-regulated in cells treated with 6-DMAP for 3 h. No up-regulated gene was found. Real-time PCR revealed a significant decrease in mRNA of proliferating cell nuclear antigen, insulin-induced gene 1, serine proteinase inhibitor 2 and v-myc. Pathway analysis also revealed the interaction of genes on down-regulation. These findings suggest that intracellular calcium ions and mitochondrial caspase-dependent pathways play major roles in 6-DMAP-induced apoptosis, and protein kinase inhibition by the agent causes massive down-regulation of all genes relating to cell proliferation and progression of the cell cycle to induce apoptosis.