Cancer is often a systemic disease and cancer cells can be disseminated during surgery, so we have to keep in mind the possibility of residual tumor cells even after curative resection. Cancer surgery also induces high levels of various proinflammatory cytokines and their induction is proportional to the extent of surgery. Cytokines stimulate the growth, invasion, and metastasis of cancer cells, either directly or via the induction of adhesion molecules and angiogenesis factors.
Therefore, we have to avoid dissemination of cancer cells during surgery and perform less invasive surgery to avoid excessive cytokine release. When cancer is diagnosed as a systemic disease, postoperative adjuvant chemotherapy is needed. Recent advances in molecular biology have made it easy to determine the presence or absence of cancer cells in blood, lymph nodes, and bone marrow. These methods can also be used to avoid unnecessary adjuvant chemotherapy, reducing the risk of side effects.

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Protons can be produced by depriving hydrogen atoms of electrons. When accelerated to a high energy level in an accelelator, protons form an ionized beam with strong penetration power. Unlike the conventional radiation beam, the proton beam has a unique dose distribution. It has a peak area (Bragg-peak) in which rapidly increasing doses are deposited at the end of the beam range defined by the particular beam energy. Therefore, proton therapy has an advantage in that a large dose of radiation can be focused only on the target, with a very limited irradiation of surrounding nontumor tissues. Thus the proton can be used to irradiate cancer while selectively avoiding normal tissues. Therefore, proton therapy is one of the modes of external radiation therapy having a potential almost equivalent to that of surgery in terms of local cure of the lesion.
We previously reported that a large dose of proton irradiation can be safely given to patients with hepatocellular carcinoma (HCC) complicated with liver cirrhosis. The aim of this report is to show the efficacy of proton radiotherapy for tracing HCC and to clarify the long-term effects and QOL of this new therapy.
Proton irradiation was administered to 114 lesions consisting of single or multinodular tumors in 117 patients who were considered either surgically inoperable or medically untreatable. Moreover, the proton-treated 62 of 117 patients with 91 HCC lesions were compared with 42 patients with 65 lesions treated with Lipiodol(R)-targeted chemotherapy (1-TAI) alone during the same period of time, as a control. For the proton therapy only (Monotherapy group), which consisted of 53 lesions in 35 patients, 1-TAI was not given because of advanced preexisting liver cirrhosis, chronic renal failure, or myelodysplastic syndrome. On the other hand, proton therapy combined with 1-TAI which resulted in insufficient accumulation of Lipiodol(R) into the tumors (Combination therapy group), which consisted of 27 patients with 38 lesions, received proton therapy in addition to 1-TAI. Total dose of 75Gy in average was given.
Cumulative local tumor control rates were 98.1% for the 1st year, 90.9% for the 3rd year, and 88.1% at 3 years after the completion of irradiation. The overall survival rates were: 48.1% for 3 years and, 37.1% for 5 years. In regard to liver function: the Child-Pugh, Child Pugh A and chronic hepatitis groups had significantly higher survival rates than the Child B and C groups. The Child A and chronic hepatitis groups showed especially have an excellent survival rates such as; 60% for 5 yrs. The cumulative local tumor control rate was significantly higher in the proton groups (Mono and Combination) than in the 1-TAI group. The follow-up survival rate in the proton groups was also significantly higher than that in the 1-TAI group. No patients died of the adverse effects of proton therapy. Excellent quality of life (QOL) was maintained in all the patients treated with proton therapy during the treatment periods.
In conclusion, proton therapy is safe and effective, and that it has the special merit of allowing an excellent QOL without any associated complaints throughout the treatment period.

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We investigated whether lung cancer-associated macrophages present tumor antigens to regional lymph node lymphocytes (RLNL), which have been proved to include tumor-reactive T cells. The proliferative response of RLNL to stimulation with tumor-associated macrophages (TAM) was examined by the mixed lymphocyte-macrophage response (MLMR) in 35 patients with primary lung cancer, and alveolar macrophages from normal lung (LM) and peripheral blood monocytes (PBM) were used as controls. The mean stimulation index in response to TMA was higher than that elicited by PBM (11.2 vs. 3.2, p<0.05). In 15 patients additionally tested for RLNL response to autologous tumor cells (mixed lymphocyte-tumor cell reaction (MLTR)), the MLMR to TAM correlated well with the MLTR (p<0.05). The response to these macrophages (RLMR) always involved CD4⁺ lymphocytes, and was largely abolished by anti-HLA class II antibody. RLNL also frequently responded to autologous macrophages from normal lung (mean stimulation index, 9.0), but the MLMR to LM did not correlate with the MLTR. These results suggest that regional lymph nodes draining lung cancer contain CD4⁺ T cells, which react with tumor-related antigens in the context of m ajor histocompatibility complex class II. In addition, lung cancer-associated macrophages may present tumor-specific antigen to primed CD4⁺ T cells.

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Clinico-pathological factors of long-surviving (more than 3 years) lung cancer patients who did not undergo resection (n=13) were compared with those of patients with resections. The latter group was comprised of short-survival (less than 3 years) (n=11) cases of pathological stagelA (T1N0M0) carcinomas. The average survival time of the long-surviving group was 51.8 months and that of the short-surviving group was 21.5 months. Chemotherapy was the most frequently used treatment (7/13, 53.8%) in the first group, in which CDDP was combined with radiotherapy. Pathological examinations from the group with resected stage lA primary tumors revealed microscopic blood vessel invasion in 6/11 cases (54.5%) and lymphatic vessel invasion in 2/11 cases (18.2%). The first relapse sites in this group were usually distant metastases. There were more females, and patients older than 75 years in the long-surviving group, and we also observed a greater number of squamous cell carcinomas in the first group (χ²-test, p<0.05). We therefore conclude that certain factors might relate to better prognosis, namely, being female and of a more advanced age, as well as the presence of squamous cell carcinoma in particular. Furthermoer, microscopic blood vessel invasion is one of the risk factors for distant metastases resulting in premature death following surgery.

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The immunoreactivity for bcl-2 and p53 oncoproteins was determined in 54 normal mucosa, 28 adenomas, and 43 adenocarcinoma of the large intestine. The percentage of positive immunoreactivity for bcl-2 oncoprotein was significantly higher in adenomas than in normal mucosa or adenocarcinoma (p<0.0001) while there was no difference in the percentage of positive immunoreactivity for bcl-2 oncoprotein between normal mucosa and adenocarcinoma. The percentage of positive immunoreactivity for p53 oncoprotein was significantly higher in adenocarcinoma than in normal mucosa or adenoma (p<0.0001) and the percentage of positive reactivity for p53 oncoprotein was significantly higher in adenoma than in normal mucosa (p<0.005). There was a significant inverse correlation between the rate of positive expression of bcl-2 and p53 colorectal adenocarcinoma (p<0.05).
There was no correlation between bcl-2 immunoreactivity and clinicopathologic variables of colorectal neoplasm. Positive immunoreactivity for p53 was associated with smaller tumor size (p<0.01) and higher grade of dysplasia (p<0.05) of adenoma but the immunoreactivity for p53 oncoprotein did not correlate with any one of clinicopathologic features of adenocarcinoma.
These findings suggest (1) bcl-2 oncoprotein may play a certain role in the early phases of colorectal tumorigenesis, (2) p53 oncoprotein plays an important role in malignant transformation of colorectal adenomas into adenocarcinoma but is not implicated in the process of invasion or metastasis, and (3) p53 oncoprotein may down-regulate expression of bcl-2 oncoprotein.

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The association between metaplastic changes seen in gallbladder cancer on the one hand and the appearance of endocrine cells, lysozyme and lactoferrin on the other was studied using serial sections of 50 cases of gallbladder cancer (9/50, early stage). The sections were examined histologically and immunohistochemically for the purpose of elucidating the histogenesis of gallbladder cancer. Gastrin-secreting, somatostatin-secreting and serotonin-secreting cells in cancer lesions were observed in each of 14 cases (28%), 10 cases (20%) and 15 cases (30%) and those in the non-cancerous mucosa each in 19 cases (38%), 16 cases (32%) and 19 cases (38%). Motilin-secreting cells were not observed in cancer lesions and were observed in only 2 cases (4%) in non-cancerous mucosa. The immunohistochemical activity of lysozyme and lactoferrin were observed in 29 cases (58%) and 6 cases (12%), respectively, in the cancer lesions and in 29 cases (58%) and 4 cases (8%), respectively, in the non-cancerous mucosa. No difference in the appearance rate of metaplastic cells was noticed between advanced and early gallbladder cancer. Metaplastic changes of endocrine cells and lysozyme are closely related to the development of gallbladder cancer. It is therefore possible that the intestinal metaplasia of gallbladder mucosa is an important lesion as regards carcinogenesis.

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Using a hand-held gene gun which accelerates DNA-coated microparticles, we examined the effect of interleukin-12 (IL-12) and/or tumor necrosis factor-α (TNF-α) gene transfection a rat solid tumor model. Yoshida sarcoma cells were inoculated subcutaneously into the chests of Donryu rats. Then 4μg of IL-12 and/or TNF-α DNA-coated gold (Au) particles was injected into the tumor by pressurized helium (He) gas at 400psi (1psi=6, 890Pa) on day 5 and 7 after tumor inoculation. The corresponding dose of β-galactosidase was given as a control. Compared with the control, injection of TNF-α, IL-12, and IL-12 plus TNF-α effectively inhibited tumor growth and improved the survival rate. TNF-α alone prolonged the survival of tumor-bearing rats, but the animals still died within 41 days after tumor injection, On the other hand, IL-12 alone and IL-12 plus TNF-α completely cured 20% and 40% of the rats, respectively. IL-12 plus TNF-α gene therapy using the gene gun showed a synergetic effect on the survival of tumor-bearing rats. This procedure might useful for the clinical treatment of solid cancer. In particular, there is a possibility of intraoperative gene transfection because the gene gun can introduce multiple genes very rapidly.

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To determine whether preoperative levels of carcinoembryonic antigen (CEA) and acute-phase reactants (APR), such as immunosuppressive acidic protein (IAP), α 1-antichymotrypsin (ACT), acid-soluble glycoproteins (ASP), and sialic acid, before immunotherapy using protein-bound polysaccharide K (PSK) can predict the clinical outcome in patients with gastric cancer. Seven hundred and twelve patients were enrolled in the study from February 1987 to November 1989 at 16 institutions throughout Japan. All patients were followed over a period of 5 years. Among the 712 patients, 694 (97.5%) eligible patients with biopsy-proven gastric adenocarcinoma underwent gastrectomy and were randomly assigned to receive supportive therapy as follows: gastrectomy alone, gastrectomy plus PSK, gastrectomy plus chemotherapy (CT), and gastrectomy+CT+PSK. The 5-year follow up rate was 94.5%. There was a significant difference in survival between patients receiving gastrectomy with or without PSK who showed abnormal serum levels of CEA (log-rank test, P=0.0175), and both CEA and APR (log-rank test, P=0.0431), and between those receiving PSK and not receiving PSK in those with parameter point 3 (log-rank test, P=0.0404). These results indicate that PSK therapy has a beneficial effect in gastric cancer patients with high levels of CEA and APR.

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