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This study was undertaken to investigate the effects of endothelin(A) receptor antagonist (ET(A)-RA) BQ485; ET(B)-RA BQ788, and nonselective ET(A/B)-RA Bosentan on the gastrointestinal transit of guinea pigs. We further analyzed the distribution of ET-R subtypes on smooth muscle cells (SMC) of the gastrointestinal tract to investigate their direct involvement on SMC in gastrointestinal tract transit. A guinea pig model was used to measure intestinal transit. The effects of Bosentan (100 mg/kg, per os), BQ485 (1 mg/kg, intraperitoneally) and BQ788 (1 mg/kg, intraperitoneally) on transit in stomach, small intestine, and colon were evaluated. We separated SMC from stomach, small intestine, cecum, and colon by collagenase and analyzed the distribution of ET-R subtypes in each part by binding assay. Gastric transit and colon transit were significantly inhibited by BQ485, BQ788, and Bosentan. Small intestinal transit was not affected by any of these agents. ET(A)-R and ET(B)-R were widely distributed on SMC of stomach, small intestine, cecum, and colon. The ratio of ET(A)-R to ET(B)-R was 1:3 in stomach, small intestine, and cecum, but was 1:10 in colon. The ratio of the total number of ET-R on SMC of stomach, small intestine, cecum, and colon was 1:3:9:1. These results indicate that both ET(A)-R and ET(B)-R are strongly involved in the transit in the stomach and colon. However, the discrepancy between the effects of the various ET-R antagonists on gastrointestinal transit and the distribution of ET-R on SMC of the gastrointestinal tract suggests that ET-R on SMC of the gastrointestinal tract is not directly involved in gastrointestinal transit. [ABSTRACT FROM AUTHOR]

Objectives: The Cancer Control Act requires the maintenance of regional cooperation pathways (RCP) for cancer treatment. In 2008, we started RCP for early detection of new gastric cancer after endoscopic submucosal dissection (ESD). In gastric cancer treatment, RCP after surgical resection had been widely used, but little is known about RCP after ESD. This study aimed to evaluate the effectiveness of RCP after ESD., Methods: This study included 465 patients on whom our RCP was implemented from 2008 to 2018. A regional family physician performed surveillance endoscopy at 3 months and 1 year after ESD and annually thereafter. We retrospectively evaluated the cumulative incidence and treatment outcomes of new gastric cancer and compared them with previous reports., Results: During a median follow-up period of 70.5 months (3-120 months), 58 patients developed new gastric cancers, and metachronous gastric cancer was detected in 55 patients more than 1 year after ESD. The 5-year cumulative incidence rate was 9.8%. Three patients did not want treatment. Among the remaining 55 patients, the initial treatment was ESD in 51 and surgical resection in 4. Eventually, 50 patients (48 in the ESD group and 2 in the surgical resection group) fulfilled the pathologic criteria for curative ESD. There were no deaths due to gastric cancer., Conclusion: Our study was the first to reveal the incidence of new gastric cancer after ESD using RCP. Most lesions were cured with ESD, and no patients died of gastric cancer. Therefore, we consider RCPs to be an option for surveillance after ESD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Study Aims: The infliximab biosimilar CT-P13 was the first biosimilar drug targeting tumor necrosis factor-α. However, its efficacy and safety in real-world clinical situations have remained insufficient. Therefore, we aimed to verify the efficacy and safety of CT-P13 in bio-naïve patients with Crohn's disease., Patients and Methods: This retrospective multicenter study compared the remission rate at week 54 between patients with Crohn's disease who were treated with originator infliximab or CT-P13. Endoscopic and laboratory findings were assessed in both groups. A total of 184 (156 originator and 28 CT-P13) patients were analyzed. Of these, 138 originator users and 19 biosimilar users completed 54-week administration., Results: The clinical remission rates in patients taking originator infliximab of CT-P13 at week 54 were 92.5 % and 100 %, respectively. The endoscopic scores of each group significantly decreased from baseline at week 54 in both groups, and the mucosal healing rate at week 54 was 53 % and 64 %, respectively. Laboratory data including C-reactive protein, serum albumin, and hemoglobin significantly improved from baseline to week 14 and 54 in both groups. Adverse events were observed more frequently in the CT-P13 group (25 % vs. 4.5 %, p = 0.0015), but severe adverse events were rare in both groups., Conclusion: The efficacy and safety of CT-P13 were comparable with those of originator infliximab in bio-naïve patients with Crohn's disease evaluated by clinical, endoscopic, and laboratory findings. This study establishes the needed groundwork for the development of a strategy for treatment with biologics in patients with Crohn's disease., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are significantly changing treatment strategies for human malignant diseases, including oral cancer. Cancer cells usually escape from the immune system and acquire proliferative capacity and invasive/metastatic potential. We have focused on the two immune checkpoints, PD-1/PD-L1 and CD47/SIRPα, in the tumor microenvironment of oral squamous cell carcinoma (OSCC), performed a retrospective analysis of the expression of seven immune-related factors (PD-L1, PD-1, CD4, CD8, CD47, CD56 and CD11c), and examined their correlation with clinicopathological status. As a result, there were no significant findings relating to seven immune-related factors and several clinicopathological statuses. However, the immune checkpoint-related factors (PD-1, PD-L1, CD47) were highly expressed in non-keratinized epithelium-originated tumors when compared to those in keratinized epithelium-originated tumors. It is of interest that immunoediting via immune checkpoint-related factors was facilitated in non-keratinized sites. Several researchers reported that the keratinization of oral mucosal epithelia affected the immune response, but our present finding is the first study to show a difference in tumor immunity in the originating epithelium of OSCC, keratinized or non-keratinized. Tumor immunity, an immune escape status of OSCC, might be different in the originating epithelium, keratinized or non-keratinized.

This study aimed to investigate the lesion and endoscopist factors associated with unintentional endoscopic piecemeal mucosal resection (uniEPMR) of colorectal lesions ≥ 10 mm. uniEPMR was defined from the medical record as anything other than a preoperatively planned EPMR. Factors leading to uniEPMR were identified by retrospective univariate and multivariate analyses of lesions ≥ 10 mm (adenoma including sessile serrated lesion and carcinoma) that were treated with endoscopic mucosal resection (EMR) at three hospitals. Additionally, a questionnaire survey was conducted to determine the number of cases treated by each endoscopist. A learning curve (LC) was created for each lesion size based on the number of experienced cases and the percentage of uniEPMR. Of 2557 lesions, 327 lesions underwent uniEPMR. The recurrence rate of uniEPMR was 2.8%. Multivariate analysis showed that lesion diameter ≥ 30 mm (odds ratio 11.83, 95% confidence interval 6.80-20.60, p < 0.0001) was the most associated risk factor leading to uniEPMR. In the LC analysis, the proportion of uniEPMR decreased for lesion sizes of 10-19 mm until 160 cases. The proportion of uniEPMR decreased with the number of experienced cases in the 20-29 mm range, while there was no correlation between the number of experienced cases and the proportion of uniEPMR ≥ 30 mm. These results suggest that 160 cases seem to be the minimum number of cases needed to be proficient in en bloc EMR. Additionally, while lesion sizes of 10-29 mm are considered suitable for EMR, lesion sizes ≥ 30 mm are not applicable for en bloc EMR from the perspective of both lesion and endoscopist factors., (© 2024. The Author(s).)

Many molecular targeted agents, including biologics, have emerged for inflammatory bowel diseases (IBD), but their high prices have prevented their widespread use. This study aimed to reveal the changes in patient characteristics and the therapeutic strategies of IBD before and after the implementation of biologics in Japan, where the unique health insurance system allows patients with IBD and physicians to select drugs with minimum patient expenses. The analysis was performed using a prospective cohort, including IBD expert and nonexpert hospitals in Japan. In this study, patients were classified into two groups according to the year of diagnosis based on infliximab implementation as the prebiologic and biologic era groups. The characteristics of therapeutic strategies in both groups were evaluated using association analysis. This study analyzed 542 ulcerative colitis (UC) and 186 Crohn's disease (CD). The biologic era included 53.3% of patients with UC and 76.2% with CD, respectively. The age of UC (33.9 years vs. 38.8 years, P < 0.001) or CD diagnosis (24.3 years vs. 31.9 years, P < 0.001) was significantly higher in the biologic era group. The association analysis of patients with multiple drug usage histories revealed that patients in the prebiologic era group selected anti-tumor necrosis factor (TNF)-α agents, whereas those in the biologic era group preferred biologic agents with different mechanisms other than anti-TNF-α. In conclusion, this study demonstrated that both patient characteristics and treatment preferences in IBD have changed before and after biologic implementation., (© 2023. Springer Nature Limited.)

To gain a better understanding of the effects of biologics, we evaluated clinical outcomes in patients with moderate to severe exacerbations of ulcerative colitis (UC). This retrospective, multicenter study retrieved the entire clinical courses of UC patients who began treatments between 2004 and 2018. All exacerbations and clinical parameters, including treatment details for exacerbations and both remission and re-exacerbation dates, were identified during the observation period. Two different endpoints, the cumulative incidence rates of surgical resection and re-exacerbation, were evaluated separately in moderate to severe exacerbation events. Among 1401 patients, 1626 exacerbation events were determined according to a partial Mayo score (remission: < 2, mild: 2-4, moderate: 5-7, and severe: > 7). During the observation period, as administration rates of biologics increased, both surgical resection and hospitalization rates decreased, for 959 moderate to severe exacerbation events. We confirmed that biologics significantly reduced the cumulative re-exacerbation rate in moderate to severe exacerbation events during the study period compared with suboptimal therapies (a 0.507-fold decreased risk according to COX regression analysis, P < 0.001). However, they had not enough impact in reducing the cumulative incidence rate of surgical resection in moderate to severe exacerbation events that were corticosteroid-refractory or dependent (a 0.878-fold decreased risk according to COX regression analysis, P = 0.606). Biologics may improve remission duration, but these agents had no significant impact in reducing the risk of surgical resection in moderate to severe active UC., (© 2022. The Author(s).)

Background: Hepatitis B e antigen (HBeAg)-negative inactive carriers, the majority of hepatitis B virus (HBV) carriers, are considered to have a good prognosis. The definition of the inactive HBV carrier state has been based on HBV DNA and alanine aminotransferase (ALT) levels. Here we conducted a prospective study involving 18 hospitals to clarify the prognosis of HBeAg-negative inactive carriers., Methods: Three hundred eighty-eight HBeAg-negative inactive carriers at the baseline were observed prospectively from January 2011 to November 2015. We evaluated the primary end point, defined as the development of cirrhosis, hepatocellular carcinoma (HCC), or liver-related death. Also, we analyzed the factors associated with inactive carrier dropout and markedly increased levels of ALT or HBV DNA or both during the follow-up period., Results: At the baseline, the mean age was 57.5 ± 13.1 years and 42 % of patients were male. No individual developed cirrhosis, HCC, or liver-related death during the follow-up period (1035 ± 252 days). Loss of inactive carrier status was seen in 75 patients (19.3 %). Factors associated with failure to meet the inactive carrier criteria in the multivariate analysis were the levels of ALT (hazard ratio 1.13, 95 % confidence interval 1.07-1.19, p < 0.001), HBV DNA (hazard ratio 2.70, 95 % confidence interval 1.63-4.49, p < 0.001), and γ-glutamyl transpeptidase (hazard ratio 1.01, 95 % confidence interval 1.00-1.02, p = 0.003) at the baseline., Conclusions: Most inactive carriers in Japan had a good prognosis. However, despite the short observation period, some patients had loss of IC status. The long-term prognosis of inactive carriers remains unclear; therefore, careful follow-up of inactive carriers is needed.

A patient with distal myopathy with rimmed vacuoles (DMRV) exhibited Parkinsonism with a severe writing tremor that responded poorly to levodopa. Molecular genetic analysis revealed that the patient had the D176V/V572L compound heterozygous mutation in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. Histopathological examination of a biopsied muscle specimen yielded findings compatible with those of DMRV, which is characterized by the presence of rimmed vacuoles without inflammatory cell infiltration in muscle fibers. The finding of normal cardiac meta-iodobenzylguanide uptake makes the possibility of incidental Parkinson's disease in this patient unlikely. These observations raise the possibility that atypical Parkinsonism is a rare complication of DMRV associated with GNE mutation., ((c) 2008 Movement Disorder Society.)

We used the CAG regimen (low-dose cytarabine [10 mg/m2 per 12 hours, days 1-14], aclarubicin [14 mg/m2 per day, days 1-4], and granulocyte colony-stimulating factor [200 micrograms/m2 per day, days 1-14]) for the treatment of patients with primary resistant acute myelogenous leukemia (AML) and previously untreated elderly patients with AML, secondary AML, and refractory anemia with excess blasts in transformation (RAEB-T) in addition to relapsed AML. Forty-three of 69 (62%) patients achieved complete remission (CR), including 29 of 35 (83%) patients with relapsed AML, 1 of 8 patients with primary resistant AML, 5 of 8 elderly patients with previously untreated AML, and 8 of 18 patients with previously untreated secondary AML or RAEB-T. Ten of 22 (45%) patients > or = 65 years old achieved CR. The patients who achieved CR received at least 1 course of modified CAG therapy as the first consolidation therapy, followed by various second consolidation and intensification therapies. The median disease-free survival and overall survival were 8 and 15 months, respectively, for relapsed AML; 11 and 8 months for the elderly patients; and 8 and 17 months for secondary AML and RAEB-T. Myelosuppression was mild to moderate, and other than fever, severe nonhematologic toxicity was rare. CAG as the induction therapy seems promising for the treatment of various categories of poor-prognosis AML.

In order to determine whether tachykinins alter the function of chief cells and to characterize the receptors mediating the effect, we investigated the abilities of various substance P (SP)-related peptides to inhibit the binding of 125I-Bolton-Hunter labeled substance P (125I-BH-SP) and their abilities to alter cell function in dispersed chief cells from guinea pig stomach. Binding of 125I-BH-SP was saturable, reversible, time- and temperature-dependent and was inhibited by several SP-related peptides with relative potencies of SP = physalaemin (IC50:0.19 nM) > SP methyl ester (SP-ME) (IC50:3.3 nM) > eledoisin (IC50:6.1 nM) > neurokinin A (NKA) (IC50: 65 nM) > neurokinin B (NKB) (IC50:80 nM). Analyses of these binding data demonstrated that chief cells possess a high and low affinity class of binding sites. Neither 125I-NKA nor [phenylalanyl-3,4,5-3H]senktide demonstrated saturable binding to chief cells. Acid stripping experiments demonstrated rapid ligand internalization with 55% of the bound radioligand internalized by 10 min. Phospholipase C activating agents (carbachol, CCK-8), adenylate cyclase activating agents (secretin, VIP), TPA and the calcium ionophore, A23187, all inhibited the binding of 125I-BH-SP and it was due to inhibition of ligand internalization with no change in surface bound parameters. SP (0.1 microM) stimulated pepsinogen secretion but was 4-times less efficacious than CCK-8 (10 nM) or carbachol (1 mM). 10 nM SP stimulated a rapid increase in cytoplasmic free calcium concentration ([Ca2+]i) followed by a sustained elevation lasting 2 min. Single cell spectroscopy demonstrated SP (10 pM to 1 microM) did not cause calcium oscillations. The NK1 receptor antagonist, CP96,345 specifically inhibited the SP-stimulated changes in [Ca2+]i and pepsinogen secretion. The relative potencies of SP-related peptides to stimulate pepsinogen secretion and [Ca2+]i demonstrated a close agreement with their abilities to inhibit the binding of 125I-BH-SP, and comparison of the dose-response curves suggests occupation of the low affinity sites mediate changes in biologic activity. In conclusion, the present study demonstrates that chief cells possess a NK1 subtype of tachykinin receptor, occupation of the low affinity sites of this receptor cause calcium mobilization and pepsinogen secretion, and that binding to this receptor is regulated by agents that activate phospholipase C, adenylate cyclase, protein kinase C and calcium mobilization.

The effect of highly purified eicosapentaenoic acid ethyl ester (EPA-E) on colitis was investigated using a guinea pig model. The technique for preparing a degraded carrageenan with a molecular weight of about 30,000 from commercial iota-carrageenan was first refined. When this degraded carrageenan was fed to guinea pigs, localized ulcerations occurred in the cecum with infiltration of numerous mononuclear phagocytes. Oral administration of 300 mg.kg-1.day-1 of EPA-E for 3 weeks significantly prevented the development of colitis. The amounts of prostaglandin E2, thromboxane B2, and leukotriene B4 released from the cecal mucosa were also measured. The release of prostaglandin E2 and thromboxane B2 was significantly decreased in the animals fed EPA-E compared with those given olive oil or a vehicle alone. In addition, there was a positive correlation between the amounts of these eicosanoids and the degree of ulcer formation. However, there was no difference in the amount of leukotriene B4 among various experimental groups of animals. Furthermore, EPA-E feeding induced a significant decrease in the level of arachidonic acid and a significant increase in that of EPA in peritoneal macrophages. These results suggest that EPA has a prophylactic effect on the development of carrageenan-induced colitis, which may be ascribed in part to reduced eicosanoid production.

To evaluate the clinical efficacy of intraperitoneal hyperthermic perfusion (IPHP) for far-advanced gastric cancer, particularly with peritoneal seeding, we investigated the survival times of 59 patients who underwent distal subtotal gastrectomy, total gastrectomy, or total gastrectomy combined with concomitant resection of some of the remaining intra-abdominal organs. In all the 30 patients given IPHP, no cancer cells were present posthyperthermically in the lavage from the Douglas pouch. The 30 patients given IPHP lived longer than the 29 patients not given IPHP (p = 0.001), with a 1-year survival rate of 80.4% in the former group compared to 34.2% in the latter. With respect to a comparison of survival time of patients with peritoneal seeding, 7 patients not given IPHP had a 6-month survival rate of 57.1% and did not survive more than 9 months, whereas 20 patients given IPHP had 1- and 2-year survival rates of 78.7% and 45.0%, respectively; here the difference was significant (p = 0.001). The IPHP and control groups without peritoneal metastasis included 10 and 22 patients, respectively, and the 1-year survival rates are 85.4% and 45.3%, respectively. The survival rates of the former exceeded those of the latter, with p = 0.015 by the generalized Wilcoxon test. Thus this combined therapy offers the promise of extended survival for patients with far-advanced gastric cancer.

Immunoreactive CEA (IR-CEA) in feces or sera from 20 volunteers and 20 patients with colorectal cancer were measured before and at various intervals after surgery by a radioimmunoassay utilizing a "one step sandwich method." Elevated fecal IR-CEA level was observed in 17 of 20 patients with colorectal cancer; elevated serum CEA levels were observed in only 7 of all patients. There could not be found any correlation between fecal IR-CEA levels and Dukes' classification; there was but a little correlation between serum and fecal IR-CEA levels. In 8 of 14 patients treated by surgery, fecal IR-CEA levels obviously dropped, but in 2 patients with hepatic metastasis they were found rising in spite of colon tumor removal. It was speculated from these data that high values of fecal CEA depend on mass production of CEA by cancer cells. From these observations, it appears that fecal IR-CEA level presents a more ideal diagnostic competency in colorectal cancer than serum CEA level.

Correlation of monocyte with T lymphocyte or IgG-FcR+ T lymphocyte was studied in 57 gastrointestinal cancer patients and 24 healthy volunteers as control. In 24 volunteers, no correlation was found between them. Forty gastrointestinal cancer patients with curative tumor showed pre-and postoperatively a close correlation between monocyte and T lymphocyte, but there was little correlation, both pre-and postoperatively, between monocyte and IgG-FcR+ T lymphocyte. Seventeen patients with recurrent and/or inoperable gastrointestinal cancer, had a reverse correlation of monocyte with IgG-Fc R+T lymphocyte. It was suggested from these data that mononuclear phagocyte system (monocyte), which fulfils its function as an antigen presentation, has an intimate relationship, both directly and indirectly, to T lymphocyte.

Immunoreactive carcinoembryonic antigen (IR-CEA) levels in colorectal cancer and mucosal tissues, feces and blood were measured in 14 colorectal cancer patients to study the correlation. IR-CEA levels in colorectal cancer tissues were about 30 times higher than those in colonic mucosal tissues. The correlation coefficient between IR-CEA levels in the tumor tissue and serum was 0.654 (p less than 0.02). We assumed that the total tumor IR-CEA levels were the product of the tumor IR-CEA level, by the estimated tumor weight. The correlation coefficient between the serum IR-CEA level and total tumor IR-CEA level was 0.750 (p less than 0.001). When the patients were divided into two groups with more and less a total tumor IR-CEA level of 65,000 ng, respectively, the statistical difference in serum IR-CEA levels was p less than 0.001. The differences in fecal IR-CEA levels between these two groups, however, are statistically insignificant (p less than 0.3). We assumed that there was a positive correlation between the IR-CEA levels in blood and tumor from the consideration that circulating IR-CEA originates from the metabolic imbalance of its production in colorectal cancer tissues over its degradation in the liver. Moreover, it is essential to consider that the fecal IR-CEA levels may be influenced by the following three factors: the intraluminal direct release of CEA from tumor, no degradation process of CEA in the gut lumen, and the intraluminal transport rate of colonic contents.

Ninety-nine specimens obtained from 53 patients with stomach cancer were cultured for about 3 days by means of the stainless steel grid method. In vitro effects of antitumor drugs on the cancer cells were evaluated autoradiographically or biochemically using a liquid scintillation counter to measure the uptake of 3H-thymidine. The radioactivity of the labeled tumor cells of both control fragments and fragments affected by drugs varied greatly among individual tumors. Therefore, the in vitro efficacy of antitumor drugs was represented as a comparison with that of control fragments. Positive correlation between in vitro tests and the clinical effects of antitumor drugs was observed in the specimens of 18 cases.

Indirect calorimetry was performed in 48 postsurgical critically ill patients including those with multiple organ failure. The patients were divided into two groups, organ failure group (OF group) and postsurgical control group (C group), according to the presence of postsurgical organ failure and severe infection. The following results were obtained. The ratio of energy expenditure to basal energy expenditure, reflecting a degree of hypermetabolism, was 1.44 +/- 0.38 in OF group and 1.26 +/- 0.23 in C group respectively. The change in respiratory quotient by caloric intake was greater in OF group than in C group, indicating that it is more important to maintain an adequate intake for the prevention of increased respiratory work and excess lipogenesis in OF group. When nitrogen intake as amino acids was sufficient (0.1-0.2 g/kg/day), nitrogen balance could be maintained around 0 by a caloric intake being equal to measured energy expenditure. A positive correlation was observed between arterial ketone body ratio reflecting energy charge in hepatocytes and respiratory quotient, indicating that in patients with impaired mitochondrial function in hepatocytes as shown by a decrease in ketone body ratio, glucose cannot be utilized effectively. These results let us conclude that calorimetry is indispensable in the management of critically ill patients and that adequate energy intake should be cautiously determined according to the calorimetry.

Heated albumin microspheres 45 +/- 8 microns dia. containing 5% mitomycin C were infused into rabbit femoral artery to assess the depot effects. MMC levels were measured in the muscle and VX -2 tumor tissues fed by the femoral artery as well as in the drainage vein blood. Furthermore, the histologic changes in the VX -2 tumor and the MMC microspheres entrapped in the arterioles were surveyed microscopically. Drug concentration in the case of MMC microspheres was maintained at high levels in both tissue and venous blood over 4 hours, but in the rabbits infused conventional MMC, drug levels decreased below the assay limitation 2 hours after injection. The microscopic findings 2 weeks later revealed necrotic VX -2 tumor tissue as well as the MMC microspheres remaining in the arterioles .

To treat six patients with peritoneal recurrence after radical operation for gastrointestinal cancer, an intraperitoneal hyperthermic perfusion (IPHP), combined with surgical resection of recurrent tumors, intestinal by-pass anastomosis, or both, was carried out. Immediately after complete resection of the intraperitoneal recurrent tumors, a 2- to 3-hour IPHP was performed under hypothermic general anesthesia at about 32 degrees C, using a perfusate containing 10 micrograms/ml or 20 micrograms/ml of mitomycin C (MMC) warmed at the inflow temperature of 46.6 degrees C to 46.9 degrees C. The apparatus used for IPHP was designed for intraperitoneal perfusion as a closed circuit. Although five of the six patients had a malignant peritoneal effusion at the time of admission, the effusion disappeared soon after IPHP, and no cancer cell was present in the lavage from Douglas' pouch. The other patient had a recurrent tumor at the anastomotic region after low anterior resection for rectal cancer and complete resection of the recurrent tumor, combined with IPHP, was carried out. One patient with a recurrent gastric cancer died of hepatic metastasis and cancerous pleuritis 5 months after this treatment, and the other five are in good health 12.8 +/- 5.1 months after IPHP. On the other hand, five patients with intra-abdominal recurrent gastric cancer, who received only surgical treatment within the same period of time, died 3.0 +/- 2.1 months after the surgery. Postoperatively, in the six patients with IPHP, transitory hepatic dysfunction, hypoproteinemia, and thrombocytopenia occurred. These results show that IPHP using MMC combined with surgery is a safe, reliable treatment for patients with peritoneal recurrence of gastrointestinal cancer.

For the purpose of enhancing antitumor effects, we prepared heated albumin microspheres containing an antitumor drug, mitomycin C. The biodegradable MMC microspheres which have an average diameter of 45 +/- 8 mum contain approximately 10% of MMC and release in vitro approximately 20% of the MMC over 3-day period. The microspheres were injected into albino rabbit femoral artery of the hind leg into which a VX-2 tumor had been implanted. Peripheral blood levels of MMC were reduced as compared to the conventional MMC group, within 60 minutes after injection. Subsequently in the MMC-microsphere administered rabbits, the level was higher than in the conventional MMC administered group. The survival of VX-2 tumor-bearing rabbits prolonged markedly with MMC microspheres.

Five patients with colorectal cancer and unresectable synchronous liver metastases have survived for over five years at this writing. Four of the five had multiple metastases over both lobes, as diagnosed preoperatively, and the other had multiple metastases in the right lobe not evident preoperatively. The primary foci were excised completely in four patients. For one patient with multiple metastases limited to the right lobe, the postoperative cancer chemotherapy prescribed was intravenous mitomycin C (MMC; 12 mg) and oral ftorafur (a derivative of 5-FU) for a total dose of 291 gm over 63 weeks. The remaining four patients underwent postoperative intra-arterial infusion therapy with the average total dose of 20.5 mg of MMC plus 5600 mg of 5-FU; subsequently, they received protracted chemotherapy with oral ftorafur of 354 gm as an average, with little or no side effects. In these four patients, duration of intra-arterial treatment was an average of 3.2 weeks, and the subsequent oral treatment continued for an average of 85 weeks. Recent hepatic echography and CEA determinations show these patients to be free from intrahepatic metastasis.

A retrospective study of 37 colorectal cancer patients with synchronous liver metastases was made. Of these patents, 6 who had undergone primary tumor removal were treated with considerable success by hepatic arterial infusion of 5-FU and mitomycin C. Ten patients who underwent primary tumor excision were treated by oral chemotherapy using fluorinated pyrimidines. These patients survived about 23 months. On the other hand, 12 patients after primary tumor removal without cancer chemotherapy survived for about 10 months. Six patients without antitumor treatment for both primary tumor and hepatic metastasis survived about 5.2 months. The overall results of this study suggest that intrahepatic arterial infusion is of practical importance for hepatic metastases from colorectal cancer and that oral chemotherapy is indeed effective for selected patients.

A clinical trial of a protracted adjuvant cancer chemotherapy was carried out on 207 patients with operable gastric cancer, from April, 1977, in the First Department of Surgery, Chiba University Hospital and two closely related hospitals. These patients were given intravenously 0.4 mg/kg and 0.2 mg/kg of mitomycin C on the day of operation and the next day, respectively, and then 16 mg/kg intravenously of Futraful (FT-207) daily from the 10th postoperative day until discharge, followed by oral administration of FT-207, 12 mg/kg, for 24 to 36 months after discharge. Two mg/kg of phenobarbital and 30 mg/kg of glutathione were administered randomly to half the number of patients (induction group) to induce hepatic drug-metabolizing enzymes. Significantly higher levels of serum 5-Fluorouracil (5-FU) released from FT-207 were found in the induction group than in the controls. Five-year overall survival rates in the induction and control groups revealed no difference. However, the survival rates in Stage III patients in the induction group were significantly superior in the 3-5 postoperative years, compared to those in the Stage III of the control group, while Stage I, II and IV patients apparently received no benefit from this induction treatment.