Hagiwara A

Prophylaxis with carbon-adsorbed mitomycin against peritoneal recurrence of gastric cancer

Attempts to prevent peritoneal carcinomatosis after surgery for gastric cancer by intraperitoneal administration of anticancer drugs have not been successful, largely because the drugs are not retained in the peritoneal cavity. We have assessed the prophylactic efficacy of a delayed-release preparation--mitomycin adsorbed onto activated charcoal (M-CH). 50 patients with gastric cancer and serosal infiltration were randomly assigned intraperitoneal treatment with M-CH (50 mg mitomycin intraoperatively) or no anticancer prophylaxis (control). Survival rates for the 3 years of follow-up were significantly higher among the 24 M-CH recipients (1 was lost to follow-up) than among the 25 controls (p less than 0.01). There were significant differences in survival between the groups at 1.5 years after randomisation (difference 34.6% [95% confidence interval 8.5-60.8%]; p less than 0.01) and at 2.0, 2.5, and 3.0 years (41.7% [14.2-69.1%]; p less than 0.005). The concentration of mitomycin was significantly higher in peritoneal exudate than in plasma for 24 h after drug administration. Side-effects were slight and well tolerated. Thus, peroperative intraperitoneal treatment with M-CH seems to improve survival after gastrectomy for gastric cancer, presumably by a prophylactic effect on peritoneal recurrence.

Clinicopathological characteristics of gastric cancer in the elderly.

The clinicopathological features of 380 elderly patients 70 years of age or older with gastric cancer were reviewed retrospectively from hospital records between 1969 and 1993. They were then compared with 1134 middle-aged patients between 40 and 69 years. The elderly constituted 18.4% of all gastric cancer patients 20 years ago but now comprise 24.4% of all patients in the most recent decade, despite the overall decrease in the rate of gastric cancer. The distinguishing histological features of gastric cancer in the elderly were an intestinal type of cancer, expansive tumour growth and synchronous multiplicity of the lesions. Elderly patients had a similar rate of tumour extension but had poorer survival as compared with the middle-aged patients. Post-operative death within 30 days after surgery was also higher in the elderly than in the middle-aged patients.

Chromosomal aberrations in human hepatocellular carcinomas associated with hepatitis C virus infection detected by comparative genomic hybridization

SummaryThirty-five hepatocellular carcinomas (HCCs) associated with hepatitis C virus (HCV) were analysed by comparative genomic hybridization (CGH), to screen for changes in copy-number of DNA sequences. Chromosomal losses were noted in 1p34–36 (37%), 4q12–21 (48%), 5q13–21 (35%), 6q13–16 (23%), 8p21–23 (28%), 13q (20%), 16q (33%) and 17p13 (37%). Gains were noted in 1q (46%), 6p (20%), 8q21–24 (31%) and 17q (43%). High level gains indicative of gene amplifications were found in 7q31 (3%), 11q13 (3%), 14q12 (6%) and 17q12 (3%); amplification at 14q12 may be characteristic for HCCs. No significant difference in chromosomal aberrations was noted between carcinomas associated with HCV-infection in our study and those reported earlier in HCCs infected with hepatitis B virus (HBV), indicating that both HBV- and HCV-related carcinomas may progress through a similar cascade of molecular events.

Monoclonal antibody A7-superparamagnetic iron oxide as contrast agent of MR imaging of rectal carcinoma

Superparamagnetic iron oxide (SPIO)-based colloid has been used clinically as a tissue-specific magnetic resonance contrast agent. We coupled monoclonal antibody A7 (Mab A7), which reacts specifically with human colorectal carcinoma, to Ferumoxides (SPIO) and examined the accumulation of this conjugate in xenografted tumours in nude mice. We examined in vitro immunoreactivity of Mab A7 coupled to Ferumoxides and its in vivo distribution in nude mice with human colorectal carcinoma. Magnetic resonance imaging of tumour-bearing nude mice was performed 72 h after injection of A7-Ferumoxides. A7-Ferumoxides retained binding activities that were nearly identical to intact Mab A7. More of the radiolabelled A7-Ferumoxides accumulated in the tumour than normal mouse IgG-Ferumoxides from 12 h onwards after injection (P<0.05). Both A7-Ferumoxides and normal mouse IgG-Ferumoxides disappeared from blood linearly over time. The accumulation levels in normal tissue decreased linearly over time but were lower than levels in tumours from 6 h. In magnetic resonance T2-weighted imaging of the tumour-bearing nude mice, signal intensity was reduced at the margin of the tumour by injection of A7-Ferumoxides. Mab A7 coupled to Ferumoxides is potentially suitable as a magnetic resonance contrast agent for detecting local recurrence of rectal carcinoma.

Site-specific implantation in the milky spots of malignant cells in peritoneal dissemination : immunohistochemical observation in mice inoculated intraperitoneally with bromodeoxyuridine-labelled cells

To investigate the site-specific implantation of cancer cells in peritoneal dissemination, we inoculated CDF1 mice intraperitoneally with mouse P388 leukaemia cells labelled with bromodeoxyuridine (BrdU) and then observed immunohistochemically the distribution of the cells in the greater omentum taken from the mice using an anti-BrdU antibody. We found the BrdU-labelled cells infiltrating selectively into the milky spots in the omentum. Furthermore, we intraperitoneally inoculated the BrdU-labelled P388 cells at 10(5), 10(6) and 10(7) cells per mouse into three groups of ten CDF1 mice and then quantified the distribution of the BrdU-labelled cells by counting the number of the labelled cells per unit area at each milky spot and non-milky spot site in the omentum. Inoculations of 10(5), 10(6) and 10(7) BrdU-labelled P388 cells per mouse resulted in 15.8 +/- 13.3, 120 +/- 46.5 and 504 +/- 208 cells mm-2 respectively in the milky spot sites and 9.14 x 10(-3) +/- 1.58 x 10(-2), 1.14 x 10(-1) +/- 7.82 x 10(-2) and 7.07 x 10(-1) +/- 5.98 x 10(-1) cells mm-2 respectively in the non-milky spot sites. The ratios of the mean labelled cell numbers in the milky spot sites vs those in the non-milky spot sites were 1728:1, 1049:1 and 713:1 respectively. In all cases, there were statistically significant differences in the number of BrdU-labelled cells mm-2 between milky spot sites and non-milky spot sites. However, the ratios decreased as the numbers of inoculated cells increased. In addition, we inoculated C57/BL mice intraperitoneally with B-16 PC melanoma cells, which were easily differentiated from the other cells by the intrinsic black melanin, and examined the distribution of the cells macro- and microscopically. The B-16 PC melanoma cells were also found to be infiltrating preferentially into the milky spots in the omentum. These results suggest that cancer cells seeded intraperitoneally specifically infiltrate the milky spots in the early stages of peritoneal dissemination.

Analysis of histological therapeutic effect, apoptosis rate and p53 status after combined treatment with radiation, hyperthermia and 5-fluorouracil suppositories for advanced rectal cancers

The tumour-suppressor gene p53 encodes a transcription factor that plays a critical role in the induction of G1 cell cycle arrest and apoptosis after DNA damage. To clarify the role of the p53 gene and apoptosis in combined hyperthermia, chemotherapy and radiation (hyperthermochemoradiotherapy, HCR therapy) for rectal cancer, we examined the histological response, rate of apoptosis, DNA fragmentation and p53 status in tumours from 28 patients undergoing HCR therapy before surgery and from 22 patients who did not have preoperative treatment. The therapeutic effect of HCR therapy was closely correlated with the rate of apoptosis; the correlation was statistically significant, suggesting that this effect occurs through apoptosis. The incidence of p53 mutations in the treated group were as follows: in tumours resistant to HCR therapy, four of seven (57.1%); intermediately sensitive, 7 of 13 (53.9%); or sensitive, three of eight (37.5%), suggesting that the therapeutic effect and apoptosis rate were related to the p53 status of the tumours to some extent, but the relation was not statistically significant. In the 22 control tumours (non-treated group), the apoptosis rate was 2.0 +/- 1.1%, and there was no significant difference in p53 status compared with the HCR group. Our study indicates that the pathological response to HCR therapy correlates with the rate of apoptosis with statistical significance and that it induces the therapeutic effect more significantly in rectal cancer cells with wild-type p53, although HCR therapy-induced apoptosis also occurs in some rectal cancers with mutated p53. Therefore, this combination therapy can induce an additive or synergistic anti-tumour effect in rectal cancers with wild-type p53 as well as in those with mutated p53 through apoptosis, offering new therapeutic opportunities and a better prognosis.

Chronologic changes in the clinicopathologic findings and survival of gastric cancer patients.

PURPOSE To determine the chronologic changes in the clinicopathologic features of gastric cancer patients. PATIENTS AND METHODS The clinicopathologic findings of 1,795 patients with gastric cancer were examined retrospectively from hospital records obtained between 1969 and 1995. The patients were divided into three generations on the basis of chronologic order. The first generation included patients treated over the period 1969 to 1977; the second generation, 1978 to 1986; and the third generation, 1987 to 1995. RESULTS The chronologic changes in the clinicopathologic findings for all gastric cancers included increases in the superficial type based on macroscopic appearance (P < .005), small-sized tumor (P < .025), superficial depth of invasion (P < .005), and earlier histologic stages (P < .005), in addition to a decrease in lymph node metastasis (P < .005). Overall, the postoperative survival rate has improved over time in gastric cancer patients, with 5-year survival rates of 36.0%, 53.3%, and 68.6% in the first, second, and third generations, respectively. In stages 1,2, and 3, the survival rate in the third generation was the highest of the three generations, whereas in stage 4, the survival rate did not differ between the three generations. Patients who underwent a D2 dissection showed a higher survival rate than those with D1 or D3 dissections, but there was no statistical difference in the survival of patients with D1, D2, and D3 dissections when stage 4 patients were excluded. CONCLUSION The chronologic changes in gastric cancer patients over the past 27 years have included an increase in the incidence of earlier-staged gastric cancers, which has had a significant impact on the improved postoperative survival rate.

Intensive Intraoperative Local Chemotherapy for Lymph Node and Peritoneal Metastases in Gastric Cancer

V uplynulých letech bylo v Evropě registrovano několik nových preparatů pro lecbu pokrocileho karcinomu prostaty – abirateron, enzalutamid a cytostatikum cabazitaxel. Pravě diky novým lekům, lecebným postupům a poznatkům v patogenezi choroby jsme schopni nemocným nejen zlepsit kvalitu života, ale dokonce jej i významně prodloužit.Two types of local chemotherapies were combined intraoperatively with gastric resection for gastric cancer. One chemotherapy was intralymph nodal injection of mitomycin C adsorbed on small activated c

Early gastric cancer mimicking advanced gastric cancer

The clinicopathological features of 37 early gastric cancers mimicking advanced gastric cancer were reviewed retrospectively, and were compared with 596 other early gastric cancers and 126 mp gastric cancers, defined as gastric cancer invading the muscularis propria of the stomach. A greater tumour size (P < 0.005), submucosal invasion (P < 0.005), lymph node and lymph vessel invasion (P < 0.005) and vascular invasion (P < 0.025) were found more frequently in early gastric cancers mimicking advanced gastric cancers than in other early gastric cancers. There were no significant differences in the clinicopathological findings between early gastric cancers mimicking advanced gastric cancers and mp gastric cancers. Patients with early gastric cancers mimicking advanced gastric cancers showed a lower survival rate than patients with other early gastric cancers, but a higher survival than those with mp gastric cancers. The macroscopic appearance of an advanced gastric cancer was an indicator of massive submucosal invasion and lymph node metastasis in early gastric cancer. As early gastric cancers mimicking advanced gastric cancers showed similar clinicopathological findings to mp gastric cancers, these cancers should be treated as mp gastric cancers.

Role of peritoneal lymphatics for peritoneal metastasis and chemotherapy with mitomycin C bound to activated carbon particles

SummaryBackgroundBased on the knowledge that omental milky spots take up cancer cells seeded in the peritoneal cavity as well as carbon particles, mitomycin C bound to activated carbon particles (MMC-CH) was examined in patients with advanced gastric cancer in a prospective randomized study.Methods104 patients who underwent gastrectomy for gastric cancer with definite serosal involvement were entered in this trial. Patients in the MMC-CH group were given 50 mg mitomycin C as MMC-CH dispersed throughout the peritoneal cavity just before surgical closure.Results3-year survival rates for all-over patients treated with MMC-CH was 48% and for patients without MMC-CH was 28%, the differences between these 2 groups being significant (p<0.05). In the patients with macroscopic peritoneal carcinomatosis, there was no difference in survival between these 2 groups. There were no operative deaths in this series but bowel fistula developed in 2 patients given MMC-CH.ConclusionsChemotherapy with MMC-CH improves the survival of patients with gastric cancer involving the serosa, but does not improve the survival of patients with evidence of macroscopic peritoneal carcinomatosis.ZusammenfassungGrundlagenDer Nachweis, daß an sogenannten «milky spots» des Peritoneums Kohlepartikel in gleicher Weise wie intraperitoneale Tumorzellen aufgenommen werden, führte zu einer prospektiven, randomisierten Studie über die Wirksamkeit von intraperitoneal verabreichtem, an Kohlepartikel gebundenem Mitomycin C bei Patienten mit lokal fortgeschrittenen Magenkarzinomen.Methodik104 Patienten mit Magenkarzinomen, entweder mit Serosainfiltration oder Carcinosis peritonei, wurden nach Gastrektomie in die Studie aufgenommen. Den der Therapiegruppe zugeordneten Patienten wurde vor Verschluß der Abdominalhöhle 50 mg an Kohlepartikel gebundenes Mitomycin C intraperitoneal instilliert.ErgebnisseDie 3-Jahres-Überlebensrate für Patienten der Therapiegruppe betrug 48%, für Patienten der unbehandelten Kontroll-gruppe 28% (statistisch signifikanter Unterschied, p<0,05). In der Subgruppe der Patienten mit makroskopisch bereits sichtbarer Carcinosis peritonei konnte kein Unterschied zwischen Therapie- und Kontrollgruppe hinsichtlich der Überlebenszeit gefunden werden. Operationsbedingte Todesfälle traten keine auf, in der Therapie-gruppe entwickelten sich bei 2 Patienten Darmfisteln.SchlußfolgerungenIntraperitoneale Chemotherapie mit an Kohlepartikel gebundenem Mitomycin C verbessert die Überlebensrate bei Patienten mit Magenkarzinomen mit Serosadurchbruch, beeinflußt jedoch nicht die Überlebensprognose bei bereits makroskopisch sichtbarer Carcinosis peritonei.