Recently, various types of multidimensional data analysis have been applied. Quantification method III or correspondence analysis is a kind of multidimensional data analysis which is used to explore the data structure in cases where the type of data is qualitative, i. e., the data are expressed in categorical forms. This theory was originally published thirty five years ago and became popular with the development of the computer. At present this method is frequently used in various fields including natural and human-social sciences because it is useful for the exploration of reality through the data structure revealed by this method.
We have investigated whether HLA and its related genes such as the TNF gene act as predictive, prognostic factors or as indicators of bioresponse modification of the response to postoperative adjuvant therapy for the risk of lymph node metastasis in gastric and lung cancer patients. We found 3 interesting observations as follows from our own studies with the HLA serological test and TNF-DNA-PCR-RFLP method. (1) The 5-year survival rates for patients with HLA-B40 antigen who received chemotherapy plus PSK after gastrectomy and those with HLA B51 antigen who received chemotherapy alone after gastrectomy were 100% in both groups, whereas patients without HLA-B40 and patients with HLA-B51 who received chemotherapy plus PSK after gastrectomy had survival rates of 67.3% and 37.7%, respectively (P<0.05 and P<0.05 in log-rank test). (2) The HLA-B40 and HLA-Cw3 antigens were associated with a decreased risk of lymph node involvement, whereas HLA-A24 was associated with an increased risk of lymph node involvement in Japanese gastric cancer patients. (3) TNF B 10.5/10.5 gene may be a resistant factor for oncogenesis of lung cancer and may function as a prognostic factor. The mechanisms of the abovementioned observations are still not clear. There have been many studies concerning MHC and disease susceptibility in human and mice, but few studies on the positive association between HLA and/or HLA related gene and disease prognosis and treatment have recently been reported38-42). Other immunological factors such as, TCR, HLA restriction and cytokine production should be investigated in future studies. It is recognized and accepted that the TNM classification proposed by the International Union Against Cancer in 1987 is an important observation of prognosis and treatment in oncology. However, the TNM classification is directed to the tumor itself but not to the host. Therefore we would like to propose further establishment of additional factors in the TNM classification43) such as TNMH. H factor, which means host factors, may consist of these factors; 1) HLA typing, 2) HLA related genes, such as TNF B gene, 3) immunological responses and 4) others. In this chapter review including our preliminary studies, we presented 1) HLA update, 2) TNF B in lung cancer, 3) HLA in gastric cancer and finally propose a new concept, i. e., TNMH instead of TNM in future preventive oncology. ACKNOWLEDGMENT We thank Mr. K. Sato for HLA serology typing and Dr. F. KATO and Y. Hayata for providing blood samples from lung cancer patients in Tokyo Medical College. These studies were supported, in part, by a grant from the Smoking Research Foundation and by a Grant-in-Aid for Cancer Research (04-29) from the Ministry of Health and Welfare, Japan.
Protective effect of intraperitoneal (i. p.) injection of recombinant human granulocyte colony stimulating-factor (rhG-CSF) in combination with protein-bound polysaccharide (PSK) against Pseudomonas aeruginosa (E-2) was studied in cyclophosphamide (CPA)-induced neutropenic tumor-bearing mice. Meth A tumor (1×106) was inoculated subcutaneously (s. c.) ten days before infection, and CPA (200mg/kg) was i. p. injected four days before infection and G-CSF (500μg/kg) was i. p. injected daily for four days before or after infection. PSK (500mg/kg) was orally administered daily for four days before infection or from the day of infection. Pseudomonas of 2.0×105 colony forming unit (cfu) was inoculated intravenously (i. v.) for the analysis of prophylactic effect of G-CSF, 2.0×104 cfu was inoculated i. v. for that of therapeutic effect, and the number of viable bacteria in liver was counted serially after infection. After infection with 2.0×105 cfu, all CPA-induced neutropenic mice without G-CSF died by two days after infection, however, 50% of G-CSF pretreated mice survived. Moreover, mice pretreated with G-CSF in combination with PSK showed significant suppression of bacterial growth in the liver compared with mice treated with G-CSF alone, and all survived. After infection with 2.0×104 cfu, mice post-treated with G-CSF in combination with PSK showed a prominent anti-pseudomonas effect with 70% survival and suppression of bacterial growth in the liver, in contrast to untreated controls which all died by 2 days after infection or mice treated only with G-CSF with 20% survival. For the analysis of the anti-pseudomonas mechanism, phagocytic activity and 2', 7'-dichlorofluorescin (DCFH) oxidative activity, and Mac-1 positive neutrophils were measured. Both phagocytic and DCFH oxidative activities were allebiated to normal level by G-CSF or in combination with PSK, however, deferoxamine mesylate (DFM) treatment inhibited the improvement of DCFH oxidative activity. The percentage of Mac-1 positive neutrophils was alleviated to normal level by these treatments. In conclusion, both a prophylactic and a therapeutic use of G-CSF greatly enhanced the host anti-pseudomonas activity in combination with PSK in CPA-induced neutropenic tumor-bearing mice, and it was suggested that the ferric ion would greatly contribute to this mechanism.
As the enhanced expression of c-myc protooncogene is specifically associated with human colon cancers and adenomas, this gene may be involved in cancer development in the human colon. The two-stage chemical carcinogenesis model in rats provides a pertinent system to test this hypothesis. Rat colon tumors were produced by 14 daily intrarectal instillations of carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 17μmol), followed by 30 weekly instillations of tumor promoter deoxycholate (12μmol). Tumor incidence was 88% in the 8 rats killed at 33 and 43 weeks. Northern blots of RNAs from the tumors revealed that the levels of c-myc mRNA were 1.8 to 8.4 (mean, 4.2) fold higher than those in the adjacent tissues (15 out of 15 tumors), whereas the amount of c-fos, H-ras, and ornithine decarboxylase mRNAs did not significantly increase in any tumor. The results are in good agreement with those in human colon cancers in that the enhanced expression of c-myc is strongly associated with colon tumors. A single intrarectal instillation of either MNNG or deoxycholate led to a 5-fold increase in the c-myc mRNA level at 3 to 4 hours in the rat colon tissue, the basal level was reverted 6 to 8 hours later. The effect of deoxycholate was dose dependent; the maximum effect noted at 12 to 48μmol. The same effect was not observed in rat stomach tissue, thereby indicating that enhancement of the c-myc expression by this agent was tissue-specific. It is tempting to speculate that, after repeated stimuli with these agents, some colon cells become capable of expressing c-myc, without exogenous stimulation, hence, acquire the potential to grow tumors.
Recently many studies have indicated that allogenic blood transfusion can cause immunosuppression and have adverse effects on survival for malignant tumors. Therefore we undertook a retrospective study to determine if such perioperative blood transfusion adversely affects survival rates in patients with carcinoma of the stomach. An overall comparison of transfused (n=145) versus non-transfused (n=102) patients by the log-rank and the generalized Wilcoxon analysis revealed a statistically significant adverse effect of blood transfusion on survival (p=0.0040, p=0.0014, respectively). However, in contrast, the Cox proportional hazard regression analysis, adjusted for other prognostic variables, showed that blood transfusion was no longer prognosticly significant. According to further detailed investigations, this transfusion effect was not evident in the patients with stage I cancer, but in contrast to patients with stage I cancer, survival rates for stages 2, 3, 4 not given transfusions were significantly higher than those for patients receiving transfusions (p=0.0177, p=0.0057). When we applied the Cox analysis to patients with stage 2, 3, 4 cancers, perioperative transfusion became a sensitive prognostic indicator of cancer death (risk ratio of 2.182 for death). Consequently, we concluded that blood transfusions may affect survival rates in the advanced stages of gastric cancer, but not in the early stage.
One hundred seventy-seven gastric cancer patients who underwent total or proximal gastrectomy were examined for serum immunosuppressive acidic protein (IAP), which is an acute phase reactant protein and has immunosuppressive competence in serum. We evaluated whether IAP is a predictive marker for indication of splenectomy and postoperative immunotherapy using a nonspecific immunopotentiator, protein-bound polysaccharide P (PSK). Multivariate analysis utilizing Cox's model was performed with seven variables including age, sex, pTNM stage, postoperative adjuvant therapy, preoperative serum levels of IAP and histopathological grading. In Cox's multivariate regression model, postoperative chemotherapy with or without PSK was the most significant prognostic factor in patients with abnormal levels of IAP, especially in those with splenectomy. These results indicate that if patients with abnormal levels of IAP who had immunosuppressive status induced by the spleen underwent splenectomy, they showed good results with postoperative immunotherapy, and therefore, the preoperative IAP value is a possible indicator for splenectomy and the effectiveness of immunotherapy using PSK.