To develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS.
The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions.
Results and Recommendations:
AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of ∼50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of ∼50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors, as pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C).
Minimally invasive interventional cancer therapy of drug-carrying lipid nanoparticles (liposomes) via convection enhanced delivery generally applied by the use of an infusion pump can increase intratumoral drug concentration and retention while facilitating broad distribution throughout solid tumors. We investigated the utility of liposome-carrying β-emitting radionuclides to treat head and neck cancer in nude rats by direct intratumoral infusion.
Four groups of nude rats were subcutaneously inoculated with human tongue cancer cells. After tumors reached an average size of 1.6 cm3, the treatment group received an intratumoral infusion of liposomal rhenium-186 (186Re) (185 MBq (5 mCi)/cm3 tumor). Three control groups were intratumorally infused with either, 1) unlabeled liposomes, 2) unencapsulated 186Re-perrhenate, or 3) unencapsulated intermediate 186Re-compound (186Re-BMEDA). In vivo distribution of 186Re-activity was measured by planar gamma camera imaging. Tumor therapy and toxicity were assessed by measurements of tumor size, body weight, and hematology.
Average tumor volume of the 186Re-liposome group on post-treatment day-14 decreased to 87.7±20.1%, while tumor volumes increased to 395.0% - 514.4% on average in other three groups (P<0.001 vs 186Re-liposome group). 186Re-liposomes provided much higher intratumoral retention of 186Re-activity, resulting in an average tumor radiation absorbed dose of 526.3±93.3 Gy, whereas 186Re-perrhenate and 186Re-BMEDA groups had only 3.3±1.2 and 13.4±9.2 Gy tumor doses respectively. No systemic toxicity was observed.
Liposomal 186Re effectively treated the head and neck cancer with minimal side effects after convection enhanced interventional delivery. These results suggest the potential of liposomal 186Re for clinical application in interventional therapy of cancer.
This report presents the case of a 70-year-old woman with a previous history of a left nephrectomy for renal cell carcinoma (RCC), who developed general malaise and fatigue. Abdominal computed tomography demonstrated an enhancing 6 × 7 cm necrotic lesion in the lower pole of the spleen suggestive of a metastasis. Given the highly suspicious nature of the lesion we proceeded to splenectomy. The tumour did not breach the splenic capsule, and there was no local diaphragmatic involvement. The mass was concluded to be a true metastasis of the original RCC rather than local recurrence of the disease. The causes of isolated solid splenic lesions are wide and varied, however a past or present history of malignancy should lead to a high index of suspicion for a splenic metastasis. We report an extremely unusual case of spread from a RCC.
Spleen; Metastasis; Renal cell carcinoma
Surgical resection for colorectal liver metastases may only be considered when an adequate functional residual volume can be preserved. Selective portal venous embolisation may be used to increase this volume, whilst chemotherapy and radiofrequency ablation (RFA) can be used to treat inoperable lesions. A 73-year-old man with liver metastasis proceeded to surgery, with the intention to perform a right hemi-hepatectomy. Unexpectedly at laparotomy, despite adequate pre-operative imaging, both the right and middle hepatic veins were involved. At that time extended right hemi-hepatectomy was contraindicated by insufficient residual volume and RFA was performed. Follow-up imaging revealed atrophy of the lesion. Significantly, there was also left lateral lobe hypertrophy sufficient to permit resection, which was performed without complication. Thrombosis of intra-hepatic portal veins is a recognised complication of RFA but here it appears to have been beneficial. The case highlights the need for regular review of unresectable hepatic disease by a liver surgeon and could suggest new modalities of portal embolisation.
Radiofrequency ablation; Liver metastasis; Resectability
Meningiomas are slow-growing intracranial/intraspinal tumours, with a wide range of histopathological variants. The more aggressive atypical and malignant types can disseminate via the venous system, lymphatics or cerebrospinal fluid, with the lungs and pleura being the most common site of extracranial metastasis. We look at a 68-year-old woman presenting with abdominal pain, who had previously been treated for an intracranial meningioma with a ventriculo-peritoneal shunt in situ. Investigation revealed a lesion in segment 4 of the liver with the shunt tip being in close proximity. Biopsy was consistent with metastatic meningioma. A liver resection was subsequently performed. We postulate that this is the first reported case of dissemination of an intracranial meningioma via cerebrospinal fluid by means of a ventriculo-peritoneal shunt.
Hepatic metastasis; Meningioma; Ventriculo-peritoneal shunt
Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy.
Methods: A 20-member committee evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and October 2007.
Results: Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in amounts that may be clinically important. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative.
Recommendations: Supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant may be considered (Level C). Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered (Level B) and monitoring of levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C). A paucity of evidence limited the strength of many recommendations.
Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy.
Methods: Systematic review of relevant articles published between January 1985 and June 2007.
Results: It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possible compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to monotherapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive outcomes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7.
Recommendations: If possible, avoidance of valproate (VPA) and antiepileptic drug (AED) polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations (Level B). If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered to prevent reduced cognitive outcomes (Level B). If possible, avoidance of phenytoin and phenobarbital during pregnancy may be considered to prevent reduced cognitive outcomes (Level C). Pregnancy risk stratification should reflect that the offspring of women with epilepsy taking AEDs are probably at increased risk for being small for gestational age (Level B) and possibly at increased risk of 1-minute Apgar scores of <7 (Level C).
Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy in WWE compared to other women, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy.
Methods: A 20-member committee including general neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and February 2008.
Results: For WWE taking antiepileptic drugs, there is probably no substantially increased risk (greater than two times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (greater than 1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. Seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84%–92%) of remaining seizure-free during pregnancy.
Recommendations: Women with epilepsy (WWE) should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high rate (84%–92%) of remaining seizure-free during pregnancy (Level B). However, WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery during pregnancy (Level C).
In selecting and defining composite end points in clinical trials, are we trading off clinical significance for statistical significance?
clinical trials; coronary heart disease; end points
Background/Aims. At present, there is no simple test for predicting severity in acute pancreatitis. We investigated the use of an assay of soluble E-cadherin (sE-cadherin). Methods. Concentrations of sE-cadherin, from 19 patients with mild acute pancreatitis, 7 patients with severe acute pancreatitis, 11 patients with other acute gastrointestinal pathologies, and 12 healthy subjects were measured using a commercially available sandwich ELISA kit based on two monoclonal antibodies specific to the extracellular fragment of human E-cadherin. Measurements were made at 12 hours or less from onset of pain and also at 24 and 48 hours after onset of pain. Results. Mean (standard deviation) concentration of sE-cadherin in patients with severe acute pancreatitis at <12 hours was 17780 ng/mL (7853), significantly higher than that of healthy volunteers 5180 ng/mL (1350), P = .0039, patients with other gastrointestinal pathologies 7358 ng/mL (6655), P = .0073, and also significantly higher than that of patients with mild pancreatitis, 7332 ng/mL (2843), P = .0019. Discussion. Serum sE-cadherin could be an early (within 12 hours) objective marker of severity in acute pancreatitis. This molecule warrants further investigation in the form of a large multicentre trial.
Cholinergic neurons of the striatum play a crucial role in controlling output from this region. Their firing is under the control of a relatively limited glutamatergic input, deriving principally from the thalamus. Glutamate transmission is effected via three major subtypes of receptors, including those with affinity for N-methyl-d-aspartate (NMDA) and the properties of individual receptors reflect their precise subunit composition. We examined the distribution of NMDA2C and NMDA2D subunits in the rat striatum using immunocytochemistry and show that a population of large neurons is strongly immunoreactive for NMDA2D subunits. From their morphology and ultrastructure, these neurons were presumed to be cholinergic and this was confirmed with double immunofluorescence. We also show that NMDA2C is present in a small number of septal and olfactory cortical neurons but absent from the striatum.
Receptors that include NMDA2D subunits are relatively insensitive to magnesium ion block making neurons more likely to fire at more negative membrane potentials. Their localization to cholinergic neurons may enable very precise regulation of firing of these neurons by relatively small glutamatergic inputs.
interneuron; ultrastructure; synapse; endoplasmic reticulum
Objective: To evaluate the association between baseline homocysteine concentrations and restenosis rates in patients electively undergoing their first percutaneous coronary intervention (PCI) without stenting.
Design: Prospective, single centre, observational study.
Setting and patients: Patients electively undergoing their first PCI without stenting at a tertiary referral centre between 1990 and 1998.
Methods: Blood samples were collected from all patients at baseline and assayed to determine the patients’ homocysteine concentrations. Patients whose PCI was successful underwent repeat angiography at a median of 6.4 (interquartile range 6–6.8) months. Their baseline and follow up angiograms were compared by quantitative coronary angiography to assess the incidence of restenosis. For the analysis, the patients were divided into two groups based on whether their baseline homocysteine concentrations were above or below the median value. These two groups were compared to determine whether there was any association between their baseline homocysteine concentrations and the incidence of restenosis at six months.
Results: 134 patients had a successful first PCI without stenting (involving 200 lesions). At six month angiography, restenosis was observed in 33 patients (49.3%) with baseline homocysteine concentrations above the median value and in 31 patients (46.3%) with concentrations below the median value (p = 0.74). There was no difference in the percentage of lesions developing restenosis (38 (39.6%) v 40 (38.5%), respectively, p = 0.87) or late lumen loss (0.40 mm v 0.31 mm, respectively, p = 0.24). On multivariable analysis, there was no association between homocysteine concentrations and late lumen loss (r = −0.11, p = 0.11) or the percentage diameter stenosis at follow up (r = −0.07, p = 0.32).
Conclusion: Baseline homocysteine concentrations were not associated with six month restenosis rates in patients electively undergoing their first PCI without stenting.
homocysteine; percutaneous coronary intervention; restenosis
Objective: To determine the associations between changes on the presenting ECG, in-hospital revascularisation, and four year mortality in patients with non-ST elevation acute coronary syndromes.
Design: Prospective evaluation of all consecutive patients admitted in 1993 to the Green Lane Hospital coronary care unit, Auckland, New Zealand. Late follow up was undertaken at a median of 52 months. The ECGs were analysed after the hospital admission.
Setting: Tertiary referral centre with direct local coronary care unit admissions.
Interventions: Patients underwent physician recommended in-hospital revascularisation or initial conservative management.
Results: The four year survival was 88% in the 115 patients who underwent revascularisation (65 (19%) percutaneous and 53 (16%) surgical revascularisation), compared with 75% in 316 patients managed conservatively (p = 0.024). Four year survival for patients undergoing revascularisation versus initial conservative management with respect to ECG groups was: no ECG changes (n = 101), 97% v 92% (p = 0.35); T wave inversion or 0.5 mm ST depression (n = 108), 89% v 78% (p = 0.18); ST depression ≥ 1 mm (n = 122), 80% v 58% (p = 0.014); χ2 = 29, p < 0.001 for the linear trend across the groups. On multivariate analysis, independent predictors of four year mortality were: age (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01 to 1.08; p = 0.0046); ECG group (OR 1.88, 95% CI 1.21 to 2.95; p = 0.043); radiological pulmonary oedema (OR 2.81, 95% CI 1.18 to 7.05; p = 0.025); and revascularisation (OR 0.43, 95% CI 0.20 to 0.90; p = 0.023).
Conclusions: Among unselected patients with non-ST elevation acute coronary syndromes, in-hospital revascularisation is associated with decreased mortality at up to four years after admission. This association appears greater in patients with ST depression of ≥ 1 mm on the presenting ECG.
mortality; revascularisation; acute coronary syndrome
Insulin is neuroprotective in animal stroke models but its
effects in acute stroke in humans are unknown. The Glucose Insulin in
Stroke Trial (GIST-UK) is a randomised controlled trial investigating the benefits of maintaining euglycaemia in hyperglycaemic patients with
acute stroke. Data are reported from a GIST-UK substudy which sought to
determine the influence of glucose potassium insulin (GKI) infusion on
blood pressure in acute stroke. All adult patients admitted to hospital
with acute stroke with hyperglycaemia (plasma glucose 6.1-17 mmol/l)
were potentially eligible. Randomised patients received either a GKI
infusion (500 ml 10% glucose, 20 mmol potassium chloride, 16 units of
insulin) or control therapy with 154 mmol/l (0.9%) saline at 100 ml/h
for 24 hours. BM test strip glucose monitoring was performed 2 hourly,
blood pressure monitoring 4hourly, and plasma glucose sampling 8 hourly. Insulin concentration in the GKI infusate was altered according
to test strip values to maintain test strip values between 4-7 mmol/l
in the GKI group. Neurological impairment was determined using the
European stroke scale (ESS). 145 patients were studied (73 GKI, 72 control). Mean systolic blood pressure was significantly lower during
GKI infusion between 4 hours and 24 hours except at 8 hours. Median
total ESS scores improved significantly between admission and day 7 in
the GKI group (p<0.001) although there was no significant difference in total ESS score between groups at day 7. The significant reduction of systolic blood pressure in acute stroke associated with GKI therapy
was not associated with neurological deterioration and may have been beneficial.
Pancreatic cancer is an aggressive and potent disease, which is largely resistant to conventional forms of treatment. However, the discovery of antigens associated with pancreatic cancer cells has recently suggested the possibility that immunotherapy might become a specific and effective therapeutic option. T cells within many epithelia, including those of the pancreas, are known to express the αEβ7-integrin adhesion molecule, CD103. The only characterised ligand for CD103 is E-cadherin, an epithelial adhesion molecule which exhibits reduced expression in pancreatic cancer. In our study, CD103 was found to be expressed only by activated T cells following exposure to tumour necrosis factor beta 1, a factor produced by many cancer cells. Significantly, the expression of this integrin was restricted mainly to class I major histocompatibility complex-restricted CD8+ T cells. The human pancreatic cancer cell line Panc-1 was transfected with human E-cadherin in order to generate E-cadherin negative (wild type) and positive (transfected) sub-lines. Using a sensitive flow cytometric adhesion assay it was found that the expression of both CD103 (on T cells) and E-cadherin (on cancer cells) was essential for efficient adhesion of activated T cells to pancreatic cancer cells. This adhesion process was inhibited by the addition of antibodies specific for CD103, thereby demonstrating the importance of the CD103→E-cadherin interaction for T-cell adhesion. Using a 51Cr-release cytotoxicity assay it was found that CD103 expressing T cells lysed E-cadherin expressing Panc-1 target cells following T cell receptor stimulation; addition of antibodies specific for CD103 significantly reduced this lysis. Furthermore, absence of either CD103 from the T cells or E-cadherin expression from the cancer cells resulted in a significant reduction in cancer cell lysis. Therefore, potentially antigenic pancreatic cancer cells could evade a local anti-cancer immune response in vivo as a consequence of their loss of E-cadherin expression; this phenotypic change may also favour metastasis by reducing homotypic adhesion between adjacent cancer cells. We conclude that effective immunotherapy is likely to require upregulation of E-cadherin expression by pancreatic cancer cells or the development of cytotoxic immune cells that are less dependent on this adhesion molecule for efficient effecter function.
British Journal of Cancer (2002) 87, 1034–1041. doi:10.1038/sj.bjc.6600597 www.bjcancer.com
© 2002 Cancer Research UK
pancreatic cancer; immunotherapy; cytotoxic; T cells; E-cadherin
OBJECTIVES—To review the New Zealand coronary artery bypass priority score instituted in May 1996, and specifically to determine whether it prioritises patients at high risk of cardiac events while waiting. The New Zealand score is compared with the Ontario urgency rating score, and waiting times for surgery are compared with the maximum times recommended by the Ontario consensus panel.
DESIGN—Retrospective review of patients accepted for isolated coronary artery bypass surgery between 1 January 1993 and 31 January 1996.
SETTING—Green Lane Hospital, Auckland, New Zealand.
MAIN OUTCOME MEASURES—Waiting time, cardiac death, myocardial infarction, and cardiac readmission.
RESULTS—The median waiting times were five days for hospital cases (n = 721) and 146 days for out of hospital cases (n = 701). Of the latter group, 28% waited more than a year, 33% had their surgery expedited because of worsening symptoms, and 19% failed to meet the cut off point set by the New Zealand score for acceptance onto the list. Twenty two patients died, 18 on the outpatient waiting list (waiting list mortality 2.6%, risk 0.28% per month of waiting), and 132 were readmitted, 12% with myocardial infarction and 76% with unstable angina. Risk factors for a composite end point of death or myocardial infarction and/or cardiac readmission were: previous coronary artery bypass surgery (p = 0.001), class III or IV angina (p = 0.002), and hypertension (p = 0.005). The New Zealand score did not identify those at risk. Excluding hospital cases, 32% had surgery within the time recommended by the Ontario consensus panel.
CONCLUSIONS—Waiting times for coronary artery bypass surgery in New Zealand are considerably longer than those in Ontario, Canada. By using a numerical cut off point, implementation of the New Zealand priority scoring system has restricted access to coronary surgery on the basis of funding constraints rather than clinical appropriateness. The score does not add greatly to the clinicians' prioritisation in predicting those patients who will suffer events while waiting.
Keywords: coronary artery bypass surgery; prioritisation
Objective—To assess whether the 90 minute corrected thrombolysis in myocardial infarction frame count (CTFC) in the infarct related artery predicts left ventricular function at 48 hours in patients with myocardial infarction treated with aspirin, streptokinase, and either heparin or Hirulog.
Design and setting—Analysis of 251 patients with acute myocardial infarction enrolled in the international, multicentre Hirulog early reperfusion/occlusion (HERO-1) trial, who underwent both 90 minute coronary angiography and 48 hour left ventriculography.
Main outcome variables—The CTFC was determined in the infarct related artery 90 minutes after starting intravenous streptokinase (1.5 × 106 U over 30 to 60 minutes), and compared with indices of left ventricular function assessed by contrast ventriculography at 48 hours.
Results—A CTFC of ⩽ 27 frames (previously reported mean + 2 SD in coronary arteries of patients without acute infarction) occurred in 29% of infarct related arteries, and was associated with a lower infarct zone mean chord score (−2.06 v −2.54, p = 0.01), a lower fraction of chords > 2 SD below normal (37% v 51%, p = 0.005), and trends towards higher left ventricular ejection fractions (60.9% v 58.2%, p = 0.11) and lower end systolic volumes (50.1 ml v 55.9 ml, p = 0.23). A CTFC of ⩽ 40 at 90 minutes occurred in 50% of infarct related arteries, and was associated with a significantly lower mean chord score (−2.20 v −2.60, p = 0.02), a smaller fraction of chords > 2 SD below normal (41% v 52%, p = 0.025), a smaller end systolic volume (49.1 ml v 59.3 ml, p = 0.02), and a higher left ventricular ejection fraction (60.4% v 56.5%, p = 0.03).
Conclusions—The 90 minute CTFC predicts left ventricular function at 48 hours following streptokinase. The CTFC associated with better ventricular function may be higher than values determined from a non-infarct population.
Keywords: streptokinase; Hirulog; perfusion; ventricular function; frame count
Atrial fibrillation is an important and independent risk factor
for cerebrovascular disease and vascular dementia. There is increasing
evidence that atrial fibrillation is associated with an increased risk
of asymptomatic or silent cerebral infarction and as a result may
confer an increased risk of progressive cognitive impairment on a
person. In this study we sought to determine whether this hypothesis
could be explored in a prospective case controlled design. Twenty seven
patients with non-valvular atrial fibrillation (NVAF) and no history of
stroke, transient ischaemic attack, dementia, and thyrotoxicosis were
compared with 54 age and sex matched controls in sinus rhythm. All
cases underwent clinical examination, ECG, and psychological assessment
using a battery of nine neuropsychological tests. Between group
analysis and a comparison of mean test scores of paired controls with
cases were undertaken. The presence of atrial fibrillation was
consistently associated with poorer performances on all the subtests of
the neuropsychological battery. There was no association between
duration of atrial fibrillation and performance. These results provide
evidence to justify further examination of the hypothesis in a larger
prospective study to determine whether antithrombotic therapy may
protect against cognitive decline in patients at maximal risk of silent
cerebral ischaemia and associated cognitive decline.