Masahiko Harano

Clinical outcomes and learning curve of a laparoscopic adrenalectomy in 103 consecutive cases at a single institute

Objective:  We examined the clinical outcomes and the learning curve for a laparoscopic adrenalectomy (LA) in 103 consecutive cases performed by three surgeons at our institute, according to the type of adrenal disorder.

Laparoscopic adrenalectomy for malignant tumors

Objectives:  The treatment of malignant adrenal tumors using laparoscopic surgery remains controversial. We thus compared the perioperative outcome of the laparoscopic adrenalectomy for the treatment of malignant tumors with the outcome for benign tumors. We also evaluated the oncological outcome of the laparoscopic adrenalectomy for a malignancy.

Donor CD4 T Cells Are Critical in Allogeneic Stem Cell Transplantation against Murine Solid Tumor

Nonmyeloablative allogeneic stem cell transplantation (SCT) has been used for various malignancies, although detailed mechanisms of antitumor effects remain unclear. We showed that a nonmyeloablative allogeneic SCT regimen, which consists of mixed chimerism induced by an injection of donor spleen and bone marrow cells followed by cyclophosphamide treatment and a donor lymphocyte infusion (DLI), exerted antitumor effects on established murine bladder tumor, MBT-2. An expansion of donor CD4 T cells accompanied by transient but vigorous IFN-gamma production was detected shortly after DLI. In vivo neutralization of IFN-gamma or depletion of CD4 T cells from DLI abolished the antitumor effects, indicating an indispensable role of donor CD4 T cells producing IFN-gamma. Donor as well as host CD8 T cells accumulated in the tumor region with time. Importantly, depletion of CD8 T cells from DLI did not reverse the suppression of tumor growth, indicating that CD4 T cells play a more essential role in mediating early antitumor effects. Furthermore, tumor-specific response of host CD8 T cells was suggested. These results not only provide the first evidence of nonmyeloablative allogeneic SCT for the treatment of bladder tumor but also elucidate detailed mechanisms of antitumor effects provoked by DLI.

Renal Cancer Treatment with Low Levels of Mixed Chimerism Induced by Nonmyeloablative Regimen Using Cyclophosphamide in Mice

Recently, much attention has been paid to nonmyeloablative allogeneic stem cell transplantation for the treatment of metastatic renal cancer. Mature donor T cells cause graft-versus-host disease (GVHD) although they are also the main mediators of the beneficial graft-versus-tumor activity associated with this treatment. Hence, the segregation of the graft-versus-tumor activity from GVHD is an important challenge in managing the clinical course of treatment. We previously reported a series of studies regarding the allograft tolerance induced by allogeneic spleen cells (with bone marrow cells) and cyclophosphamide in mice. Here, we show a modified cyclophosphamide-induced tolerance system for the treatment of murine renal cell carcinoma, RENCA, by shifting the equal balance between graft-versus-host and host-versus-graft reactions toward graft-versus-host reaction with donor lymphocyte infusion. Our results clearly show the antitumor activity against RENCA with only low levels of mixed chimerism in the periphery and the in vivo and in vitro acquired immunity against RENCA even when mixed chimerism is almost undetectable. Because the withdrawal of mixed chimerism reduces the risk of GVHD, the antitumor activity is thus sequentially segregated from the initial GVHD in our model. We believe that this is the first unique model system of nonmyeloablative allogeneic hemopoietic cell transplantation to ever be reported for the treatment of renal cancer.

Posttransplant administration of cyclophosphamide and donor lymphocyte infusion induces potent antitumor immunity to solid tumor

Purpose: Nonmyeloablative allogeneic stem cell transplantation (SCT) has been increasingly used for the treatment of hematologic and solid malignancies, and mature donor T cells are considered to be the main effectors of the graft-versus-tumor (GVT) activity. However, the association between degree of donor chimerism and intensity of GVT effects has not been fully elucidated. We recently proposed a unique nonmyeloablative cell therapy using posttransplant cyclophosphamide and donor lymphocyte infusion, by which a significant antitumor effect against murine renal cell carcinoma, RENCA, was induced, although the level of mixed chimerism was relatively low. In this study, we attempted to clarify a role of chimerism for in vivo antitumor effects on GVT effects in radiation-associated nonmyeloablative SCT. Experimental Design: We assessed antitumor effects on RENCA tumors and the degree of donor chimerism after several doses of irradiation followed by allogeneic SCT and compared the results with those of cyclophosphamide-based cell therapy. Results: Allogeneic SCT following sublethal irradiation (6 Gy) induced almost complete donor chimerism, whereas cyclophosphamide-based cell therapy produced low levels of donor chimerism. Nonetheless, GVT activity was much more potent in cyclophosphamide-based cell therapy than irradiation-conditioned SCT. Furthermore, cyclophosphamide-conditioned SCT induced more potent immune reconstitution with less severe graft-versus-host disease than irradiation-conditioned SCT. Conclusions: Our results indicate that a high level of chimerism is not essential for the in vivo antitumor effect of nonmyeloablative allogeneic cell therapy against solid tumor and that the recovery of peripheral lymphocytes after the initial immunosuppression might be a critical event for the elicitation of in vivo antitumor effects of that treatment modality.

Dendritic cell therapy in combination with interferon-α for the treatment of metastatic renal cell carcinoma

Objectives:  To evaluate the safety and efficacy of dendritic cell (DC) therapy in combination with interferon‐α (IFN‐α) in patients with advanced renal cell carcinoma.

A pilot study of the assessment of the quality of life, functional results, and complications in patients with an ileal neobladder for invasive bladder cancer

Objective:  To assess the functional results, health‐related quality of life (QOL) outcomes, and complications in patients with an ileal neobladder in comparison to those with cutaneous diversion (ileal conduit and cutaneostomy).

What Affects the Results of a Laparoscopic Adrenalectomy for Pheochromocytoma? Evaluation with Respect to Intraoperative Blood Pressure and State of Tumor

PURPOSE To investigate the factors that affect the operative data and to evaluate the validity of a laparoscopic adrenalectomy (LA) for pheochromocytoma. PATIENTS AND METHODS Between July 1993 and January 2008, 172 LAs were performed in this department, and 34 of them were for pheochromocytoma. The characteristics and operative data of LAs for pheochromocytoma were examined with respect to the intraoperative systolic blood pressure (SBP) and the side of tumor. RESULTS The intraoperative SBP rose to 180 mm Hg or more in 17 (50%) cases of LAs for pheochromocytomas. The analysis of SBP (<180 versus >180 mm Hg), however, showed that there were no differences in the operative data between the two groups. The tumor size was significantly associated with operative time (P < 0.05) or the blood loss (P < 0.05) in an LA for pheochromocytoma. The blood loss in LAs for right adrenal tumors was greater (150 versus 79 mL) than for left tumors (P < 0.01). In particular, some procedures for right large tumors had considerable blood loss and long procedural time. In a comparison of the operative data between pheochromocytoma and other adrenal tumors, the tumor was larger (4.3 versus 2.5 cm) and the blood loss was greater (100 versus 30 mL) than for other adrenal tumors. CONCLUSIONS The operative data showed no correlation with the intraoperative high SBP, but they were associated with the tumor state. Although the procedure seems to be influenced by the size and state of tumor, LA is not contraindicated for pheochromocytoma, and it can therefore be performed safely.

The efficacy of laparoscopic radical nephrectomy for renal cell cancer in the elderly: An oncological outcome analysis

Objectives:  The efficacy and outcome of a laparoscopic radical nephrectomy (LRN) were retrospectively evaluated in patients aged ≥70 years, and the results were compared with those obtained from patients younger than 70 years undergoing laparoscopic surgery for the same indications.

Cyclophosphamide-Using Nonmyeloablative Allogeneic Cell Therapy against Renal Cancer with a Reduced Risk of Graft-versus-Host Disease

Purpose: Much attention has been paid to nonmyeloablative allogeneic stem cell transplantation for the treatment of renal cancer. We recently proposed a cyclophosphamide-using nonmyeloablative cell therapy in which donor lymphocyte infusion (DLI) was carried out after the tolerance induction to donor cells. In considering the clinical application of the cyclophosphamide-using cell therapy, attempts to reduce graft-versus-host disease (GVHD) are crucial. The aim of the present study was to modify the cyclophosphamide-using cell therapy to reduce the risk of GVHD while preserving the antitumor activity against renal cancer. Experimental Design: We assessed whether a delay in performing DLI from day 1 to day 5 after the cyclophosphamide treatment could reduce the risk of GVHD while preserving antitumor activity against RENCA, a murine carcinogen-induced renal cell carcinoma, in the cyclophosphamide-using cell therapy. Results: Regarding the in vivo antitumor effect, there was no difference between DLI on day 1 and day 5 after the cyclophosphamide treatment, whereas the histologic findings of the small intestine showed that the cyclophosphamide-using cell therapy with DLI on day 5 decreased the risk of GVHD. In addition, the acquired immunity against RENCA was also observed in the RENCA-rejected mice that had been treated with DLI on day 5. Conclusions: Our results show that a delay in DLI during cyclophosphamide-using nonmyeloablative cell therapy can dissociate graft-versus-tumor effects from GVHD by reducing the risk of GVHD.