Primary adenocarcinoma of the appendix is a rare, seldom diagnosed neoplasm, even as incidental finding during appendectomy. Relatively little is known about its pathology and management. It is found in approximately 0.1% of appendectomies, with an incidence rate of 0.2 per 100, 000 people per year. The mean age at presentation is around 60 years old and males are affected 1.5 times more frequently than females. It presents as either a colonic type tumor, which is poorly differentiated and more aggressive, or as a mucinous type, which may show abundant extra-cellular mucin and is well differentiated. Clinically, it usually presents as acute appendicitis or as an abdominal mass. It is often associated with other synchronous malignancies, such as colonic or ovarian lesions, as well as a higher incidence of metachronous tumors, creating a need for lifelong follow-up after treatment. Right hemicolectomy is the preferred treatment for both colonic and mucinous type lesions. Some studies still suggest that an appendectomy is sufficient if the tumor is confined to the mucosa or if no residual tumor is found in the colon in the mucinous type. However, the high rate of perforations argues against this approach. For the mucinous type of cancer, bilateral oophorectomy, especially if the patient is post-menopausal, is sometimes advised. Post-operative chemotherapy, with or without radiotherapy, may improve the morbidity and mortality rates of pseudomyxoma peritonei. The prognosis, as in colonic tumors, is defined by stage and histology. The overall 5-year survival rates are 71% for the mucinous type and 41% for the colonic type, and 100%, 67%, 50%, and 6% for stages A, B, C, and D, respectively, or 68%, 51%, and 7% for grades I, II, and III respectively.
In patients with cancer, the number of circulatory lymphocytes decrease and the in vitro proliferative response is impaired. The hypothesis has been advanced that both the degree of lymphocytopenia and recovery times are individually well correlated with the magnitude of surgical damage. We retrospectively studied whether the changing pattern of circulatory lymphocytes in patients with breast cancer differs peri-operatively between the lymph node-positive and node-negative groups. We re-emphasized in the present report that the number of circulatory lymphocytes is a simple and useful prognostic parameter after surgical intervention. Eighty-nine female patients who underwent modified radical mastectomy with lymph node dissection (Kodema's method) at Omiya Medical Center, Jichi Medical School, from 1991 to 1995 were retrospectively studied to compare the changing pattern of the peri-operative number of circulatory lymphocytes. Thirty-one patients with lymph node-positive (n=31), and fifty-eight were lymph node-negative (n=58). The survival rates of these patients were confirmed during 1998. There are no statistically significant differences in the surgical parameters between the two groups. Recovery from lymphocytopenia was notably longer in the lymph node-positive patients on post-operative days one and seven. However, in both patient groups, the number of circulatory lymphocytes was markedly reduced immediately post-operatively but returned to the pre-operative level on post-operative day 14. No significant difference was seen in the changing patterns of peripheral neutrophils and C-reactive protein. These observations suggest that the immune surveillance system of patients with a potentially poor prognosis may be easily disturbed by surgical intervention and may thus result in delayed recovery. The changing pattern of circulatory lymphocytes in patients with breast cancer should be reconsidered as a simple prognostic parameter, especially after surgical intervention.
Using a hand-held gene gun, we examined the effects of murine interleukin-12 IL-12) gene transfection on metastatic tumors. AH 130 cells at high (1×107) and low (1 ×106) doses were inoculated into the liver of Donryu rats through the portal vein. On the twelfth day following tumor inoculation, the hepatic surface was bombarded with IL-12 cDNA (4μg)-coated gold particles emitted by pressurized helium gas (300 psi). The corresponding amount of β-galactosidase (β-gal) cDNA was injected as a control in the same manner. The high-dose model was highly fatal and used for estimation of the survival rate. The low-dose model was investigated to evaluate alterations in the number of tumors, histological findings, and cytokine expression in the liver and spleen. Nontumor-bearing rats were employed for study of any adverse effects gene gun shots induce on body weight, peripheral blood cell counts, and liver function. The IL-12 gene therapy was effective in terms of the 60-day survival rate (IL-12 50% vs. control 15%, p<0.05). Seven days after DNA transfer the average number of metastatic tumors in the liver increased in the control group, while it diminished in the gene therapy group. Histological examination revealed that most tumor cells in the control group were viable, whereas some of those in the IL-12 group underwent necrotic changes accompanied by massive lymphocytic infiltration. IL-12 and IFN-γ were expressed in the liver and spleen in greater amounts in the IL-12 group than in the control. No remarkable adverse effects were expressed in non-tumor-bearing rats undergoing gene bombazdment either with β-gal or IL-12 genes. Thus, this procedure may be applied clinically as a promising therapeutic option for metastatic tumor of the liver. A hand-held gene gun seems especially useful for transfection during laparotomy due to its ability to accurately and instantaneously inject exogenous genes under direct vision.
We reviewed 78 patients with soft tissue sarcomas to evaluate the difference in treatment results and prognosis between two groups: those who underwent a prompt additional wide resection and those who underwent a wide margin procedure after subsequent local recurrence. Twenty-two patients underwent a prompt additional wide resection within three months after a simple excision (Group A), and 26 underwent a wide margin procedure when there was local recurrence following a simple excision (Group B). Group C was a control group consisting of 30 patients with a planned wide resection after pathological diagnosis following biopsy. The five-year disease-free survival rate in group A was 87.3%, 57.4% in group B, and 80.5% in group C. The patients in group A had a significantly higher survival rate than patients in group B. In summary, even if the initial surgery was unplanned, a subsequent prompt additional wide resection is an appropriate salvage procedure for patients who received an inadequate simple excision. Wide resection of tissues in the compartment or region of the tumor according to a detailed plan based on preoperative imaging studies is the conventional surgical management of soft tissue sarcomas. However, unplanned simple excision may be occasionally performed by a surgeon without specific training and experience in the management of these challenging neoplasms. A patient referred by a surgeon who performed a simple excision of soft tissue sarcoma will visit an orthopedic oncologist. In such circumstances, after a definitive pathologic diagnosis of malignancy, either a prompt additional wide resection or observation with the expectation of a wide margin procedure after local recurrence is chosen as a management strategy. However, only two studies have reported on the outcome of an unplanned simple excision of soft tissue sarcomas (Gherlinzoni, Bacci et al., 1986 Giuliano and Eilber, 1985); a comparative study between the two strategies has not previously been reported. This report evaluates the effect of each strategy on prognosis.
The point mutation of K-ras codon 12 in the paraffin-embedded blocks of colorectal cancer from 19 patients was analyzed with a newly developed detection technique, enzyme linked mini-sequence assay (ELMA). The results were compared with those obtained using conventional dot-blot hybridization (DBH) to examine the consistency between these two techniques and the usefulness of the ELMA method. The results of DBH showed that the point mutation of K-ras was present in 12 of 19 patients (63.2%), while ELMA in the first trial showed it in 14 of 19 patients (73.7%). A comparison of the results of DBH with those of ELMA revealed that the presence of the mutation and its arrangement of base patterns agreed in 14 of the 19 patients (73.7%). Then ELMA was repeated for the five patients in whom the results of the two techniques did not agree. It showed that the second ELMA provided the results consistent with those of DBH in four patients, but not in one patient. In three of these four patients, the color intensity of mutation for the first trial of ELMA was (1+). However, the comparison with DBH showed that the results agreed in 90% of the patients judged as (3+) by the first trial of ELMA. The mutations examined by DBH and ELMA and the reproducibility of ELMA agreed in 18 of 19 cases (94.7%) in accordance with the color intensity of 1(+) which should be judged as a negative mutation. We conclude that these results confirmed that ELMA for paraffin-embedded sections was useful in detecting the point mutation of the K-ras gene.
In order to evaluate the influence of Th1-related cytokines on disease progression, the levels of interleukin-12 (IL-12), interferon-gamma (INF-γ) and tumor necrosis factor-alpha (TNF-α), helper T cell (Th) subsets, and natural killer (NK) cells were examined in 337 Japanese patients with histologically confirmed primary adenocarcinomas of the stomach and colorectal and in 172 control subjects. Levels of IL-12, IFN-γ, TNF-α, and Th1 cells were significantly lower in cancer patients than those in the control group. On the other hand, levels of Th2 cells and NK cells were significantly higher in cancer patients than those in the control group. Th1-related cytokines were suppressed even in early-stage patients. Results of the present study suggest that Th1-related immune parameters were suppressed in cancer patients, even in early-stage patients, and that they were useful as immunological markers for detecting groups of patients at high risk for cancer.
Estrogen receptor alpha (ERα) variant proteins lacking the hormone-binding domains translated from their splice variant mRNAs were examined by Western blot analysis of 80 cases of human breast cancer. Wild ERα protein (ERwtP) was expressed in 68 cases (85.0%), and of these cases, 40 (58.8%) co-expressed ERα variant protein corresponding in size to 41kDa (ERd5P). There was a significant correlation between co-expression of ERd5P and the splice variant mRNA lacking exon 5 (ERd5M) examined by reverse transcription-polymerase chain reaction. No protein bands for ERα variant corresponding in size to 52kDa (ERd7P) were observed in spite of the splice variant mRNA lacking exon 7 (ERd7M) being co-expressed with wild-type mRNA. Our results suggest that ERd5P persists and is stable in a large proportion of samples of human breast cancer tissue, whereas ERd7P is not. The functional difference between ERwtP and ERd5P has yet to be established, and its discovery may demonstrate the importance of ERd5P for anti-estrogen resistance in human breast cancer.
Four hundred forty-two patients underwent gastrectomy for carcinoma of the stomach to determine the impact of various gastrectomy procedures on patients' prognosis, and to assess the phenotypes of lymphocytes before and after gastrectomy. During the 3-6 postoperative months, there were significant differences between patients who received total gastrectomy and subtotal gastrectomy as regards the CD4+/CD8+ ratio. The 10-year survival rates of patients who received a subtotal gastrectomy were significantly better than those of patients who underwent total gastrectomy. A Cox multivariate analysis revealed that the extent of resection was a significantly related to independent covariate with patient prognosis.
Micro-satellite instability (MSI) may underlie one of the etiologies in multistep gastric carcinogenesis, which is strongly related with the alteration of DNA mismatch repair genes. There are many reports for this abnormality in sporadic or familial gastric cancer, but only a few in multiple gastric cancer. In order to elucidate the difference between these two groups, we performed the assessment of MSI by 10 micro-satellite markers in 4 multiple and 25 single gastric cancers using fluorescent DNA auto-sequencer. We detected replication errors (RER) in one (25%) of 4 cases of multiple gastric cancer and 2 (8%) of 25 cases of single gastric cancer, which showed no statistical significance between these two groups. Both cases of single cancer were advanced cancers, of which histological types were poorly differentiated adenocarcinoma, and they showed less than 2 positive markers. On the other hand, in the RER positive case of multiple gastric cancer, histological types were well-differentiated adenocarcinoma and early cancers, in which of one lesion indicated that 7 micro-satellite markers were positive. And the other lesion in the same case showed RER negative, which showed that genetic heterogeneity was recognized. For clinicopathological factors according to RER status, no significant differences were observed in age, gender, tumor localization and size, histological type, depth of invasion, lymph node metastasis, venous invasion or pTNM classification. In conclusion, it is suggested that the carcinogenic etiology of these two groups may be different from our results.
We evaluated the pharmacokinetics of anticancer drugs, drug concentration in tissues of the liver and the pancreas, and the hematological changes in aortic stop-flow infusion with hypoxic abdominal perfusion (ASI with HAP) using Beagle dogs under general anesthesia. Concerning the of blood concentrations of both mitomycin C (MMC) and 5-fluorouracil (5-FU), the area under the curve (AUC) with perfusion circuit (PC) in the ASI with HAP group was significantly higher than in the control group. On the contrary, there was no significant difference for AUC in the non-PC as compared with that in the control group. From these results, this method is effective to increase the blood concentration of drugs in target organs. It is suggested that the maximum dose of anticancer drugs in ASI with HAP should not greatly exceed the dose given in systemic administration by rapid intravenous injection. Drug concentrations of both MMC and 5-FU in the ASI with HAP group were significantly higher than those in the control group in the liver and in the pancreas. Concentrations of MMC and 5-FU in hepatic tissue were lower than those in pancreatic tissue, and there was a tendency for the concentration in hepatic tissue to decline more rapidly in comparison of pancreatic tissue. This is ascribed to the fact that the catabolism of both agents occurs mainly in the liver. The measurements of blood gas indicated that a hypoxic condition was maintained only in PC, and PC became lower in pH during perfusion. The results of blood biochemical examinations revealed that the variations in each parameter peaked between 15 and 30 minutes after completion of perfusion and that they all reached a plateau 60 minutes after completion. The increases of hepatic enzymes such as AST, ALT and LDH were ascribed to ischemia due to the aorta stop-flow and to the reperfusion injury of the liver following release of stop-flow. Superoxide dismutase (SOD) exhibited a sharp increase immediately after administration of anticancer drugs, which was ascribed to the influence of MMC administration. However, these biochemical changes in ASI with HAP were believed to be reversible and of short duration.
The succinate dehydrogenase inhibition (SDI) test and human tumor clonogenic assay (HTCA) have some methodological differences. However, the effects that these differences have on cytotoxicity estimates of antineoplastic agents have not been rigorously examined. To re-examine the SDI test, the AUC (area under the concentration-time curve) values producing 50% inhibition of cisplatin (CDDP), carboplatin (CBDCA) and mitomycin C (MMC) in the conventional SDI test, without a drug-free incubation period after drug-exposure; the modified SDI test, with a drug-free incubation period; and the HTCA using a panel of PC-7, PC-9, PC-14 and K562 cells were compared with that of respective AUC in clinical pharmacokinetics. DNA histograms determined by flow cytometry using propidium iodide were estimated for cells during the drug-free incubation. CDDP, CBDCA and MMC were all confirmed to have AUC dependent cytotoxicity. The AUC50/AUCclin. ratio for MMC as determined by the conventional SDI, were significantly higher in all four cell lines than those for CDDP and CBDCA. While, in the modified SDI, the AUC50/AUCclin. values were decreased and in agreement with those obtained by the HTCA. In the DNA histogram after the drug-free incubation, MMC showed the most cytotoxic change, which was a severe decrease in G1 and G2 phase and increased fragmented particles indicating apoptosis. Drugs with strong cytotoxicity that persists after exposure, such as MMC, are underestimated with respect to their cytotoxicity when the conventional SDI test without a drug-free incubation is used.
There are no strategies to predict a patient's response to therapy. In a previous report, we classified Japanese patients into four groups according to the incidence of HLA antigens, by using quantification method III. In that study, we examined the patients' incidence of HLA antigens before surgery and evaluated their outcome according to the HLA classification by quantification method III. The aim of the present study is to evaluate whether HLA classification should be used in the treatment of individual cancer patients. A consecutive series of 76 Japanese patients who had undergone gastrectomy between July 1998 and January 2000 was evaluated to compare the patients HLA classifications, derived from quantification method III, with their prognoses following gastrectomy. Retrospective analysis of 193 gastric cancer patients revealed that HLA type I, type II, and type IV patients who had received postoperative adjuvant chemotherapy concomitant with PSK survived longer than those who had received postoperative adjuvant chemotherapy, whereas HLA type III patients who had received postoperative adjuvant chemotherapy showed significantly longer survival than those with chemotherapy+PSK. Following these results, we started a prospective study; we treated patients with HLA type I, type II, and type IV for postoperative chemotherapy+PSK, and those with HLA type III for postoperative chemotherapy following gastrectomy. The prospective study showed that patients who had been examined for HLA antigens showed significantly longer survival than those who had not been examined for HLA antigens. From the results of our retrospective and prospective studies, it can be inferred that it is necessary to examine gastric cancer patients for HLA antigens, and that HLA-oriented therapy is a very promising strategy for cancer treatment. We are planning to conduct an important study with control subjects.