Esophageal cancer after distal gastrectomy.

The effect of gastrectomy on the subsequent development of esophageal cancer was investigated. Duodenogastroesophageal reflux is thought to be common in patients after distal gastrectomy, but whether this contributes to the development of esophageal cancer in such patients is controversial. We retrospectively evaluated 153 patients who underwent subtotal esophagectomy for thoracic esophageal cancer between January 2002 and July 2005. They were divided into two groups, according to whether or not they had previously undergone a gastrectomy: group 1, comprising 14 patients who had undergone gastrectomy and group 2, comprising 139 patients who had not. Clinical profiles of the patients were obtained from the medical records and the whole resected esophagus was histopathologically examined. The interval between gastrectomy and esophagectomy in group 1 was significantly shorter in the patients who had undergone gastrectomy for gastric cancer (10.5 +/- 4.2 years) than in those who had undergone gastrectomy for a peptic ulcer (28.9 +/- 3.0 years). The interval was also somehow shorter in the patients for whom anastomosis had been performed by Billroth I (21.3 +/- 5.6 years) compared with Billroth II (29.7 +/- 3.2 years), although the difference did not reach its statistical significance (P = 0.11). Moreover, the proportion of lower third tumors in patients after gastrectomy was significantly higher compared with that of the patients with intact stomach. These findings suggest that a history of gastrectomy is associated with more lower-third squamous cell esophageal carcinoma.

Two cases of histopathologically advanced (stage IV) early gastric cancers.

We report two cases of early gastric cancer with distant metastases (stage IV). At our institute 1428 cases of primary gastric cancer were resected between 1980 and 1997; 536 were diagnosed as early gastric cancer based on the resected specimens (304 cases of mucosal cancer, Tis--TNM classification--and 232 of submucosal cancer, T1). 528 of these 536 cases were classified as histological stage I, six as stage II, none as stage III and two as stage IV. The incidence of stage IV early gastric cancer was 0.14% of all gastric cancers and 0.37% of the early gastric cancers. The two patients with stage IV early gastric cancer were women. Both tumors were defined as early cancer because they were confined to the submucosa. One was a type 0 IIc + III early cancer, histologically classifiable as a small, moderately differentiated adenocarcinoma (tub2 according to the Japanese Classification of Gastric Carcinoma, G2; TNM classification: ICD-O C16), size 10 x 8 mm; the other was a surface spreading type 0 IIc, classifiable as a signet-ring cell carcinoma (sig, G3), size 50 x 35 mm. Stage IV factors were N3 in the first and ovarian metastasis (Krukenberg tumor) in the second case.

Clinicopathological evaluation of T2-gastric cancer among age groups.

BACKGROUND/AIMS: Although the recent results of surgical treatments for T2-gastric cancer (defined as: tumor invasion of the muscularis propria or the subserosa) have been comparatively favorable, frequency of lymph node metastasis is high and recurrence often happens. METHODOLOGY: A retrospective study on T2-gastric cancer in 347 patients who underwent curative resection between 1975 and 1995 was performed to address this issue. These 347 patients were divided into 3 groups according to age: group I (72 cases) < 50 years old; group II (202 cases) not < 50 years but < 70 years old; and group III (73 cases) > or = 70 years old. RESULTS: There was an apparent tendency that gastric cancer in aged patients is more likely to become differentiated cancer and spread easily to the liver. CONCLUSIONS: The data suggest that aged patients should be more carefully followed for any hematogenous metastases including liver metastases. Removal of hepatic metastases or regional hepatic infusion chemotherapy may then salvage some patients even elderly patients.

Inhibition of liver metastases from neuraminidase-treated colon 26 cells by an anti-Thomsen-Friedenreich-specific monoclonal antibody.

Thomsen-Friedenreich antigen (TF; Galbeta1-3GalNAcalpha1-) is expressed on many human carcinomas. Evidence suggests that TF-carrying tumor cells specifically bind asialoglycoprotein receptors on hepatocytes resulting in metastasis formation in the liver. We used an animal model to examine the feasibility of preventing metastasis formation by an antibody to TF. Treatment of Colon 26 cells with neuraminidase led to the exposure of TF, and consequently to a higher frequency of liver metastases in syngeneic Balb/c mice. This could be prevented by an antibody to TF (A78-G/A7), but not by a control antibody. The results may open up a new strategy for the prophylaxis of metastatic spread to the liver.

A new preoperative immunochemotherapy for the treatment of locally advanced esophageal cancer.

A promising preoperative immunochemotherapy regimen for locally advanced esophageal cancer is herein described. A 67-year-old man suffering from severe dysphagia was diagnosed with unresectable esophageal cancer at initial examination because of a tumor of 11 cm in length and suspicion of trachea invasion. Neoadjuvant immunochemotherapy was undertaken for the down-staging. Interleukin-2 (IL-2) (3.5 x 10(5) Japan reference units), nedaplatin (7 mg/m2) and 5-FU (300 mg/m2) were administered intravenously daily for 5 days a week for three weeks. The gross findings of a barium esophagogram and esophagoscopy revealed significant tumor regression in both size and shape. The patient underwent an esophagectomy through a laparotomy followed by a right thoracotomy. The surgical specimens were serially sectioned and examined microscopically. All of the surgical margins were clear (upper and lower margins as well as the adventitia), and there was no evidence of lymph node metastasis. The surgical specimen revealed neoplastic squamous ghost cells surrounding significant lymphocyte infiltration. This appears to be a unique feature of this particular neoadjuvant immunochemotherapy.

Involvement of liver-associated immunity in hepatic metastasis formation.

AIMS: Hepatic metastasis formation and prevention were studied from the viewpoint of liver-associated immunity. METHODS: RCN-9, a colonic cancer cell line derived from Fischer rats, and its subclone RCN-H4, in which the cancer is highly metastatic to the liver, were used. Fischer rats that were inoculated with parent RCN-9 colonic cancer cells (5 x 10(6)) via the portal vein showed liver metastasis in less than 60% of the animals. In contrast, all rats (100%) that received RCN-H4 produced multiple liver metastases. To investigate the difference of hepatic metastasis formation, we assessed the susceptibility of both cell lines against hepatic sinusoidal lymphocytes (HSL) by 51Cr-release assay, and the expression of MHC class I and class II of both cell lines by flow cytometry. In addition, we examined whether activation of HSL by interleukin-12 (IL-12) can prevent liver metastasis of highly metastatic clone RCN-H4. RESULTS: The RCN-H4 clone showed decreased susceptibility to lysis by natural cytotoxic cells in HSL. This decrease in cell susceptibility was attributable to an increase in cell surface expression of MHC class I antigen. Administration of IL-12, a potent NK/CTL stimulatory cytokine, augmented the cytotoxic activity against the RCN-H4 clone and prevented liver metastasis of RCN-H4 inoculated into the portal vein. CONCLUSIONS: Liver metastasis formation is positively correlated with the strength of the hepatic immune system which mainly consists of ontogenetically primitive T cells. As these effectors exert their cytotoxicity in a MHC-nonrestricted fashion, tumor cells that highly express MHC class I antigen can readily avoid hepatic surveillance and apt to cause liver metastasis. Augmentation of the hepatic immune system, for instance, with IL-12 administration, can prevent liver metastasis even in tumor cells with a high potential for liver metastasis.

Adjuvant hepatic arterial IL-2 and MMC, 5-FU after curative resection of colorectal liver metastases.

BACKGROUND/AIMS: Based on our favorable results of interleukin-2-based immuno-chemotherapy in the treatment of unresectable liver metastases from colorectal cancer, we utilized this therapy for the prevention of liver recurrence after liver resection. MATERIALS AND METHODS: Eighteen patients with colon cancer metastatic to the liver underwent successful hepatic resection and adjuvant immunochemotherapy that included hepatic arterial infusion of interleukin-2 and mitomycin C, 5-fluorouracil. The regimen consisted of weekly interleukin-2 (1.4-2x 10(6) units), 5-fluorouracil (250 mg) by 2-hour infusion and bolus mitomycin C (4 mg) for 6 months. RESULTS: Fourteen of 18 patients are alive and disease-free with a median postoperative follow-up of 28.5 months. Recurrent cancer has developed in 4 of the 18 patients (22%). The site of first recurrence was the lung in three patients (17%) and the pelvis in one (6%); no patients recurred in the liver. CONCLUSIONS: We recommend this adjuvant immuno-chemotherapy for the prevention of liver recurrence after curative resection of colorectal liver metastases.

IL-2 perfusion to the liver augments the hepatic extraction rate of accompanying anticancer drugs.

A pilot study we conducted on hepatic infusion chemotherapy combined with interleukin-2 (IL-2) for metastatic liver malignancies revealed very encouraging results indicating that this treatment modality is more effective than either of the anticancer drugs used alone. To clarify the mechanisms underlying the synergism of these modalities, the pharmacokinetics of anticancer drugs were examined in a rat model. Adult rats were given 5-fluorouracil (5-FU) or mitomycin C (MMC) combined with various doses of IL-2 up to 7500 JRU/kg per minute for the measurement of hepatic extraction rates (HER). The HER of 5-FU was significantly increased (P < 0.01) in combination with IL-2 in a dose-dependent fashion while that of MMC also showed a tendency to increase. Thus, it is conceivable that the increase of vascular permeability caused by IL-2 results in augmentation of the HER of associated anticancer drugs. This effect may improve the delivery of anticancer drugs to the liver and alleviate general toxicity by reducing the amount of circulating anticancer agents.

A high level of prostaglandin E2 (PGE2) in the portal vein suppresses liver-associated immunity and promotes liver metastases.

Prostaglandin E2 (PGE2) is generally accepted to be an immunosuppressant produced by cancer cells and their surrounding macrophages. Although several investigators have reported detecting high concentrations of PGE2 in the portal veins of patients with colorectal cancer, the relationship between these high concentrations of PGE2 in the portal vein and liver-associated immunity remains unclear. In this study, we attempted to determine if the portal administration of PGE2 suppresses the immune function of the liver in a rat model. Donryu rats were administered PGE2 via the portal vein for 7 days, following which the cytotoxic activity of hepatic sinusoidal lymphocytes (HSL) against natural killer (NK)-sensitive YAC-1 and rat syngeneic AH60C tumor cells was assessed. Purified HSL are spontaneously cytolytic; however, the continuous administration of PGE2 dramatically suppressed the cytotoxic activity of HSLs in a dose-dependent fashion. Flow cytometric analysis showed that the large granular lymphocyte (LGL) fraction, hepatic natural killer (pit) cells, and CD4-8+ killer/suppressor T cells were mainly reduced in number in the HSLs following PGE2 infusion. In this rat AH60C metastasis model, the continuous administration of PGE2 increased the number and size of metastatic tumor nodules in the liver, suggesting that high concentrations of PGE2 in the portal vein suppress liver-associated immunity and promote the formation of hepatic metastasis.

Effect of packed red cell and whole blood transfusion on liver-associated immune function.

In order to clarify the effect of allogeneic blood transfusion on liver metastases from primary cancer, liver-associated immune function after blood transfusion was evaluated in a murine model. Hepatic sinusoidal lymphocytes (HSL) were strongly cytotoxic to conventional natural killer cell-sensitive target (YAC-1), as well as to natural killer cell-resistant solid adenocarcinoma cells (colon 26), compared with splenic lymphocytes. Allogeneic whole blood transfusion strikingly suppressed the cytotoxic activities of HSL. Red blood cell transfusions also suppressed cytotoxicity to the same degree. In an animal model, allogeneic transfusion increased the rate of liver metastases. Flow cytometric analysis showed that transfusion caused a temporary decrease in the class II antigen positive cell fraction, mainly Kupffer's cells. This phenomenon occurred in parallel with changes in hepatic antitumor activity, indicating the possible importance of the involvement of Kupffer's cell in the development of the killer activity of HSL. These results suggest that blood transfusion may be a significant risk factor for hepatic metastasis by transiently suppressing the immunocompetence of the liver.

[Selective effectiveness of galactose-containing liposome IL-2 on liver lymphocytes].

We have performed immunochemical intraarterial infusion immunochemotherapy containing IL-2, mitomycin C and 5-FU as the main active ingredient for metastatic liver tumor and obtained favorable results. However, we are obliged to perform intra-hepatic arterial infusion once or twice a week, because of the short half-life of IL-2. Thus, we are using a drug delivery system to activate lymphocytes of the liver. We noticed many galactose-receptors in the liver and prepared galactose-containing liposome preparations using various carriers/bases. As a result, galactose-containing liposome preparations showed the highest accumulation and the highest localized enhancing effect on the antitumor activity of lymphocytes in the liver sites.

Hepatic arterial infusions of interleukin-2-based immunochemotherapy in the treatment of unresectable liver metastases from colorectal cancer.

In preclinical studies, hepatic arterial infusion of interleukin-2 (IL-2) in dogs significantly induced lymphocyte proliferation and augmented antitumor killing activity in the liver. Based on these findings, a pilot study of hepatic arterial infusions of IL-2-based immunochemotherapy was conducted in 21 patients (15 men, 6 women) with unresectable liver metastases from colorectal cancer, to determine whether the addition of IL-2 improved the therapeutic efficacy of chemotherapy alone. Interleukin-2 was given to all patients as 7 to 8 x 10(5) Japanese reference units (JRU) in addition to 5-fluorouracil (5-FU) 250 mg daily and mitomycin C (MMC) 4 mg once weekly, through a subcutaneous port for 3 weeks. After completion of the initial course, patients were discharged from the hospital and continued on a modified regimen for outpatient therapy: IL-2, 2.0 to 2.1 x 10(6) JRU and 5-FU 250 mg twice weekly; MMC 4 mg once weekly. Patient response rate was 76%, and the median survival from initiation of treatment was 24 months. Toxicity of the combined regimen was minimal. Peripheral lymphocyte phenotype study showed notable decreases in CD8+, CD16+, and CD57+ cells and an increase in CD4+ cells (ie, elevation of 4:8 ratio) during therapy. Electron microscopic analysis of the resected liver of a patient receiving the IL-2-mitomycin-C/5-fluorouracil (IL-2.MF) infusion showed a pronounced accumulation of lymphocytes, penetrating from the space of Disse, around the cancer cells. The present study explores hepatic arterial infusion of IL-2-based immunochemotherapy as a new strategy, based on the activation of liver-associated immune response; this technique may provide improved response and survival for unresectable liver metastases.

In vivo effects of doxorubicin on kinase C in cultured cells.

The ability of doxorubicin to inhibit kinase C in vivo in cultured BALB/c 3T3 mouse fibroblasts was determined by the phosphorylation of the myristoylated alanine-rich C kinase substrate (MARCKS) and the induction of c-fos transcription following treatment with 200 nM phorbol 12-myristate 13-acetate. A concentration of 60 microM doxorubicin did not inhibit MARCKS phosphorylation but completely inhibited c-fos expression. The inhibition of c-fos expression was not specifically mediated via kinase C, since both the total RNA synthesis as measured by [3H]-uridine uptake and the fraction of serum-induced c-fos expression that was not attributable to kinase C were inhibited by doxorubicin. The present data do not support the hypothesis that the cytotoxic effect of doxorubicin is attributable to the inhibition of kinase C in vivo.

[Clinical studies on the utility of ofloxacin for lower respiratory infections].

One hundred and thirteen patients who were treated at the Kyushu University Hospital and other related hospitals were randomly assigned to 2 groups to compare the effect of twice daily administration of 200 mg each and that of 300 mg each of ofloxacin (OFLX). The patients included 41 cases with pneumonia, 18 with acute bronchitis, 33 with chronic bronchitis, 15 with bronchiectasis with infection, 3 with diffused panbronchiolitis, and 3 with other secondary infectious diseases. Fifty-five cases were administered 400 mg OFLX a day and 58 cases received 600 mg. The number of severe cases in the 600 mg group was greater than that in the 400 mg group. The ratios of general amelioration of clinical symptoms were 92.6% in the 400 mg group and 82.1% in the 600 mg group. Thus, the ratio of the 400 mg group was better than that of the 600 mg group. However, the ratio of significant amelioration in the 600 mg group was 35.7% which was better than that in the 400 mg group, 27.8%. For bacteriological effects the rate of disappearance and decrease in number of bacteria was 92% in the 400 mg group and was significantly better than that of the 600 mg group, 70%. The incidence of side effects in the 600 mg group was 22.4% and this was high in contrast to that in the 400 mg group, 3.6%. Most of the side effects in the 600 mg group involved symptoms of the central nervous system such as sleeplessness. No significant differences were observed in incidences of abnormalities of laboratory tests at 1.8% and 1.7%, respectively. Safety in the 400 mg group were 96.4% which was significantly higher in number than those in the 600 mg group, 77.6%. Efficacy rates of twice daily administrations each with 200 mg and 300 mg OFLX for lower respiratory infections were 94.4 and 79.3%, respectively. In conclusion, the daily dose of 400 mg was the most effective.

Regulation of the retinoblastoma anti-oncogene in aging human diploid fibroblasts.

Cell cycle expression of the retinoblastoma (RB) gene was investigated in young and aging IMR 90 human diploid fibroblasts and in the immortalized but untransformed A31 BALB/c 3T3 mouse fibroblasts. RB RNA levels increased about 75% during late G1/S in both the young and old IMR 90 cells. Young and old cells had similar normalized amounts of RB RNA per cell. Kinase C activation did not stimulate RB transcription. The A31 cells showed a constant RB RNA level throughout G0/S. The data is consistent with the hypothesis that RB activity is regulated primarily post-transcriptionally and indicates that a change in the regulation of RB transcription is not part of the senescence phenomenon.

Early kinase C dependent events in aging human diploid fibroblasts.

Two early kinase C dependent events, the induction of c-fos transcription and the phosphorylation of an 87 kDa protein, were investigated in aging IMR 90 human diploid fibroblasts. C-fos induction and 87-kDa protein phosphorylation were similarly regulated in aging cells and their young counterparts. The data suggests that G0 exit or the competence phenomenon is intact in aging cells and that the proliferative block occurs later in G0/S.

c-fos regulation in untransformed as compared to transformed Balb/c 3T3 fibroblasts.

The regulation of c-fos expression was studied in the untransformed A31 Balb/c 3T3 mouse fibroblast cell line and in the derivative benzo(a)pyrene (BPA31), dimethylbenz(a)anthracene (DA31) and the Kirsten sarcoma virus (KA31) transformed cell lines. The peak induced c-fos RNA levels varied by about 20-fold among the cell lines. Differences in the peak level of c-fos RNA were due primarily to differences in the de novo transcriptional rate rather than in the stability of the message. Superinduction of 6-12x occurred after combined cycloheximide and phorbol ester treatment in the 4 cell lines. Superinduction of 20x in the untransformed A31 cells but only 1-3x in the transformed cells occurred when cycloheximidine and 10% serum were used. Superinduction of 5x in the A31 cells and of 1-2x in the transformed cells was found using cycloheximide and A23187. The data suggest the possibility that a labile protein which degrades the c-fos RNA is stabilized or increased in the transformed cells.