Characterization of beta-tricalcium phosphate as a novel immunomodulator.

Calcium phosphate (CaP) ceramics including hydroxyapatite (HA) and beta-tricalcium phosphate (ß-TCP) have been widely used for bone substitution in orthopedic, maxillofacial and dental surgery, as well as in tumor resections. CaP particles are also known to cause inflammatory responses, which are thought to be an unfavorable characteristic of prosthetic coating materials. On the other hand, the immunostimulatory effect of ß-TCP induces an anti-tumor effect in xenograft tumor models in athymic mice. To date, in depth analysis of the biological effects of ß-TCP has not been studied in mice. In the present study, in vivo biological effects of ß-TCP were investigated by subcutaneously injecting ß-TCP particles into mice. This induced extensive migration of immune cells to the area surrounding the injection. In addition, we found that in vitro treatment with ß-TCP in murine monocyte/macrophage cells (J774A.1) induced up-regulation of surface expression of CD86, and increased production of TNF-α, MIP-1α, and sICAM-1. Furthermore, conditioned medium from J774A.1 cells treated with ß-TCP facilitated migration of murine splenocytes in a transwell migration assay. These findings clarify that ß-TCP induces an immunostimulatory effect in mice, and suggest a potential for ß-TCP as a novel adjuvant for cancer therapy.

Implementation of individualized medicine for cancer patients by multiomics-based analyses­the Project HOPE­.

The Project HOPE (High-tech Omics-based Patient Evaluation) for cancer medicine aims to evaluate biological characteristics of each cancer tissue as well as diathesis of each patient in around 1,000 consecutive cases per year, who receive operations at the Shizuoka Cancer Center. Cancer tissues are investigated by whole-exome sequencing for 18,835 genes, focusing on 12,776 in-house cancer hotspots from 483 cancer-associated genes. To confirm cancer-specific genetic changes, we analyzed blood cells to collate with data of cancer tissues, and we reevaluate cancer tissues by comprehensive cancer panel for 409 genes. In order to investigate diathesis of the patients, we evaluate 43,015 hotspots associated with non-cancerous diseases. In terms of gene expression profiling, we analyze cancer-specific alterations for 29,833 genes using tumor and adjacent normal tissues. If and when necessary, we investigate tumor and normal tissues by proteomics and metabolomics. The model experiments using glioblastoma cell lines demonstrated that the method is appropriate for clinical application. The Project HOPE makes it possible to implement individualized medicine and to practice preventive and presymptomatic medicine for cancer patients. Furthermore, the project can create important seeds for research and development in cancer medicine.

Prognostic significance of thymidylate synthase expression in the adjuvant chemotherapy after resection for pulmonary metastases from colorectal cancer.

BACKGROUND: Recent studies have discussed on the prognostic value of thymidylate synthase (TS) assessment in metastases of colorectal cancer (CRC). The aim of this study was to evaluate the prognostic significance of molecular biomarkers including TS expression, after pulmonary metastasectomy followed by 5-fluorouracil-based adjuvant chemotherapy. PATIENTS AND METHODS: A total of 80 patients who underwent metastasectomy for pulmonary recurrence from CRC were included in this study. Tumor sections were stained by immunohistochemistry for TS, orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase (DPD), excision repair cross-complementation group 1 (ERCC1), breast cancer susceptibility gene 1 (BRCA1), vascular endothelial growth factor (VEGF), microvessel density (MVD) assessed by CD34 and p53. RESULTS: Survival after pulmonary metastasectomy was significantly longer in patients treated by adjuvant chemotherapy than those without adjuvant therapy. TS, OPRT, ERCC1, BRCA1 and CD34 expression was significantly associated with better outcome from the use of adjuvant chemotherapy. CONCLUSION: Expression level of TS, OPRT, ERCC1, BRCA1 and MVD in resected colorectal lung metastases may play an important role for predicting outcome after 5-fluorouracil-based adjuvant therapy.

Efficacy of preoperative donation of autologous blood in patients undergoing radical retropubic prostatectomy.

BACKGROUND: Radical retropubic prostatectomy (RRP) has resulted in substantial blood loss and the frequent need for homologous blood transfusion. In this study, the efficacy of autologous blood transfusion, from medical and financial perspectives, was evaluated in patients undergoing RRP. METHODS: Between 1994 and 2000, 80 patients with localized prostate cancer underwent RRP in our institute. Based on informed consent, preoperative donation of autologous blood (PDA) was performed in 65 out of 80 patienets. Four or six units were donated during the first 3 years; however, donation units were reduced to a maximum of 4 units since 1997 onwards. The discard rate of donated blood and frequency of homologous transfusion were examined. Changes of hematocrit (Ht) and hemoglobin (Hb) levels through donation and surgery and important factors that may affect postoperative levels of Ht and Hb were evaluated in 56 patients receiving 4-unit donations. RESULTS: Overall, 2 or 4 units of donated blood were discarded in four patients and homologous transfusion was required in two patients. In 56 patients receiving 4-unit donation, the mean Ht level at predonation was 43.3%. Following donation, this decreased to 35.7%. The administration of recombinant human erythropoietin (rHuEpo) relieved declining Ht levels following donation, but changes in Ht levels after surgery were minor. Important factors related to postoperative decline of Ht and Hb levels were operative time and blood loss. CONCLUSIONS: The program of 4-unit PDA can be performed safely without rHuEpo injection, and it is useful to reduce the risk of requiring homologous transfusion. However, more efficient programs to relieve patient burden and to reduce medical cost are needed.