Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous hyperthermic peritoneal perfusion with mitomycin C

Continuous hyperthermic peritoneal perfusion (CHPP) with a solution that contains mitomycin C (CHPP-M) has been clinically introduced as a prophylactic treatment for peritoneal recurrence of gastric cancer with serosal invasion. Two studies, each with a treated and a control group, were performed. In the historical control study the postoperative 3-year survival rate of patients (73.7%) in the treated group (n = 38) was significantly higher than the survival rate (52.7%) of those in the control group (n = 55) (P less than 0.04). In the random control study the survival rate (83%) of patients in the treated group (n = 26) was also higher than that (67.3%) of those in the control group (n = 21) in the 30 months that followed gastric surgery. However, there was no significant difference. In the historical control study with respect to the postoperative complications, anastomotic leak was observed in 8.5% of patients who were given CHPP-M and 12.8% patients who did not have CHPP-M. In the random control study anastomotic leak was observed in 3.1% of patients who had CHPP-M and 7.1% of patients who did not have CHPP-M. The incidence of adhesive ileus in patients having CHPP-M did not increase in historical or random control groups. Postoperative prolonged intestinal paresis or chemical peritonitis were not induced by CHPP-M. These results indicate that CHPP-M is a simple, safe, and readily available prophylactic therapy for peritoneal recurrence that may follow gastric cancer surgery.     

The effect of continuous hyperthermic peritoneal perfusion using high-dose cis-diamminedichloroplatinum for peritoneal dissemination of gastric cancers

A continuous hyperthermic peritoneal perfusion using high-dose cis-diamminedichloroplatinum (CDDP) and its antidote, sodium thiosulfate, was applied to eight patients with peritoneal metastasis from gastric cancers. Two of eight patients showed partial response and the rate of decrease of ascites was 38%. Renal failure and leukopenia were observed in one and two patients, respectively, but no severe or lethal dysfunction was observed and all were tolerated. These results showed that CDDP exerted anti-tumor effects on peritoneal metastasis from gastric cancers when used in high doses in combination with hyperthermia.     

Continuous hyperthermic peritoneal perfusion with cisplatin and mitomycin C for peritoneal dissemination in gastric cancer

Thirty-four patients with advanced gastric cancers had received continuous hyperthermic peritoneal perfusion (CHPP) for prevention or treatment of peritoneal dissemination (PD). These patients received intra-abdominal perfusion 30-40 minutes by about 10-liter saline heated to 50-52 degrees C dissolving 200-300 mg cisplatin (CDDP) and 20-30 mg mitomycin C (MMC). The perfusate was infused in the peritoneal cavity through the peritoneal cavity expander (PCE Nihon Kayaku Co. Ltd.) newly developed for sufficient irrigation in our clinic. Eleven patients with macroscopic serosal invasion without PD (P0) or with mild PD (P1) underwent prophylactic CHPP for prevention of peritoneal recurrence. (Pn means degree of PD according to The General Rules for the Gastric Cancer Study.) Twenty-three patients with moderate PD (P2) or severe PD (P3) underwent therapeutic CHPP. The prognosis of patients having undergone prophylactic or therapeutic CHPP (CHPP (+) group) was compared with those not having done CHPP (CHPP (-) group) in the historical control study. In the prophylactic study two-year-survival rates of CHPP (+) group was 90% significantly higher than 63% in CHPP (-) group. There was no significant difference between two-year-survival rates of CHPP (+) (11%) and CHPP (-) (0%) in the therapeutic CHPP. But ascites was observed to disappear in five of twelve (41.7%). Surprisingly second look operation disclosed macroscopic and microscopic disappearance of PD in three of nine (33.3%). The side-effects in those patients had consisted of leakage, bone marrow suppression, perforation of small bowel and so on. But there was no mortality after introduction of PCE. About laboratory data, rises in WBC, BUN, creatinine and LDH and drops in total lymphocytes counts and platelets were all normalized within four weeks. The maximal concentrations of total and free, which emerged at five minutes after CHPP, were 2.19 and 1.29 micrograms/ml. These results suggested that CHPP with CDDP and MMC was well tolerated and effective for prevention of peritoneal recurrence and treatment of peritoneal dissemination in the gastric cancer.     

Malignant peritoneal mesothelioma treated by continuous hyperthermic peritoneal perfusion chemotherapy

Malignant mesothelioma of the peritoneum is a rare tumour for which thetherapeutic approach has not yet been standardized. The efficacy of thecurrent regimes is limited. Effective locoregional therapy is crucial, sincethis tumour is most often confined to the peritoneal cavity at the time of theinitial diagnosis and remains there for much of its clinical course. If andwhen haematogenous metastases occur, they rarely contribute to the death ofthe patient, which is often caused by the overgrowth of the primary tumour andits local complications. A case of diffuse malignant peritoneal mesotheliomatreated by cytoreductive surgery and continuous hyperthermic peritonealperfusion with cisplatin is reported. The patient received systemiccombination chemotherapy postoperatively. She is in good condition and freeof disease 28 months after her treatment. Continuous hyperthermic peritonealperfusion chemotherapy has recently been used in patients with secondaryperitoneal carcinomatosis from digestive and gynecological malignancies withpromising results. It is also possible that the same treatment alone or incombination with systemic chemotherapy may be effective in the treatment ofprimary peritoneal malignancies, as in the case of diffuse peritonealmesothelioma.     

Treatment of gastric cancer patients with peritoneal metastasis by continuous hyperthermic peritoneal infusion with mitomycin C and cisplatin

Following the resection of its primary lesion, continuous hyperthermic peritoneal perfusion (CHPP) with anticancer drug (mitomycin C, cisplatin) containing warmed physiological saline was performed on gastric cancer having peritoneal dissemination, and the effect of CHPP was examined by second look operation (SLO). The subjects were 41 cases of gastric cancer with peritoneal dissemination but without hepatic metastasis, which we have experienced in the past 7 years. The prognosis of these CHPP-treated cases was such that 50% survival period, 3 year survival rate and 5 year survival rate were 398 days, 28.5 and 12%, respectively. Comparison of the effects of CHPP by SLO revealed remarkable diminution of the peritoneal dissemination in 7 (44%) of 16 cases and disappearance of the ascites with a single course of CHPP in 7 of ascitic cases. Long-term survival (greater than 3 years) was noted in 4 of the CHPP-treated cases. Side effects were renal insufficiency, leukopenia and small intestinal perforation in 2(5), 2(5) and 1 cases (2%), respectively. The above results suggested the effectiveness of CHPP for the treatment of gastric cancer having peritoneal dissemination.     

Effectiveness of continuous hyperthermic peritoneal perfusion for the peritoneal dissemination of gastric cancer

We investigated the effectiveness of continuous hyperthermic peritoneal perfusion (CHPP) for the peritoneal dissemination of gastric cancer. A total 124 patients with advanced gastric cancer were enrolled in this study. Prophylactic CHPP (P-CHPP) was performed in 45 patients who had macroscopic serosal invasion without peritoneal dissemination, and 79 patients without CHPP were a control group. Therapeutic CHPP (T-CHPP) was performed in 21 patients with peritoneal dissemination, and 52 patients without CHPP were a control group. There was no significant difference in 5 year survival between patients treated and not treated with P-CHPP. Univariate analysis showed that location of tumor, tumor diameter, and lymph node metastasis influenced prognosis, but there was no prognostic factor in the Cox proportional regression hazard model. There was no significant difference in 5-year survival between patients treated and not treated with T-CHPP. Univariate analysis showed that degree of peritoneal dissemination and adjuvant chemotherapy influenced prognosis, and the Cox proportional regression hazard model showed that the macroscopic types and degree of peritoneal dissemination affected prognosis. In the patients with CHPP, the incidences of respiratory failure and renal failure were each statistically greater than in the patients undergoing CHPP.     

Closed continuous hyperthermic peritoneal perfusion model in mice with peritoneal dissemination of colon 26

An original model of closed continuous hyperthermic peritoneal perfusion (CHPP) in mice is presented and was found to support the efficacy of intraperitoneal hyperthermia. Closed CHPP was performed after intraperitoneal inoculation of transplantable colon 26 cells into a mouse. Colon 26 cells (5 × 10⁴) were injected into 18 mice. The mice were then allocated to six groups of three each and subjected to peritoneal perfusion over time. Peritoneal washings from each mouse were sampled and counted by the cytosmear method. On day 10 after inoculation, colonies of the disseminated tumour were seen on the mesentery by staining with 0.1% methylene blue for 5?min. The number of tumour nodules on the mesentery was counted. The number of washed-out tumour cells decreased the most at 24?h after inoculation, and 76% of the inoculated cells did not wash out during the peritoneal perfusion procedure. CHPP was performed after 24?h when colon 26 cells were injected into the peritoneal cavity because this status may represent micrometastasis. The total number of nodules on the mesentery in the CHPP group was significantly smaller than that in the control (p<0.02). In conclusion, because this treatment model is similar to the clinical CHPP, the biostaining model might be useful for the evaluation of peritoneal dissemination and it was unique and valuable in demonstrating an effective treatment for the prevention of peritoneal dissemination.     

Closed continuous hyperthermic peritoneal perfusion model in mice with peritoneal dissemination of colon 26.

An original model of closed continuous hyperthermic peritoneal perfusion (CHPP) in mice is presented and was found to support the efficacy of intraperitoneal hyperthermia. Closed CHPP was performed after intraperitoneal inoculation of transplantable colon 26 cells into a mouse. Colon 26 cells (5 x 10(4)) were injected into 18 mice. The mice were then allocated to six groups of three each and subjected to peritoneal perfusion over time. Peritoneal washings from each mouse were sampled and counted by the cytosmear method. On day 10 after inoculation, colonies of the disseminated tumour were seen on the mesentery by staining with 0.1% methylene blue for 5 min. The number of tumour nodules on the mesentery was counted. The number of washed-out tumour cells decreased the most at 24 h after inoculation, and 76% of the inoculated cells did not wash out during the peritoneal perfusion procedure. CHPP was performed after 24 h when colon 26 cells were injected into the peritoneal cavity because this status may represent micrometastasis. The total number of nodules on the mesentery in the CHPP group was significantly smaller than that in the control (p < 0.02). In conclusion, because this treatment model is similar to the clinical CHPP, the biostaining model might be useful for the evaluation of peritoneal dissemination and it was unique and valuable in demonstrating an effective treatment for the prevention of peritoneal dissemination.     

Cytohistologic assessment of antitumor effects of intraperitoneal hyperthermic perfusion with mitomycin C for patients with gastric cancer with peritoneal metastasis.

For 15 patients with refractory gastric cancer and peritoneal metastasis, intraperitoneal hyperthermic perfusion (IPHP) using mitomycin C combined with extensive surgery was prescribed. The antitumor effects were assessed cytohistologically in pre-IPHP and post-IPHP specimens of the abdominal effusion and peritoneal tissue. Gastric cancer cells in the abdominal effusion and/or lavage vanished from post-IPHP peritoneal exudate obtained from the pouch of Douglas. Peritoneal tissues from nine patients were harvested just after the IPHP treatment. All the nuclei of cancer cells were pyknotic in three of nine patients, and two of these three patients are alive with no local recurrence; one patient died of hepatic metastasis. In the remaining six patients, four with preoperative ascitic effusion and positive post-IPHP histologic findings died of peritoneal, intraabdominal, and pericardial metastases. The other two had some residual microscopic foci in the subperitoneal deep layer; one patient died of pleural recurrence, and the other is alive with no evidence of recurrence 42 months after the IPHP. Among the other six patients, whose post-IPHP peritoneal tissues were not available because of disappearance of disseminating foci as a result of the IPHP, two are living with no recurrence and, of the remaining four patients, three died of hepatic and intraabdominal metastases and the other one died of other causes. The histologic findings are suggestive of the following: (1) uniform heat and drug distribution in the abdominal cavity with IPHP treatment, except for an area adjacent to the inflow point of the perfusate; and (2) limited penetration of heat and drug through the subperitoneal layer. Thus, IPHP treatment results in complete destruction of cancer cells in the abdominal effusion and on and just beneath the peritoneum.     

Pharmacokinetic analysis in intraperitoneal hyperthermic perfusion using mitomycin C in far-advanced gastric cancer

Postoperative intraperitoneal hyperthermic perfusion (IPHP) using MMC was performed with marked success on 15 gastric cancer patients with peritoneal dissemination or serosal invasion (first surgery group) and on 5 recurrent gastric cancer patients with ascitic retention (recurrent cancer group), and the MMC concentrations was studied in the perfusate and circulating blood. The perfusate contained MMC 10 micrograms/ml at the onset of IPHP, except one recurrent case of 20 micrograms/ml, and IPHP was performed for 120 minutes except in one case given 20 micrograms/ml of MMC. There was little difference in the hepatorenal functions and perfusate temperatures between the first surgery group and the recurrent cancer group. The drug levels were measured by HPLC method with minimal assay levels of 2 ng/ml. Perfusate drug levels in the first surgery group reduced by half at 12 minutes after the start of IPHP, whereas in the recurrent cancer group, they decreased by half about 60 minutes later. Perfusate drug levels in the first surgery group decreased twice as rapidly as in the recurrent cancer group. The area under the curve (AUC) and average drug levels in the first surgery group were 7,900 micrograms.hr/l and 3.3 micrograms/ml, respectively, and those in the recurrent cancer group were 12,620 micrograms.hr/l and 5.3 micrograms/ml, respectively. On the other hand, the drug levels in peripheral blood were almost the same between the two groups. These data suggest that although recurrent gastric cancer is well suited for IPHP because of high AUC, it is worthwhile performing IPHP combined with surgery for gastric cancer with peritoneal seeding, with due consideration for AUC of 7,900 micrograms.hr/l and the average drug level of 3.3 micrograms/ml.     

A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small-volume residual ovarian cancer

Purpose: Because intraperitoneal (i.p.) therapy may provide a therapeutic advantage and because hyperthermia enhances carboplatin (CBDCA) cytotoxicity, we evaluated the feasibility, toxicity, and pharmacokinetics of CBDCA given via continuous hyperthermic peritoneal perfusion (CHPP) in patients with small-volume residual ovarian cancer. Patients and Methods: Six patients underwent optimal cytoreductive procedures (residual disease ≤5 mm) as initial treatment of stages II and III epithelial ovarian adenocarcinoma. All patients received a 90-min CHPP at a CBDCA dose of 800–1200 mg/m², with the perfusate being recirculated rapidly from a reservoir through a heat exchanger, resulting in i.p. temperatures of 41–43 °C. Plasma, perfusate, and urine samples were collected and platinum was quantified by flameless atomic absorption spectrophotometry. Results: At no time did any patient's core temperature exceed 40 °C. Peak perfusate platinum concentrations were 8- to 15-fold higher than peak ultrafilterable plasma concentrations. The permeability-area product was extremely high and variable (14–90 ml/min), resulting in a regional advantage of 1.9–5.3. The percentage of the dose absorbed ranged widely from 27% to 77%. Dose-limiting hematologic toxicity was observed at a dose of 1200 mg/m² and this was associated with a CBDCA AUC in plasma of 11 mg min ml⁻¹. Conclusions: CHPP with CBDCA was safely given to three patients at a dose of 800 mg/m², and dose-limiting hematologic toxicities observed at 1200 mg/m², correlated with the plasma CBDCA exposure established when lower doses of CBDCA are given systemically. The pharmacokinetic data are consistent with the expected effect of vigorous mixing on the exposed peritoneal surface area. Variable drug absorption and clearance make the prediction of systemic exposure highly uncertain. These findings may have important implications for novel therapies given i.p. Received: 9 March 1998 / Accepted: 11 June 1998     

Treatment of implanted peritoneal cancer in rats by continuous hyperthermic peritoneal perfusion in combination with an anticancer drug

To study the feasibility of combined hyperthermic and anticancer drug treatment for peritoneal cancer, we devised a continuous hyperthermic peritoneal perfusion system in combination with mitomycin C. The model uses i.p.-transplantable rat ascites hepatoma 100B cells. Hyperthermic peritoneal perfusion alone or combined with mitomycin C was performed after i.p. inoculation of the tumor cells into rats. In rats treated with combined peritoneal perfusion (41.5 degrees) and mitomycin C, the mean survival times were significantly prolonged as compared to those of rats treated with peritoneal perfusion at 41.5 degrees alone. Our results suggest that combined hyperthermic peritoneal perfusion and mitomycin C treatment may represent a therapeutic and prophylactic treatment for peritoneal metastasis after gastric cancer surgery in humans.     

Clinical pharmacokinetics of high-dose mitomycin C

Summary The pharmacokinetic profile of high-dose mitomycin C was determined in blood plasma and urine of twelve patients with advanced malignancies in a program including autologous bone marrow transplantation. A total dose of 60 mg/m² was given, either as a single 60-min infusion or divided into infusions of 30 mg/m² on each of 2 days or 15 mg/m² on each of 4 days. One group was given 15-min infusions. Samples of blood plasma and urine were analyzed by high-performance liquid chromatography. Drug concentrations in plasma followed a biphasic pattern, with a terminal elimination half-life of 45 min. This half-life value and other parameters were unaffected by dose level, infusion time, and repeated doses. The lower peak plasma concentrations following 30 mg/m² given as 60-min infusions compared to the same dose given over 15 min may have accounted for a dramatic drop in the incidence of a severe hemorrhagic colitis. Mitomycin C was excreted in urine at about the same rate as it was eliminated from plasma, but a larger percentage of the dose appeared in urine after 15-min infusions than after 60-min infusions. The pharmacokinetic profile, together with clinical observations, suggests that the dose-limiting toxicity of mitomycin C may be related to peak drug levels, and that both these levels and the toxicity are lessened as the infusion time is increased.     

Pharmacokinetics of mitomycin C after resection of peritoneal carcinomatosis and intraperitoneal chemohyperthermic perfusion

Over the last few years surgery on patients with abdominal malignancies has become more aggressive but the majority of patients present locoregional recurrence as peritoneal dissemination. Cytoreductive surgery followed by intraperitoneal chemohyperthermic perfusion (ICHP) has been described for treatment and prevention of locoregional cancer spread from various origins. This paper reports our study of the pharmacokinetics of mitomycin C (MMC) administered by intraperitoneal chemohyperthermic perfusion (ICHP) in patients with peritoneal carcinomatosis. 28 patients received MMC 20 mg/m2 intraperitoneally as a perfusion over 60 min. MMC was determined in perfusate, plasma and urine samples with a UV-HPLC method. A compartmental model was used to fit the drug concentrations in plasma and perfusate. Our results showed a mean maximum plasma concentration (Cmax) of 0.14 +/- 0.086 microg/ml with a peak time (Tmax) of 48..7 +/- 5.61 min. The mean area under the curve (AUC) and terminal half-life (t1/2) were 15.8 +/- 9.8 mg x min/L and 83.7 +/- 31.74 min respectively. Clearance (CL) was estimated by fitting the data by a compartmental model and the mean value was 72 +/- 66 L/h. The percent of the dose absorbed was very variable and ranged between 14 and 57% (mean 37 +/- 14%). The mean percentage of dose recovered unchanged in the urine during 24 hours was 7.21 +/- 3.73%. We conclude that ICHP in patients with peritoneal surface malignancies seems to have clinical value since it gives high peritoneal and tumor MMC concentrations with limited systemic exposure and toxicity.     

Total body hyperthermia and continuous hyperthermic peritoneal perfusion as an adjuvant therapy in advanced gastric cancer

Between September 1986 and July 1989, adjuvant hyperthermic therapy, consisting of either total body hyperthermia (TBHT) or continuous hyperthermic peritoneal perfusion (CHPP), was given to a total of 41 patients immediately following gastric resection for cancer. TBHT was performed in 1 curative- and 11 noncurative-gastrectomized patients (1 stage III and 11 stage IV), and CHPP in 18 curative- and 11 noncurative-gastrectomized patients (6 stage I/II, 10 stage III and 13 stage IV). For TBHT, the blood was warmed and maintained at 42 degrees C for 3 hours by means of a V-V bypass connected to an extracorporeal heater-pumping system. When the hyperthermic condition was established, anti-cancer drugs were administered intravenously. In CHPP, 46 degrees C saline containing anti-cancer drugs were infused at a constant rate through a tube placed at the Douglas fossa. The perfusate was drained out through another tube positioned at an uppermost part of the abdominal cavity. The hyperthermic condition was monitored by measuring the outflow temperature. Complications encountered were bone marrow depression, liver damage and pyrexia, and were more frequently experienced by the TBHT patients. Patients under 65 years of age who had had an absolute noncurative gastrectomy but with TBHT survived significantly longer than those without TBHT. When the patients who had undergone gastrectomy with CHPP for a cancer of more than se penetration were compared with those without CHPP, there was no significant difference in survival found between these two populations. This unsatisfactory result could be partly attributable to difficult maintenance of appropriate (sufficiently high) and constant perfusate temperature.     

腹腔热灌注化疗联合静脉化疗治疗晚期胃肠道肿瘤的疗效

目的探讨腹腔热灌注化疗联合静脉化疗对晚期胃肠道肿瘤患者的治疗效果。方法选择70例晚期胃肠道肿瘤患者,按照临床试验数字随机法分为治疗组和对照组,每组35例。对照组患者予以静脉化疗进行治疗,治疗组患者在对照组的基础上加用腹腔热灌注化疗进行治疗,比较两组患者的治疗效果、生存时间、不良反应以及免疫功能变化。结果治疗组患者的治疗有效率为68.6%,显著优于对照组的40.0%(P<0.05)。治疗组患者生存期显著高于对照组(P<0.05)。治疗组患者不良反应发生率低于对照组,但差异无统计学意义(P>0.05)。治疗组患者术后CD3+T细胞、CD4+T细胞水平升高,CD8+T细胞水平降低(P<0.05)。对照组患者CD3+T细胞、CD4+T细胞、CD8+T细胞水平变化不大(P>0.05)。结论与单纯静脉化疗相比,腹腔热灌注联合静脉化疗能有效治疗晚期胃肠道肿瘤患者,治疗有效率高,患者生存率高,不良反应率低。     

Selective delivery of high levels of mitomycin C to peritoneal carcinomatosis using a new dosage form

Selective delivery of a high level of Mitomycin C (MMC) in intraperitoneal disseminated lesions was studied using a new dosage form of MMC, called MMC-CH. Intracavitary MMC-CH delivered a much higher level of MMC selectively to intraperitoneal tissues, with a much lower level of MMC in the whole body, in comparison with MMC solution. The index [MMC level in the intraperitoneal organs]: [MMC level in blood] was much higher and increased with time in the MMC-CH group, but not in the MMC solution group.     

Desmoplastic small round cell tumor: review of therapy including surgery followed by continuous hyperthermic peritoneal perfusion of chemotherapy

Desmoplastic small round cell tumor (DSRCT) is a very rare disease of children, adolescents, and young adults and involves the abdominal cavity. DSRCT has characteristic fusion gene involving EWS1 and WT1 translocation, t(11;22)(p13;q12). Unlike Ewing’s sarcoma of bone, DSRCT usually presents with diffuse peritoneal implants that are prone to recur. The primary organ of origin of DSRCT is mesenchyme of the peritoneum. This makes it a very unique tumor that is difficult to treat because of the infiltrative and diffuse nature of the peritoneum. The challenge of local control is to remove dozens to hundreds of tumors studding the peritoneal cavity, and then eliminate microscopic disease. We review a sequential multimodality strategy to reduce macroscopic and microscopic disease including neoadjuvant chemotherapy, aggressive surgery including an emerging new therapy to use after surgery to treat microscopic residual disease: continuous hyperthermic peritoneal chemotherapy, then radiation and adjuvant chemotherapy.     

Multifocal soft tissue sarcoma: limb salvage following hyperthermic isolated limb perfusion with high-dose tumor necrosis factor and melphalan

BACKGROUND AND OBJECTIVES: The prognosis for recurrent multifocal limb soft tissue sarcoma (STS) is dismal due to systemic spread. However, many of these patients undergo amputation due to ineffective local control. The purpose of the present study was to determine whether isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan permits limb salvage and palliation for such patients. METHODS: Of 53 STS patients treated with hyperthermic ILP with TNF (3-4 mg) and melphalan (1-1.5 mg/kg), 13 (25%) had multifocal STS and were candidates for amputation. RESULTS: The overall response rate was 92% (12/13) with 38% complete response and 54% partial response. Two patients died during the early postoperative period. Limb salvage was achieved in 85% of patients. One patient (8%) had only stable disease and underwent amputation. Local recurrence occurred in 38% but did not result in amputation. CONCLUSIONS: Although the number of patients in this study is too small to allow definitive conclusions, it seems that ILP/TNF offer limb salvage and palliation for recurrent multifocal STS patients.