Youichi Mizutani

Ectopic aberrant adrenals with epididymal abnormality

We report a rare case of ectopic aberrant adrenals associated with epididymal abnormality found during exploration for a left undescended testis. Two ectopic adrenals were found, one on the epididymis and the other adjacent to the spermatic cord. We believe the simultaneous occurrence of epididymal abnormality and ectopic aberrant adrenals has not been reported before.

Nerve-sparing retroperitoneal lymph node dissection for advanced testicular cancer after chemotherapy

Background: Nerve‐sparing techniques are commonly used in retroperitoneal lymph node dissection (RPLND) in patients with early stage testicular germ cell tumors to preserve postoperative ejaculation. The indications for nerve‐sparing procedures have been extended to patients who have residual retroperitoneal tumor postchemotherapy with an increase in the incidence of local recurrence. Here, we report on 26 Japanese men with advanced testicular cancer who underwent nerve‐sparing RPLND after partially successful chemotherapy.

ADRIAMYCIN-MEDIATED POTENTIATION OF CYTOTOXICITY AGAINST FRESHLY ISOLATED BLADDER CANCER CELLS BY AUTOLOGOUS NON-ACTIVATED PERIPHERAL BLOOD LYMPHOCYTES AND TUMOR INFILTRATING LYMPHOCYTES

PURPOSEnPrevious studies indicated that cancer patients lack functional anti-tumor cytotoxic lymphocytes. However, anti-tumor cytotoxic lymphocytes may coexist with immunoresistant tumor cells. We reasoned that anti-tumor cytotoxic activity of lymphocytes may be revealed if the tumor cells are sensitized to killing. It has been reported that adriamycin (ADR) exhibits various immunomodulating activities. In the present study, we investigate the effect of ADR on the susceptibility of freshly isolated bladder cancer cells to lysis by autologous non-activated peripheral blood lymphocytes (PBL) and tumor infiltrating lymphocytes (TIL).nnnMATERIALS AND METHODSnCytotoxicity was determined by a 1-day microculture tetrazolium dye assay.nnnRESULTSnTreatment of ADR-resistant fresh bladder cancer cells with ADR at 0.1 microg./ml. or more for 3 hours or more enhanced their susceptibility to lysis by autologous PBL. This ADR-induced enhancement of susceptibility of fresh bladder cancer cells to lysis by PBL was also observed when lymphokine activated killer cells, purified natural killer cells and T lymphocytes were used as effector cells. Furthermore, while cytotoxicity of freshly derived TIL against autologous bladder cancer cells was minimal, significant cytotoxicity was observed with ADR-treated bladder cancer cells. The ADR analogs, epirubicin and pirarubicin, also enhanced the susceptibility of bladder cancer cells to lysis by autologous PBL. Treatment of bladder cancer cells with ADR had no effect on the expression of MHC class I on the cancer cells or the frequency of bladder cancer target cell conjugates to autologous PBL. Treatment of bladder cancer cells with ADR augmented their sensitivity to anti-Fas monoclonal antibody and tumor necrosis factor-a. Pretreatment of effector cells with ADR had no effect on their cytotoxic function.nnnCONCLUSIONSnThese findings demonstrate that PBL and TIL in patients with bladder cancer exhibit anti-tumor cytotoxic function, but their function is not manifested due to development or acquisition of tumor cell resistance to killing. However, the resistance of bladder cancer cells to killing by cytotoxic lymphocytes is overcome if cancer cells are sensitized by subtoxic concentrations of ADR. These findings suggest that treatment of bladder cancer patients with low doses of ADR may sensitize the cancer cells to killing by autologous circulating and tumor infiltrating lymphocytes and may be a novel immunotherapeutic modality for the treatment of drug-resistant and/or immune-resistant bladder cancer.

Increased intracellular doxorubicin by anti-Fas monoclonal antibody: a mechanism that enhances the cytotoxicity in renal cell carcinoma cells

OBJECTIVESnTo investigate the effect of anti-Fas monoclonal antibody (mAb) on the intracellular concentration of doxorubicin in renal cell carcinoma (RCC) cells. Little is known about the influence of anti-Fas mAb on the intracellular concentration of chemotherapeutic agents.nnnMETHODSnThe concentration of intracellular doxorubicin was determined by high-performance liquid chromatography. The mRNA and protein levels of multidrug resistance-associated protein gene were evaluated by reverse transcriptase-polymerase chain reaction and immunocytochemistry, respectively.nnnRESULTSnAn increased concentration of doxorubicin inside the cells was found: 2.4-fold in ACHN cells (a human RCC cell line) after treatment with doxorubicin combined with anti-Fas mAb compared with doxorubicin alone. Of the five cases of freshly derived RCC cells treated with doxorubicin and anti-Fas mAb, the intracellular concentration of doxorubicin was increased 2.3 and 2.7-fold in two of them, respectively. Furthermore, both the mRNA and the protein levels of the multidrug resistance-associated protein gene were downregulated after treatment of ACHN cells with anti-Fas mAb. Treatment of ACHN cells with a combination of anti-Fas mAb and doxorubicin resulted in a potentiation of the doxorubicin-mediated cytotoxicity.nnnCONCLUSIONSnThe increased intracellular concentration of doxorubicin by anti-Fas mAb might be one of the mechanisms responsible for the enhancement of doxorubicin-mediated cytotoxicity in RCC cells.

A series of immune responses leading to the induction ofT cell IL-12/IL-18 responsiveness in patientswith relatively large tumor burdens

Abstract. The induction of interleukin-12 (IL-12) responsiveness in T cells depends on T cell receptor (TCR) triggering, and is regarded as a parameter of recently TCR-sensitized T cells. Here, we investigated whether IL-12 responsiveness could be detected in freshly prepared T cells from tumor-bearing patients, and if so whether such patients exhibited additional immunological parameters related to IL-12 responsiveness. CD4+ and CD8+ T cell populations from an appreciable proportion of tumor-bearing patients exhibited high levels of IL-12 responsiveness as evaluated by IL-12-stimulated interferon-gamma (IFN-γ) production. T cell populations with high IL-12 responsiveness were observed in the group of patients with moderate to large tumor mass or tumor metastases rather than in patients with small tumors. The frequency of such a T cell population was also lower in post-surgery tumor-free patients, showing the correlation between IL-12 responsiveness and the presence of a certain extent of tumor burden. More importantly, a higher incidence of IL-12 responsiveness was observed in tumor-bearing patients exhibiting detectable plasma IL-12 levels, and correlated with IL-18 responsiveness. T cell IL-12 and IL-18 responsiveness is induced by TCR triggering and subsequent IL-12 stimulation respectively. Furthermore, TCR-triggered T cells stimulate antigen-presenting cells (APC) to produce IL-12. Therefore, the present observations suggest that an immune response loop from TCR sensitization to the induction of IL-12/IL-18 responsiveness via IL-12 production operates in tumor-bearing patients, particularly in those with relatively large tumor burdens.