Jun Hanaoka

Human adipose-derived stem cells: Potential clinical applications in surgery

Regenerative medicine is emerging as a rapidly evolving field of research and therapeutics. Stem cells hold great promise for future translational research and clinical applications in many fields. Much research has focused on mesenchymal stem cells isolated from bone marrow in vitro and in vivo; however, bone marrow procurement causes considerable discomfort to the patient and yields a relatively small number of harvested cells. By contrast, adipose tissue represents an abundant and easily accessible source of adult stem cells, termed adipose-derived stem cells (ADSCs), with the ability to equally differentiate along multiple lineage pathways. These stem cells have angiogenic properties, possibly because of their secretion of cytokines. They may also play a role in healing acute and chronic tissue damage. Subsequently, they have a wide range of potential clinical implications. This article reviews the potential preclinical and clinical applications of mesenchymal stem cells, especially ADSCs, in surgery.

Expression and Immunogenicity of a Tumor- Associated Antigen, 90K/Mac-2 Binding Protein, in Lung Carcinoma The Possibility of Its Clinical Use as a Tumor Marker and a Target Antigen in Cancer Immunotherapy

The authors attempted to obtain shared proteins among lung carcinoma cells by column chromatographies. A glycoprotein with approximately 500 kDa isolated from QG56 cells showed an identical amino acid sequence to 90K/Mac‐2 binding protein (M2BP). This protein has been reported to be highly expressed and to modulate the expression of surface molecules involved in immune responses on cultured cancer cells. Therefore, it would be beneficial for M2BP to be targeted in cancer immunotherapy.

Novel vaccination protocol consisting of injecting MUC1 DNA and nonprimed dendritic cells at the same region greatly enhanced MUC1-specific antitumor immunity in a murine model

In order to induce specific antitumor immunity in mice, we attempted to immunize C57BL/6 mice with DNA vaccine encoding MUC1 polypeptide. When the mice immunized with MUC1 DNA were challenged with EL4-muc, MUC1-transfected syngeneic lymphoma cells, they completely rejected tumors. When DNA vaccine was given to the EL4-muc tumor-bearing mice, this vaccination was insufficient to suppress tumor growth in the mice. However, activated, but nonprimed dendritic cells (DCs) obtained from syngeneic mice and MUC1 DNA vaccine were given simultaneously to the same site of EL4-muc tumor-bearing mice, tumor growth was markedly suppressed accompanying prolongation of survival time. MUC1 antigen was detected on the DCs at the vaccination site and in regional nodes in the mice which received MUC1 DNA vaccine and DCs. These mice showed markedly enhanced cellular immune responses specific for MUC1 compared to those in mice vaccinated with MUC1 DNA alone. No significant difference in titers of antibodies to MUC1 between the two groups was observed. These results suggest that nonprimed DCs inoculated at the DNA vaccine site are essential for eliciting strong antitumor cellular immunity to suppress tumor growth efficiently in DNA-vaccinated mice. This animal model is useful for developing DNA vaccine for anti-cancer immunotherapy.

Impact of splenectomy in patients with liver cirrhosis: Results from 18 patients in a single center experience.

Aim:  With the recent advances in medical or surgical treatments in chronic hepatic disorders, the indications for splenectomy in hepatic disorders have greatly expanded. We performed splenectomy for cirrhotic patients and investigated the effects of splenectomy on hepatic functional reserve and nutrition metabolism.

Inhibition of Transforming Growth Factor-β–Mediated Immunosuppression in Tumor-Draining Lymph Nodes Augments Antitumor Responses by Various Immunologic Cell Types

Tumor-draining lymph nodes (DLN) are the most important priming sites for generation of antitumor immune responses. They are also the location where an immunosuppressive cytokine, transforming growth factor-beta (TGF-beta), plays a critical role in suppressing these antitumor immune responses. We focused on TGF-beta-mediated immunosuppression in DLNs and examined whether local inhibition of TGF-beta augmented antitumor immune responses systemically in tumor-bearing mice models. For inhibition of TGF-beta-mediated immunosuppression in DLNs, C57BL/6 mice subcutaneously bearing E.G7 tumors were administered plasmid DNA encoding the extracellular domain of TGF-beta type II receptor fused to the human IgG heavy chain (TGFR DNA) i.m. near the established tumor. In DLNs, inhibition of TGF-beta suppressed the proliferation of regulatory T cells and increased the number of tumor antigen-specific CD4(+) or CD8(+) cells producing IFN-gamma. Enhancement of antitumor immune responses in DLNs were associated with augmented tumor antigen-specific cytotoxic and natural killer activity in spleen as well as elevated levels of tumor-specific antibody in sera. The growth of the established metastatic as well as primary tumors was effectively suppressed via augmented antitumor immune responses. Inhibition of TGF-beta-mediated immunosuppression in DLNs is significantly associated with augmented antitumor responses by various immunocompetent cell types. This animal model provides a novel rationale for molecular cancer therapeutics targeting TGF-beta.

Outcome of hepatectomy in super-elderly patients with hepatocellular carcinoma.

Aim:  The aim of this study was to investigate the characteristics of super‐elderly hepatocellular carcinoma (HCC) patients aged 80 years or more who underwent hepatectomy and to clarify whether elderly patients with HCC benefit from hepatectomy.

Argon gas embolism in the application of laparoscopic microwave coagulation therapy

BACKGROUND A major concern in the use of the argon beam coagulator system is the potential risk of argon gas embolism. METHODS Seven cases with argon gas embolism in the English literature were reviewed along with the current case. The latter case was a 77-year-old female having laparoscopic hepatectomy after application of the microwave coagulation system on the cutting planes. RESULTS Immediately following shots of an argon beam to control local bleeding at the needle hole in the liver caused by microwave coagulation, the end-tidal carbon disappeared, followed by cardiovascular collapse. After 18 min of cardiovascular resuscitation, the tumors were resected under laparotomy. CONCLUSIONS After reviewing the cases, pneumoperitoneum (57.1%), hepatic needle punctures (42.8%) and direct application of the argon beam to the liver (28.6%) can be considered as risky processes in such events. Caution is necessary in the use of an argon beam in liver surgery to avoid life-threatening gas embolism.

High expression of cancer stem cell markers in cholangiolocellular carcinoma

PurposeCholangiolocellular carcinoma (CLC) is an extremely rare malignant liver tumor. It is thought to originate from the ductules and/or canals of Hering, where hepatic stem cells (HpSC) are located, but there are few reports on cancer stem cell markers in CLC. Thus, we evaluated the significance of cancer stem cell markers, including CD133, CD44, and EpCAM, in CLC.MethodsThe subjects of this study were three patients with CLC and one patient with an intermediate type of combined hepatocellular cholangiocarcinoma (CHC). The cancer cell markers, CK7, CK19, and EMA, were evaluated immunohistochemically.ResultsHistological examination of the CLC revealed morphologically cholangiolar features and immunohistochemical examination revealed positivity for CD133, CD44, and EpCAM. On the other hand, in the intermediate type of CHC, only CD44 was positive, whereas CD133 and EpCAM were negative.ConclusionCLC may have stronger features derived from HpSCs than an intermediate type of CHC.

Encapsulated pericardial fat necrosis treated by video-assisted thoracic surgery: report of a case.

A 55-year-old moderately obese man who was admitted to a local hospital following a traffic accident reported having experienced an episode of sharp and sudden pleuritic pain in the left anterior lower chest 2 days earlier. A computed tomographic scan on admission demonstrated a nonhomogeneous mass in the anterior left side of the chest, abutting the left cardiac margin, and a left-sided pleural effusion. As a mediastinal tumor was suspected, he was referred to our hospital for investigation and treatment. An exploratory thoracotomy was performed by video-assisted thoracic surgery (VATS) about 3 weeks later, which revealed a firm, yellowish mass on the oral side of the pericardial fat pad, adhering to the anterior chest wall. The mass was easily removed. The resected specimen consisted of a lobulated fragment of adipose tissue measuring 5.0 × 3.5 × 2.0cm, and the final pathologic diagnosis was pericardial fat necrosis. The patient had an uneventful postoperative recovery and has remained free of symptoms for 10 months since his operation. Pericardial fat necrosis remains a rare clinical entity. Surgical excision by VATS achieves symptomatic cure and probably continues to be the treatment of choice because of the need to exclude a neoplasm in the differential diagnosis.

Cancer‐associated fibroblast‐targeted strategy enhances antitumor immune responses in dendritic cell‐based vaccine

Given the close interaction between tumor cells and stromal cells in the tumor microenvironment (TME), TME‐targeted strategies would be promising for developing integrated cancer immunotherapy. Cancer‐associated fibroblasts (CAFs) are the dominant stromal component, playing critical roles in generation of the pro‐tumorigenic TME. We focused on the immunosuppressive trait of CAFs, and systematically explored the alteration of tumor‐associated immune responses by CAF‐targeted therapy. C57BL/6 mice s.c. bearing syngeneic E.G7 lymphoma, LLC1 Lewis lung cancer, or B16F1 melanoma were treated with an anti‐fibrotic agent, tranilast, to inhibit CAF function. The infiltration of immune suppressor cell types, including regulatory T cells and myeloid‐derived suppressor cells, in the TME was effectively decreased through reduction of stromal cell‐derived factor‐1, prostaglandin E2, and transforming growth factor‐β. In tumor‐draining lymph nodes, these immune suppressor cell types were significantly decreased, leading to activation of tumor‐associated antigen‐specific CD8+ T cells. In addition, CAF‐targeted therapy synergistically enhanced multiple types of systemic antitumor immune responses such as the cytotoxic CD8+ T cell response, natural killer activity, and antitumor humoral immunity in combination with dendritic cell‐based vaccines; however, the suppressive effect on tumor growth was not observed in tumor‐bearing SCID mice. These data indicate that systemic antitumor immune responses by various immunologic cell types are required to bring out the efficacy of CAF‐targeted therapy, and these effects are enhanced when combined with effector‐stimulatory immunotherapy such as dendritic cell‐based vaccines. Our mouse model provides a novel rationale with TME‐targeted strategy for the development of cell‐based cancer immunotherapy.