High-pressure intrapleural chemotherapy: feasibility in the pig model.

International audienceABSTRACT: BACKGROUND: The usual treatments for pleural malignancies are mostly palliative. In contrast, peritoneal malignancies are often treated with a curative intent by cytoreductive surgery and intraperitoneal chemotherapy. As pressure has been shown to increase antitumor efficacy, we applied the concept of high-pressure intracavitary chemotherapy to the pleural space in a swine model. METHODS: Cisplatin and gemcitabine were selected because of their antineoplasic efficacy in vitro in a wide spectrum of cancer cell lines. The pleural cavity of 21 pigs was filled with saline solution; haemodynamic and respiratory parameters were monitored. The pressure was increased to 15-25 cm H2O. This treatment was associated with pneumonectomy in 6 pigs. Five pigs were treated with chemotherapy under pressure. RESULTS: The combination of gemcitabine (100 mg/l) and cisplatin (30 mg/l) was highly cytotoxic in vitro. The maximum tolerated pressure was 20 cm H20, due to haemodynamic failure. Pneumonectomy was not tolerated, either before or after pleural infusion. Five pigs survived intrapleural chemotherapy associating gemcitabine and cisplatin with 20 cm H2O pressure for 60 min. CONCLUSIONS: High-pressure intrapleural chemotherapy is feasible in pigs. Further experiments will establish the pharmacokinetics and determine whether the benefit already shown in the peritoneum is also obtained in the pleura

Maternal Blood Lead Levels and the Risk of Pregnancy-Induced Hypertension: The EDEN Cohort Study

International audienceBACKGROUND: Prior studies revealed associations of environmental lead exposure with risks of hypertension and elevated blood pressure. OBJECTIVE: We examined the effect of blood lead levels on blood pressure and the incidence of pregnancy-induced hypertension (PIH) in the second and third trimesters of pregnancy. METHODS: One thousand seventeen pregnant women were enrolled in two French municipalities between 2003 and 2005 for the EDEN (Etude des Déterminants pré et post natals du développement et de la santé de l' Enfant) cohort study. Blood lead concentrations were measured by atomic absorption spectrometry in mothers between 24 and 28 weeks of gestation. RESULTS: PIH was diagnosed in 106 subjects (10.9%). Age, parity, weight gain, alcohol, smoking habits, and calcium supplementation were comparable between hypertensive and nonhypertensive women. Lead levels were significantly higher in PIH cases (mean +/- SD, 2.2 +/- 1.4 mug/dL) than in normotensive patients (1.9 +/- 1.2 mug/dL; p = 0.02). Adjustment for potential confounder effects slightly attenuated but did not eliminate the significant association between blood lead levels and the risk of PIH (adjusted odds ratio of PIH = 3.3; 95% confidence interval, 1.1-9.7). We also observed geographic differences in lead exposure and in the incidence of PIH and found significant correlations between blood lead levels and unadjusted as well as adjusted systolic and diastolic blood pressures after 24 weeks of gestation. CONCLUSIONS: These findings confirm the relationship between blood lead levels at mid-pregnancy and blood pressure and suggest that environmental lead exposure may play an etiologic role in PIH

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Using a heating cable within the abdomen to make hyperthermic intraperitoneal chemotherapy easier: Feasibility and safety study in a pig model.

International audienceBACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) is a complex, expensive and time-consuming procedure. Despite its good results in the treatment of peritoneal carcinomatosis, these factors have precluded the wider use of this procedure around the world. We hypothesized that HIPEC could be performed by heating the liquid within the abdomen and thus avoiding the need for an external heating circuit and a pump. The aim of this study was to assess the feasibility and safety of an internal heating device for hyperthermic intraperitoneal chemotherapy in an experimental model. METHODS: Four large-white pigs underwent one-hour open intraperitoneal hyperthermia with closed abdomen using this new device. Constant stirring of the liquid around the viscera was performed in the first three animals, but not in the fourth one. At the end of the procedure, all of the viscera were carefully examined to look for thermal injury. Any lesion or doubtful area was removed and sent to pathologic examination. RESULTS: No adverse events occurred during surgery in any of the animals. A temperature of 42 degrees C was reached in an average time of 14min and maintained homogeneously between 42 degrees C and 43 degrees C for one hour. No visceral injury was detected in the first three animals. Three foci of thermal injury to the mucosa were detected in the absence of stirring (fourth animal). CONCLUSION: Heating the solution within the abdomen during hyperthermic intraperitoneal chemotherapy is feasible, safe and achieves perfect thermal homogeneity. This device provides a time-saving inexpensive way to perform intraperitoneal hyperthermic chemotherapy

Hypoxic single-pass isolated hepatic perfusion of hypotonic Cisplatin: safety study in the pig.

International audienceBACKGROUND: Isolated hepatic perfusion (IHP) of chemotherapy has been proposed to deliver high doses of drug while avoiding systemic toxicity. Hypotonic cisplatin has a high in vitro activity on human colon cancer cells. We studied the safety of a 30-min hypoxic single-pass IHP with hypotonic cisplatin. METHODS: A preliminary in vitro assay was performed to compare the cytotoxicity of cisplatin and oxaliplatin, in either a normotonic or hypotonic medium. Cisplatin in hypotonic medium was then chosen for the in vivo IHP. Eleven pigs underwent 30 min of IHP with 0, 50, 75, or 100 mg/L of cisplatin in a hypotonic solution under total vascular exclusion of the liver. Clinical and biological parameters were recorded for 30 days, and liver histology was performed at necropsy. The cytotoxic activity of the effluent against resistant human colon cancer cells was tested in vitro. RESULTS: No hepatic failure was recorded after IHP with cisplatin, but limited foci of necrosis were found at necropsy in animals receiving 75 or 100 mg/L of cisplatin. No clinical, biological, macroscopic, or microscopic toxicity was observed after IHP with 50 mg/L of hypotonic cisplatin. The liver effluent showed high in vitro cytotoxic activity against colon cancer cells. CONCLUSIONS: A hypoxic single-pass isolated liver perfusion with hypotonic cisplatin is feasible and safe. Effluent from the liver is highly cytotoxic on cancer cells. A clinical study with 50 mg/L of hypotonic cisplatin is warranted in patients with unresectable liver metastases from colon cancer

Which method to deliver hyperthermic intraperitoneal chemotherapy with oxaliplatin? An experimental comparison of open and closed techniques.: Experimental comparison of open and closed HIPEC

International audienceBACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) achieves good results in selected patients with peritoneal carcinomatosis. There are two main procedures to deliver this therapy: the open abdomen and the closed abdomen techniques. A true comparison of the two techniques has never been performed. The aim of this study was to compare blood and abdominal tissue concentrations of oxaliplatin after open and closed techniques to deliver HIPEC. METHODS: Nine pigs underwent HIPEC at 42-43 degrees C for 30 min with oxaliplatin (400 mg/m(2)) according to two techniques: closed (three animals) or open (six animals). The open technique used either an external heater with a pump (three animals) or an intra-abdominal heating cable (three animals) to achieve hyperthermia. Temperature homogeneity, systemic absorption, and abdominal tissue mapping of the penetration of oxaliplatin with each technique were studied. Two additional pigs underwent hyperthermia with dyes instead of oxaliplatin to depict the distribution of the liquid within the abdomen with both techniques. RESULTS: Hyperthermia was satisfactory with both techniques. The closed technique achieved higher temperatures within the diaphragmatic area, while the open technique obtained higher temperatures in the mid and lower abdomen (P < 0.001 for both comparisons). The systemic absorption of oxaliplatin was higher with the open technique (P < 0.04 for all comparisons), as was the accumulation within the abdominal cavity. The operating time for the two techniques was not greatly different. CONCLUSIONS: Intraperitoneal hyperthermia can be achieved with both techniques. The open technique had far higher systemic absorption and abdominal tissue penetration of oxaliplatin than the closed technique

Isolated lung perfusion as an adjuvant treatment of colorectal cancer lung metastases: a preclinical study in a pig model.

BACKGROUND: The lung is a frequent site of colorectal cancer (CRC) metastases. After surgical resection, lung metastases recurrences have been related to the presence of micrometastases, potentially accessible to a high dose chemotherapy administered via adjuvant isolated lung perfusion (ILP). We sought to determine in vitro the most efficient drug when administered to CRC cell lines during a short exposure and in vivo its immediate and delayed tolerance when administered via ILP. METHODS: First, efficacy of various cytotoxic molecules against a panel of human CRC cell lines was tested in vitro using cytotoxic assay after a 30-minute exposure. Then, early (operative) and delayed (1 month) tolerance of two concentrations of the molecule administered via ILP was tested on 19 adult pigs using hemodynamic, biological and histological criteria. RESULTS: In vitro, gemcitabine (GEM) was the most efficient drug against selected CRC cell lines. In vivo, GEM was administered via ILP at regular (20 µg/ml) or high (100 µg/ml) concentrations. GEM administration was associated with transient and dose-dependant pulmonary vasoconstriction, leading to a voluntary decrease in pump inflow in order to maintain a stable pulmonary artery pressure. After this modulation, ILP using GEM was not associated with any systemic leak, systemic damage, and acute or delayed histological pulmonary toxicity. Pharmacokinetics studies revealed dose-dependant uptake associated with heterogenous distribution of the molecule into the lung parenchyma, and persistent cytotoxicity of venous effluent. CONCLUSIONS: GEM is effective against CRC cells even after a short exposure. ILP with GEM is a safe and reproducible technique