Morio Shirasu

Sigmoidofiberscopic incision plus balloon dilatation for anastomotic cicatricial stricture after anterior resection of the rectum.

Abstract. We describe the procedure and examine the therapeutic efficacy of a combination of sigmoidofiberscopic incision plus balloon dilatation for tubular stricture by thick, long scar tissue at the colorectal anastomosis after anterior resection for rectal cancer. Balloon dilatation alone does not always relieve the strictures, although this method is the usual therapy for this condition. Five patients were identified in whom the stricture was not improved with balloon dilatation alone. Of these five patients, three complained of difficulty defecating, a feeling of incomplete evacuation, residual feces, and lower abdominal fullness. The remaining two patients, who had transverse colostomy to treat major leakage at the anastomosis, showed no symptoms. All five patients underwent the combination therapy described below. Two or three small radial incisions were made in the scar of the stricture with electrocautery under fiberscopic vision. Then the strictural scar was split and loosened bluntly along the incisions over a 15- to 20-minute period with a balloon dilator. This procedure was performed once or twice at a 2-week interval. In all five patients the stricture was improved according to objective criteria. There was also an improvement in the subjective symptoms suffered by three patients. The improvements were maintained over observation periods of 9 to 15 months. No complications were observed. Sigmoidofiberscopic incision plus balloon dilatation is an effective, safe therapy for cicatricial strictures after anterior resection for rectal cancer when the strictures have failed to improve following balloon dilatation alone.

Selective drug delivery to peri-tumoral region and regional lymphatics by local injection of aclarubicin adsorbed on activated carbon particles in patients with breast cancer???a pilot study

ACR-CH, which consists of aclarubicin (ACR) adsorbed onto activated carbon particles, was developed for locoregional chemotherapy for breast cancer. Thirty patients with breast cancer received an ACR (10 mg) injection intra- and peritumorally, either as ACR-CH or as ACR aqueous solution (ACR-AQ) 5 min before the operation for breast cancer. The ACR concentrations were significantly higher in the peritumoral regions and regional lymph nodes, and were also significantly lower in the blood plasma in patients given ACR-CH versus patients given ACR-AQ

Therapeutic effects of the angiogenesis inhibitor TNP-470 against carcinomatous peritonitis in mice.

The therapeutic effects of the new anti-angiogenesis factor TNP-470 were examined against carcinomatous peritonitis in mice. In the first experiment using carcinomatous peritonitis caused by i.p. inoculation of 10(6) M5076 tumor cells, TNP-470 solution was injected i.p. in a bolus of 50 mg/kg body weight into two groups of 10 mice either 1 or 8 days after the i.p. inoculation. The administration of TNP-470 on day 1 extended the survival time of the mice compared with 10 control mice receiving no treatment, whereas TNP-470 given on day 8 did not affect the survival time. In the next experiment on the M5076 tumor, TNP-470 solutions at 100 or 300 mg/kg were injected i.p. in a bolus into two groups of 20 mice 1 day after the inoculation 10(6) tumor cells, respectively. The administration of TNP-470 at 100 mg/kg also had an inhibitory effect. However, TNP-470 at 300 mg/kg caused toxic death in half of the mice. Next, we examined the effects of TNP-470 on another type of carcinomatous peritonitis model, which was caused by i.p. inoculation of 10(6) B16 melanoma cells. In this experiment, TNP-470 solutions in a bolus of 150 mg/kg were injected i.p. into six groups of 10 mice each on day 1 only (group 1), on days 1 and 4 (group 2), on days 1, 4 and 7 (group 3), on day 8 only (group 4), on days 8 and 11 (group 5), or on days 8, 11 and 14 (group 6), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of peritoneal metastasis of cancer with dextran sulfate???an experimental study in mice

Peritoneal metastases occur most often in the greater omentum, where tumor implantation sites are densely distributed. We used dextran sulfate (S-Dex) as an anti-cell-adherence agent to prevent i.p. seeded malignant cells from causing peritoneal metastases. S-Dex was tested for its anti-adherent activity against B-16 melanoma cells on plastic, and was examined for its ability to prevent implantation in the omentum and to improve survival in mice after B-16 melanoma was inoculated i.p. S-Dex prevented B-16 melanoma cells from adhering to the plastic wall. S-Dex reduced the number of B-16 melanoma cells implanted into the greater omentum and improved the survival of mice inoculated with B-16 melanoma cells. We conclude that S-Dex attenuated peritoneal metastases when B-16 melanoma cells were seeded i.p.

Intraperitoneal injection of dextran sulfate as an anti-adherent drug for the prevention of peritoneal metastasis of cancer shows low toxicity in animals.

Intraperitoneal dextran sulfate with a mean molecular weight of 5×105 has been developed for use in an anti-adherent therapy against peritoneal carcinomatosis. The present study examined acute toxicity of i.p. injection of dextran sulfate in mice and rabbits. The 10, 50 and 90% lethal dose values are 0.213 (0.146-0.252), 0.336 (0.291-0.405) and 0.530 mg/g (0.431-0.873 mg/g: 95% confidence interval) in mice, respectively. These are markedly larger than the efficacious dose of 0.005-0.01 mg/g obtained previously. Death or symptoms of intoxication were seen within 3 days after administration of toxic doses. Rabbits received i.p. injection of dextran sulfate at 0.02 mg/g, which was close to the efficacious dose. At 2, 4, 6, 8 and 13 days after administration, blood was taken for biochemical and hematological analyses. Dextran sulfate at 0.02 mg/g induced no remarkable abnormal findings. These results suggest that the i.p. dextran sulfate is safe as an anti-adherent agent against peritoneal metastasis of cancer.

Polymerase chain reaction for detection of carcinoembryonic antigen-expressing tumor cells on milky spots of the greater omentum in gastric cancer patients: a pilot study.

Our recent studies indicate that omental milky spots are frequently involved in the early stage of peritoneal cancer dissemination. We have used carcinoembryonic antigen (CEA)‐specific RT‐PCR for omental milky spots to predict peritoneal recurrence in gastric cancer patients. CEA mRNA was found to be positive in both 10 peritoneal washes and 16 greater omenta of 30 gastric cancer patients, including all 6 patients who showed positive results for both cytology and RT‐PCR of peritoneal wash and omentum. Three of the 6 cases with positive RT‐PCR in the greater omentum but not in the peritoneal wash showed recurrence of peritoneal carcinomatosa within 2 years after operation. Micrometastasis on omental milky spots was histologically confirmed in 6 of 30 gastric cancer cases. Non‐specific band was detected only in the omentum of 1 case of 15 benign disease (7%), but not in peritoneal washes (0%), probably due to weak expression of CEA in mesothelial cells. Our results show that CEA‐specific RT‐PCR targeting micro‐metastases on omental milky spots is more sensitive than targeting the peritoneal wash or conventional cytology, and suggest that this method is useful for the prediction of peritoneal recurrence in gastric cancer patients.

Therapeutic effects of 5-fluorouracil microspheres on peritoneal carcinomatosis induced by Colon 26 or B-16 melanoma in mice

The delivery formulation 5-FU-MS [5-fluorouracil (5-FU) incorporated in microspheres composed of a poly(glycolide-co-lactide) matrix] slowly releases 5-FU over 3 weeks. 5-FU-MS delivers higher concentrations of the drug to the i.p. tissues for a longer period of time with lower blood plasma concentrations than does an aqueous 5-FU solution and reduces toxicity. In this study, we evaluated the therapeutic effects of 5-FU-MS on peritoneal carcinomatosis in mice. Four days after an i.p. inoculation with Colon 26 or B-16 PC melanoma, 5-FU at 200 mg/kg was administered i.p. as 5-FU-MS or as an aqueous solution of 5-FU. 5-FU-MS extended the survival of mice bearing Colon 26 or B-16 PC melanoma significantly better than the equivalent dose of aqueous 5-FU solution.

Endoscopic local injection of a new drug delivery formulation, anticancer drug bound to carbon particles, for digestive cancers: Pilot study

A new dosage formulation consisting of an anticancer drug bound to activated carbon particles was developed for the treatment of digestive cancer in patients in whom operation is contraindicated. The new formulation is designed to distribute higher levels of anticancer drug to the regional lymph nodes and at the injection site compared to distribution of the drug in aqueous solution. In 12 patients with histologically proven carcinoma (7 with superficial esophageal cancer and 5 with early or proper muscle layer-infiltrating gastric cancer), an anticancer drug bound to carbon particles (total dose, 40–100mg peplomycin or 250–500mg methotrexate per person) was injected endoscopically into the primary lesions. Eleven of the 12 patients are currently alive, 12–64 months after therapy, or they died without evidence of cancer 12–98 months after the treatment. One patient has remained cancer-free for 32 months after a second course of the new formulation therapy given to treat a recurrence detected 26 months after the first treatment. Endoscopic injection of this new dosage formulation seems to control these digestive cancers in patients in whom operation is contraindicated.

Role of omentum-associated lymphoid tissue in the progression of peritoneal carcinomatosis

The peritoneal cavity is vulnerable to the implantation of cancer cells that have escaped from a primary tumor into the peritoneal cavity. Although peritoneal metastases have been assumed classically to occur at random in every portion of the peritoneal membrane, they actually occur at anatomically or physiologically preferred sites, such as the greater omentum, diaphragm, and pelvic peritoneum [1]. An important function of the peritoneum is associated with the lymphatic system of the peritoneal cavity that helps to maintain its homeostasis [2]. In the greater omentum there are many omentum-associated lymphoid tissues (OALT), known as milky spots. The OALT acts a filter through which lymph and various substances are rapidly taken up, and it participates in the immune defense of the peritoneal cavity [3]. The OALT also plays an important role in the initial stages of peritoneal carcinomatosis.

Increased Apoptosis Rate by Hyperthermochemoradiotherapy for Advanced Rectal Cancers

Apoptosis induced in cancer cells by ionizing radiation, hyperthermia, and 5-fluorouracil (5-FU), termed “hyperthemochemoradiotherapy” (HCR), has been well studied in vitro; however, the role of apoptosis in the tumocidal effect of HCR for primary rectal cancers has not yet been clarified. Therefore, we examined the relationship between the therapeutic effect and induction rate of histological apoptosis in 16 patients with rectal cancers after HCR. Numerous Tunel-positive apoptotic cells were found in the tumor tissue after HCR, but few were found in the tumors which had not received HCR. The histological therapeutic effect was closely correlated to the rate of apoptosis. Thus, we suggest that HCR induces a therapeutic effect mainly through apoptosis in human rectal cancers.