Irinotecan loaded in eluting beads: preclinical assessment in a rabbit VX2 liver tumor model.

PURPOSE: The purpose of this study was to study the pharmacokinetics of irinotecan injected intravenously, intra-arterially, or loaded onto a delivery platform. MATERIAL AND METHODS: Fifty-four New Zealand White rabbits with VX2 liver tumor, divided in 3 groups of 17 rabbits, each received irinotecan either by intravenous (IV) route, intra-arterial hepatic (IA) route, or loaded on drug-eluting beads (DEBIRI). Animals were killed at 1, 6, and 24 h. Irinotecan and SN-38 concentrations were measured at different time points in serum, tumor, and normal liver. RESULTS: Twelve milligrams of irinotecan were injected IV and IA, whereas 6-16.5 mg were injected loaded onto DEBIRI. Normalized serum irinotecan reached a peak of 333 ng/ml (range 198.8-502.5) for IV, 327.1 ng/ml (range 277.1-495.6) for IA, and 189.7 ng/ml (range 111.1-261.9) for DEBIRI (P < 0.001) delivery. The area-under-the-curve value from 10 to 60 min of serum irinotecan concentration was significantly lower for DEBIRI (P = 0.0009). Tumor irinotecan levels for IV, IA, and DEBIRI (in ng/200 mg of tissue followed by ranges in parentheses) were, respectively, 23.6 (0.3-24.9), 36.5 (7.7-1914.1), and 20.2 (2.9-319) at 1 h; 4.2 (1-27.9), 99.3 (46.6-159.5), and 42.1 (11.3-189) at 6 h; and 2.7 (2.5-6.9), 18.3 (1.5-369.1), and 174.4 (3.4-5147.3) at 24 h (P = 0.02). At 24 h, tumor necrosis was 25% (10-30), 60% (40-91.25), and 95% (76.25-95) for IV, IA, and DEBIRI, respectively (P = 0.03). CONCLUSION: Compared with IV or IA, DEBIRI induces lower early serum levels of irinotecan, a high and prolonged intratumoral level of irinotecan, and a greater rate of tumor necrosis at 24 h. Further evaluation of the clinical benefit of DEBIRI is warranted.

Carotid artery rupture and cervicofacial actinomycosis.

Cervicofacial actinomycosis is an uncommon, progressive infection caused by bacilli of the Actinomyces genus. Actinomyces are common commensal saprophytes in the oral cavity which may have medical importance as facultative pathogens. Subsequent to local injuries to the oral mucosa, they may penetrate the deep tissues and be responsible for suppurative or granulomatous infections. We herein report a case of a 65-year-old man who underwent surgery followed by chemotherapy and radiotherapy for a tonsillar carcinoma. An ulcerous lesion in the base of the tongue developed and spread to the carotid artery wall. The man died of a massive hemorrhage due to left carotid artery rupture. Postmortem computed tomography angiography performed prior to autopsy allowed the precise localization of the source of bleeding to be detected. Postmortem biochemical investigations confirmed the presence of inflammation associated with local bacterial infection. Histological investigations revealed the rupture of the left carotid artery surrounded by numerous colonies of Actinomyces. Acute and chronic inflammation with tissue necrosis as well as post-actinic, fibrotic changes were also found in the tissues surrounding the ruptured artery wall.

The NLRP3 inflammasome: a sensor for metabolic danger?

Interleukin-1beta (IL-1beta), reactive oxygen species (ROS), and thioredoxin-interacting protein (TXNIP) are all implicated in the pathogenesis of type 2 diabetes mellitus (T2DM). Here we review mechanisms directing IL-1beta production and its pathogenic role in islet dysfunction during chronic hyperglycemia. In doing so, we integrate previously disparate disease-driving mechanisms for IL-1beta, ROS, and TXNIP in T2DM into one unifying model in which the NLRP3 inflammasome plays a central role. The NLRP3 inflammasome also drives IL-1beta maturation and secretion in another disease of metabolic dysregulation, gout. Thus, we propose that the NLRP3 inflammasome contributes to the pathogenesis of T2DM and gout by functioning as a sensor for metabolic stress.

Impaired glucose metabolism in the heart of obese Zucker rats after treatment with phorbol ester.

OBJECTIVE: To investigate the influence of obesity on the regulation of myocardial glucose metabolism following protein kinase C (PKC) activation in obese (fa/fa) and lean (Fa/?) Zucker rats. DESIGN: Isolated hearts obtained from 17-week-old lean and obese Zucker rats were perfused with 200 nM phorbol 12-myristate 13-acetate (PMA) for different time periods prior to the evaluation of PKC and GLUT-4 translocation. For metabolic studies isolated hearts from 48 h starved Zucker rats were perfused with an erythrocytes-enriched buffer containing increased concentrations (10-100 nM) of PMA. MEASUREMENTS: Immunodetectable PKC isozymes and GLUT-4 were determined by Western blots. Glucose oxidation and glycolysis were evaluated by measuring the myocardial release of 14CO2 and 3H2O from [U-14C]glucose and [5-3H]glucose, respectively. RESULTS: PMA (200 nM) induced maximal translocation of ventricular PKCalpha from the cytosol to the membranes within 10 min. This translocation was 2-fold lower in the heart from obese rats when compared to lean rats. PMA also induced a significant translocation of ventricular GLUT-4 from the microsomal to the sarcolemmal fraction within 60 min in lean but not in obese rats. Rates of basal cardiac glucose oxidation and glycolysis in obese rats were approximately 2-fold lower than those of lean rats. Perfusion with increasing concentrations of PMA (10-100 nM) led to a significant decrease of cardiac glucose oxidation in lean but not in obese rats. CONCLUSION: Our results show that in the heart of the genetically obese Zucker rat, the impairment in PKCalpha activation is in line with a diminished activation of GLUT-4 as well as with the lack of PMA effect on glucose oxidation.

The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression.

Metformin demonstrates anorectic effects in vivo and inhibits neuropeptide Y expression in cultured hypothalamic neurons. Here we investigated the mechanisms implicated in the modulation of feeding by metformin in animals rendered obese by long-term high-fat diet (diet-induced obesity [DIO]) and in animals resistant to obesity (diet resistant [DR]). Male Long-Evans rats were kept on normal chow feeding (controls) or on high-fat diet (DIO, DR) for 6 months. Afterward, rats were treated 14 days with metformin (75 mg/kg) or isotonic sodium chloride solution and killed. Energy efficiency, metabolic parameters, and gene expression were analyzed at the end of the high-fat diet period and after 14 days of metformin treatment. At the end of the high-fat diet period, despite higher leptin levels, DIO rats had higher levels of hypothalamic neuropeptide Y expression than DR or control rats, suggesting a central leptin resistance. In DIO but also in DR rats, metformin treatment induced significant reductions of food intake accompanied by decreases in body weight. Interestingly, the weight loss achieved by metformin was correlated with pretreatment plasma leptin levels. This effect was paralleled by a stimulation of the expression of the leptin receptor gene (ObRb) in the arcuate nucleus. These data identify the hypothalamic ObRb as a gene modulated after metformin treatment and suggest that the anorectic effects of the drug are potentially mediated via an increase in the central sensitivity to leptin. Thus, they provide a rationale for novel therapeutic approaches associating leptin and metformin in the treatment of obesity.

Mls: a link between immunology and retrovirology.

The nature of the mysterious minor lymphocyte stimulating (Mls) antigens has recently been clarified. These molecules which were key elements for our current understanding of immune tolerance, have a strong influence on the mouse immune system and are encoded by the open reading frame (orf) of endogenous and exogenous mouse mammary tumor viruses (MMTV's). The knowledge that these antigens are encoded by cancerogenic retroviruses opens an interdisciplinary approach for understanding the mechanisms of immune responses and immune tolerance, retroviral carcinogenesis, and retroviral strategies for infection.

O-mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding.

Alpha-dystroglycan (alpha-DG) is a cell-surface glycoprotein that acts as a receptor for both extracellular matrix proteins containing laminin-G domains and certain arenaviruses. Receptor binding is thought to be mediated by a posttranslational modification, and defective binding with laminin underlies a subclass of congenital muscular dystrophy. Using mass spectrometry- and nuclear magnetic resonance (NMR)-based structural analyses, we identified a phosphorylated O-mannosyl glycan on the mucin-like domain of recombinant alpha-DG, which was required for laminin binding. We demonstrated that patients with muscle-eye-brain disease and Fukuyama congenital muscular dystrophy, as well as mice with myodystrophy, commonly have defects in a postphosphoryl modification of this phosphorylated O-linked mannose, and that this modification is mediated by the like-acetylglucosaminyltransferase (LARGE) protein. These findings expand our understanding of the mechanisms that underlie congenital muscular dystrophy.

Differential proteoglycan expression in two spinal cord regions after dorsal root injury.

Dorsal root injury leads to reactive gliosis in the spinal cord dorsal root entry zone and dorsal column, two regions that undergo Wallerian degeneration, but have distinct growth-inhibitory properties. This disparity could in part be due to differences in the number of degenerating sensory fibers, differences in glial cell activation, and/or to differential expression of growth-inhibitory molecules such as chondroitin sulfate proteoglycans. Laser capture microdissection of these two spinal cord white matter regions, followed by quantitative analysis of mRNA expression by real-time PCR, revealed that glial marker transcripts were differentially expressed post-injury and that the chondroitin sulfate proteoglycans Brevican and Versican V1 and V2 were preferentially up-regulated in the dorsal root entry zone, but not the dorsal column. These results indicate that reactive gliosis differs between these two regions and that Brevican and Versican are potential key molecules participating in the highly inhibitory properties of the dorsal root entry zone.

Evolutionary and biomedical consequences of internal melanins.

The adaptive function of melanin located in the integument is well known. Although pigments are also deposited in various internal organs, their function is unclear. A review of the literature revealed that 'internal melanin' protects against parasites, pollutants, low temperature, oxidative stress, hypoxemia and UV light, and is involved in the development and function of organs. Importantly, several studies have shown that the amount of melanin deposited on the external body surface is correlated with the amount located inside the body. This finding raises the possibility that internal melanin plays more important physiological roles in dark than light-colored individuals. Internal melanin and coloration may therefore not evolve independently. This further emphasizes the major role played by indirect selection in evolutionary processes.

Acute seizures in acute ischemic stroke: does thrombolysis have a role to play?

Seizures appear at stroke presentation, during the acute phase or as a late complication of stroke. Thrombolysis has not been investigated as a risk factor despite its potential neurotoxic effect. We try to identify risk factors for seizures during the acute phase of ischemic stroke in a cohort including thrombolysed patients. We undertook a case-control study at a single stroke center using data from Acute Stroke Registry and Analyse of Lausanne (ASTRAL). Patients with seizure occurring during the first 7 days following stroke were retrospectively identified. Bi-variable and multivariable statistical analyses were applied to compare cases and randomly selected controls. We identified 28 patients experiencing from seizures in 2,327 acute ischemic strokes (1.2 %). All seizures occurred during the first 72 h. Cortical involvement, thrombolysis with rt-PA, arterial recanalization, and higher initial NIHSS were statistically associated with seizures in univariated analysis. Backward linear regression identified cortical involvement (OR 7.53, 95 % CI 1.6-35.2, p < 0.01) and thrombolysis (OR 4.6, 95 % CI 1.6-13.4, p = 0.01) as being independently associated with seizure occurrence. Overall, 3-month outcome measured by the modified Rankin scale (mRS) was comparable in both groups. In the subgroup of thrombolysed patients, outcome was significantly worse at 3 months in the seizure group with 9/12 (75 %) patients with mRS ≥3, compared to 6/18 (33.3 %) in the seizure-free group (p = 0.03). Acute seizures in acute ischemic stroke were relatively infrequent. Cortical involvement and thrombolysis with rt-PA are the principal risk factors. Seizures have a potential negative influence on clinical outcome in thrombolysed patients.

Can we afford to add chemotherapy to radiotherapy for glioblastoma multiforme? Cost-identification analysis of concomitant and adjuvant treatment with temozolomide until patient death.

BACKGROUND: Adding temozolomide (TMZ) to standard radiotherapy as a first-line therapy for glioma may increase costs to a disproportionate degree compared with the resulting survival benefits. METHODS: Forty-six consecutive patients (28 males and 18 females; median age, 52 years; age range, 24-70 years) received concomitant TMZ with radiotherapy for 6 weeks followed by adjuvant TMZ for 6 cycles, and they were followed until disease recurrence and then until death. The authors assessed the costs associated with the four phases of treatment from a hospital-centered perspective. RESULTS: Treatment was discontinued early in 3 patients, 9 patients, and 15 patients during concomitant TMZ, before adjuvant TMZ, and during adjuvant TMZ, respectively. Karnofsky index values varied between 85% (at the beginning of treatment) and 76% (at the end of treatment). The nature of care after disease recurrence was diverse. Overall survival ranged from 1.4 months to 64.3 months (median, 15.8 months) and was better if surgical debulking could be carried out before treatment. Global costs amounted to Euros 39,092 +/- Euros 21,948 (concomitant TMZ, Euros 14,539 +/- Euros 4998; adjuvant TMZ, Euros 13,651 +/- Euros 4320; follow-up, Euros 6363 +/- Euros 6917; and recurrence, Euros 12,344 +/- Euros 18,327), with 53% of these costs being related to the acquisition of TMZ; this represented an eightfold increase in cost compared with radiotherapy alone. CONCLUSIONS: TMZ may be an effective but costly adjuvant outpatient therapy for patients with glioblastoma multiforme. Definite cost-effectiveness/utility must be assessed in a randomized Phase III trial.

Physical considerations on discrepancies in target volume delineation.

BACKGROUND AND PURPOSE: To compare the delineations and interpretations of target volumes by physicians in different radio-oncology centers. MATERIALS AND METHODS: Eleven Swiss radio-oncology centers delineated volumes according to ICRU 50 recommendations for one prostate and one head and neck case. In order to evaluate the consistency of the volume delineations, the following parameters were determined: 1) the target volumes (GTV, CTV and manually expanded PTV) and their extensions in the three main axes and 2) the correlation of the volume delineated by each pair of centers using the ratio of the intersection to the union (called proximity index). RESULTS: The delineated prostate volume was 105+/-55cm(3) for the CTV and 218+/-44cm(3) for the PTV. The delineated head and neck volume was 46+/-15cm(3) for the GTV, 327+/-154cm(3) for the CTV and 528+/-106cm(3) for the PTV. The mean proximity index for the prostate case was 0.50+/-0.13 for the CTV and 0.57+/-0.11 for the PTV. The proximity index for the head and neck case was 0.45+/-0.09 for the GTV, 0.42+/-0.13 for the CTV and 0.59+/-0.06 for the PTV. CONCLUSIONS: Large discrepancies between all the delineated target volumes were observed. There was an inverse relationship between the CTV volume and the margin between CTV and PTV, leading to less discrepancies in the PTV than is the CTV delineations. There was more spread in the sagittal and frontal planes due to CT pixel anisotropy, which suggests that radiation oncologists should delineate the target volumes not only in the transverse plane, but also in the sagittal and frontal planes to improve the delineation by allowing a consistency check.

Prévention du syndrome post-thrombotique [Prevention of post-thrombotic syndrome].

Post-thrombotic syndrome (PTS) is the most frequent chronic complication of deep vein thrombosis (DVT) with an estimated prevalence of 30-50%. PTS is a significant cause of disability, especially when complicated by venous ulcers. Therefore, PTS has important socio-economic consequences for both the patient and the health care system. Actually, the efficacy of PTS treatment is very limited; therefore, best treatment remains prevention. Compression therapy, particularly by graduated compression stockings (GCS) has a pivotal role in PTS prophylaxis. Aim of this article is to resume state of the art literature on this subject. Recommendations on PTS prevention have even been reported.

Training in flexible intensive insulin therapy improves quality of life, decreases the risk of hypoglycaemia and ameliorates poor metabolic control in patients with type 1 diabetes.

AIM: Intensified insulin therapy has evolved to be the standard treatment of type 1 diabetes. However, it has been reported to increase significantly the risk of hypoglycaemia. We studied the effect of structured group teaching courses in flexible insulin therapy (FIT) on psychological and metabolic parameters in patients with type 1 diabetes. METHODS: We prospectively followed 45 type 1 diabetic patients of our outpatient clinic participating in 5 consecutive FIT teaching courses at the University Hospital of Basel. These courses consist of 7 weekly ambulatory evening group sessions. Patients were studied before and 1, 6, and 18 months after the course. Main outcome measures were glycated haemoglobin (HbA1c), severe hypoglycaemic events, quality of life (DQoL), diabetes self-control (IPC-9) and diabetes knowledge (DWT). RESULTS: Quality of life, self-control and diabetes knowledge improved after the FIT courses (all p<0.001). The frequency of severe hypoglycaemic events decreased ten-fold from 0.33 episodes/6 months at baseline to 0.03 episodes/6 months after 18 months (p<0.05). Baseline HbA1c was 7.2+/-1.1% and decreased in the subgroup with HbA1c > or = 8% from 8.4% to 7.8% (p<0.05). CONCLUSIONS: In an unselected, but relatively well-controlled population of type 1 diabetes, a structured, but not very time consuming FIT teaching programme in the outpatient setting improves psychological well-being and metabolic parameters.