Locoregional immunotherapy of malignant effusion from colorectal cancer using the streptococcal preparation OK-432 plus interleukin-2: induction of autologous tumor-reactive CD4+ Th1 killer lymphocytes.

In total, 16 patients with cytologically proven malignant effusion from colorectal cancer were treated by locoregional administration of the streptococcal preparation OK-432 alone or OK-432 plus the T-cell growth factor interleukin (IL)-2, and the action mechanism of the treatment was studied. A positive clinical response, showing a cytologic disappearance of cancer cells and decrease of effusion, was observed in nine of 11 (82%) patients treated with OK-432 alone and in all five patients treated with OK-432 plus IL-2. Flow cytometric analysis revealed that OK-432 plus IL-2 locally induced acute inflammation-like responses, including serial cellular infiltrations of granulocyte migration within a matter of hours, and activation of macrophages and T lymphocyte involvement within the following days, and that a predominant expansion of CD3+CD4+ lymphocytes (CD: cluster of differentiation) was induced by in vitro stimulation with IL-2 of locoregional cells after the OK-432 administration (OK/IL-2AK cells). The OK/IL-2AK cells produced tumour necrosis factor-alpha and interferon-gamma, but these cells did not produce IL-4 and IL-6. The OK/IL-2AK cells expressed potent killing activity against autologous tumour cells. This activity was abrogated by treatment of the lymphocytes with anti-CD3, -CD4, -TCRalphabeta antibody, and by the treatment of target cells with anti-human leukocyte antigen (HLA)-DR antibody. The OK/IL-2AK cells expressed Fas-L gene, and flow cytometric analysis demonstrated HLA-DR expression in approximately 75% of CEA+ or cytokeratin+ effusion cells. TCRVbeta gene analysis of the OK/IL-2AK cells showed an oligoclonal usage of TCRbeta20, which was also involved in the cytotoxic mechanism of the OK/IL-2AK cells. Single-strand conformational polymorphism analysis demonstrated the clonotypes for the TCRVbeta20 gene, and the CDR3s of the gene were sequenced. The clonotypic PCR using the TCRVbeta20-CDR3 sequences could detect the CDR3-identical TCRs in effusion lymphocytes from the other patients. Taken together, it is suggested that locoregional administration of OK-432 plus IL-2 is highly effective for the management of malignant effusion from colorectal cancer. OK-432 plus IL-2 induces autologous tumour-reactive CD4+ Th1 killer lymphocytes, which recognise tumour antigen(s) presented with HLA class II molecules on effusion tumour cells by means of preferential usage of TCRVbeta20. The clonotypic PCR using the TCRVbeta20-CDR3 sequences may be informative for treating malignant effusion from colorectal cancer using OK-432 plus IL-2.

Cellular expressions and serum concentrations of Fas ligand and Fas receptor in patients with infectious mononucleosis.

Although lymphocytosis and neutropenia are commonly associated with infectious mononucleosis (IM), the precise mechanisms involved remain unclear. Accumulated evidence has revealed that the apoptosis-mediating system, Fas receptor/Fas ligand (Fas-R/Fas-L), plays an important role in this disease. Recently, lymphocytes, monocytes, and neutrophils have been reported to constitutively express Fas-R, and the Epstein-Barr virus (EBV) has been shown to activate, in addition to B cells, peripheral blood CD8+ T cells, monocytes, and neutrophils. We elucidated cell surface expression and serum concentrations of Fas-R and Fas-L in patients with IM in an effort to more clearly define the role and contribution of apoptosis in this disease. The expression of lymphocyte surface Fas-L and Fas-R was significantly increased in patients with IM (P < .005 and P < .001, respectively), and among lymphocytes, CD4+ or CD8+ populations contained Fas-R+ as well as Fas-R- subpopulations. The constitutive Fas-R expression levels of monocytes and neutrophils were also increased in IM. Moreover, serum levels of both soluble Fas-L and Fas-R were significantly higher in patients with IM than in healthy volunteers (P < .001 and P < .0001, respectively). Positive relationships between the number of peripheral blood CD95+ lymphocytes and white blood cell count, number of lymphocytes, or number of CD4+ or CD8+ lymphocytes were observed. Our results suggest that the Fas-R/Fas-L system might play a role in eliminating EBV-infected or -activated peripheral blood cells by cell-to-cell contact or in an autocrine and/or paracrine fashion in patients with IM.

[Diaminodiphenyl sulfone therapy for refractory idiopathic thrombocytopenic purpura--long-term effectiveness and possible mechanisms].

Eight patients with idiopathic thrombocytopenic purpura (ITP) refractory to corticosteroids were given oral diaminodiphenyl sulfone (DDS) (75 mg to 150 mg/day). Responses to DDS were observed in 5 patients, and their platelet counts significantly increased to more than 10 x 10(4)/microliter. The duration of treatment required to obtain platelet counts of more than 10 x 10(4)/microliter ranged from 35 to 64 days. In 3 of the 5 responsive patients, platelet counts stabilized at over 10 x 10(4)/microliter during DDS therapy for 3 to 6 years. Although adverse effects including local skin rash and itching were observed in 3 patients, they disappeared after suspension of DDS or in response to medication with antihistamines. Although the exact mechanism by which it increases the platelet counts in ITP patients is still obscure, DDS may inhibit the reticuloendothelial system by excessive red blood cell destruction. We concluded that DDS therapy is well-tolerated and seems to be an effective alternative treatment for patients with ITP that is refractory to other conventional therapies.

Undifferentiated carcinoma with lymphoid infiltration of the esophagus: a case report.

This paper reports a surgically treated case of undifferentiated carcinoma with lymphoid infiltration of the esophagus. Histologically, most of the tumor consisted of undifferentiated carcinoma (non-small cell type) with lymphoid infiltration and a small portion showed features of poorly differentiated squamous cell carcinoma. Carcinoma with lymphoid infiltration in the stomach, breast or nasopharynx has a good prognosis, but in the esophagus this histological type is extremely rare and its characterization is unclear. This is only the sixth report to date of undifferentiated carcinoma with lymphoid infiltration of the esophagus.

[Prevalence of intestinal parasites among Japanese residents in developing countries].

We examined fecal specimens of Japanese residents in developing countries in order to know the prevalence of intestinal parasites in the group. One fecal specimen was collected from each 981 (in 1995) and 1275 (in 1996) Japanese living in Asia, the Middle East, Europe, Africa and Latin America. The specimens were fixed with 10% formalin in each area, and were examined in Japan by concentration method (formalin-ether sedimentation) to find protozoan cysts or helminth eggs. The infection rate of intestinal parasites was 3.0% in 1995 and 2.4% in 1996. The rate was high in Africa (1995: 5.7%, 1996: 4.7%) and Asia (1995: 3.8%, 1996: 3.0%). Regarding to the species of the parasites, Giardia lamblia (17 cases), Trichuris trichiura (14) and Ascaris lumbricoides (11) were detected frequently. Additionally, 7 cases of Heterophyes heterophyes infection were found in Asia and the Middle East. The infection rate was higher in adults than that in children, and a positive relationship between the infection rate and duration of stay was observed. Among the Japanese infected with intestinal parasites, abdominal symptoms such as diarrhea or abdominal pain were common (36.8%). It is also noteworthy that 28.1% of the Japanese infected had a history of gastric diseases such as gastric ulcer. Although the infection rate of intestinal parasites among Japanese residents in developing countries was low, compared to that of the natives in the countries, the rate is still higher than that in Japanese living in the home country. It is necessary to continue preventive measures such as health education in order to eradicate intestinal parasitic infections from this group.