Brain serotonin transporter distribution in subjects with impulsive aggressivity: a positron emission study with [11C]McN 5652

OBJECTIVE: The serotonin system is believed to play a role in modulating impulsivity and violence. Previous imaging studies have implicated the anterior cingulate and orbitofrontal cortex in impulsive aggression. This study evaluated regional serotonin transporter distribution in the brain of individuals with impulsive aggression by using positron emission tomography (PET) with the serotonin transporter PET radiotracer [(11)C]McN 5652. METHOD: Ten individuals with impulsive aggression and 10 age- and sex-matched healthy comparison subjects underwent [(11)C]McN 5652 PET. All individuals were medication free at the time of scanning. Regional total distribution volumes were derived by using a one-tissue compartment kinetic model with arterial input function. Outcome measures of serotonin transporter availability included the binding potential and the specific-to-nonspecific partition coefficient (V(3)'). RESULTS: Serotonin transporter availability was significantly reduced in the anterior cingulate cortex of individuals with impulsive aggression compared with healthy subjects, as noted by differences in both binding potential (mean=3.1 ml/g [SD=1.9] versus 5.0 ml/g [SD=2.0], respectively) and V(3)' (mean=0.15 [SD=0.09] versus 0.26 [SD=0.09]). In other regions examined, serotonin transporter density was nonsignificantly lower in individuals with impulsive aggression compared with healthy subjects. CONCLUSIONS: Pathological impulsive aggressivity might be associated with lower serotonergic innervation in the anterior cingulate cortex, a region that plays an important role in affective regulation.     

Knee dislocations: experience at the H?pital du Sacré-Coeur de Montréal

Introduction

Although many options exist for ligament reconstruction in knee dislocations, the optimal treatment remains controversial. Allografts and autografts have both been used to reconstruct the cruciate ligaments. We present the results of reconstruction using artificial ligaments at Hôpital du Sacré-Coeur in Montréal.

Methods

We reviewed the treatment of all patients with knee dislocations seen between June 1996 and October 1999. The Lysholm score, ACL-quality of life (QoL) questionnaire, physical examination and Telos instrumented laxity measurement were used to evaluate the results.

Results

Twenty patients (21 knees) participated in the study. The mean (and standard deviation [SD]) Lysholm score was 71.7 (18). Results from the ACL-QoL questionnaire showed a global impairment in QoL. Mean (and SD) range of motion and flexion were 118° (10.9°) and 2° (2.9°) respectively. Mean (and SD) radiologic laxity evaluated with Telos for the anterior and posterior cruciate ligaments were 6.1 (5.7) mm and 7.3 (4.5) mm respectively.

Conclusions

Knee reconstruction with artificial ligaments shows promise, but further studies are necessary before it can be recommended for widespread use. This is the first study to show specifically a severe impairment in QoL in this patient population.     

Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer

Marimastat, low molecular weight heparins and captopril have antiangiogenic activity in vitro and in animal models. We studied the safety and efficacy of the combination of these drugs in patients with advanced cancer. In all, 50 patients were enrolled. Captopril was given orally at a dose of 50 mg bd daily. Fragmin was administered as a daily subcutaneous injection of 200 units kg(-1) for the first 28 days and 5000 units thereafter. Marimastat was given at 10 mg bd orally. Serum, plasma and urinary angiogenic factors were measured at baseline and after 1 month of treatment. Inhibition of release of tumour necrosis factor alpha (TNF-alpha) from peripheral lymphocytes was used as a surrogate pharmacodynamic end point. There was one case of haemorrhagic stroke and one upper gastrointestinal haemorrhage. The commonest toxicity was myalgia. One of 10 patients with renal cancer had a partial response, and three patients had a prolonged period of stable disease. The treatment significantly inhibited phytohaemagglutinin (PHA)-stimulated TNF-alpha release from patient's lymphocytes. The combination of marimastat, fragmin and captopril is well tolerated and has in vivo activity. Inhibition of PHA-stimulated TNF-alpha release from lymphocytes is a surrogate pharmacodynamic marker of metalloprotease inhibition.     

A phase I and pharmacological study of the matrix metalloproteinase inhibitor BB-3644 in patients with solid tumours

BB-3644 is an oral, broad-spectrum matrix metalloproteinase inhibitor (MMPI) structurally related to marimastat and BB-94. It is also >10-fold more active than marimastat in inhibiting the processing of cell-bound TNF-alpha. Preclinical studies suggested a favourable toxicity profile when compared to marimastat, and therefore it was selected for clinical evaluation. Patients with advanced solid tumours against which established treatments had failed, or for which no satisfactory treatment exists and of good performance status, were eligible. Treatment consisted of twice daily (bd) oral BB-3644 for 84 days. The initial dose was 5 mg bd, and subsequent cohorts were treated with 10, 20 and 30 mg bd. In all, 22 patients were enrolled. The dose-limiting toxicity (DLT) was musculoskeletal pain. For 28 days of treatment with BB-3644, 20 mg bd was the maximum tolerated dose (MTD), as at 30 mg bd, six of nine patients developed significant musculoskeletal toxicity by day 28. Following chronic oral dosing (>28 days) with BB-3644, three of five patients treated at 10 mg bd developed musculoskeletal DLT by day 84, defining the MTD as 5 mg bd. As dose-limiting musculoskeletal toxicity was encountered at doses of BB-3644 unlikely to provide an advantage over currently available MMPIs, further evaluation is not recommended.     

Contralateral axillary sentinel lymph node drainage in breast cancer: a case report

BACKGROUND: Since the introduction of sentinel node (SN) mapping in breast cancer, extra-axillary lymph node sites of breast tumor drainage are discovered in about one-quarter of cases, especially after intraparenchymal injection. In most such cases, an ipsilateral axillary SN is associated with an extra-axillary SN. Non visualization of ipsilateral axillary SN and extra-axillary SN drainage are often associated with an increased risk of axillary involvement. CASE: We report a case of contralateral axillary SN drainage on lymphoscintigraphy in a breast cancer patient with a history of bilateral reduction mammoplasty and no ipsilateral axillary lymph node involvement.