Treatment of diffuse malignant peritoneal mesothelioma (DMPM) by cytoreductive surgery and HIPEC.

AIM: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and locally aggressive tumor with poor prognosis, related in most cases to asbestos exposure. It is increasing in frequency, but currently no standard therapy is available. The biology of this disease is still poorly understood. Several highly specialized centers have recently reported improved survival by means of an innovative local-regional approach. The purpose of this article is to evaluate the survival benefit and the morbidity rate of patients affected by DMPM treated at our institution by cytoreductive surgery (CRS) associated with hyperthermic intraperitoneal perioperative chemotherapy (HIPEC). METHODS: This study includes 42 patients affected by DMPM treated by an uniform approach consisting of cytoreductive surgery associated with HIPEC using cisplatin and doxorubicin. The primary end point was overall survival and morbidity rate. The secondary end point was evaluation of prognostic variables for overall survival. RESULTS: The median follow-up period was 72 months (range 1-235 months). Thirty-five patients (83.3%) presented epithelial tumors and 7 were affected by multicystic mesothelioma. The mean peritoneal cancer index (PCI) was 13. Thirty-eight patients (90.4%) had complete cytoreduction (CC-0/1). The overall morbidity rate was 35.7% associated to a perioperative mortality of 7.1%. Median overall survival rate was 65 months with a 1- and 5-year survival rates of 63% and 44%, respectively. CONCLUSION: The treatment of DMPM by CRS+HIPEC in selected patients is a feasible technique that allows to achieve encouraging results in terms of overall survival rate, with an acceptable morbidity rate. Further investigations are needed to clarify the role and the timing of this promising technique.

Treatment of peritoneal carcinomatosis from ovarian cancer by surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC).

AIM: Ovarian cancer may be considered as an "intraperitoneal disease" by itself. When surgical removal associated with systemic chemotherapy fails, usually, the history of the patients is characterized by poor prognosis. Some encouraging results have been reported by the treatment of peritoneal carcinomatosis (PC) from ovarian cancer by complete surgical cytoreduction, peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC). The purpose of this article was to evaluate the survival benefit and the morbidity of patients with ovarian cancer treated at our institution by cytoreductive surgery associated with hyperthermic intraperitoneal perioperative chemotherapy (HIPEC). METHODS: Between October 1995 and December 2012 more than 600 operations for PC were performed; in 308 cases surgical cytoreduction associated with HIPEC was carried out. Eighty-five patients treated by cytoreduction associated with HIPEC were affected by recurrent epithelial ovarian cancer (EOC). Statistical analysis was performed on 70 patients (last 15 patients were too recent for evaluation). Two trials were applied: 1) patients presenting first peritoneal relapse after surgery and systemic chemotherapy (CT), 6 months later from last CT administration; 2) multiple relapse patients. RESULTS: On 70 patients, morbidity and mortality rates were 35.7% and 7.1%, respectively. Overall median survival was 42.0 months, but in primary EOC was 48.0 months and in recurrent EOC was 28 months (P=0.12). Statistical analysis revealed that the completeness of cytoreduction was the most statistically significant factor related to survival: in completely citoreduced patients, overall survival was 48 months. CONCLUSION: Citoreductive surgery associated to platinum compounds HIPEC is feasible and relatively safe in recurrent and primary PC from ovarian cancer. Better selection of patients and second-look surgery in high risk-patients have to be investigated to improve those encouraging results.

Treatment of peritoneal carcinomatosis from colonic cancer by cytoreduction, peritonectomy and HIPEC: preliminary results in highly selected patients.

AIM: Peritoneal carcinomatosis (PC) is one of the routes of spread of abdominal neoplasms and is generally considered a lethal disease, with a poor prognosis by conventional chemotherapeutic treatments. While systemic chemotherapy has little impact on the treatment of peritoneal disease, some centers have reported encouraging results on overall survival (OS) and disease-free survival (DFS) with surgical cytoreduction associated with hyperthermic intraperitoneal chemotherapy (HIPEC). The purpose of this article is to evaluate the survival benefit and the morbidity in patients affected by colorectal PC treated at our institution by cytoreductive surgery associated with HIPEC. METHODS: In our institution, from October 1995 to June 2012, about 550 operations for PC were performed; in 300 cases cytoreduction plus HIPEC was carried out. Out of 90 operations for colonic cancer: 50 cytoreduction plus HIPEC, 12 cytoreduction and EPIC (early postoperative intraperitoneal chemotherapy) and 28 debulking or explorative laparoscopies/laparotomies were performed. For the present study, 50 patients who had undergone cytoreduction and HIPEC for PC of colorectal cancer origin (CRC) were considered. RESULTS: The morbidity and mortality rates were 34% (17/50) and 2% (1/50), respectively. The patients were divided in two groups according to PCI (peritoneal cancer index, range 0-39) and CC score (completeness of cytoreduction): in Group A (23 patients, PCI>16, CC-2) the median survival time was 15 months compared to 48.1 months for Group B (27 patients, PCI≤16, CC-0/1). The poor survival of Group A seemed to be related to higher PCI and CC score. CONCLUSION: Patient selection based on a maximum PCI of 16 associated with a complete cytoreduction (CC-0) produced encouraging results.

Treatment of pseudomyxoma peritonei with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC): a single center experience.

AIM: Pseudomyxoma peritonei (PMP) is a rare form of peritoneal carcinomatosis characterized by abnormal quantity of extracellular mucinous material. It almost originates from a primary appendiceal tumor with different malignancy degrees. The purpose of this study was to evaluate outcome and long-term survival on 80 patients affected by PMP after cytoreductive surgery (CRS) associated with hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: From October 1995 to June 2012, about 550 operations for PC were performed; in 300 cases surgical cytoreduction in association with HIPEC was carried out. Regarding PMP, 80 procedures of CRS and HIPEC were performed. This approach is based on surgical removal of the primitive cancer, peritonectomy (stripping of implants on the peritoneal surface) and HIPEC performed with cisplatinum and C mytomicin. The rationale of this treatment is to obtain, after macroscopic disease removal, an elevated and persistent drug concentration in the peritoneal cavity, with limited systemic effects. RESULTS: The complication rate was 52.5% (42/80) with no postoperative deaths. The median overall and progression-free survival were 144 and 88 months, respectively. Not complete cytoreductive surgery (P<0.001), tumor histology (P=0.02) and previous systemic chemotherapy (p = 0.03) were identified in the univariate analysis as independent predictors for a poorer long-term survival. In the multivariate analysis, the completeness of cytoreduction was the only significant variable influencing the outcome. Incomplete cytoreduction (P<0.01) resulted the only statistically significant variable associated with a higher incidence of postoperative complications. CONCLUSION: PMP can be treated with curative intent in a large percentage of cases by cytoreductive surgery associated with HIPEC. This new approach could be performed safely with acceptable morbidity and mortality in selected patients treated in specialized centers. Completeness of cytoreduction allows to achieve the best results.

Protective effect of poly(ADP-ribose) synthetase inhibition on multiple organ failure after zymosan-induced peritonitis in the rat.

BACKGROUND AND METHODS: In the present study, we tested the hypothesis that peroxynitrite and subsequent activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS) play a role in the pathogenesis of multiple organ failure induced by peritoneal injection of zymosan in the rat. Animals were randomly divided into six groups (ten rats for each group). The first group was treated with ip administration of saline solution (0.9% NaCl) and served as the sham group. The second group was treated with ip administration of zymosan (500 mg/kg suspended in saline solution). In the third and fourth groups, rats received ip administration of 3-aminobenzamide (10 mg/kg) 1 and 6 hrs after zymosan or saline administration, respectively. In the fifth and sixth groups, rats received ip administration of nicotinamide (50 mg/kg) 1 and 6 hrs after zymosan or saline administration, respectively. After zymosan or saline injection, animals were monitored for 72 hrs to evaluate systemic toxicity (conjunctivitis, ruffled fur, diarrhea, and lethargy), loss of body weight, and mortality. RESULTS: A severe inflammatory response, characterized by peritoneal exudation, high plasma and peritoneal levels of nitrate/nitrite (the breakdown products of nitric oxide), and leukocyte infiltration into peritoneal exudate, was induced by zymosan administration. This inflammatory process coincided with the damage of lung, small intestine, and liver as assessed by histologic examination and by an increase of myeloperoxidase activity, which is indicative of neutrophil infiltration. Zymosan-treated rats showed signs of systemic illness, significant loss of body weight, and high mortality rates. Peritoneal administration of zymosan in the rat also induced a significant increase in the plasma levels of peroxynitrite as measured by the oxidation of the fluorescent dihydrorhodamine 123. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific "footprint" of peroxynitrite, in the lung of zymosan-shocked rats. In vivo treatment with ip administration of 3-aminobenzamide (10 mg/kg, 1 and 6 hrs after zymosan injection) or nicotinamide (50 mg/kg, 1 and 6 hrs after zymosan injection) significantly decreased mortality, inhibited the development of peritonitis, and reduced peroxynitrite formation. In addition, PARS inhibitors were effective in preventing the development of organ failure because tissue injury and neutrophil infiltration, by myeloperoxidase evaluation, were reduced in the lung, small intestine, and liver. CONCLUSIONS: In conclusion, the major findings of our study are that peroxynitrite and the consequent PARS activation exert a role in the development of multiple organ failure and that PARS inhibition is an effective anti-inflammatory therapeutic tool.

Intrathecal injection of lysine acetylsalicylic acid in the rat: a neurotoxicological study.

Lysine acetylsalicylic acid has been reported to induce analgesic effects in humans after intrathecal (i.t.) injection. Before conducting further studies in humans with this drug, it is important to evaluate potential toxicological effects on the spinal cord in animals. In the present study the effects of chronic intrathecal administration of provocative doses of lysine acetylsalicylic acid (L-ASA) on the rat spinal cord were evaluated using light and electron microscopy and a quantitative morphometric method. We also investigated the effects of single doses of the drug on the spinal cord blood flow (SCBF) using the laser-Doppler flowmetry technique. No histopathological changes or differences in number or density of neuronal cells could be seen after chronic administration of L-ASA as compared to controls. The SCBF decreased immediately after i.t. injection of a large dose (4 mg) of L-ASA and returned to predrug levels within 10 min. At the end of the experiment metabolic acidosis was detected, indicating a systemic effect of acetylsalicylic acid. It is concluded that no neurotoxic effects on the spinal cord were seen after chronic i.t. injection of L-ASA. From a neurotoxicological point of view, our findings do not contraindicate the spinal use of L-ASA in humans.