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For the first time comparative study of open and closed techniques of hyperthermic intraperitoneal chemoperfusion (HIPEC) in terms of safety and efficacy was performed in a rat model of ascetic ovarian cancer transplanted intraperitoneally. Original device and implantation technique of the device into peritoneal cavity were developed and used in the study. All animals after tumor implantation were randomized into 4 groups: 1 - control, intraperitoneal administration of 0.5 ml of saline (n=19); 2 - closed HIPEC with cisplatin, 20 mg/ kg (n=15); 3 - open HIPEC with cisplatin, 16 mg/kg (n=16); 4 - open HIPEC with mitomycin C (n=10). In preliminary stage while working out the original open technique of HIPEC we established that it requires dose reduction for cisplatin from 20 to 16 mg/kg compared to closed technique of HIPEC. We didn't find significant difference between groups 1, 2 and 3 in terms of number of postoperative complications. According to the results of analysis of body weight changes in postoperative period open HIPEC was worse tolerated compared to close HIPEC. Median survival of rats in group 2 was 53 days which was significantly higher compared to median survival in group 2-25 days (p=0,044). Open HIPEC with mitomycin C turned out to be less effective than open HIPEC with cis-platin but equally effective compared to closed HIPEC with cisplatin. However this is preliminary result and more rats have to be included in group 4 in order to make confident conclusion. Overall open HIPEC with cisplatin in accordance with suggested technique seem to be more promising than closed HIPEC in terms of improving outcomes of patients with peritoneal carcinomatosis.

A comparative statistical study of the results of eight independent experiments on the efficacy of intraperitoneal chemotherapy has been performed. The regiments of cathether intraperitoneal chemotherapy (CIPC), normothermic and hyperthermic chemoperfusion (NIPEC and HIPEC) with antitumor drug dioxadet were investigated in 288 female Wistar rats with ascitic ovarian cancer. Ovarian cancer was transplanted intra-peritoneally (i.p.) 48 hours prior to a single chemotherapy at a number of 1*107 tumor cells. Dioxadet was administered at the maximum tolerated doses: CIPC - via syringe - 1.5 mg/kg body weight; NIPEC (36,5-37,5°С) and HIPEC (40,5-41,5°С) - infused for a continuous circulation using an experimental setting - at respective doses 30 and 15 mg/kg body weight. The rats in the control groups were administered in the same manner with physiological saline solution. The antitumor effects of the treatment were estimated as an increase in survival time. The statistical analysis was based on the principles of harmonization of statistical evidence and predictions. The mean survival time in the control group without treatment (i.p. saline injection) was 15 days with 95% confidence interval (CI) from 12 to 19 days. IPC, NIPEC and HIPEC increased mean survival time by 85, 97 and 202% (p

Survival of rats with advanced ovarian cancer after intraperitoneal (i.p.) administration and hyperthermic intraperitoneal chemoperfusion (HIPEC) with dioxadet and effects of these treatment modalities on leukocyte count were evaluated in two independent series of experiments. Hyperthermic intraperitoneal chemoperfusion with dioxadet (15 mg/kg) provided median survival of rats of 49 days (95% CI 28-70), i.p. administration of dioxadet (1.5 mg/kg) of 28 days (95% CI 16-36; P = 0.020). Single i.p. injection of dioxadet caused a significant decrease in total number of leukocytes (17-52%), granulocytes (18-75%), lymphocytes (18-62%) and monocytes (12-46%) in the peripheral blood of tumour-bearing rats compared to untreated animals. After HIPEC with dioxadet, the total number of leukocytes, granulocytes, lymphocytes and monocytes in peripheral blood of rats remained significantly higher than the corresponding values in the group with dioxadet.

Background and Objectives Hyperthermic Intraperitoneal Chemotherapy (HIPEC) at the time of Cytoreductive Surgery (CRS) is an actively researched treatment in patients with advanced ovarian cancer. Relative contribution of heat and chemotherapeutic agents during HIPEC as well as efficacy of a new agent dioxadet for regional chemotherapy in a rat model of ovarian cancer was studied. Methods Sixty rats were divided into three groups: no treatment control group (n = 19), hyperthermia without chemotherapy (HIPEP) (n = 14), HIPEC + cisplatin (n = 14), HIPEC + dioxadet (n = 13). The intra-abdominal tumor was not resected. End points were: median survival (primary), cause of death (secondary). Results The median survival of the animals in the control group, HIPEP group, HIPEC + cisplatin, HIPEC + dioxadet were 9 (CI; 8–23), 22.5 (CI; 12–43), 25.5 (CI; 13–62), 49 (Cl; 28–70) days, respectively. The P-values control versus HIPEP, HIPEC + cisplatin versus HIPEC + dioxadet were 0.006, 0.002, and 0.001, respectively. Conclusion During HIPEC both the heat and the cytotoxic drug had antitumor effects in a rat ovarian cancer model. Dioxadet showed potential as a drug for regional chemotherapy. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc.

Experimental perfusion system and technology for normothermic and hyperthermic intraperitoneal chemoperfusion are developed for the treatment of abdominal carcinomatosis in rats with transplanted ovarian cancer. MTD of cisplatin in normothermic intraperitoneal chemoperfusion and hyperthermic perfusion are 40 and 20 mg/kg, i.e. by 10- and 5-fold higher than the dose of this cytostatic for routine intraperitoneal injection. Normothermic intraperitoneal chemoperfusion with cisplatin increases median survival time by 200% (p=0.039) in comparison with intraperitoneal injection.

The choice of an optimal administration route for intraperitoneal (IP) chemotherapy and a suitable chemotherapeutic regime in the treatment of ovarian cancer remains a controversy. We investigated survival outcomes according to catheter intraperitoneal chemotherapy (CIPC), normothermic and hyperthermic chemoperfusion (NIPEC and HIPEC) with cytostatic drugs dioxadet and cisplatin in rats with transplantable ascitic ovarian cancer.Ascitic liquid containing 1 × 10Compared to the untreated control CIPC, NIPEC and HIPEC with dioxadet significantly increased ALE byDioxadet and cisplatin show similar efficacy in the CIPC route. Compared with CIPC IP chemotherapy by chemoperfusions is more effective for both the drugs. Dioxadet in HIPEC showed highest survival benefit whereas largest effect during NIPEC is achieved with cisplatin.

A systematic review of the studies where HIPEC combined with cytoreductive surgery was used in patients with primary advanced ovarian cancer was performed to understand is there a role for this treatment modality not only in recurrent but in primary advanced ovarian cancer. The results are controversial but there is a strong trend for improvement of the long-term outcomes of patients with primary advanced ovarian cancer after HIPEC.

Outcomes of hyperthermic intraperitoneal chemoperfusion (HIPEC) added to cytoreductive surgery were studied in experimental and clinical settings. 32 female Wistar rats with peritoneal carcinomatosis were used in the experiment. Rats were randomized into 4 groups (8 rats each): I – control group; II – cytoreduction; III – hyperthermic intraperitoneal perfusion without drugs (HIPEP); IV – cytoreduction + HIPEP. In clinical part of the study 7 patients with pseudomixoma peritonei underwent cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (HIPEC). As the result of the experiment post-operative morbidity taken as post-operative complications and the restoration of body weight after surgery was more severe in animals who received combination of cytoreductive surgery + HIPEP compared to animals who received the surgery or HIPEP alone. The median survival of rats in the control group, cytoreduction, HIPEP and cytoreduction + HIPEP were 8.5, 25 (p=0.007 compared to control), 23.5 (p=0.003 compared to control) and 19.5 (p=0.034 compared to control) days respectively. In clinical part of the study post-operative complications were registered in 2 patients, one of them died on day 12 after the surgery. The pattern of complications was mainly determined by the volume of cytoreductive surgery. Two more patients died due to the tumor progression. Four patients are currently alive with follow-up 4−28 months. Cytoreductive surgery combined with HIPEC should be performed in patients with pseudomyxoma peritonei to increase their survival time. Morbidity from this approach has to be reduced by formulating the strategy of optimal cytoreduction in the studies including larger number of patients.

To study the results of intraperitoneal chemoperfusion combined with cytoreductive procedure in patients with peritoneal pseudomyxoma.For the period 2006--2015 seven patients with peritoneal pseudomyxoma underwent aggressive treatment using hyperthermic intraperitoneal chemoperfusion combined with cytoreductive procedure at the Department of General Oncology of N.N. Petrov Research Institute of Oncology.Two patients had postoperative complications. One of them died after 12 days postoperatively. Features of postoperative complications were predominantly determined by volume of cytoreduction. Advanced tumoral process caused death in 2 patients additionally. Other patients are still alive during 4--28 months after surgery.Hyperthermic intraperitoneal chemoperfusion combined with cytoreductive procedure is advisable for peritoneal pseudomyxoma to improve survival. Optimal cytoreduction should be developed in researches with large number of patients to decrease incidence of complications.Цель. Оценка результатов лечения пациентов с псевдомиксомой брюшины. Материал и методы. В отделении общей онкологии НИИ онкологии им. Н.Н. Петрова с 2006 по 2015 г. при лечении 7 пациентов с псевдомиксомой брюшины был использован агрессивный комбинированный метод, включавший циторедуктивную операцию и гипертермическую интраперитонеальную химиоперфузию (ГИПХ). У 2 пациентов развились послеоперационные осложнения, один из них умер на 12-й день после операции. Характер осложнений был, главным образом, обусловлен объемом выполненной циторедукции. Причиной смерти еще 2 пациентов стало прогрессирование опухолевого процесса. Остальные пациенты живы на сегодняшний день на протяжении 4-28 мес с момента операции. Результаты. Циторедуктивную операцию в сочетании с ГИПХ рационально использовать при псевдомиксоме брюшины с целью увеличения выживаемости больных, а для снижения количества осложнений необходима выработка тактики оптимальной циторедукции в исследованиях, включающих большее количество пациентов.

e22180 Background: Gemcitabine is known to exert a therapeutic effect on brain tumors despite the limited permeability of the blood-brain barrier (BBB). Experimental studies to explore the mechanis...

Background: Combination of cytoreductive surgery with following intraperitoneal chemoperfusion is considered as one of the most effective treatment strategies in patients with advanced ovarian cancer. However hyperthermic intraperitoneal perfusion (HIPEP) without chemotherapy is known for its antitumor activity while normothermic intraperitoneal perfusion (IPEP) hasn't shown to provide antitumor action. The purpose of the study is to evaluate antitumor efficacy of IPEP and HIPEP in ovarian cancer model in rats. Methods: The study was carried out in 56 Wistar female rats with ovarian cancer inoculated intraperitoneally (i.p.). Transplanted epithelian ovarian cancer strain used was originated from the rat subjected to transplacental administration of 7,12-dimethylbenz(a)anthracene. After ovarian cancer inoculation rats were randomized in four groups: i.p. administration of o.5 ml of saline (control group, n = 19); IPEP with saline heated at temperature 36-37 C (n = 11); HIPEP with saline heated at temperature 40.5-41.5 C (n = 14); i.p. administration of cisplatin in a maximum tolerated dose of 4 mg/kg of body weight (n = 12). These procedures were performed once in 48 hours after ovarian cancer inoculation. Antitumor effects of the treatment were estimated by increase in survival time (IST) comparing median survival time (MST) of rats in different groups. Results: MST of rats in the control group was 9 days (95% CI from 9 to 19). IST for IPEP and HIPEP were 78% (p = 0.307) and 150% (p = 0.006) correspondingly compared to the control group. IST for i.p. administration of cisplatin was 117% (p = 0.007) compared to the control group which was stronger than antitumor action of IPEP (p = 0.006) but comparable to the action of HIPEP (p = 0.38). Conclusion: Hyperthermia itself provides strong antitumor action comparable to the effect of i.p. administration of cisplatin while normothermic intraperitoneal perfusion has no significant influence on the survival of rats with advanced ovarian cancer.

Background: Intraperitoneal (i.p.) chemotherapy in patients with peritoneal carcinomatosis could be an more effective treatment strategy than intravenous (i.v.) chemotherapy. The purpose of the study is to compare antitumor activity of different drugs at their i.p. and i.v. administration in rats with peritoneal carcinomatosis. Metods: The study was carried out in 100 Wistar female rats with ovarian cancer which was inoculated intraperitoneally (i.p.) to simulate peritoneal carcinomatosis. Transplanted epithelial ovarian cancer strain used was originated from the rat subjected to transplacental administration of 7,12-dimethylbenz(a)anthracene. After ovarian cancer inoculation rats were randomized in 10 groups, 10 rats in each group. There were five groups where saline (2 ml, i.p. control group) or the drugs (dioxadet 1.5 mg/kg, cisplatin 4mg/kg, melphalan 2 mg/kg, mitomycin C 1.5 mg/kg) were administered i.p. In other five groups saline (2 ml, i.v. control group) and the named above drugs at the same doses were administered i.v. Dioxadet is original Russian antineoplastic drug from the group of ethyleneimine alkylating agents. Antitumor effects of the treatment were estimated by increase in survival time (IST) comparing median survival time of rats in different groups. Results: IST for i.p. administration of dioxadet, cisplatin, melphalan and mitomycin C were 76.5% (p Conclusion: I.p. chemotherapy with alkylating agents dioxadet, cisplatin and melphalan is much more effective then their i.v. administration while antitumor antibiotic mitomycin C is more active at i.v. administration.

e13005 Background: Gemcitabine has a very modest potency to penetrate blood-brain barrier (BBB). So far it's therapeutic activity in intracranial tumors is unknown. Methods: we explored the effect of gemcitabine (G) on overall survival in models of intracranial Ehrlich's tumor and lymphosarcoma LIO-1. As a comparison for the investigation group we've chosen drugs with different ability to penetrate into brain. We injected BCNU (50 mg/kg), cyclophosphamide (C) (150 mg/kg) and CDDP (9 mg/kg) intraperitoneally once 24 hours after transplantation. Results: The mean overall survival (OS) of mice in a selected model is 9,6+/-0,4 days. The injection of G resulted in substantial increase in OS up to 16,2 +/-0,4 (69%, p = 0,0000). In comparative groups administration of BCNU resulted in an increase in OS of 49% (the average OS 14,3+/-0,8, p = 0.000289), C - in 20% OS increase (11,5+/-0,4, p = 0.00272) and CDDP did not influence OS comparing with control group (10,2+0,4 days, p = 0.315). In other experiment mice with intracranial transplantated lymphosarcoma LIO-1 lived 15.4+1.3 days after single i.p. administration of G (25 mg/kg in 24 hours after transplantation) in comparison with 11.2+0.4 days in control group. The absolute increase of life expectancy was 37.5% (p = 0.013). In control group at 14 day after the transplantation all animals died whereas in G group only 3 mice out of 10 (30 %, g = 0.0003) died. Single i.p. administration of 25 mg/kg G on the 5th day after the intracranial transplantation of LIO-1, increased average OS of the animals from 10,9+ 0,4 days in control group to 13.5±0.5 days (increase in OS 24%, p = 0.0003). Conclusions: In our series of experiment we showed the potency of gemcitabine in treatment of various intracranial tumors. Until our work we can not find any data obtained on efficacy of gemcitabine in this tumor types.