Hormonal status effects on the electrophysiological correlates of performance monitoring in women.

Fluctuations in ovarian hormones are thought to play a role in the increased prevalence of mood and anxiety disorders in women. Error-related negativity (ERN) and error positivity (Pe) are two putative electrophysiological biomarkers for these internalizing disorders. We investigated whether female hormonal status, specifically menstrual cycle phase and oral contraceptive (OC) use, impact ERN and Pe. Additionally, we examined whether the relationship between the ERN and negative affect (NA) was moderated by hormonal status and tested whether the ERN mediated the relation between ovarian hormones and NA. Participants were healthy, pre-menopausal women who were naturally cycling (NC) or using OCs. Using a counterbalanced within-subject design, all participants performed a speeded-choice reaction-time task twice while undergoing electroencephalography measurements. NC women (N = 42) performed this task during the early follicular and midluteal phase (when estrogen and progesterone are both low and both high, respectively), while OC users (N = 42) performed the task during active OC use and during their pill-free week. Estradiol and progesterone levels were assessed in saliva. Comparing the two cycle phases within NC women revealed no differences in the (Δ)ERN, (Δ)Pe or NA. We did observe a negative relation between phase-related changes in the ΔERN and changes in NA. Mediation analysis additionally showed that phase-related changes in estradiol were indirectly and negatively related to NA through a reduction of ΔERN amplitudes. When comparing active OC users with NC women, we observed increased ΔPe- but not (Δ)ERN amplitudes in the former group. No evidence was found for moderating effects of menstrual cycle phase or OC use on the relation between the ERN and NA. These findings suggest that hormonal status may impact the neural correlates of performance monitoring and error sensitivity, and that this could be a potential mechanism through which ovarian hormones influence mood.

Mistakes that matter: An event-related potential study on obsessive-compulsive symptoms and social performance monitoring in different responsibility contexts.

Mistakes that affect others often are linked to increased feelings of responsibility and guilt. This especially holds for individuals high in obsessive-compulsive symptoms (OCS), who are characterized by inflated feelings of responsibility and a fear of causing harm to others. This event-related potential study investigated individual differences in OCS in social performance monitoring with a focus on the role of responsibility for other's harm and the error-related negativity (ERN). Healthy volunteers low (N = 27) or high (N = 24) in OCS performed a Flanker task in the presence of a gender-matched peer in three conditions. Mistakes could either have negative monetary consequences for 1) oneself, 2) the other, or 3) no one. Results showed enhanced ERNs for mistakes that harmed others instead of the self for individuals high in OCS, whereas individuals low in OCS showed decreased amplitudes specifically for mistakes affecting no one versus oneself. Amplitudes of the error positivity but not the ERN also were larger in the high OCS group. These findings indicate that high OCS are associated with enhanced performance monitoring in a social responsibility context, when mistakes harm others instead of the self, and demonstrate the importance of integrating the social context in performance monitoring research as a way to shed more light on obsessive-compulsive symptomatology.

Being right, but losing money: the role of striatum in joint decision making.

Joint decision-making entails that you sometimes have to go along with the other's choice even though you disagree. In this situation, a resulting negative outcome may, however, elicit a feeling of satisfaction and an impulse to say "I told you so". Using fMRI, we investigated the neural correlates of this complex process comprised of both positive and negative outcomes. During a social visual search task, 19 participants gave their advice to a co-actor who then made the decision resulting in a mutual loss or gain. This design allowed direct comparisons of situations that resulted in the same monetary outcome but that differed with respect to the correctness of the initial advice of the participant. Increased striatal activations were found for gains compared to losses and for correct compared to incorrect advice. Importantly, ROI analyses also showed enhanced striatum activation for monetary losses that were preceded by correct compared to incorrect advices. The current study therefore suggests that reward-related neural mechanisms may be involved when being right even in situations that end in monetary losses.

Does oxytocin lead to emotional interference during a working memory paradigm?

BACKGROUND: Oxytocin administration may increase attention to emotional information. We hypothesized that this augmented emotional processing might in turn lead to interference on concurrent cognitive tasks. To test this hypothesis, we examined whether oxytocin administration would lead to heightened emotional interference during a working memory paradigm. Additionally, moderating effects of childhood maltreatment were explored. METHODS: Seventy-eight healthy males received 24 IU of intranasal oxytocin or placebo in a randomized placebo-controlled double-blind between-subjects study. A working memory task was performed during which neutral, positive, and negative distractors were presented. RESULTS: The main outcome observed was that oxytocin did not enhance interference by emotional information during the working memory task. There was a non-significant trend for oxytocin to slow down performance irrespective of distractor valence, while accuracy was unaffected. Exploratory analyses showed that childhood maltreatment was related to lower overall accuracy, but in the placebo condition only. However, the maltreated group sample size was very small precluding any conclusions on its moderating effect. CONCLUSIONS: Despite oxytocin's previously proposed role in enhanced emotional processing, no proof was found that this would lead to reduced performance on a concurrent cognitive task. The routes by which oxytocin exerts its effects on cognitive and social-emotional processes remain to be fully elucidated.

Spectral EMG Changes in Cervical Dystonia Patients and the Influence of Botulinum Toxin Treatment.

Botulinum toxin (BoNT) injections in the dystonic muscles is the preferred treatment for Cervical Dystonia (CD), but the proper identification of the dystonic muscles remains a challenge. Previous studies showed decreased 8-14 Hz autospectral power in the electromyography (EMG) of splenius muscles in CD patients. Cumulative distribution functions (CDF's) of dystonic muscles showed increased CDF10 values, representing increased autospectral powers between 3 and 10 Hz, relative to power between 3 and 32 Hz. In this study, we evaluated both methods and investigated the effects of botulinum toxin. Intramuscular EMG recordings were obtained from the splenius, semispinalis, and sternocleidomastoid muscles during standardized isometric tasks in 4 BoNT-naïve CD patients, 12 BoNT-treated patients, and 8 healthy controls. BoNT-treated patients were measured 4-7 weeks after their last BoNT injections and again after 11-15 weeks. We found significantly decreased 8-14 Hz autospectral power in splenius muscles, but not in the semispinalis and sternocleidomastoid muscles of CD patients when compared to healthy controls. CDF10 analysis was superior in demonstrating subtle autospectral changes, and showed increased CDF10 values in all studied muscles of CD patients. These results did not change significantly after BoNT injections. Further studies are needed to investigate the origin of these autospectral changes in dystonia patients, and to assess their potential in muscle selection for BoNT treatment.

Dystonic neck muscles show a shift in relative autospectral power during isometric contractions.

OBJECTIVE: To identify effects of a deviant motor drive in the autospectral power of dystonic muscles during voluntary contraction in cervical dystonia patients. METHODS: Submaximal (20%) isometric head-neck tasks were performed with the head fixed, measuring surface EMG of the sternocleidomastoid, splenius capitis and semispinalis capitis in CD patients and controls. Autospectral power of muscle activity, and head forces was analyzed using cumulative distribution functions (CDF). A downward shift between the theta/low alpha-band (3-10Hz) and the high alpha/beta-band (10-30Hz) was detected using the CDF10, defined as the cumulative power from 3 to 10Hz relative to power from 3 to 30Hz. RESULTS: CDF10 was increased in dystonic muscles compared to controls and patient muscles unaffected by dystonia, due to a 3-10Hz power increase and a 10-30Hz decrease. CDF10 also increased in patient head forces. CONCLUSIONS: Submaximal isometric contractions with the head fixed provided a well-defined test condition minimizing effects of reflexive feedback and tremor. We associate shifts in autospectral power with prokinetic sensorimotor control. SIGNIFICANCE: Analysis of autospectral power in isometric tasks with the head fixed is a promising approach in research and diagnostics of cervical dystonia.

Improved identification of dystonic cervical muscles via abnormal muscle activity during isometric contractions.

BACKGROUND: The preferred treatment for cervical dystonia (CD) is injection of botulinum toxin in the dystonic muscles. Unfortunately, in the absence of reliable diagnostic methods it can be difficult to discriminate dystonic muscles from healthy muscles acting in compensation. We investigated if dystonic muscle activation patterns could be identified in cervical dystonia patients during a harmonized isometric contraction task. Furthermore, we investigated whether dystonia worsens at higher levels of voluntary contraction, which might further improve the identification of dystonic muscle activity. METHODS: An isometric device was used to investigate muscle activation during voluntary contraction tasks in 10 controls and 10 CD patients. Surface electromyography (EMG) of the sternocleidomastoidus, splenius capitis, and semispinalis capitis muscles was evaluated during a rest task and when performing submaximal (20%) and maximal voluntary contractions for eight head transversal force directions and for head twist. Two measures were developed to identify dystonic activation: 1) Muscle activity in the contraction direction in which the contribution of the muscle was lowest (Minimum EMG), and 2) the average muscle activity over all contraction directions (Total Mean EMG). RESULTS: Patients showed increased dystonic activity in the rest task and during submaximal contractions relative to controls, but not during maximal contractions. Increases in Minimum EMG indicated an inability of patients to deactivate dystonic muscles counteracting the task. Increases in Total Mean EMG indicated dystonic activity in all task directions. During maximal contractions these effects were absent in dystonic muscles. Dystonia is therefore found not to worsen at higher levels of isometric voluntary contraction. The activity of dystonic muscles modulated with different loading directions similar to controls. Using Minimum EMG 54% of the muscles clinically diagnosed as dystonic and 91% of non-dystonic muscles were predicted correctly. CONCLUSIONS: Dystonic muscle activity was found in cervical dystonia patients during submaximal contractions in all task directions using a harmonized isometric task, but no differences were found during maximal contractions. With some adaptation this method may prove useful to identify dystonic muscles.

EEG correlates of impaired self-other integration during joint-task performance in schizophrenia.

Deficits in a wide variety of social cognitive processes are well established in schizophrenia. However, research focusing on actual interacting individuals is surprisingly scarce. Problems in low-level processes such as self-other integration may importantly underlie often-reported higher-level deficits. The current study aimed at measuring possible disturbances in self-other integration in schizophrenia using both behavioral and event-related potential (ERP) measures. Sixteen healthy controls and fifteen schizophrenia patients performed a social Simon task in both a joint and an individual setting. Behaviorally, patients showed general slower reaction times, but comparable self-other integration as reflected in the social Simon effect. The ERP results for the healthy controls revealed increased no-go P3 amplitudes in the joint compared with the individual setting. Crucially, patients did not show this increase in no-go P3 amplitude. In line with previous research, the present ERP findings demonstrate that healthy volunteers needed more effort to inhibit their responses in the joint compared with the individual setting. Patients however, showed altered self-other integration when they had to withhold their responses while their co-actor had to act. These outcomes indicate that schizophrenia patients have deficits in low-level processes required for successful joint action.

EMG coherence and spectral analysis in cervical dystonia: discriminative tools to identify dystonic muscles?

OBJECTIVE: Botulinum toxin injections in the dystonic muscles are the preferred treatment for cervical dystonia (CD), but proper selection of the dystonic muscles remains a challenge. We investigated the use of EMG coherence and autospectral analysis as discriminative tools to identify dystonic muscles in CD patients. METHODS: We compared the occurrence of 8-14 Hz autospectral peaks and 4-7 Hz intermuscular coherences between 10 CD patients and 10 healthy controls. Secondly, we compared the muscles with significant 4-7 Hz coherences with the muscles that were selected clinically for botulinum toxin treatment. RESULTS: Autospectral peaks between 8 and 14 Hz were significantly more often absent in the splenius capitis (SPL) muscles of CD patients compared to controls (p<0.01). Contrary to previous findings, there was no significant difference in the occurrence of 4-7 Hz intermuscular coherences between patients and controls and the diagnostic accuracy of coherence analysis to identify the clinically dystonic muscles was low. CONCLUSION: Intermuscular EMG coherence analysis cannot reliably discriminate patients from controls. Autospectral changes in the SPL muscles are a more discriminative feature of CD. In patients, coherence analysis does not seem to be a reliable method to identify dystonic muscles. The clinical relevance and the origin of the autospectral changes need further study.

The acute effects of MDMA and ethanol administration on electrophysiological correlates of performance monitoring in healthy volunteers.

RATIONALE: Knowing how commonly used drugs affect performance monitoring is of great importance, because drug use is often associated with compromised behavioral control. Two of the most commonly used recreational drugs in the western world, 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and ethanol (alcohol), are also often used in combination. The error-related negativity (ERN), correct-related negativity (CRN), and N2 are electrophysiological indices of performance monitoring. OBJECTIVES: The present study aimed to investigate how ethanol, MDMA, and their co-administration affect performance monitoring as indexed by the electrophysiological correlates. METHODS: Behavioral and EEG data were obtained from 14 healthy volunteers during execution of a speeded choice-reaction-time task after administration of ethanol, MDMA, and combined ethanol and MDMA, in a double-blind, placebo-controlled, randomized crossover design. RESULTS: Ethanol significantly reduced ERN amplitudes, while administration of MDMA did not affect the ERN. Co-administration of MDMA and ethanol did not further impair nor ameliorate the effect of ethanol alone. No drug effects on CRN nor N2 were observed. DISCUSSION: A decreased ERN following ethanol administration is in line with previous work and offers further support for the impairing effects of alcohol intoxication on performance monitoring. This impairment may underlie maladaptive behavior in people who are under influence. Moreover, these data demonstrate for the first time that MDMA does not affect performance monitoring nor does it interact with ethanol in this process. These findings corroborate the notion that MDMA leaves central executive functions relatively unaffected.

The nicotinergic receptor as a target for cognitive enhancement in schizophrenia: barking up the wrong tree?

RATIONALE: Cognitive symptoms have increasingly been recognized as an important target in the development of future treatment strategies in schizophrenia. The nicotinergic neurotransmission system has been suggested as a potentially interesting treatment target for these cognitive deficits. However, previous research yielded conflicting results, which may be explained by several methodological limitations, such as the failure to include both a group of smoking and non-smoking schizophrenic patients, the use of only a single nicotine dose, and the inclusion of a very limited cognitive battery. OBJECTIVES: The present study aims at investigating the cognitive effects of nicotine in schizophrenia while addressing these methodological issues. METHODS: In a double-blind placebo-controlled randomized crossover design, cognitive effects are assessed in smoking (n =16) and non-smoking (n =16) schizophrenic patients after receiving active (1 or 2 mg) or placebo oromucosal nicotine spray. RESULTS: A modest improving effect of nicotine on attention in the smoking but not the non-smoking group was found. No enhancing effects were found on measures of visual memory, working memory, processing speed, psychomotor speed, or social cognitive functioning in either patient group. CONCLUSIONS: These findings suggest that the nicotinic receptor only has limited value as a cognitive treatment target in schizophrenia.

Feedback-related negativity codes outcome valence, but not outcome expectancy, during reversal learning.

Optimal behavior depends on the ability to assess the predictive value of events and to adjust behavior accordingly. Outcome processing can be studied by using its electrophysiological signatures--that is, the feedback-related negativity (FRN) and the P300. A prominent reinforcement-learning model predicts an FRN on negative prediction errors, as well as implying a role for the FRN in learning and the adaptation of behavior. However, these predictions have recently been challenged. Notably, studies so far have used tasks in which the outcomes have been contingent on the response. In these paradigms, the need to adapt behavioral responses is present only for negative, not for positive feedback. The goal of the present study was to investigate the effects of positive as well as negative violations of expectancy on FRN amplitudes, without the usual confound of behavioral adjustments. A reversal-learning task was employed in which outcome value and outcome expectancy were orthogonalized; that is, both positive and negative outcomes were equally unexpected. The results revealed a double dissociation, with effects of valence but not expectancy on the FRN and, conversely, effects of expectancy but not valence on the P300. While FRN amplitudes were largest for negative-outcome trials, irrespective of outcome expectancy, P300 amplitudes were largest for unexpected-outcome trials, irrespective of outcome valence. These FRN effects were interpreted to reflect an evaluation along a good-bad dimension, rather than reflecting a negative prediction error or a role in behavioral adaptation. By contrast, the P300 reflects the updating of information relevant for behavior in a changing context.

DBH -1021C>T and COMT Val108/158Met genotype are not associated with the P300 ERP in an auditory oddball task.

OBJECTIVE: The amplitude and latency of the P300 may be associated by variations in dopaminergic genes. The current study was conducted to determine whether functional variants of the catechol-O-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) gene were associated with P300 amplitude and latency in an auditory oddball task. METHODS: The P300 ERP was assessed by a two-tone auditory oddball paradigm in a large sample of 320 healthy volunteers. The Val108/158Met polymorphism (rs4680) of the COMT gene and the -1021C>T polymorphism (rs1611115) of the DBH gene were genotyped. P300 amplitude and latency were compared across genotype groups using analysis of variance. RESULTS: There were no differences in demographic characteristics in subjects for genotypic subgroups. No genotype associations were observed for the P300 amplitude and latency on frontal, central and parietal electrode positions. CONCLUSIONS: COMT Val108/158Met and DBH -1021C>T polymorphisms do not show evidence of association with characteristics of the P300 ERP in an auditory oddball paradigm in healthy volunteers. SIGNIFICANCE: We failed to find evidence for the association between dopaminergic enzymatic polymorphisms and the P300 ERP in healthy volunteers, in the largest study undertaken to date.

Trait and state aspects of internal and external performance monitoring in schizophrenia.

Disturbed internal performance monitoring has been repeatedly demonstrated in schizophrenia. Along with internal monitoring, efficiently processing external task-relevant performance feedback that goes unnoticed by the internal monitoring system is crucial for adequate performance. It is unknown whether external monitoring is disturbed in schizophrenia and whether it is trait or state dependent. The current study investigated the effects of treatment on both internal and external performance monitoring in schizophrenia. Twelve schizophrenia patients and twelve matched healthy controls performed a modified flanker task while ERPs and behavioral measures were obtained. Both groups were assessed twice, with a six-week interval, during which the patients received antipsychotic treatment. Internal monitoring was investigated by means of the response-locked error-related negativity (Ne/ERN), an event-related potential component elicited by erroneous responses. External monitoring was investigated by analyzing the feedback-locked P300 elicited by task-relevant external response-time feedback (late feedback). Compared to controls, schizophrenia patients showed diminished Ne/ERN amplitudes, which were insensitive to six weeks of treatment. Patients also had reduced P300 amplitudes in response to late feedback at the first assessment, but these were normalized at the second assessment. Also, patients showed increased performance following negative external feedback at the second session. This study demonstrates the importance of considering both forms of performance monitoring in schizophrenia. Diminished internal error processing seems to be an important 'trait' marker of the disorder, while processing of externally presented feedback appears to have a 'state' character, susceptible to treatment at both a neurophysiological and a behavioral level.

Mistakes that affect others: an fMRI study on processing of own errors in a social context.

In social contexts, errors have a special significance and often bear consequences for others. Thinking about others and drawing social inferences in interpersonal games engages the mentalizing system. We used neuroimaging to investigate the differences in brain activations between errors that affect only agents themselves and errors that additionally influence the payoffs of interaction partners. Activation in posterior medial frontal cortex (pMFC) and bilateral insula was increased for all errors, whereas errors that implied consequences for others specifically activated medial prefrontal cortex (mPFC), an important part of the mentalizing system. The results demonstrate that performance monitoring in social contexts involves additional processes and brain structures compared with individual performance monitoring where errors only have consequences for the person committing them. Taking into account how one's behavior may affect others is particularly crucial for adapting behavior in interpersonal interactions and joint action.

Neural correlates of error-related learning deficits in individuals with psychopathy.

BACKGROUND: Psychopathy (PP) is associated with a performance deficit in a variety of stimulus-response and stimulus-reinforcement learning paradigms. We tested the hypothesis that failures in error monitoring underlie these learning deficits. METHOD: We measured electrophysiological correlates of error monitoring [error-related negativity (ERN)] during a probabilistic learning task in individuals with PP (n=13) and healthy matched control subjects (n=18). The task consisted of three graded learning conditions in which the amount of learning was manipulated by varying the degree to which the response was predictive of the value of the feedback (50, 80 and 100%). RESULTS: Behaviourally, we found impaired learning and diminished accuracy in the group of individuals with PP. Amplitudes of the response ERN (rERN) were reduced. No differences in the feedback ERN (fERN) were found. CONCLUSIONS: The results are interpreted in terms of a deficit in initial rule learning and subsequent generalization of these rules to new stimuli. Negative feedback is adequately processed at a neural level but this information is not used to improve behaviour on subsequent trials. As learning is degraded, the process of error detection at the moment of the actual response is diminished. Therefore, the current study demonstrates that disturbed error-monitoring processes play a central role in the often reported learning deficits in individuals with PP.

A cognitive neuropsychiatric analysis of psychomotor symptoms in major depression and schizophrenia.

A cognitive neuropsychiatric analysis will be proposed by presenting recent research on -1-motor control, and -2-action monitoring in two psychiatric disorders i.e. major depression and schizophrenia. Motor control is best studied from the broader cognitive neuropsychological perspective of action control. Even very simple actions implicate quite diverse brain activities reflecting the cognitive processes of planning, selection, visuomotor integration, timing, force adjustment, and action monitoring. The extent to which deficits in these cognitive processes cause slowed or stereotypic actions can be experimentally studied in clinical settings by means of graphic tasks, as will be illustrated. A central process in motor/action control is error monitoring. The last decade research on this higher cognitive control process has been booming, also because the detection of errors is accompanied by a clear peak in the EEG, known as the error-related negativity (ERN). Deficient error monitoring has been observed in several psychiatric disorders. ERN studies in major depression and schizophrenia will be discussed. Psychiatric disorders can best be understood by considering three perspectives, i.e. psychopathology, cognitive neuropsychology and neuroscience. The findings support the view that cognitive neuropsychiatry should involve the combined study of psychiatric symptoms, cognitive dimensions and neurological structures.

A phase I dose-finding clinical pharmacokinetic study of an oral formulation of irinotecan (CPT-11) administered for 5 days every 3 weeks in patients with advanced solid tumours.

BACKGROUND: Oral administration of irinotecan (CPT-11) should allow sustained exposure to the drug without the inconvenience of intravenous delivery and with fewer side-effects. PATIENTS AND METHODS: The present phase I trial of CPT-11, administered orally as a powder-filled capsule for 5 consecutive days every 3 weeks at doses ranging from 30 to 90 mg/m(2)/day, was conducted in 47 patients for whom a satisfactory standard treatment option was no longer available (24 males/23 females; median age 51 years, range 26-85). Tumour types included melanoma (11), colorectal (4), urinary tract (3), lung/pleura (4), thyroid (3), liver (3), gallbladder (2), cervix/uterus (3), breast (2), pancreas (2), carcinoma and other cancer types (10). RESULTS: A total of 171 cycles were administered (median 3, range 1-11). Dose limiting toxicities (DLTs) occurred during the first cycle in five of 31 patients in the dose-escalation part of the study: one patient at the 50 mg/m(2)/day dose level (diarrhoea grade 4); one patient at the 80 mg/m(2)/day dose level (prolonged neutropenia grade 4 and diarrhoea grade 3); and three patients at the 90 mg/m(2)/day dose level (diarrhoea, vomiting and neutropenia). The 80 mg/m(2)/day dose level was expanded, as a feasibility study, to include 16 additional patients, five of whom had received extensive prior pelvic irradiation. A further three patients in this cohort experienced DLTs, two of whom had received extensive prior pelvic irradiation. One patient died on study day 15 during the first cycle of oral CPT-11 following grade 3 diarrhoea, febrile neutropenia and a necrotic enterocolitis. Overall the grade 3/4 toxicities in 47 patients were asthenia (19%), anorexia (17%), neutropenia (14.9 %), diarrhoea (13%), nausea (12.7%), vomiting (8.5%) and thrombocytopenia (8.5%). Partial responses were observed in two melanoma patients and disease stabilisation was noted in 17 (36.1%) patients. Pharmacokinetic parameters were recorded for 46 patients. CONCLUSIONS: At the maximum tolerated dose, defined as 80 mg/m(2)/day for 5 days every 3 weeks, oral CPT-11 was shown to be well tolerated and safe with few of the haematological toxicities associated with the intravenous formulation.

Balloon catheter hypoxic pelvic perfusion with mitomycin C and melphalan for locally advanced tumours in the pelvic region: a phase I-II trial.

AIMS: To investigate the feasibility of hypoxic pelvic perfusion (HPP), using balloon catheter techniques as treatment modality for locally advanced pelvic malignancies. METHODS: In a phase I--II study, 16 patients with various non-resectable pelvic tumours were treated with two HPP with MMC and melphalan, followed by radiotherapy (25 Gy) and surgical resection if feasible. Toxicity and procedure related complications were documented. Tumour responses were assessed by MRI or CT. Pain reductive effects were assessed by evaluation of pain registration forms. RESULTS: HPP resulted in augmented regional drug concentrations with relatively low systemic levels. Some severe systemic toxicity was observed. One procedure related death occurred. Pain reduction effects were short-lived. Ten patients had radiological NC, two PD and one PR. In 11 patients surgical resection was performed, which was microscopically radical in six cases. Mean survival was 26.8 months (range 1--86). CONCLUSION: The seemingly favorable pharmacokinetic profiles observed with HPP in this and other studies can still lead to severe systemic toxicity. In terms of survival, local (re-)recurrence and pain reduction there seems no benefit of addition of HPP to pre-operative radiotherapy. HPP with MMC and melphalan, does not seem a therapeutic option in patients with locally advanced pelvic tumours.

Sensitive and specific quantification of the anticancer agent ZD1839 (Gefitinib) in plasma by on-column focusing capillary liquid chromatography-tandem mass spectrometry.

The development of an on-column focusing gradient capillary LC method coupled to tandem mass spectrometry (quadrupole-linear ion trap) for the quantitative determination of the anticancer agent ZD1839 (Gefitinib, Iressa) in blood plasma is described. Plasma samples (0.2 ml) were extracted with methyl tert-butyl ether. The analytes of interest, ZD1839 and the internal standard [(2)H8]ZD1839 (ZD1839-d8) were eluted on a 50 mm x 1 mm, 5 microm particle size, capillary ODS Hypersil column using an aqueous ammonium acetate gradient at 40 microl/min. Mass spectrometric detection was performed by a Q-Trap tandem mass spectrometer with electrospray positive ionisation, and monitored in the multiple reaction monitoring transitions 447 >128 and 455 >136, respectively. The limit of quantification of ZD18395 was 0.1 ng/ml. The method proved to be robust, allowing quantification of ZD1839 with sufficient precision, accuracy and sensitivity.