Intraperitoneal hyperthermic perfusion with mitomycin C for colorectal cancer with peritoneal metastases

In 94 our of 2570 individuals vaccinated against tick-borne encephalitis (TBE) with FSME-Immun the level of IgG antibodies to TBE virus were tested. The examination was performed before and 2.5 years after the first dose of full cycle vaccination, which according to the manufacturer, consists of three doses. The maintenance of specific seroconversion was detected in 91.9% of the studied subjects. No statistically significant differences in antibody levels were found in the different age groups. None of the immunized subject developed TBE up to the present time.     

Clinical result of intraperitoneal hyperthermic chemoperfusion for gastric cancer with serosal invasion to prevent peritoneal recurrence

In order to evaluate clinical effects of intraperitoneal hyperthermic chemoperfusion (IHCP) to prevent peritoneal recurrence in gastric cancer patients with serosal invasion, the clinical outcome was studied in 126 gastric cancer patients with macroscopic serosal invasion. Results of 59 patients who had surgery combined with IHCP (IHCP group) were compared with those of 67 patients who had surgery alone (control group). IHCP was performed for 120 minutes just after surgery under hypothermic general anesthesia with perfusate containing 10 micrograms/ml of mitomycin C. The inflow temperature and the outflow temperature of the perfusate were controlled to be 44.5 approximately 45 degrees C, and 43 approximately 44 degrees C, respectively. The 2-, 4- and 8-year survival rates for the IHCP group were 86%, 74% and 66%, respectively, against 78%, 59% and 50%, respectively, in the control group. The survival rates of the IHCP group were significantly better than those of the control group. Peritoneal recurrences after surgery were encountered in one of 59 patients in the IHCP group and 17 of 67 patients in the control group. The peritoneal recurrence rate of the IHCP group was significantly lower than that of the control group. These results suggest that IHCP treatment is effective in prevention of peritoneal recurrences after surgery for gastric cancer patients with serosal invasion.     

A case of gastric cancer with peritoneal dissemination and malignant biliary stenosis treated by loco-regional cancer therapy

A 68-year-old male diagnosed as Borrmann 2 type gastric cancer (T3N3P3H0M0: Stage IVb) was treated by distal gastrectomy and administration of CDDP 50 mg+MMC 10 mg intraperitoneally. After operation intraperitoneal chemotherapy was continued until adhesional ileus occurred four months later. At reoperation peritoneal dissemination was not found either macroscopically or microscopically. After four months, and expandable metallic stent (Wallstent) was applied for malignant biliary stenosis due to lymph node metastasis. Although the patient died 23 months after the first operation, our loco-regional cancer therapy seemed effective for support of quality of life.     

Intraperitoneal hyperthermic treatment of implanted peritoneal cancer in rats

The feasibility and efficacy of treating peritoneal cancer implants by applying heat to the peritoneal surfaces were studied in inbred Buffalo A rats given i.p. injections of Morris hepatoma 5123TC tumor cells. Heat was delivered to the peritoneum by contact with a heated physiological salt solution (Normosol-R) in the peritoneal cavity. A treatment temperature of 43.3 +/- 0.3 degrees was maintained for 30 min by an immersed stainless steel coil through which hot liquid circulated. Rats implanted with 0.5 to 1.0 x 10(8) tumor cells were treated at 1 to 4 hr (Group I), 4 to 5 days (Group II), and 22 to 24 days (Group III) after tumor implantation to simulate treatment for the clinical conditions of surgically spilled cancer cells, established microscopic cancer implants, and macroscopic cancer implants, respectively. A statistically significant improvement in survival was observed in Groups I and II compared with sham-treated control animals; 58% of the heat-treated animals were cured. Only a slight but statistically insignificant improvement was noted in Group III. These observations indicate that i.p. surface heat treatment of peritoneal implanted cancer is feasible and effective.     

Intraperitoneal hyperthermic chemotherapy in gastric cancer: rationale for a new approach

A survey of ectoparasites from 219 meadowlarks conducted during 2 consecutive fall-winter periods in a coastal prairie found immature Amblyomma maculatum Koch to be the most abundant parasite. Peak larval infestations occurred in December with 80-100% of collected birds infested and with a monthly mean of up to 34 larvae per bird. Peak nymphal infestations occurred in February or March with 95-100% of birds infested and with a monthly mean of up to 11 nymphs per bird. Seasonal dynamics of these stages offered possible insight into the persistence of A. maculatum in an area long infested with the red imported fire ant, Solenopsis invicta Buren. Four other species of ticks also were collected but in substantially lower numbers; Amblyomma cajennense (F.), Amblyomma inornatum (Banks), Haemaphysalis chordeilus (Packard), and Haemaphysalis leporispalustris (Packard). This appears to be the 1st host record of A. cajennense from meadowlarks. A collection of 17 northern bobwhite quail indicated that most of these birds were infested with A. maculatum but at a lower level than meadowlarks. The collections of 2 species of Mallophaga from meadowlarks and 4 species from the northern bobwhite quail are discussed.     

Four long-surviving cases of gastric cancer with peritoneal dissemination treated by intraperitoneal administration of mitomycin C adsorbed on activated carbon particles

A new dosage format (MMC-CH) of mitomycin C, which is composed of mitomycin C on activated carbon particles, was efficacious for prevention of peritoneal recurrence of gastric cancer. However, it had no such excellent therapeutic effect on the survival of patients with peritoneal dissemination. Out of 50 patients with peritoneal dissemination of gastric cancer treated by intraperitoneal administration of MMC-CH, 4 patients have survived for long periods of time (39-80 months). However, all of the other 50 patients, who did not receive intraperitoneally administered MMC-CH, died of peritoneal carcinomatosis within two years.     

Low-dose CDDP and continuous 5-FU treatment of advanced gastric cancer with peritoneal dissemination: a case with long disease-free survival

The patient was diagnosed to have gastric cancer (T3 N3 M0 P3, Stage IV b). We conducted LcFP therapy. CDDP, 7 mg/m2/day, day 1-5 i.v. drip for 2 hours, and 5-FU, 170 mg/m2/day, day 1-7, i.v. continuously for 24 hours. After 3 courses (one course: 4 LcFPs followed by one rest week), down staging (T3 N2 M0 P1. Stage IV a) and improvement of performance status were obtained, and then surgical resection was undertaken. After operation one course of LcFP therapy served as adjuvant chemotherapy. The patient has survived over one year and 8 months to date in a tumor-free condition. LcFP therapy promises to be useful in the clinical management of advanced gastric cancer.     

Whole abdominal irradiation for peritoneal dissemination of alimentary tract cancers

Between January 1986 and August 1991, 19 patients with alimentary tract cancers complicated by peritoneal dissemination received whole abdominal irradiation combined with intraperitoneal chemotherapy postoperatively. Using a moving-strip technique of irradiation, 12.0 Gy was delivered in three fractions to the entire abdominal contents with partial liver and kidney shielding. The primary tumor sites were the stomach in 12 patients, the colorectum in five, and the gall bladder in two. Nine patients with gross residual disease also received a limited field boost of 30.6 Gy in 17 fractions after completion of treatment to the whole abdomen. None of the patients failed to complete the planned dose despite acute gastrointestinal toxicity (nausea and vomiting, 84%, diarrhea and cramping, 78%) and acute hematologic toxicity (leukocytopenia, 84%, thrombocytopenia, 68%). Our follow-up study revealed that the actuarial one-year survival rate was 28.4% and the median survival time was 9.0 months. Survival rates at one-year for patients with colorectal and gastric cancer were 75.0% and 16.7%, respectively. Patients with gastric cancer (n = 12) had a poorer outcome than those with colorectal cancer (n = 5) in the present study. One reason for this difference may have been the presence of cancerous pleuritis, which was frequently observed in patients with gastric cancer. Therefore, more intensive treatment to prevent cancerous pleuritis seems to be necessary to improve the efficacy of whole abdominal irradiation.     

Postoperative chemotherapy including intraperitoneal and intradermal administration of the streptococcal preparation OK-432 for patients with gastric cancer and peritoneal dissemination: a prospective randomized study

We studied the effects on survival time of postoperative immuno-chemotherapy, including the streptococcal preparation OK-432, in patients with gastric cancer and synchronous peritoneal dissemination. The patients were prospectively randomized and a valid statistical assessment could be made for 109. Patients randomized to group B received therapy that is widely used in Japan to treat patients with gastric cancer: mitomycin C (MMC) and UFT, a combination of tegafur and uracil in a molar ratio of 1:4, for 1 year. Patients randomized to group A received the same drugs as were given to group B patients plus OK-432 i.p. for 7 days, beginning on postoperative day 0, and OK-432 by intradermal injection for 1 year, at 2-week intervals. There were no differences between the two groups in any known prognostic factor or in the dose of any drug administered except for OK-432. There was no difference in the toxicity rate between the groups. In this negative trial, there was no improvement in survival time with the addition of OK-432 to MMC and UFT for patients with gastric cancer and peritoneal dissemination.     

Role of peritoneal lavage smears and gastric wall brushing smears in gastric cancer surgery

Examinations of peritoneal lavage smears (LC) and gastric wall brushing smear cytology (BC) appear to be important for determining accurately the stage of gastric cancer. We have been carrying out such examinations during gastric cancer surgery for 7 years. In the present study, we evaluated the results obtained from 287 patients with gastric cancer. Tumor invasion and peritoneal dissemination were correlated with a positive incidence of cancer cells in LC and/or BC. Gastric cancer showing serosal invasion was classified into positive for LC and/or BC and negative for LC and/or BC. Patients positive for LC and/or BC had a poorer prognosis. For future gastric cancer treatment, patients positive for peritoneal cytology are expected to be targeted for intensive treatment during or before surgery.     

Regional hyperthermic perfusion with cisplatin following surgery for malignant melanoma of the extremities

BACKGROUND: The study was undertaken to review our experience in the treatment of extremity melanoma with hyperthermic isolated limb perfusion (HILP), using cisplatin as the chemotherapeutic agent. We also evaluated the best timing for regional lymph node dissection in relation to the perfusion. PATIENTS AND METHODS: Sixty patients with advanced malignant melanoma of the limbs were treated with HILP used mainly as an adjuvant treatment. There were 56 lower- and 4 upper-limb HILPs. Cisplatin was used at a dose of 20 mg/L of limb volume. Temperature at the tumor site was 39 degrees C to 40 degrees C. Postoperative complications, disease-free period, and time to recurrence were recorded. RESULTS: There were no deaths related to the procedure. Forty-seven percent of the patients developed local complications; most complications were minor and resolved within 60 days. The local complication rate was higher when HILP was performed shortly after or simultaneously with regional lymph node dissection. None of the patients had systemic complications. Mean survival time from treatment was 87.2 months. Currently, 35 patients (58%) are alive and free of disease 52.7 +/- 22.5 months after HILP. Twelve patients (20%) are alive with recurrent disease, of which 5 recurred locally. The average time (+/- standard error of the mean) to recurrence was 24.5 +/- 13.8 months after perfusion. CONCLUSIONS: HILP with cisplatin is a relatively safe procedure, which seems to increase locoregional control of advanced malignant melanoma of the extremity. Separating the timing of lymph node dissection from HILP by 6 to 8 weeks reduces the complication rate.     

Anesthesiologic characteristics of isolated hyperthermic liver perfusion with mitomycin C

The isolated hyperthermic liver perfusion with mitomycin C presents a new technique of regional therapy for irresectable liver tumours. The advantage is a high local concentration of the antitumour agent with reduced systemic side-effects. Isolated hyperthermic liver perfusion is an extensive surgical procedure requiring a veno-venous bypass and a heart-lung machine. Disturbances affecting the base-acid hemostasis, the coagulation system and the cardiocirculatory function can occur. To date, there has been little experience with this technique. The intraoperative changes during the isolated hyperthermic liver perfusion in our series were similar to those seen during orthotopic liver transplantation. In contrast to orthotopic liver transplantation, heparin is given during the anhepatic phase. The reperfusion after isolated hyperthermic liver perfusion was not complicated by severe cardiocirculatory changes. A decrease in body temperature was not observed probably due to the absence of cold, potassium-rich perfusate flowing into the systemic circulation. Two patients developed signs of a reperfusion syndrome within the first hour after reperfusion (decrease in peripheral systemic resistance).     

Two distinct patterns of peritoneal involvement shown by in vitro and in vivo ovarian cancer dissemination models

We established an in vitro peritoneal dissemination model using six ovarian cancer cell lines and cultured mesothelial cells. Ovarian cancer cells were classified into two types, invasive or adhesive, on the basis of their interaction with the mesothelial cell monolayer. The ovarian cancer cell lines derived from mucinous cystadenocarcinoma, poorly differentiated adenocarcinoma and undifferentiated carcinoma, which belonged to the invasive type, began to invade beneath the mesothelial monolayer from several hours after seeding in vitro, expelling the mesothelial cells at the periphery and forming colonies directly on the dish surface. On the other hand, cancer cell lines of clear cell carcinoma, which belonged to the adhesive type, showed colony formation with adhesion on the mesothelial monolayer even 18 h after seeding. Invasive-type cell lines invaded into the mesothelial monolayer at various rates in vitro, and the degree of invasiveness showed good correlation with the degree of peritoneal dissemination in vivo after intraperitoneal injection of cancer cells into nude mice. Adhesive-type cells showed rather higher dissemination rates in vivo. Microscopic observation of in vivo peritoneal dissemination at one day after inoculation also revealed two patterns of peritoneal involvement similar to those in vitro. In the in vitro model, anti-integrin alpha 2- and beta 1-antibodies inhibited the infiltration of invasive-type cells into the mesothelial monolayer, but did not affect colony formation by adhesive-type cells on the monolayer, indicating that invasion by both cell types was mediated by different molecules. This in vitro model is thought to be useful for analysis of the molecular mechanisms of peritoneal dissemination.     

The hemodynamic changes during the intraperitoneal hyperthermic perfusion under induced hypothermia

We investigated the whole body oxygen consumption (VO2) and the hemodynamic changes during the intraperitoneal hyperthermic perfusion (IPHP), which was coupled with induced hypothermia to prevent the cerebral disorder. IPHP was carried out for 90-120 min with 45-47 degrees C perfusate after the operation. We induced hypothermia using the surface cooling method and the infusion of triflupromazin. In no patient, the pulmonary artery temperature (PAT) rose above 40 degrees C. In the IPHP, there was a significant correlation between VO2 and PAT. If PAT reached 42 degrees C during the IPHP, VO2 would increase to 130-140% of the value at 37-38 degrees C. This rise is smaller than that during the total body hyperthermia (TBH), in which VO2 at 42 degrees C reached 130-190% of the value at 38 degrees C. Heart rate increased in proportion to the rising rate of body temperature. During the IPHP, PAT sometimes rose remarkably about 8 degrees C (from 32 degrees C to 40 degrees C) with a marked rise in heart rate. This rising rate of PAT is greater than that of TBH, in which PAT rose about 4-5 degrees C (from 37-38 degrees C to 42 degrees C). We consider that IPHP is not applicable to the patients with ischemic heart disease. During the rise of PAT, other circulatory parameters related to IPHP, changed in the same direction as those related to TBH. The rate of change of these parameters related to IPHP was smaller than that of the TBH, because during the IPHP the highest PAT was lower than that during TBH.     

Comparison of temperatures from 7 points in the patients under intraperitoneal hyperthermic perfusion

We measured the temperatures from 7 points in the patients under intraperitoneal hyperthermic perfusion (IPHP), associated with induced hypothermia. The temperatures from the 7 points were as follows, pulmonary artery blood temperature (PAT), bladder temperature (BT), sole deep body temperature (ST), forehead deep body temperature (FT), external aural cannal temperature (EAT), esophageal temperature (ET), and rectal temperature (RT). We studied the relationship between PAT and the other 6 temperatures. During IPHP, DT rose up to nearly 40 degrees C, and we considered it very useful to judge the temperatures of the other intra-abdominal organs, which were in contact with the perfusate of IPHP. Judging from the difference of PAT and ST, ST was found useful to estimate the degree of insufficiency of the peripheral circulation. We calculated the correlation coefficients with PAT among the four points, and the order of the correlation coefficients was EAT > ET > FT > RT. EAT showed the highest correlation coefficient with PAT (r = 0.981), and we considered EAT can be a substitute for PAT during IPHP. ET also showed a high correlation with PAT (r = 0.959), but it showed an unusual rise in a case of hydrothorax with hot perfusate for IPHP. Therefore, ET cannot be used solely as a substitute for PAT, but ET can be used as a marker to find a complication of IPHP, hydrothorax.     

Isolated hyperthermic limb perfusion with melphalan and tumor necrosis factor in malignant melanoma

OBJECTIVE: To analyse a personal series of cases of malignant melanoma of a limb with regional metastasis treated by isolated cytostatic perfusion of both recombinant human tumour necrosis factor (rhTNF-alpha) and melphalan, reported to produce a response rate of up to 100%. PATIENTS AND METHODS: 23 isolated hyperthermic regional perfusions were performed between 1993 and 1995 in 21 patients (17 women, four men) with proven regionally metastatic malignant melanoma of the limb, using rhTNF-alpha and melphalan in combination. Perfusion time was 90 min, at a tissue temperature of 38 degrees to 40 degrees C and a perfusion pressure 10-15 mm Hg below mean arterial. RESULTS: All systemic effects of the limb perfusions were easily manageable under intensive care monitoring. There were no severe disturbances (WHO grade 3/4) of cardiovascular or pulmonary functions. One patient, who had sustained a marked leak during the perfusion, died two days after the perfusion of severe pneumonia and pulmonary emboli from a femoral vein thrombosis. Two further perfusions were terminated because of a leakage rate of more than 10%. A rise in bilirubin and the transaminases occurred in 11 of the 23 perfusions up to WHO grade 2 (n = 9) and 3 (n = 2). Renal functions were temporarily impaired in three of the 21 patients (WHO grade 1). Complete tumour regression was obtained in 13 patients, a partial one in three (response rate 80%). After a median follow-up period of 15 months five of the 13 patients developed a regional recurrence. CONCLUSION: The observed response rate is higher than that with melphalan alone as reported in the literature. To clarify this difference a randomized phase III study comparing the two methods has been initiated.