Dario Civalleri

Pleural space perfusion with cisplatin in the multimodality treatment of malignant mesothelioma: A feasibility and pharmacokinetic study

INTRODUCTION Malignant pleural mesothelioma is an ideal model for testing new locoregional multimodality approaches because of its aggressive local behavior. METHODS This study was planned to investigate the feasibility, safety, and pharmacokinetics of a multimodality therapy including an operation, pleural space perfusion (60 minutes) with cisplatin (100 mg/m2), hyperthermia (41. 5 degrees C), and postoperative radiotherapy (55 Gy to chest wall incisions). The effects of the extent of resection and perfusion temperature on cisplatin pharmacokinetics were evaluated. Ten patients with epithelial or mixed, stage I or II, malignant pleural mesothelioma underwent the following procedures: group A (3 patients), pleurectomy/decortication and normothermic pleural space antineoplastic perfusion; group B (3 patients), pleurectomy/decortication and hyperthermic perfusion; and group C (4 patients), pleuropneumonectomy and hyperthermic perfusion. Operations were selectively applied depending on tumor extent. Platinum levels were serially measured by atomic absorption in systemic blood, perfusate, lung, and endothoracic fascia. RESULTS The overall procedure was completed in every case, without any death or toxicity. No lung damage was demonstrated after treatment. Major complications included 1 wound infection and 1 diaphragmatic prosthesis displacement. The mean peak platinum plasma levels were reached within 45 to 60 minutes after perfusion was started. Systemic drug concentrations were greater after pleurectomy/decortication than after pleuropneumonectomy (P =.006). The local tissue/perfusate ratio of platinum concentrations tended to be higher after hyperthermic perfusion rather than normothermic perfusion. CONCLUSION This multimodality approach is feasible, pharmacokinetically advantageous, and safe enough to undergo further clinical investigations.

Isolated lung perfusion with platinum in the treatment of pulmonary metastases from soft tissue sarcomas

A multimodality approach including operation and isolated lung perfusion with platinum was used in six patients with lung metastases from soft tissue sarcomas. Staged thoracotomies were used in two patients with bilateral lesions. The inclusion criteria generally applied for surgical excision were adopted in this study. The pulmonary artery and a portion of the left atrium were isolated from systemic circulation and cannulated. The cannulas were then connected to a perfusion circuit and normothermic isolated lung perfusion was done for 60 minutes. The lung was then flushed and metastasectomy was done. Serial blood (systemic and pulmonary), tissue (normal lung and tumor), and urine samples were obtained for platinum content measurement by flameless atomic absorption spectroscopy. Lung damage was assessed by light and electron microscopy examination and by serial respiratory tests. Isolated lung perfusion was accomplished in all patients without any death, operative complication, or systemic toxicity. After operation, interstitial and alveolar edema developed in two patients (48 hours after treatment), necessitating respiratory support in one case. Total platinum concentrations in pulmonary plasma were about 43 times greater than those in systemic plasma. No differences in platinum concentrations between normal lung and metastatic tissue were found. Thus the proposed isolated lung perfusion technique is feasible and safe enough to be offered as a valid model to study combined chemosurgical approaches in the treatment of lung metastases.

Liver and tumor uptake and plasma pharmacokinetic of arterial cisplatin administered with and without starch microspheres in patients with liver metastases.

Arterial chemoembolization of liver tumors should improve regional treatment by reducing native blood flow of the whole organ and redistributing residual flow toward hypovascular masses. Plasma cisplatin pharmacokinetics and its tissue uptake and relative tumor and liver vascularity were studied during surgical placement of arterial catheters in four patients and in four patients with colorectal metastases given intraoperative arterial cisplatin (DDP, 25 mg/m2), with and without coadministration of 600 mg degradable starch microspheres (DSM). Mean (± standard deviation) filterable plasma platinum levels peaked later (2 minutes) and were significantly lower after DDP with DSM (1.23 ± 0.69 μg/ml) than after DDP alone (2.13 ± 0.43 μg/ml, P less than 0.05), with the area under the curve (AUC10–30 min) values of 15.8 ± 5.5 and 25.1 ± 3.8 μg × min/ml (P less than 0.05), respectively. No differences in urine excretion, total body clearance, or plasma protein binding of platinum were observed. Tissue biopsies were started 15 minutes after DDP administration and completed in all cases within 5 minutes. Tumor platinum concentrations were significantly higher after DDP with DSM (3.03 ± 1.60 μg/g) than after DDP alone (0.67 ± 0.49 μg/ml, P less than 0.05). Liver concentrations and tumor‐liver ratios of platinum also were higher, although not significantly, after DDP with DSM. Preoperative vascularization, studied with arterial perfusion scan, influenced individual tissue drug uptake in cases given DDP alone, with the lowest tumor levels in cold masses. Very high and almost superimposable liver and tumor concentrations were measured in those receiving DDP and DSM. The latter phenomenon was irrespective of native vascularization, indicating that DSM administration induced both an increased whole‐liver extraction of the drug and a redistribution of blood flow and flow‐dependent tissue uptake of platinum.

Screening study of abdominal aortic aneurysm in a general population: lipid parameters

The level of blood lipids and apolipoproteins in subjects being screened for abdominal aortic aneurysms have been investigated. As part of an ultrasound screening programme in a population of 65- to 75-year-olds, blood samples were collected from 1460 of 1504 subjects with a normal aorta (97.1%) and 69 of 70 patients with an abdominal aortic aneurysm > 29 mm (99%). Samples were also taken from 22 of 27 patients (81%) with an ectatic aorta (26-29 mm). Total cholesterol, HDL-cholesterol, LDL-cholesterol, Apo-AI and Apo-B levels were significantly higher in women than in men (P < 0.01). Levels of HDL-cholesterol and Apo-AI were significantly lower in patients with an abdominal aortic aneurysm than in normal subjects (P < 0.001). The mean(s.d.) body mass index was 25.1(3.9) in women and 25.5(3.2) in men with aneurysms and not significantly greater than that of normal subjects (25.2(3.61) and 25.2(3.38) respectively).

Changes in vascularity of liver tumours after hepatic arterial embolization with degradable starch microspheres

The role of vascularity as a prognostic factor was investigated in 35 patients undergoing arterial chemotherapy for liver tumours. Compared with parenchyma, tumour vascularity was classified as hot (18 cases), cold (12 cases), and mixed (12 cases) using 99mTc-macroaggregated albumin (MAA) hepatic arterial scans. The proportion of patients showing complete and partial responses to treatment was higher in the hot group (56 per cent) than in the combined cold and mixed group (12 per cent). In 15 cases (six hot, six cold and three mixed lesions), additional MAA scans were performed immediately after arterial embolization with degradable starch microspheres (DSMs). Either complete or partial reversal of tumour vascularity was observed after DSM-embolization in five and seven cases respectively, two and two of them respectively showing native cold lesions. As tumour vascularity appears to be a prominent prognostic factor, DSM-embolization should improve the efficacy of treatment by improving liver extraction of drugs and causing flow redistribution towards hypovascular areas.

Starch microsphere‐induced arterial flow redistribution after occlusion of replaced hepatic arteries in patients with liver metastases

In four patients with major anomalies of the hepatic artery undergoing intra‐arterial chemotherapy, aberrant lobar vessels were ligated and catheters were inserted into the contralateral artery. Catheter perfusion scans performed early after ligation with 99mTc‐macroaggregated albumin (MAA) showed a defective perfusion of the lobe supplied by the occluded artery (0.43, 0.23, 0.11, and 0.28, respectively, as compared to the contralateral lobe). Further MAA scans performed after catheter infusion of 90,000,000 parts of degradable starch microspheres (DSM) showed a near normal perfusion of the ischemic lobe (0.91, 0.96, 0.87, and 0.98). On the contrary, simple MAA scans performed in the first two patients 114 and 135 days after ligation showed a still defective arterial perfusion of the ischemic lobe (0.60, and 0.24). The DSM‐induced redistribution of flow towards ischemic portions of the liver suggests a possible new role of DSM in regional treatment of liver tumors in cases with either occlusion of aberrant vessels or “hypovascular” tumors.

Relationships of Serum Leptin to Clinical and Anthropometric Findings in Obese Patients

Background: The authors evaluated the relationship between leptin and the clinical, anthropometric and metabolic variables connected to the metabolic syndrome in obese individuals. Methods: A large group of patients with different degrees of obesity was investigated: body mass index (BMI) values, serum leptin, fasting glucose and insulin, triglycerides and HDL-cholesterol concentrations, insulin resistance index and blood pressure were measured. Results: On multiple regression analysis, serum leptin levels appeared to be positively correlated to the BMI and to the serum HDL-cholesterol concentration. Principal component factor analysis revealed three factors, explaining 61.3% of the total variance of the sample. General features of these factors were: factor 1 - BMI values and serum leptin and fasting glucose concentration; factor 2 - systolic and diastolic blood pressure and serum triglycerides and HDL-cholesterol concentration; factor 3 - fasting serum insulin concentration and insulin resistance index. Conclusions: In obese subjects multiple factors underlie the metabolic syndrome and therefore more than one mechanism may account for the clustering characteristics. In obese patients leptin loads only one factor, and therefore leptin does not appear to be a key feature in the metabolic syndrome. On the contrary, multiple correlation and factor analysis data give rise to the hypothesis that in obese patients, leptin may play a protective role against cardiovascular risk.

Hair and plasma zinc levels following exclusion of biliopancreatic secretions from functioning gastrointestinal tract in humans

Pancreatic secretions have been shown to be important in zinc absorption in experimental animals. Recently, complete surgical diversion of biliary and pancreatic secretions from the functioning small intestine has been utilized in Europe to treat morbid obesity. To determine the importance of pancreatic secretions in zinc absorption in the human, we measured hair and serum zinc levels in 14 patients having undergone complete biliopancreatic bypass 12–56 months earlier and compared these values with those obtained from 11 patients subjected to only partial biliopancreatic bypass as well as to six morbidly obese controls. No differences were observed in either hair or serum zinc levels between any of these groups of patients. Pancreatic secretions do not appear to be necessary for adequate zinc absorption in humans.

Gemfibrozil and mediterranean diet for patients with high plasma levels of lipoprotein [Lp(a)] and cholesterol—Pilot study

SummaryPlasma levels of lipoprotein-a [Lp(a)] >30 mg/dl represent an independent risk factor for cardiovascular diseases with both proatherosclerotic and prothrombotic activity. The results of dietary or pharmacological treatment are not encouraging and are often controversial. We have evaluated a combination of medical treatment with Gemfibrozil (600 mg bid) and a Mediterranean diet for 2 months in 15 patients with both hypercholesterolemia (>240 mg/dl) and high levels of Lp(a) (>30 mg/dl). Three patients dropped out within the first 2 weeks, complaining of epigastric pain and burning; the remainder (5 females and 7 males, mean age 70 years) completed the treatment without any side effects. The median values of Lp(a) decreased from 36.5 to 8.4 mg/dl (p<0.0002) and total cholesterol from 254.5 to 208.0 mg/dl (p<0.0001). The small number of patients does not permit any definitive conclusion on effectiveness to be drawn, but the results indicate further randomized studies might prove worthwhile.

Bolus vs. continuous hepatic arterial infusion of cisplatin plus intravenous 5-fluorouracil chemotherapy for unresectable colorectal metastases.

A multicenter, randomized Phase 2 study that compared patients, affected by colorectal liver metastases, who received intrahepatic arterial infusion with two different schedules of cisplatin, bolusvs. continuous infusion, and systemic 5-fluorouracil. PURPOSE: The aim of this study was to validate results of a previous Phase 2 trial on bolus cisplatin intrahepatic arterial infusion, which reported a 47 percent response rate and a 32 percent 4-year survival rate for Gennaris Stage 2 patients, with a high rate of neurologic, gastrointestinal, and hematologic toxicity. METHODS: One hundred nine patients were randomized in a Phase 2 study to receive cisplatin intrahepatic arterial infusion (24 mg/m2/day, 1→5, bolusvs. continuous infusion) and systemic intravenous 5-fluorouracil (250, 375, or 500 mg/m2/day, 1→5; escalating doses, respectively, at cycles I, II, III, and VI). To avoid neurotoxicity a maximum of six cycles was administered. RESULTS: Preliminary results for the 78 evaluable patients are similar to those of the previous study: response rate 46 percent and at a median follow-up of 16.5 months, the overall survival was 16.5 months, with 45 percent of the patients who received more than 3 cycles alive at 3 years. Toxicity, evaluable in 99 patients, showed a decreased incidence of neurotoxicity and a tolerable gastrointestinal and hematologic toxicity, lower in the cisplatin continuous infusion arm. CONCLUSION: This study clearly shows that cisplatin intrahepatic arterial infusion is able to provide a good palliative effect with a tolerable toxicity.