Biological Reconstruction Using Liquid Nitrogen-Treated Tumor Bearing Bone

In general, a tumor prosthesis is used for reconstruction after removal of osteosarcoma. However, the durability of artificial materials becomes a problem in the long term, and many patients inevitably undergo revision due to loose or damaged prostheses. Moreover, preservation of articular surface is the key to maintain better limb function for long duration. Reconstruction of affected limbs using biological materials has been sought to overcome the aforementioned problems. In some countries, it is significantly difficult to obtain allograft as a biological reconstruction material because of socio-religious or cost problem. Thus, a biological reconstruction method has been developed in which the patient’s affected bone is treated and used for reconstruction. Especially in recycling treatment for affected autologous bone, liquid nitrogen treatment has several favorable characteristics. There is optimal morphological fit because the treated bone itself is one’s own, and bone strength is maintained after treatment. Satisfactory bone union and bone regeneration are expected to be achieved due to good osteoconduction and osteoinduction because proteins and enzymes are preserved in the bone

Cryoimmunology for malignant bone and soft-tissue tumors

Several new methods have recently been developed for the treatment of malignant bone and soft-tissue tumors, and many of these targeted therapies have yielded promising initial results in clinical settings. As more sarcomas become amenable to effective molecular-targeting therapy, the need to evaluate the synergistic effects of combination therapies with anticancer drugs will grow. Other immunologic therapies have also been reported, such as exogenous cytokines, dendritic cell (DC) therapy and peptide vaccines. Cryoimmunology has shown promising results in some malignant tumors after cryosurgery and is expected to influence the next generation of tumor immunotherapy. In this report, we describe the induction of a systemic antitumor immune response following liquid nitrogen cryotreatment of a destructive murine osteosarcoma. Combining tumor cryotreatment with DCs to promote tumor-specific immune responses enhanced systemic immune responses and inhibited metastatic tumor growth. We also describe the induction of a systemic antitumor immune response following reconstruction for malignant bone tumors using frozen autografts treated with liquid nitrogen. © Japan Society of Clinical Oncology 2011

Tumor-targeting Salmonella typhimurium A1-R prevents experimental human breast cancer bone metastasis in nude mice.

Bone metastasis is a lethal and morbid late stage of breast cancer that is currently treatment resistant. More effective mouse models and treatment are necessary. High bone-metastatic variants of human breast cancer cells were selected in nude mice by cardiac injection. After cardiac injection of a high bone-metastatic variant of breast cancer, all untreated mice had bone metastases compared to only 20% with parental cells. Treatment with tumor-targeting Salmonella typhimurium A1-R completely prevented the appearance of bone metastasis of the high metastatic variant in nude mice (P < 0.001). After injection of the highly bone-metastatic breast cancer variant to the tibia of nude mice, S. typhimurium A1-R treatment significantly reduced tumor growth in the bone (P < 0.001). These data indicated that S. typhimurium A1-R is useful to prevent and inhibit breast cancer bone metastasis and should be of future clinical use for breast cancer in the adjuvant setting

A Prospective Cohort Study Showing No Association Between Serum Sclerostin Level and Mortality in Maintenance Hemodialysis Patients

Background/Aims: Potential relationships between serum sclerostin levels and the levels of bone metabolic markers in maintenance hemodialysis (MHD) patients have yet to be evaluated. This study sought to determine whether serum sclerostin levels are associated with mortality in MHD patients. Methods: We measured serum sclerostin levels in a Japanese MHD cohort, classified the patients into tertiles according to these levels, and followed their course for a 42-month period. Results: The cohort consisted of 389 MHD patients and there were 75 deaths. Kaplan-Meier analyses showed that the tertile of serum sclerostin was not associated with mortality risk. Cox analyses showed that there were no significant associations between serum sclerostin level and mortality. Conclusion: Serum sclerostin level was not an independent predictor of mortality in MHD patients after adjustment for several confounders. However, whether clinical interventions to modulate serum sclerostin levels in MHD patients would improve their survival remains to be determined

Inhibition of spontaneous and experimental lung metastasis of soft-tissue sarcoma by tumor-targeting Salmonella typhimurium A1-R.

Prognosis of patients with lung metastases of soft-tissue sarcoma is still poor. Therefore, novel systemic therapy is needed to improve the survival of soft-tissue sarcoma. In the present study, tumor-targeting therapy with a genetically-modified auxotrophic strain of Salmonella typhimurium, termed A1-R, was evaluated. Mouse models of primary soft tissue sarcoma and spontaneous lung metastasis were obtained by orthotopic intra-muscular injection of HT1080-RFP human fibrosarcoma cells. S. typhimurium A1-R was administered from day 14, once a week for two weeks. On day 28, lung samples were excised and observed with a fluorescence imaging system. The number of lung metastasis was 8.8 ± 3.4 in the untreated group and 0.8 ± 0.8 in the treated group (P = 0.024). A mouse model of experimental lung metastasis was obtained by tail vein injection of HT1080-RFP cells. The mice were treated with S. typhimurium A1-R (i.v.) on day 7, once a week for three weeks. S. typhimurium A1-R significantly reduced lung metastases and improved overall survival (P = 0.004). S. typhimurium A1-R bacterial therapy has future potential for treating advanced soft tissue sarcoma and improving prognosis of patients with lung metastasis

Temozolomide combined with irinotecan caused regression in an adult pleomorphic rhabdomyosarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model.

Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and recalcitrant, highly-malignant mesenchymal tumor in need of improved therapeutic strategies. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). We previously described the development of a PDOX model of adult pleomorphic RMS where the tumor behaved similar to the patient donor. A high-grade pleomorphic rhabdomyosarcoma from a striated muscle was previously grown orthotopically in the right biceps-femoris muscle of nude mice to establish the PDOX model. In the present study, the PDOX models were randomized into the following treatment groups when tumor volume reached 100 mm3: G1, control without treatment; G2, cyclophosphamide (CPA) 140 mg/kg, intraperitoneal (i.p.) injection, weekly, for 3 weeks; G3, temozolomide (TEM), 25 mg/kg, per oral (p.o.), daily, for 21 days; G4, temozolomide (TEM) 25 mg/kg, p.o., daily, for 21 days combined with irinotecan (IRN), 4 mg/kg, i.p., daily for 21 days. After 3 weeks, treatment of PDOX with TEM combined with IRN was so powerful that it resulted in tumor regression and the smallest tumor volume compared to other groups. The RMS PDOX model should be of use to design the treatment program for the patient and for drug discovery and evaluation for this recalcitrant tumor type