Can we use gonadotropin plasma concentration as surrogate marker for BMI-related incomplete estrogen suppression in breast cancer patients receiving anastrozole?

BACKGROUND: BMI has been suggested to impact on estrogenic activity in patients receiving anastrozole resulting in a reduced treatment efficacy in obese women. Current evidence in this regard is controversially discussed. Since estradiol is inversely correlated with gonadotropins it can be assumed that an impact of BMI is also reflected by gonadotropin plasma concentrations. We aim at investigating the impact of BMI on the hormonal state of breast cancer (BC) patients receiving anastrozole indicated by LH, FSH and SHBG as well as estradiol. METHODS: We determined gonadotropin-, estradiol- and anastrozole- serum concentrations from postmenopausal, early stage breast cancer patients receiving upfront anastrozole within routine after care. Gonadotropin plasma concentrations were derived from the routine laboratory examination report. A liquid chromatography tandem mass spectrometry method was used for the measurement of anastrozole serum concentrations. BMI was assessed within the routine after-care check-up. RESULTS: The overall sample comprised 135 BC patients with a mean age of 65.3 years. BMI was significantly correlated with LH, FSH and SHBG. This association was neither influenced by age nor by anastrozole serum concentrations according to the regression model. Despite aromatase inhibition 12% of patients had detectable estrogen levels in routine quantification. CONCLUSION: Obese women have an altered hormonal situation compared to normally weight women under the same dose of anastrozole. Our study findings are a further indicator for the relevance of BMI in regard of anastrozole metabolism and possible estrogenic activity indicated by gonadotropin plasma level.

[Patients, physicians and nursing personnel in intensive care units: Psychological and psychotherapeutic interventions]. / Patienten, Ärzte und Pflegepersonal auf Intensivstationen : Psychologische und psychotherapeutische Interventionen.

During intensive care treatment patients suffer from various forms of stress. Certain psychological and psychotherapeutic interventions (e. g. cognitive behavior therapy, hypnotherapy and psychoeducation) can provide relief. Even patients with a severely reduced ability to communicate can benefit from an early psychological intervention as supportive treatment. The aim of these interventions is to reduce psychological impairments and burdens, provide strategies for coping with physical handicaps or necessary treatment and avoid long-term negative psychological impacts. Organizational and institutional constraints as well as emotional stress are a specific challenge for intensive care personnel. In order to guarantee an efficient collaboration within an interdisciplinary team it is vital to follow clearly defined methods of communication exchange, such as daily ward rounds, regular multidisciplinary meetings and team or case-focused supervision. Properly functioning teamwork increases job satisfaction and is the key to an optimal therapy for the patients.

Levels in neurotransmitter precursor amino acids correlate with mental health in patients with breast cancer.

Breast cancer is the most common cancer among females. Approximately 30% of cancer patients develop depression or depressive adaptation disorder within 5 years post diagnosis. Low grade inflammation and subsequent changes in neurotransmitter levels could be the pathophysiological link. In the current study we investigated the association of neurotransmitter precursor amino acids with a diagnosis of depression or state anxiety in 154 subjects suffering from breast cancer (BCA(+)), depression (DPR(+)), both or neither. Sociodemographic parameters, severity of depressive symptoms, and state anxiety (ANX) were recorded. Neopterin, kynurenine/tryptophan and phenylalanine/tyrosine were analysed by HPLC or ELISA. Significantly higher serum neopterin values were found in DPR(+) patients (p = 0.034) and in ANX(+) subjects (p = 0.008), as a marker of Th1-related inflammation. The phenylalanine/tyrosine ratio (index of the catecholamine pathway) was associated with the factors "breast cancer" and "depression" and their interaction (all p < 0.001); it was highest in the DPR(+)BCA(+) group. The kynurenine/tryptophan ratio (index of the serotonin pathway) was significantly associated with the factors "breast cancer" and "state anxiety" and their interaction (p < 0.001, p = 0.026, p = 0.02, respectively); it was highest in the ANX(+)BCA(+) group. In BCA(+) patients kynurenine/tryptophan ratios correlated with severity of state anxiety (r = 0.226, p = 0.048, uncorrected) and phenylalanine/tyrosine ratios with severity of depressive symptoms (r = 0.376, p < 0.05, corrected). In conclusion, levels of neurotransmitter precursor amino acids correlate with mental health, an effect which was much more pronounced in BCA(+) patients than in BCA(-) subjects. Aside from identifying underlying pathophysiological mechanisms, these results could be the basis for future treatment studies: in BCA(+) patients with depression the use of serotonin-noradrenaline reuptake inhibitors might be recommended while in those with predominant anxiety selective serotonin reuptake inhibitors might be the treatment of choice.

[Diagnosis and therapy of cognitive deficits in oncology patients]. / Diagnose und Therapie neurokognitiver Störungen bei onkologischen Patienten.

Improvements in the diagnostics and therapy of almost all types of cancer have extended the survival rates and average life expectancies of oncology patients. As a result the assessment of cognitive deficits is becoming much more important not only in cancer diagnostics but also in the disease-free period following treatment. Various cognitive deficits can occur in patients with intracranial as well as extracranial malignancies. These deficits can be caused by tumor or treatment-related factors. Previous studies have shown that cognitive deficits may negatively influence the quality of life, therapy adherence, prognosis and mortality of patients. Currently, standardized specially designed cognitive tests for oncology patients are lacking; nevertheless, neurocognitive assessment should become an integral element in the diagnostic procedure as well as in the therapeutic process of these patients. An increasing number of studies are currently evaluating pharmacological and non-pharmacological strategies to treat or prevent cognitive deficits; however, recommendations for daily clinical use are still lacking.

[Delirium in patients with neurological diseases: diagnosis, management and prognosis]. / Delir in der Neurologie : Diagnose, Behandlung und Prognose.

Delirium is a common acute neuropsychiatric syndrome. It is characterized by concurrent disturbances of consciousness and attention, perception, reasoning, memory, emotionality, the sleep-wake cycle as well as psychomotor symptoms. Delirium caused by alcohol or medication withdrawal is not the subject of the current review. Specific predisposing and precipitating factors have been identified in delirium which converge in a common final pathway of global brain dysfunction. The major predisposing factors are older age, cognitive impairment or dementia, sensory deficits, multimorbidity and polypharmacy. Delirium is always caused by one or more underlying pathologies which need to be identified. In neurology both primary triggers of delirium, such as stroke or epileptic seizures and also secondary triggers, such as metabolic factors or medication side effects play a major role. Nonpharmacological interventions are important in the prevention of delirium and lead to an improvement in prognosis. Delirium is associated with increased mortality and in the long term the development of cognitive deficits and functional impairment.

Bone mineral density and bone metabolism in patients with major depressive disorder without somatic comorbidities.

BACKGROUND: Major depressive disorder (MDD) has been linked with accelerated bone loss leading to the development of low bone mineral density (BMD). Several mechanisms have been discussed as causative factors, e.g. lifestyle, selective serotonin reuptake inhibitor (SSRI) intake, or the influence of proinflammatory cytokines. METHODS: In a cross-sectional study of in-patients with a current episode of MDD, without somatic comorbidities, we determined various parameters of bone metabolism, inflammatory parameters and parameters of depression. BMD was measured by dual x-ray absorptiometry. RESULTS: Of 50 patients, only one had low BMD in any of the measure sites. Body mass index (BMI) correlated positively with Z-scores. 83.3% of the examined patients had elevated osteoprotegerin (OPG) levels. SSRI intake did not have an effect on BMD. BMD in the femoral neck was significantly lower in smokers. We also found a positive correlation between the level of physical activity and osteocalcin levels. CONCLUSIONS: In our sample, young to middle-aged, somatically healthy, and acutely depressed patients with a history of MDD showed no reduction of BMD. This could be due to compensatory mechanisms, as suggested by elevated OPG levels. Physical activity and high BMI could also have served as protective factors. Still, as patients with MDD often suffer from comorbidities or take medication with a negative effect on bone, this population should be appreciated as a high-risk group for the development of osteopenia and osteoporosis.

Antidepressants and anti-inflammatory drugs differentially reduce the release of NGF and BDNF from rat platelets.

INTRODUCTION: Platelets store serotonin and brain-derived neurotrophic factor (BDNF) as well as amyloid precursor protein and nerve growth factor (NGF), thus platelets are of special interest in depression and Alzheimer's disease, respectively. Both diseases are associated with inflammation and release of NGF or BDNF from platelets may play a potent role. METHODS: Platelets were isolated from adult Sprague-Dawley rats and were incubated with anti-inflammatory drugs (ibuprofen and indomethacin) and antidepressants (citalopram, paroxetine and sertraline) (final concentration: 0.3 µM) with or without 2 mM calcium chloride. The release of NGF and BDNF was analyzed in comparison to serotonin release from rat platelets after 10 or 60 min. RESULTS: Spontaneous release of serotonin and BDNF was approximately 10-15% of total serotonin or BDNF content in platelets, but nearly all NGF was released within 10 min. All antidepressants increased the serotonin release from rat platelets. NGF release was reduced by sertraline, paroxetine and ibuprofen, but only when calcium was present, except for sertraline after 10 min. BDNF release was only reduced by ibuprofen when calcium was added. CONCLUSION: We conclude that antidepressants and anti-inflammatory drugs differentially influence the NGF and BDNF release, in a time-, dose- and calcium-specific pattern.

Inflammatory stimuli reduce survival of serotonergic neurons and induce neuronal expression of indoleamine 2,3-dioxygenase in rat dorsal raphe nucleus organotypic brain slices.

Neuroinflammation results in dysregulation of serotonergic neurons in the dorsal raphe nucleus (doR) and is considered to play an important role in the pathophysiology of depression. The aim of the present study was to induce neuroinflammation in a simple doR brain slice model using lipopolysaccharide (LPS), interferon-gamma (IFNγ), beta-amyloid1₋42 or tumor necrosis factor-alpha and to explore the survival of serotonergic neurons and the expression of the tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO). Administration of pro-inflammatory stimuli reduced survival of serotonergic neurons in doR slices and increased IDO expression. IFNγ most potently induced IDO expression, which co-localized with neurons, including serotonergic neurons, but not with microglia or astrocytes. IFNγ did not induce PI-positive staining in slices, but increased the average nuclei size of IDO-positive cells. The inflammation-induced decline did not return to control levels, when slices were withdrawn from inflammation, pointing to neurodegeneration. The growth factors BDNF or GDNF did not counteract the inflammation-induced decrease in serotonergic neurons, except for LPS-induced neuronal decline. The inflammation-induced effect was not blocked by the NMDA-receptor antagonist MK-801. Further LPS, but not IFNγ increased inflammatory markers and microglia activity. In conclusion, our data show that a range of inflammatory stimuli decline serotonergic neurons in doR slices and upregulate IDO expression. The data suggest that IDO does not contribute to serotonergic decline, but may serve as a marker of neurodegeneration. Neuroinflammation may contribute to the development of depression.

[Psycho-oncology - psychosocial oncology: integration in a concept of oncological treatment]. / Psychoonkologie - psychosoziale Onkologie : Integration in ein onkologisches Behandlungskonzept.

Psycho-oncology is defined by psychosocial aspects of prevention, etiology, diagnostics, treatment, and rehabilitation of cancer. It is characterized by interdisciplinary medicine, as well as cooperation between medical and nonmedical professionals. Psychosocial distress and/or psychiatric disorders are manifested in 30-60% of cancer patients. The primary target of psycho-oncological management is to retain and ideally optimize the subjective quality of life of cancer patients. It is important to understand that psycho-oncological care is part of an integrative oncological patient management. Basic psycho-oncological management is usually provided by the primary oncologist, whereas more specific psycho-oncological measures call for specially trained psychiatric/psychotherapeutic staff. Psycho-oncological interventions include psychological/psychotherapeutic, as well as psychopharmacologic interventions.

Impact of GvHD on quality of life in long-term survivors of haematopoietic transplantation.

Allogenic haematopoietic stem cell transplantation (HCT) has become an effective therapy in patients with various haematological malignancies. GvHD is known to be a major complication in this patient group and is assumed to have a major impact on patients' quality of life (QOL). Patients after BMT or transplantation of mobilized PBSCs were considered for enrolment in the study 6 months after transplantation. QOL and symptom burden were assessed using the EORTC QLQ-C30 and the QLQ-HDC29. Data from age- and sex-matched healthy controls were collected for comparison. In all, 100 patients (55.0% women; mean age 46.3 years) after allogeneic HCT were included in the study. In this patient group, we found a clinically relevant impact of GvHD on role functioning, global QOL, fatigue, dyspnoea, gastrointestinal side effects, worries/anxiety and skin problems. In comparison to healthy controls, various aspects of QOL were severely impaired. Our study revealed severe impairments of QOL in survivors of HCT, in particular in those suffering from GvHD. Taking into account, that the prevalence of GvHD might be higher in patients after PBSCT compared with patients after BMT, PBSCT is expected to lead to more severe impairments of QOL than BMT.

Six independent domains are defined by geriatric assessment in elderly cancer patients.

BACKGROUND: Geriatric assessment (GA) must be integrated into treatment concepts for elderly cancer patients. Aim of this study was to assess the coverage of a large battery of GA instruments by determining the number of independent domains measured. METHODS: Thirteen different GA scores were applied in 78 elderly tumor patients (mean age 72.9 years). Data were analyzed by exploratory factor analysis and substantiated by non-parametric correlation analyses. RESULTS: Factor analysis yielded a six-factor solution explaining 77.1% of the total variance. The six domains identified may be described as general functioning in everyday life, health-related quality of life, co-morbidities, social support, cognition, and nutritional status. This factor structure was reasonably well confirmed by correlation analyses. Notably, WHO Performance Status, Karnofsky Index, VES-13 and PPT generally revealed high correlations with functional capacities, but only low correlations with comorbidities, social support, cognitive functioning or nutritional status. CONCLUSIONS: From the six domains described a basis for efficient application of GA instruments in elderly cancer patients is worked out. The classical instruments WHO and KI as well as the screening scores VES-13 and PPT, while capturing physical functioning well, fail to cover several other important GA domains.

A new approach to combining clinical relevance and statistical significance for evaluation of quality of life changes in the individual patient.

OBJECTIVE: Empirical investigation of formerly proposed criteria for relevant changes of health-related quality of life (QOL) regarding their use for monitoring changes in the individual patient. Suggestion of a new criterion trying to overcome the drawbacks of former criteria. STUDY DESIGN AND SETTING: QOL data were collected longitudinally in 160 cancer patients receiving chemotherapy at an oncological outpatient unit, giving rise to a total of 975 QOL assessments. QOL was measured using the European Organization on Research and Treatment of Cancer Quality of Life Core Questionnaire. Several formerly suggested criteria of relevant change (distribution based, anchor based) were compared in terms of both prevalence and statistical significance of the resulting relevant changes. RESULTS: When considering criteria of relevant change suggested in the literature, high proportions (average: 42.3-48.3%) of reputedly relevant changes were found. The majority of these changes (average: 55.8-62.2%) were statistically insignificant. Combination of an increased threshold for clinical relevance with the concept of statistical significance resulted in a more meaningful change criterion. CONCLUSION: Formerly recommended thresholds of relevant change in QOL appear to be unduly low when focusing on the individual patient. A modified criterion is therefore suggested for this case. However, more research is needed for validation and refinement of the proposed criterion.

Chronic immune stimulation correlates with reduced phenylalanine turnover.

Neuropsychiatric symptoms like mood changes and depression are common in patients with chronic inflammatory disorders such as infections, autoimmune diseases or cancer. The pathogenesis of these symptoms is still unclear. Pro-inflammatory stimuli interfere not only with the neural circuits and neurotransmitters of the serotonergic, but also with those of the adrenergic system. The pro-inflammatory cytokine interferon-gamma stimulates the biosynthesis of 5,6,7,8-tetrahydrobiopterin (BH4), which is cofactor for several aromatic amino acid monooxygenases and thus is strongly involved in the biosynthesis of the neurotransmitter serotonin and the catecholamines dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). In macrophages, interferon-gamma also triggers the high output of reactive oxygen species, which can destroy the oxidation-labile BH4. Recent data suggest that oxidative loss of BH4 in chronic inflammatory conditions can reduce the biosynthesis of catecholamines, which may relate to disturbed adrenergic neurotransmitter pathways in patients.

IDO and clinical conditions associated with depressive symptoms.

In the pathogenesis of depressive symptoms the neurotransmitter serotonin plays an important role--although the underlining mechanisms are still not clear. The synthesis of serotonin is dependent on the availability of tryptophan--an amino acid that is linked to the immune system by its catabolism via the enzyme indoleamine-2,3-dioxygenase (IDO). Based on this connection research approaches addressing different clinical conditions with depressive symptoms and immunological involvement have been considered. This review provides an overview on the latest research in the field.

Equating EORTC QLQ-C30 and FACT-G scores and its use in oncological research.

OBJECTIVE: To investigate the equivalence of the European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) and the Functional Assessment for Cancer Therapy-General (FACT-G) on the basis of corresponding subscales, and where appropriate to derive a scheme for converting QLQ-C30 scores into FACT-G scores and vice versa for use in oncological research. METHOD: A calibration sample of 737 cancer patients (mean age 51.4+/-7.6 (SD), 63% female, 25% with current chemotherapy) who filled in both quality of life (QOL) questionnaires was used. Both classical test theory and the Rasch measurement model were applied. RESULTS: Three of the four subscales common to both QOL instruments (physical, emotional, functional) proved suitable for equating (acceptable inter-correlations of corresponding subscales physical (r=0.77), emotional domain (r=0.60) role/functional (r=0.63) relative to their internal consistency, sufficient unidimensionality of pooled subscales, satisfactory fit to the Rasch model). Conversion tables for these subscales were generated. CONCLUSIONS: The conversion tables developed in this study (physical, emotional and functional/role domain) appear promising for the comparison between EORTC QLQ-C30 and FACT-G scores of patient samples.

[Biological hypotheses of schizophrenia: possible influences of immunology and endocrinology]. / Biologische Hypothesen zur Schizophrenie: Mögliche Einflüsse von Immunologie und Endokrinologie.

A great number of studies show biological alterations in patients with schizophrenia, but many of these data are conflicting. Schizophrenia is a vastly heterogeneous disorder, most likely not caused by one etiological factor, but rather due to a complex network of different, interacting pathogenic influences. Variable clinical pictures may reflect different etiological factors. In a comprehensive theory of the origin of schizophrenic disorders, genetic and environmental influences cause changes in neuronal development which result in functional alterations of different neurotransmitter systems. Immunological research in schizophrenia was initially based on the "infection hypothesis" which was triggered by observing schizophrenia-like psychoses after influenza pandemic. Numerous immunological studies focusing on antibodies against specific viruses, unspecific antibodies and different other immune-phenomena were carried out in schizophrenia patients. Although the variability of the results from these studies is strikingly high, subgroups of patients with schizophrenia show an activated inflammatory response system with increased levels of proinflammatory cytokines and acute phase proteins. Furthermore, some investigations find changing activities in the T-cell system with a shift of TH-1 to an increased TH-2 activity. Endocrinological factors which may play a relevant role in the etiopathogenesis of schizophrenia include sex hormones and all changes caused by stress or other influences which are directly related to the HPA-axis. Alterations of the immune and the endocrinological systems might be caused by environmental factors like infections or exogenous stress. Due to the intensive interaction between the central nervous system, the immune system and different hormones the "development of a pathology" like schizophrenia can be seen in an integrative but multifactorial fashion. The clinical manifestation, the severity and the course of the disease might then be modulated by genetic vulnerability, the time of the "primary insult" -- which could be an infection, or psychological stress -- and its neuronal localisation and intensity. Different compensatory and decompensatory mechanisms in later life very likely play a crucial role for the further course of the disorder.

The impact of hemoglobin levels on fatigue and quality of life in cancer patients.

BACKGROUND: Although fatigue is a commonly reported symptom in cancer patients its etiology is still poorly understood. The objective of the present study was to investigate the relationship between hemoglobin (Hb) levels and the subjective experience of fatigue and quality of life in cancer patients with mild or no anemia undergoing chemotherapy. PATIENTS AND METHODS: Sixty-eight cancer patients (25 colorectal, 26 lung and 17 ovarian cancer) presently undergoing chemotherapy participated in the study. Fatigue was measured with the Multidimesional Fatigue Inventory (MFI-20), quality of life with The European Organization for Research and Treatment of Cancer QLQ-C30. In order to provide normative data for fatigue levels, the MFI-20 was also completed by a sex- and age-matched sample of 120 healthy controls. RESULTS: Compared with healthy subjects, cancer patients experienced significantly higher levels of subjective fatigue. Correlations between Hb values and subscales of the MFI-20 were moderate with a tendency to increase during chemotherapy. Hb values alone, however, do not fully account for the observed fatigue. Other symptoms, especially pain, dyspnea and sleep disturbances, also showed an association with perceived fatigue. CONCLUSIONS: Despite significant correlations, these results indicate that Hb values only partially explain subjectively experienced fatigue and quality of life in cancer patients. It is suggested therefore that the treatment of fatigue must be multidimensional and involve all areas which contribute to the syndrome.

Multidimensional scaling as a tool for analysing quality of life data.

Multidimensional scaling (MDS) is introduced and discussed as a graphical method to complement conventional descriptive and confirmatory methods in the validation and analysis of quality of life (QOL) data. An outline of M DS as a statistical technique is given, and its application in the context of QOL research is described. The use of MDS is then illustrated in an example based on a study of 300 cancer survivors who completed the functional assessment of cancer therapy-general (FACT-G) and the EORTC core quality of life questionnaire (QLQ-C30). The correlational structure of the two widely used QOL instruments is investigated by means of MDS, and differences between the two questionnaires are elaborated. Finally, the merits and drawbacks of MDS are discussed in the specific context of the example and in the general framework of QOL research.

Quality of life measurement in oncology--a matter of the assessment instrument?

Two widely used quality of life questionnaires, European Organization for Research and Treatment of Cancer Core (EORTC QLQ-C30) & Functional Assessment of Cancer Therapy-General (FACT-G), were examined for their comparability using four different groups of cancer patients. During a follow-up investigation, 418 cancer patients (Hodgkin's disease, breast cancer, bone marrow transplantation (BMT), chronic lymphatic leukaemia (CLL)) completed both the EORTC QLC-C30 and the FACT-G during the same session. For an illustration of the differences between the two Quality of Life (QoL) instruments, pairs of diagnostic groups were formed and their QoL scores using the EORTC QLQ-C30 and FACT-G compared. The corresponding subscales of the EORTC-QLC-C30 and the FACT-G show only low to moderate intercorrelations across all four groups of cancer patients studied. In particular, a comparison of pairs, namely Hodgkin's disease versus breast cancer patients and BMT versus CLL patients, highlights substantial differences in the corresponding subscales of the EORTC QLQ-C30 and the FACT-G. The results of the QoL investigations should not be interpreted independently of the instrument used and an interpretation of results must be based on the contents of items of the respective questionnaires.

Use of alternative/complementary therapy in breast cancer patients--a psychological perspective.

The objectives of this study were to assess the additional use of alternative (complementary) therapies in patients with breast cancer who were receiving conventional treatment and to compare patients using alternative therapies with patients receiving only conventional treatment with special reference to psychological adaptation, causal attribution and quality of life. A sample of 117 female out-patients with a diagnosis of breast cancer filled in the following assessment instruments: FQCI (Freiburg Questionnaire for Coping with Illness), PUK (Causal Attribution Questionnaire), EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire), POMS (Profile of Mood States), and a self-developed questionnaire on alternative therapies. Nearly half the patients (47%, n = 55) reported that they had used alternative therapies in addition to conventional treatment. The methods applied most frequently were nutrition-related measures (special drinks, vitamin preparations and whole-foods - each applied by about 50% of users), mistletoe preparations (49%), trace elements (47%), and homeopathy (31%). Compared with patients receiving only conventional treatment, the users of alternative therapy were younger and better educated. Users developed a more active style of illness coping than nonusers and showed more religious involvement. Patients using a large number of alternative therapies (>3) tended to adopt a more depressive coping style than those using only a small number (< or =3). For a substantial proportion of cancer patients alternative therapies apparently fulfil an important psychological need. However, a subgroup of patients using many alternative therapies seem to have considerable adjustment problems. In dealing with cancer patients the treatment team should be aware of both these groups.