A phase I study of PankoMab-GEX, a humanised glyco-optimised monoclonal antibody to a novel tumour-specific MUC1 glycopeptide epitope in patients with advanced carcinomas.

BACKGROUND: A phase I open-label dose-escalation study was conducted to define the safety, tolerability, and pharmacokinetics (PK) of PankoMab-GEX, a glyco-optimised humanised IgG1, with high affinity to a novel tumour-specific glycopeptide epitope of MUC1 (TA-MUC1) with excellent preclinical anti-tumour activity. PATIENTS AND METHODS: Seventy-four patients with advanced TA-MUC1-positive carcinomas received PankoMab-GEX intravenously every 3 (Q3W), 2 (Q2W), or 1 (QW) week in doses of 1-2200 mg in a three-plus-three dose-escalation design until disease progression (NCT01222624). RESULTS: No maximum tolerated dose was reached. Adverse events were mainly mild-to-moderate infusion-related reactions (IRRs) by the first infusion in 45% of patients. Only one dose-limiting toxicity, a grade III IRR, was observed. PankoMab-GEX exhibited linear PK over all doses. Mean terminal half-life was 189 ± 66 h (Q3W), without dose dependency. A target trough level ≥50 µg/mL was reached after one infusion with doses ≥1700 mg Q3W in 80% of patients. Clinical benefit in 60 evaluable patients included one complete response in a patient with ovarian cancer treated 483 d and confirmed disease stabilisation in 19 patients lasting a median (range) of 23 (10-109) weeks. All but two of the patients with clinical benefit had received a compounded total dose ≥700 mg over a 3-week period, including 8 of 12 (67%) patients with ovarian cancer. CONCLUSION: PankoMab-GEX is safe, well tolerated, and showed promising anti-tumour activity in advanced disease. A phase IIb study is ongoing evaluating the efficacy of PankoMab-GEX as a maintenance therapy in advanced ovarian cancer.

Seizures during high-dose antidepressant therapy: a case series with clinical and video-electroencephalography characteristics.

This case series identified drug causes of seizures in patients with depressive disorders. Three patients with seizures were admitted for video-electroencephalography (EEG) monitoring in the context of high-dose antidepressants and sodium valproate. Very high-dose antidepressants caused complex partial seizures with secondary generalisation that gave characteristic EEG discharges. This is the first reported series to capture the ictal EEG features associated with antidepressants.

Antidepressant therapy in epilepsy: can treating the comorbidities affect the underlying disorder?

There is a high incidence of psychiatric comorbidity in people with epilepsy (PWE), particularly depression. The manifold adverse consequences of comorbid depression have been more clearly mapped in recent years. Accordingly, considerable efforts have been made to improve detection and diagnosis, with the result that many PWE are treated with antidepressant drugs, medications with the potential to influence both epilepsy and depression. Exposure to older generations of antidepressants (notably tricyclic antidepressants and bupropion) can increase seizure frequency. However, a growing body of evidence suggests that newer ('second generation') antidepressants, such as selective serotonin reuptake inhibitors or serotonin-noradrenaline reuptake inhibitors, have markedly less effect on excitability and may lead to improvements in epilepsy severity. Although a great deal is known about how antidepressants affect excitability on short time scales in experimental models, little is known about the effects of chronic antidepressant exposure on the underlying processes subsumed under the term 'epileptogenesis': the progressive neurobiological processes by which the non-epileptic brain changes so that it generates spontaneous, recurrent seizures. This paper reviews the literature concerning the influences of antidepressants in PWE and in animal models. The second section describes neurobiological mechanisms implicated in both antidepressant actions and in epileptogenesis, highlighting potential substrates that may mediate any effects of antidepressants on the development and progression of epilepsy. Although much indirect evidence suggests the overall clinical effects of antidepressants on epilepsy itself are beneficial, there are reasons for caution and the need for further research, discussed in the concluding section.

Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients.

OBJECTIVES: To test the hypothesis that neuropsychiatric symptomatology is predictive of the success of seizure control in patients newly treated with antiepileptic drugs (AEDs), and that this predictive value adds to that provided by other clinical, imaging, and genomic factors in a multivariate model. METHODS: One hundred seventy newly treated patients with epilepsy completed the A-B Neuropsychological Assessment Scale (ABNAS) before commencing AED therapy and were prospectively followed up for 12 months. Patients were classified as nonresponsive if they had at least 1 seizure not explained by medication noncompliance or other significant provoking factors. RESULTS: Of the 138 patients in whom a drug response phenotype at 12 months was able to be determined, nonresponsive patients (n = 45) had a higher pretreatment ABNAS score than patients whose seizures were controlled (n = 93) (p = 0.007). A lesion on MRI was also associated with a higher risk of seizure recurrence (p = 0.003). On multivariate logistic regression, the ABNAS score, the MRI results, and a genomic classifier were all independently predictive of treatment outcome. For AED pharmacoresponse, this multivariate model had diagnostic values of 91% sensitivity, 64% specificity, 84% positive predictive, and 78% negative predictive values. The predictive value of the ABNAS score was validated in a second prospective cohort of 74 newly treated patients with epilepsy (p = 0.005). CONCLUSIONS: The ABNAS provides prognostic information regarding successful seizure control in patients newly treated with AEDs. Furthermore, these results demonstrate the multifactorial nature of the determinants of AED response, with neuropsychological, structural, and genomic factors all contributing to the complex response phenotype.

An open-label, multicenter study of outpatient capecitabine monotherapy in 631 patients with pretreated advanced breast cancer.

BACKGROUND: Phase II/III trials have shown that capecitabine is an active, well-tolerated therapy for metastatic breast cancer (MBC). We report clinical findings from an expanded access program enabling patients ineligible for investigative trials to receive capecitabine before its approval and availability. METHODS: Patients pretreated with at least two chemotherapy regimens, including a taxane, for MBC received oral capecitabine until disease progression or unacceptable toxicity. RESULTS: Six hundred and thirty-one patients received capecitabine (mean duration 3.8 months, range 0.1-24.7 months). The most common treatment-related grade 3/4 toxicities were diarrhea (9%) and hand-foot syndrome (8%). Grade 3/4 alopecia was absent and grade 3/4 myelosuppression was rare. Dose was modified in 172 patients (27%). Objective response rate in 349 evaluable patients was 35%. Median time to progression (n = 604) was 6.6 months (95% confidence interval, CI, 5.6-7.6) and median overall survival (n = 569) was 10.0 months (95% CI, 8.5-15.3). CONCLUSIONS: Our findings in a cohort of patients with pretreated progressive breast cancer confirm the high efficacy and tolerability of outpatient capecitabine.

Quality requirements in clinical studies: a necessary burden?

Drug development has continued to progress over the past decades and the processes involved have become more complex. The basis for these changes include advances in substance analysis and production, targeted drug development and defined guidelines for the conduct of clinical trials. The aim of standardised quality requirements is to generate scientifically sound data in clinical trials while observing strict ethical rules. The conduct of clinical trials is governed by internationally established Good Clinical Practice (GCP) guidelines. For the protection of human beings directly involved, framework conditions must be established as guidelines to accompany the research process. At the same time, these regulatory requirements enable a quality criteria standard to be defined. However, those regulations form a major challenge for clinical study centres, since they affect current clinical practice considerably. The objective of this paper is, on the one hand, to clarify the historical background relating to the development of clinical trials and the corresponding legal guidelines, on the other hand, to discuss consequences for clinical practice.

Phase II study of XR 5000 (DACA), an inhibitor of topoisomerase I and II, administered as a 120-h infusion in patients with non-small cell lung cancer.

XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II. The aim of this study was to evaluate the antitumoral activity and safety profile of XR5000 given as second-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Patients received XR5000 at the dose of 3010 mg/m(2) as a 120-h central venous infusion every 3 weeks. The 15 patients (median age 56 years, range 48-71 years) enrolled had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (3 patients), 1 (11 patients) or 2 (1 patient). A total of 32 cycles of XR5000 (median 2, range 1-6) were given to 14 patients. No objective response (assessed according to World Health Organization (WHO) criteria) was documented in the 12 evaluable patients by an external review panel; in 4 out of the 12 patients disease stabilisation was recorded. The following toxicities graded according to the Common Toxicity Criteria (CTC) version 2.0. were observed: one grade 3 and two grade 4 granulocytopenia, one grade 3 and one grade 4 thrombocytopenia, one grade 3 deep venous thrombosis, one grade 3 fatigue, and grade 3 undocumented epileptic seizures which led to death in 2 patients. With only 4 out of 12 patients reaching stable disease when using this dose and regimen, further evaluation of XR5000 in advanced NSCLC is not justified.

Epilepsy, depression and antidepressant drugs.

Apart from constituting an important management problem, depression coexisting with epilepsy is also an interesting psychiatric phenomenon, with multiple interacting biological, psychological and social factors involved in its causation. New research approaches to the study of epilepsy and depression, including neuroimaging, neurochemical and neuroendocrine techniques, and the arrival of new classes of antidepressants in recent years, suggest it is timely to reconsider this topic. We review current knowledge of the prevalence and causes of interictal depression in epilepsy, focussing mainly on neurobiological factors, and give an overview of recent concepts concerning the management of depression. We also discuss pharmacological treatment of depression in epilepsy, focussing on the association between antidepressants and seizures, and drug interactions.

[Hand-foot syndrome (palmar-plantar erythrodysesthesia]. / Das Hand-Fuss-Syndrom (palmar-plantare Erythrodysästhesie).

The hand-foot syndrome (HFS) is an erythematous skin lesion of the palma and planta of the hand and feet is most often caused by cytostatic chemotherapy. The impact on the patients' quality of life depends on the extent of the disease. The pathogenesis of the hand-foot syndrome has not yet been sufficiently clarified and it can only be treated symptomatically. We performed an extensive literature search in Medline to evaluate the current state of knowledge concerning the hand-foot syndrome and conclude with practical advice to physicians treating patients with hand-foot syndrome.

Retrospective assessment of occupational exposure to chemicals in community-based studies: validity and repeatability of industrial hygiene panel ratings.

BACKGROUND: Occupational hygiene panels are increasingly being used to rate retrospective occupational exposures to chemicals in community-based studies. This study aimed to assess the validity, reliability and feasibility of using such an expert panel in a brain tumour case-control study. METHODS: A panel of five experts was recruited to rate exposure to 21 chemicals for 298 job descriptions to investigate the level of agreement. Validity was assessed by comparing the ratings of the experts for 49 of the jobs with objective quantitative exposure data which existed for these jobs. Repeatability was assessed by comparing the results for 50 resubmissions. RESULTS: Specificity was high for reporting that exposure occurred (all above 90%), but sensitivity was variable with values between 48% and 79%. Weaker validity was found for rating exposure level and exposure frequency. The raters showed the greatest inter-rater agreement for exposure to three of the 21 chemicals considered (kappa = 0.64 for cutting fluids, kappa = 0.57 for welding fumes and kappa = 0.42 for lubricating oils). Intra-rater reliability, based on the 50 resubmitted jobs, was fair to good (kappa = 0.46, 0.73). CONCLUSIONS: The potential effect of exposure misclassification from using expert panels was quantified and found to be a significant source of bias. The optimum situation occurred where three of the five raters concurred, where an odds ratio of 2.2 was observed for a true odds ratio of 4.0. Future studies which plan to use expert panels should screen the experts for their suitability by validating their performance against jobs with known exposure data.

Association of adult glioma with medical conditions, family and reproductive history.

A population-based case-control study of 416 histologically diagnosed, incident gliomas in adults was carried out in Melbourne, Australia, to determine whether past medical, family or reproductive histories are risk factors for developing glioma. A total of 422 controls were selected from the Australian electoral roll and matched to cases for age, sex and post code of residence. An increased risk of developing glioma was observed among first-born individuals OR (95% CI) 2.0 (1.4-2.9). It is possible that this effect is due to residual confounding by socio-economic status or that it is a chance finding. Alternatively, it may be that this is due to some other effect linked to the first pregnancy, such as maternal age, birth weight or circumstances of delivery. There was no apparent association between the development of glioma and other neuropsychiatric or general medical conditions or with family history or reproductive history. Allergies (asthma and eczema) were not associated with a decreased risk of glioma, as has previously been suggested.

Tobacco smoking and alcohol consumption as risk factors for glioma: a case-control study in Melbourne, Australia.

OBJECTIVE: To investigate possible associations between tobacco smoking and alcohol consumption and the risk of adult glioma. DESIGN: This was a population based, case-control study. Relative risks (RR) were estimated using logistic regression analysis. SETTING: Melbourne, Australia. PARTICIPANTS: These comprised 416 case subjects (166 women, 250 men), 66% of those eligible; and 422 control subjects (170 women, 252 men), 43.5% of those potentially eligible. RESULTS: There was no increase in risk of glioma with having ever smoked tobacco (RR 1.29, 95% CI 0.95, 1.75) for all subjects, adjusted for age, a reference date, and gender. There was a slight increase in risk for men (RR 1.64, 95% CI 1.1, 2.45), but not for women (RR 0.99, 95% CI 0.62, 1.62). For men, there was no increase in risk with increasing pack-years of cigarette smoking, but the risk was significantly increased in subjects who had smoked for less than 10 years. There was no increase in risk associated with having ever drunk alcohol for all subjects (RR 0.96, 95% CI 0.67, 1.37), women (RR 0.69, 95% CI 0.4, 1.15) or men (RR 1.40, 95% CI 0.81, 2.43). CONCLUSIONS: This study does not support an association between either tobacco smoking or alcohol consumption and glioma. The pattern of risk associated with tobacco smoking in men appears inconsistent with a causal role, and may be due to chance, response bias, or uncontrolled confounding.

Dietary factors and the risk of glioma in adults: results of a case-control study in Melbourne, Australia.

In a population-based case-control study of 416 incident gliomas in adults carried out in Melbourne, Australia, between 1987 and 1991, 409 age-sex-matched case-control pairs (243 male and 166 female) had adequate data available to examine associations between the dietary intake of N-nitroso compounds, N-nitroso precursors, other nutrients including N-nitroso inhibitors, and the risk of glioma. Dietary intakes were based on the reported frequency of consumption of 59 food items. Increased odds ratio (OR) were observed in males who consumed high levels of bacon, corned meats, apples, melons and oil. OR less than unity were observed in men consuming cabbage and cola drinks, and in women who consumed wholegrain bread, pasta, corned meat, bananas, cauliflower, brocoli, cola drinks and nuts. Generally, N-nitroso associations were greater in men and micronutrient associations were greater in women. Elevated OR in men, but not women, were associated with the intake of N-nitroso dimethylamine (NDMA), retinol and vitamin E. The intake of nitrate (largely of vegetable origin) was protective in women but not in men. When analyzed using multiple logistic regression, the association with NDMA intake in males was not modified by dietary micronutrient intakes. In females, beta carotene alone, though not directly associated with risk, modified the effect of NDMA. On balance, this study added only limited support to the N-nitroso hypothesis of glial carcinogenesis.

Effect of placebo on office and on 24 hour noninvasive ambulatory blood pressure measurements.

Elevated BP in the clinical but not during daily activities (white coat hypertension) is a well recognised problem encountered in the diagnosis of mild hypertension. The aim of this study is to evaluate this phenomenon with a study population of 90 mild hypertensive patients subjected to 24h BP measurement, and to assess the effect of placebo on both the office and the daytime continual BP monitored values. For this purpose, 90 patients were evaluated after four weeks of single-blind placebo (Phase I) and, of these, 27 patients were evaluated after a further four weeks of double-blind placebo administration (Phase II). During Phase I treatment the mean office SBP (163.9 mmHg) and the mean office DBP (104.5 mmHg) were significantly higher than the average of the six readings obtained during the first two hours of automatic continual BP monitoring (158.6 and 98 mmHg respectively, P < 0.001) (white coat effect). These differences were much more pronounced when the comparison was made between office measurements and the average daytime values (SBP 152.8 mmHg, DBP 93.1 mmHg). At the end of Phase II, the average values of BP measurements obtained both in the office and from continual monitoring were significantly lower (placebo effect). However, the difference between the office and the daytime values persisted. Thus, notwithstanding the reduction in the BP measurements following placebo administration, the white coat effect persists.

Tumours of the brain and presence of antibodies to Toxoplasma gondii.

The possible association between prior infection with the protozoan Toxoplasma gondii and development of brain tumours was investigated as part of two Australian population-based case-control studies of adult brain tumours. One study, based in Adelaide, South Australia, collected blood from 73 subjects with glioma, 53 subjects with meningioma and 348 controls. The other study, based in Melbourne, Victoria, collected blood from 44 subjects with glioma and 67 controls. All tumours had been verified histologically. IgG antibodies to T. gondii were measured using Enzyme Linked Immunosorbent Assay (ELISA) techniques. In both the centre-specific and combined analyses, there was no difference between subjects with glioma and controls in the prevalence of antibody test-positivity (35% test-positive in glioma versus 33% in controls, age-, sex- and centre-adjusted odds ratio (OR) = 1.00, 95% confidence interval (CI): 0.64-1.56). In the Adelaide study, there was a statistically significant increased risk of meningioma associated with antibody test-positivity (47% test-positive in meningioma versus 31% in controls, P = 0.02, adjusted OR = 2.09, 95% CI: 1.14-3.83). Our results do not support the hypothesis that antibody positivity to T. gondii is a risk factor for glioma, but suggest that it might be associated with meningioma.

The role of atrial natriuretic peptide in natriuresis of fasting.

OBJECTIVE: To examine the relation between plasma atrial natriuretic peptide (ANP) and the natriuresis of fasting. DESIGN: ANP, aldosterone and renin were examined during natriuresis of fasting in 25 obese essential hypertensive patients and nine overweight normotensive subjects placed on a supervised 500-KCal diet composed of 50% carbohydrates, 30% fat and 20% protein, and unlimited salt. Twenty-four-hour urinary electrolytes were measured on days 0, 4, 7 and 10 of the diet. RESULTS: Urinary sodium concentration nearly doubled in the patients on day 4, and increased 1.4-fold in the normotensive controls. Plasma ANP rose nearly threefold in the hypertensives on day 4 and nearly doubled in the normotensives. Patients and controls showed similar patterns of natriuresis and ANP secretion during the diet. CONCLUSIONS: We conclude that there is a clear association between ANP levels and natriuresis of fasting.