Masaru Udagawa

Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and bacillus calmette-guerin cell wall skeleton stimulation

Purpose: We developed an effective immunotherapy, which could induce antitumor immune responses against shared and unique tumor antigens expressed in autologous tumors. Experimental Design: Intratumoral administration of dendritic cells is one of the individualized immunotherapies; however, the antitumor activity is relatively weak. In this study, we attempted to enhance the antitumor efficacy of the i.t. dendritic cell administration by combining dendritic cells stimulated with Bacillus Calmette-Guerin cell wall skeleton (BCG-CWS) additionally with cryoablative pretreatment of tumors and analyzed the therapeutic mechanisms. Results: These two modifications (cryoablation of tumors and BCG-CWS stimulation of dendritic cells) significantly increases the antitumor effect on both the treated tumor and the untreated tumor, which was distant at the opposite side, in a bilateral s.c. murine CT26 colon cancer model. Further analysis of the augmented antitumor effects revealed that the cryoablative pretreatment enhances the uptake of tumor antigens by the introduced dendritic cells, resulting in the induction of tumor-specific CD8+ T cells responsible for the in vivo tumor regression of both treated and remote untreated tumors. This novel combination i.t. dendritic cell immunotherapy was effective against well-established large tumors. The antitumor efficacy was further enhanced by depletion of CD4+CD25+FoxP3+ regulatory T cells. Conclusions: This novel dendritic cell immunotherapy with i.t. administration of BCG-CWS–treated dendritic cells following tumor cryoablation could be used for the therapy of cancer patients with multiple metastases.

Effect of Tumor Deposits on Overall Survival in Colorectal Cancer Patients with Regional Lymph Node Metastases

Objectives: The staging system of the International Union Against Cancer considers tumor deposits to be N1c in patients with no regional lymph node metastasis, but the significance of tumor deposits in patients with regional lymph node metastases is unclear. We investigated the effect of tumor deposits on overall survival in colorectal cancer patients with regional lymph node metastases. Patients and Methods: From 2000 to 2008, 551 patients underwent resections for colorectal cancer at our medical center. We excluded 87 patients who had distant metastases or had received neoadjuvant chemotherapy or radiotherapy from our study and statistically analyzed the remaining 464 patients. Results: Stepwise multivariate Cox proportional hazards analysis in patients with regional lymph node metastases showed only tumor deposits to be significant for overall survival (hazard ratio: 2.813; P = 0.0002). Recurrence was seen in 49.2% of patients with tumor deposits (30/61) compared with 14.4% of patients without them (58/403; P < 0.0001). Tumor deposits did not show the same effect on overall survival as lymph node metastases. Conclusions: Tumor deposits were significantly associated with poorer overall survival in colorectal cancer patients with regional lymph node metastases. The effect of tumor deposits on overall survival was between that of lymph node metastasis and distant metastasis.

Intratumoral injection of BCG-CWS-pretreated dendritic cells following tumor cryoablation.

Intratumoral administration of dendritic cells (DC) following cryoablation of tumor is one of the personalized cancer immunotherapies which is able to induce immune responses to multiple endogenous tumor antigens, including shared and unique antigens. Here we describe protocols of cryoablation of tumors, generation of cultured DC, pretreatment of DC with a Toll-like receptor (TLR)-stimulating purified component of Bacillus Calmette-Guerin cell wall fraction (BCG-CWS) and highly immunogenic keyhole limpet hemocyanin (KLH) antigen, and combined use of tumor cryoablation and intratumoral administration of BCG-CWS-pretreated DC in both a murine model and cancer patients.

Surgical Therapy for Colorectal Cancer Invading the Muscularis Propria.

大腸mp癌治療法選択の指標を明らかにすべくmp癌手術症例58例を対象に浸潤度細分類 (mp1～3), sm癌との比較, 占居部位, 原癌死症例, リンパ節転移症例の検討を行い以下の結果を得た.(1) mp1で腫瘤型が多くmp2, 3で限局潰瘍型が多かった.(2) sm癌と比較するとmp癌はリンパ管侵襲が高度であったが, sm高度浸潤例とmp1の比較では差を認めなかった.(3) 結腸に比べ直腸で限局潰瘍型が多く, 静脈侵襲も高度で, 5年生存率も不良であった.(4) 原癌死7症例はmp2, mp3の直腸癌で, 非原癌死例に比べ腫瘍径が有意に大きかった.(5) 直腸mp癌のリンパ節転移を34例中7例に認めた. 転移例は全例Ra以下で, mp2の1例に側方転移を認めた. 以上より, mp1はsm癌に準じたD2郭清を基本とした手術, mp2, mp3は適宜D3郭清を追加し, 特にRa以下のmp2, mp3はss (a1) 以深の進行癌と同様の対処が必要であると考えられた.