Kazuo Arii

In vitro augmentation of the cytotoxic activity of peripheral blood mononuclear cells and tumor-infiltrating lymphocytes by famotidine in cancer patients.

We investigated the in vitro effects of famotidine on the cytotoxic activity of peripheral blood mononuclear cells (PBMC) and tumor-infiltrating lymphocytes (TILs). The cytotoxic activity of PBMC was augmented by famotidine at a concentration of 10 ng/ml, which is equivalent to the serum level achieved by the intravenous administration of a dose of 20 mg. This response to famotidine was seen only in cancer patients. Both the cytotoxic activity and DNA synthesis of activated TILs were increased by the combination of interleukin-2 and 1 microgram/ml of famotidine. Augmentation of cytotoxic activity by famotidine occurred independently of any decrease in the population of suppressor T-cells. Thus, famotidine may have the potential to be used in adoptive immunotherapy with TILs for cancer patients.

P-glycoprotein-expressing tumor cells are resistance to anticancer drugs in human gastrointestinal cancer

The resistance to doxorubicin (DOX) by some tumor cells is mainly due to the effect of P-glycoprotein encoded by the multidrug resistance-1 (mdr1) gene. We tried to prove the correlations between P-glycoprotein expression and the sensitivity for anticancer drugs including DOX and other cytotoxic drugs that are currently used for gastrointestinal cancer patients. We quantified the P-glycoprotein expression by flow cytometry techniques, and the sensitivity for anticancer drugs using a tetrazolium salt, 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), assay in highly purified fresh human tumor cells obtained from 25 cancer patients. The inhibition rates were the lowest in DOX and mitomycin C (MMC), compared with other drugs. The most significant correlation between DOX and MMC was seen in the inhibition rates. A significant correlation was also seen between the inhibition rates for DOX and P-glycoprotein expression, whereas only a slight correlation between the sensitivity for MMC and P-glycoprotein expression was observed. We should therefore pay close attention to the effect of P-glycoprotein when treating cancer patients, especially if both the inhibition rates of DOX and MMC are low based on the findings of an MTT assay.

The promotive effect of interleukin 4 with interleukin 2 in the proliferation of tumor-infiltrating lymphocytes from patients with malignant tumor

In adoptive immunotherapy, the number of effector cells is one of the major factors relating to the therapeutic efficacy. We demonstrated that tumor-infiltrating lymphocytes (TILs) were stimulated to proliferate by incubation with interleukin 2 (IL-2) plus interleukin 4 (IL-4). TILs cultured with IL-2 plus IL-4 increased 3.1-fold more than TILs cultured with IL-2 alone. However, IL-4 did not alter the cytotoxic activity of TILs against autologous tumor cells and established tumor cell lines. It is suggested that IL-2 receptor is related to the mechanism of the proliferation of activated TILs cultured by combination with IL-2 and IL-4. Thus, the combination of IL-2 and IL-4 may increase the efficacy of adoptive immunotherapy using activated TILs.

Adenocarcinoma Arising From Heterotopic Pancreas in the Duodenum

We present a rare case of adenocarcinoma arising from a heterotopic pancreas in the duodenum, and review the associated literature. A 62-year-old woman was admitted to our hospital, complaining of vomiting and epigastralgia. Imaging studies revealed advanced gastric cancer with a gastric outlet obstruction. Whipples operation and resection of the regional lymph node were performed because of a direct invasion to the pancreas. Histopathologic examination of the resected specimen demonstrated the malignant transformation of a hetrotopic pancreas in the duodenum. At the 12-month follow-up, there was no recurrence of symptoms. The prognosis of adenocarcinoma arising from a heterotopic pancreas is not known. Further accumulation of cases and investigation of this entity are necessary.

Modulation of multidrug resistance by cepharanthine in fresh human gastrointestinal tumor cells

Resistance to doxorubicin (DOX) is mainly due to the effect of P-glycoprotein encoded by the multidrug resistance (MDR) gene. Cepharanthine (CEP) has been shown to circumvent multidrug resistance in P-glycoprotein-expressing cell lines. In the present study, we investigated the augmentation of DOX sensitivity by CEP using an MTT assay, and assessed the correlation between DOX sensitivity and P-glycoprotein expression by flow cytometry, in highly purified fresh human tumor cells obtained from 73 cancer patients. DOX sensitivity was decreased in proportion to P-glycoprotein expression. The cytotoxicity of DOX was increased by CEP in tumor cells possessing low DOX sensitivity. Moreover, there was a significant correlation between the effect of CEP on cytotoxicity and P-glycoprotein expression. Thus, CEP might be able to circumvent DOX resistance in cancer patients.

Clonal and functional analysis for the augmentation of tumour-infiltrating lymphocytes by interleukin 4.

In the adoptive immunotherapy for cancer, the amounts of induced effector cells play a major role in improving therapeutic efficacy. We have already demonstrated that interleukin 4 (IL-4) augments proliferation of tumour-infiltrating lymphocytes (TILs) without altering the cytotoxic activity against autologous tumour cells. The present study is designed to investigate how IL-4 augments TILs by using established TIL clones in terms of IL-2/IL-2 receptor system. CD4+, CD8+ and CD4+ CD8+ (double positive) TIL clones were established from cancer patients. At clonal level, IL-4 augmented the proliferation of IL-2-activated TIL clones irrespective of phenotypes. In order to clarify the mechanism of IL-4 at clonal level, the blocking assay by anti-IL-2 receptor alpha and beta chain and binding assay of IL-2 on the cell surface and the measurement of the internalisation of IL-2 in the cell were performed. It was clarified that IL-4 up-regulated the IL-2 receptor and then augmented the action of IL-2 molecule on the cell surface stimulated by IL-4. Furthermore, binding IL-2 internalised rapidly into the cells. Thus, it is suggested that signal transduction is augmented and proliferation of TILs is enhanced by IL-4 via the action of IL-2/IL-2 receptor system.

A rare case of xanthogranuloma of the stomach masquerading as an advanced stage tumor

BackgroundXanthogranuloma of the stomach is an extremely rare disease, and this lesion has only been found to coexist with early gastric cancer in 2 cases in the literature.Case presentationWe report a case of xanthogranuloma of the stomach combined with early gastric cancer that mimicked an advanced stage tumor. A 65-year-old female was referred to our hospital because of epigastralgia. During a physical examination, a defined abdominal mass was palpable in the region of the left hypochondrium. Imaging studies revealed an advanced gastric cancer, which was suspected of having infiltrated the abdominal wall. Total gastrectomy and resection of the regional lymph node and abdominal wall were performed. Histopathologic examination of the resected specimen demonstrated xanthogranuloma combined with early gastric cancer.ConclusionXanthogranuloma presenting as a form of SMT (submucosal tumor) of the stomach is an extremely rare disease, and diagnosing it preoperatively is difficult. Further accumulation and investigation of this entity is necessary.

Clinical significance of quantitative analysis of carcinoembryonic antigen assessed by flow cytometry in fresh human gastric cancer cells

The expression of carcinoembryonic antigen(CEA) on tumor cells freshly excised from 51 patients with gastric cancer was studied using flow cytometry. The expression of CEA by flow cytometry was more quantitative than that by immunohistochemical staining. There was no relationship between the fluorescence intensity assessed by flow cytometry and serum CEA levels, except for patients with a high titer of serum CEA. The patients with high grade CEA expression on tumor cells by flow cytometry had poor prognoses, compared to patients with low CEA expression in undifferentiated gastric cancer. Thus, it is suggested that the quantitative CEA expression on tumor cells by flow cytometry could be a useful prognostic marker in postoperative gastric cancer patients.

Enhancement of tumor cell susceptibility to tumor-infiltrating lymphocytes by cisplatin

Some means of enhancing the susceptibility of tumor cells to tumor-infiltrating lymphocytes (TIL) are required in adoptive immunotherapy. This study was designed to investigate whether or not tumor cell lysis by TIL was enhanced by treatment of the tumor cells with cisplatin, and also to clarify the mechanism of cisplatins action on tumor cells. Autologous tumor cells and established cancer cell lines, including KATO-III and MKN-28, were used. Cytotoxic activities of TIL, the surface antigens of tumor cells, conjugation of TIL and tumor cells, and the production of TNFα from TIL were analyzed. Tumor cells treated with 2 μg/ml cisplatin for 12 h in vitro were more susceptible to bulk-cultured TIL and TIL clones. The surface antigens of tumor cells were not altered by the treatment with cisplatin. Cisplatin-treated tumor cells showed a higher binding ratio to TIL than did non-treated tumor cells. The anti-(tumor necrosis factor) (anti-TNF) or anti-TNF receptor antibody blocked the enhancement of cytotoxic activity by cisplatin. Thus, it was clarified that cisplatin enhanced the susceptibility of tumor cells to bulk-cultured TIL and TIL clones. Furthermore, the enhancement of cytotoxic activity by TIL in cisplatin-treated tumor cells was caused by a higher binding ratio to TIL and higher susceptibility to the TNF produced by TIL.

Radiation-Induced Rectal Cancer Originating from a Rectocutaneous Fistula: Report of a Case

This report describes a patient with radiation-induced rectal cancer with an unusual history. A 51-year-old man was admitted in 2000 because of ichorrhea of the skin on the left loin. The patient had received irradiation for a suspicious diagnosis of a malignant tumor in the pelvic cavity in 1975. A subcutaneous abscess in the right loin appeared in 1989, and rectocutaneous fistula was noted in 1992. Moreover, radiation-induced rectal cancer developed in 2000. Plain computed tomography and magnetic resonance imaging of the pelvis demonstrated a presacral mass and tumor in the rectum. Finally, we diagnosed the presacral mass to be an abscess attached to the center of the rectal cancer. The rectum was resected by Miles’ operation and a colostomy of the sigmoid colon was also performed. Many cases of radiation-induced rectal cancer have been reported. However, this is a rare case of radiation-induced rectal cancer originating from a presacral abscess and rectocutaneous fistula.