Adjustment disorder in cancer patients after treatment: prevalence and acceptance of psychological treatment.

PURPOSE: To investigate the prevalence of adjustment disorder (AD) among cancer patients and the acceptance of psychological treatment, in relation to sociodemographic, clinical, and psychological factors. METHODS: Breast, prostate, and head and neck cancer patients of all stages and treatment modalities (N = 200) participated in this observational study. Patients completed the Hospital Anxiety and Depression Scale, Checklist Individual Strength, Distress Thermometer and problem list. Patients with increased risk on AD based on these questionnaires were scheduled for a diagnostic interview. Patients diagnosed with AD were invited to participate in a randomized controlled trial on the cost-effectiveness of psychological treatment. Participation in this trial was used as a proxy of acceptance of psychological treatment. Logistic regression analyses were used to investigate associated factors. RESULTS: The overall prevalence of AD was estimated at 13.1%. Sensitivity analyses showed prevalence rates of AD of 11.5%, 15.0%, and 23.5%. Acceptance of psychological treatment was estimated at 65%. AD was associated both with being employed (OR = 3.3, CI = 1.3-8.4) and having a shorter time since diagnosis (OR = 0.3, CI = 0.1-0.8). CONCLUSION: Taking sensitivity analysis into account, the prevalence of AD among cancer patients is estimated at 13 to 15%, and is related to being employed and having a shorter time since diagnosis. The majority of cancer patients with AD accept psychological treatment.

Health-related quality of life and overall survival: a prospective study in patients with head and neck cancer treated with radiotherapy.

PURPOSE: We aimed to examine whether pre-treatment, post-treatment and change in health-related quality of Life (HRQoL) is associated with survival, in patients with head and neck cancer (HNC). METHODS: We included 948 newly diagnosed HNC patients treated with primary or adjuvant (chemo)radiotherapy with curative intent. The EORTC QLQ-C30 questionnaire was assessed pre-treatment and at 6 weeks, 6 months and 12 months post-treatment. Multivariable Cox regression analyses were performed to examine whether HRQoL at all time points and changes in HRQoL over time were associated with survival, after adjusting for demographic, clinical and lifestyle-related variables. RESULTS: Higher HRQoL scores were significantly associated with improved 5-year overall survival at all time points, except for the subscale global QoL at 6 weeks. Changes in HRQoL at 6 weeks post-treatment compared to pre-treatment were not significantly associated with survival. Changes in physical (HR: 0.88 95% CI: 0.82-0.96) and emotional functioning (HR: 0.90 95% CI: 0.85-0.96) from pre-treatment to 6 months post-treatment and changes in global QOL, and physical, emotional, and social functioning from pre-treatment to 12 months post-treatment were significantly associated with survival. CONCLUSION: Higher HRQoL reported pre-treatment and post-treatment (6 weeks, 6 months and 12 months) are significantly associated with improved survival, as well as changes in HRQoL at 6 and 12 months compared to pre-treatment. Our results highlight the value of monitoring HRQoL and to identify those patients that report decreased or deteriorated HRQOL. This may help to further improve cancer care in a timely and efficient manner.

The course of symptoms of anxiety and depression from time of diagnosis up to 2 years follow-up in head and neck cancer patients treated with primary (chemo)radiation.

OBJECTIVES: To identify sociodemographic and clinical factors, health-related quality of life (HRQOL) and head and neck cancer (HNC) symptoms associated with the course of symptoms of anxiety and depression from pretreatment to 24-month follow-up among HNC patients after (chemo)radiation. MATERIALS AND METHODS: Patients (n = 345) completed questionnaires on anxiety and depression (HADS), HRQOL and symptoms (EORTC QLQ-C30/QLQ-H&N35) before treatment, and 6-weeks,3-,6-12-,18-, and 24-months after treatment. Mixed model analyses were used to investigate the course of anxiety and depression from pretreatment to 24-months in relation to factors assessed at baseline, and the course of anxiety and depression from 6- to 24-months, in relation to factors assessed at 6-months. RESULTS: Increased risk for anxiety (HADS-anxiety > 7) was 28.7% among patients before treatment, which declined to 10.0% at 24-months. Increased risk for depression (HADS-depression > 7) was 15.1% before treatment, 18.2% at 3-months, 7.2% at 12-months and 16.0% at 24-months. Factors assessed at baseline which were significantly associated with the course of anxiety were age, pain, problems with social contact, and feeling ill, whereas chemotherapy, worse emotional functioning, speech problems and weight loss were significantly associated with the course of depression. Regarding factors assessed at 6-months, chemotherapy, worse cognitive and social functioning, insomnia, swallowing problems and trouble with social eating were associated with the course of anxiety. Nausea/vomiting, dyspnea, coughing, and feeling ill were associated with the course of depression (p-values < 0.05). DISCUSSION: Factors associated with a worse course of anxiety and depression are younger age, treatment with chemotherapy, worse HRQOL and higher symptom burden.

The course of sexual interest and enjoyment in head and neck cancer patients treated with primary (chemo)radiotherapy.

INTRODUCTION: The aim of this prospective study was to investigate the course of sexual interest and enjoyment in relation to sociodemographic and clinical factors, health-related quality of life (HRQOL), and symptoms of psychological distress in head and neck cancer (HNC) patients treated with primary (chemo)radiotherapy. METHODS: HNC patients (n = 354) completed patient-reported outcome measures (PROMs) on HRQOL (EORTC QLQ-C30 and QLQ-H&N35, including the sexuality subscale covering less sexual interest and enjoyment), and psychological distress (HADS) pretreatment, at 6-week follow-up and at 3-, 6-, 12-, 18-, and 24-month follow-up (i.e., after treatment). Linear mixed models were used to analyze the course of sexuality from pretreatment to 24-month follow-up, and to investigate its relation to sociodemographic and clinical factors, HRQOL, and psychological distress as measured at baseline, and to investigate the course of sexuality from 6- to 24-month follow-up in relation to these factors measured at 6-month follow-up. RESULTS: Before start of treatment, 37% of patients reported having less sexuality, which increased to 60% at 6-week follow-up, and returned to baseline level from 12-month follow-up onwards. Older age (p = 0.037) and trouble with social contact (p < 0.001), weight loss (p = 0.013), and constipation (p = 0.041) before treatment were associated with less sexuality over time. Female gender (p = 0.021) and poor social functioning (p < 0.001) at 6-month follow-up were associated with less sexuality from 6- to 24-month follow-up. DISCUSSION: Less sexuality is often reported in HNC patients treated with (chemo)radiotherapy. Using PROMs in clinical practice may help identify patients who might benefit from supportive care targeting sexuality.

[Cushing's syndrome in a manic patient with a long-standing bipolar disorder: cause or coincidence?]. / Het syndroom van Cushing bij een manische patiënte met een lang bestaande bipolaire stoornis: oorzaak of bijvangst?

Hypercortisolism is associated with mood disorders such as depression and bipolar disorder. A 75-year-old female patient who had been diagnosed with bipolar disorder forty years ago was admitted to our hospital with a severe, therapy-resistant mania. Careful diagnostic considerations, resulted in the patient being diagnosed with Cushing's syndrome. Treatment with metyrapone led to a swift improvement of the patient's symptoms. Could Cushing's syndrome underlie this patient's psychiatric history? Or are two co-existing, intertwining causes responsible for the psychiatric symptoms? The case illustrates that even if a patient has a long history of psychiatric problems that have been plausibly diagnosed over time, clinicians and psychiatrists should always consider the possibility that there may be an underlying somatic cause for the patient's psychiatric symptoms.

Real-world cost-effectiveness of cetuximab in locally advanced squamous cell carcinoma of the head and neck.

Clinical trial EMR 62202-006 demonstrates prolonged median locoregional control (24.4 vs. 14.9 months), progression-free survival (17.1 vs. 12.4 months) and overall survival (49.0 vs. 29.3 months) for patients who receive cetuximab added to the comparator radiotherapy for locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). In the Netherlands, hospitals receive reimbursement for cetuximab conditional on cost-effectiveness in daily practice. To estimate the real-world incremental cost per quality adjusted life-year (QALY) gained for radiotherapy + cetuximab over radiotherapy alone in first line treatment of LA SCCHN, a Markov model is constructed with health states "alive without progression", "alive following progression" and "death". Transition probabilities per month are estimated from clinical trial data and retrospectively collected real-world data from two Dutch head and neck cancer treatment centres (2007-2010, n = 141). 5-year, 10-year and lifetime horizons are used, without and with discounting (4 % costs, 1.5 % effects) to calculate incremental cost-effectiveness ratios. Two scenarios explore different assumptions on prognosis of real-world versus trial patients. Adding cetuximab to radiotherapy results in increased costs and health gains in both scenarios and across each of the time horizons. Incremental costs per QALY gained range between 14,624 and 38,543 in the base-case. For a willingness to pay of 80,000 per QALY, the acceptability curves for the different scenarios show probabilities between 0.76 and 0.87 of radiotherapy + cetuximab being cost-effective compared to radiotherapy alone. Current results show the combined treatment of radiotherapy + cetuximab to be a cost-effective treatment option for patients with LA SCCHN.

Type 2 diabetes mellitus interacts with obesity and common variations in PLTP to affect plasma phospholipid transfer protein activity.

BACKGROUND: Phospholipid transfer protein (PLTP) is an emerging cardiometabolic risk marker that is important in high-density lipoprotein (HDL) and triglyceride metabolism. Plasma PLTP activity is elevated in type 2 diabetes mellitus, whereas glucose may regulate PLTP gene transcription in vitro. Of interest, common PLTP variations that predict cardiovascular disease have been identified recently. We investigated whether the diabetic state is able to amplify relationships between obesity and PLTP gene variations with circulating PLTP levels. SUBJECTS AND METHODS: Plasma PLTP activity (using a phospholipid vesicles-HDL system), PLTP gene score [number of PLTP activity-decreasing alleles based on two tagging polymorphisms (rs378114 and rs60- 65904)] and waist circumference were determined in two Dutch cohorts comprising 237 patients with type 2 diabetes and 78 control subjects. RESULTS: Patients with diabetes were more obese (P < 0.001 for prevalence of increased waist circumference) and had 13% higher plasma PLTP activity (P < 0.001). PLTP gene score was not different in diabetic and control subjects (P = 0.40). PLTP activity was highest in patients with diabetes with an enlarged waist and lowest in control subjects with a normal waist circumference (P < 0.001). Multiple linear regression analysis revealed a positive interaction between diabetes status and waist circumference on PLTP activity (ß = 0.200, P = 0.005). Furthermore, diabetes status (ß = -0.485, P = 0.046) or HbA1c (ß = -0.240, P = 0.035) interacted with PLTP gene score to affect PLTP activity. CONCLUSIONS: Type 2 diabetes and enlarged waist circumference interact to impact on plasma PLTP activity. Diabetes may also amplify the association between plasma PLTP activity and common PLTP gene variations. Our findings support the hypothesis that diabetes-environment and diabetes-gene interactions govern plasma PLTP activity.

Postoperative elective nodal irradiation for squamous cell carcinoma of the head and neck: outcome and prognostic factors for regional recurrence.

BACKGROUND: This study describes the results of elective irradiation in the N0 neck and tries to identify prognostic factors for regional recurrence. MATERIALS AND METHODS: Between 1985 and 2000, 785 cN0 or pN0 necks were treated with elective nodal irradiation in 619 head and neck squamous cell carcinoma patients. RESULTS: Regional control at 3 years was 94% in the cN0 (nondissected) neck compared with 97% in the pN0 (dissected) neck and 90% in the ipsilateral compared with 96% in the contralateral neck (P = 0.08 and P = 0.006, respectively). Regional control in the ipsilateral cN0 neck was 78% compared with 96% in the contralateral cN0 neck. Surgical margin of the primary tumor was an additional prognostic factor in all N0 and pN0 necks. CONCLUSIONS: Neck control rates in electively irradiated N0 necks were excellent. Regional control was worse in the cN0 neck compared with the pN0 neck and in the ipsilateral neck compared with the contralateral side. Additionally, in case of positive surgical margins of the primary tumor, elective nodal irradiation should be applied, even in case of a pN0 neck.

Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol.

OBJECTIVES: The current literature provides little information on the frequency of mutations in the ATP-binding cassette transporter A1 (ABCA1) in patients with low high-density lipoprotein cholesterol (HDL) levels that are referred to the clinic. In 78 patients with low plasma levels of HDL cholesterol that were referred to our clinic, we routinely screened for ABCA1 gene mutations and studied the functionality of newly identified ABCA1 missense mutations. METHODS: The coding regions and exon-intron boundaries of the ABCA1 gene were sequenced in 78 subjects with HDL cholesterol levels below the 10th percentile for age and gender. Novel mutations were studied by assessing cholesterol efflux capacity (using apolipoprotein A-I as acceptor) after transient expression of ABCA1 variants in BHK cells. RESULTS: Sixteen out of 78 patients (21%) were found to carry 19 different ABCA1 gene variants (1 frameshift, 2 splice-site, 4 nonsense and 12 missense variation) of which 14 variations were novel. Of three patients with homozygous mutations and three patients having compound heterozygous mutations only one patient presented with the clinical characteristics of Tangier Disease (TD) in the presence of nearly complete HDL deficiency. Seven out of eight newly identified ABCA1 missense mutations were found to exhibit a statistically significant loss of cholesterol efflux capacity. CONCLUSION: This study shows that one out of five patients who are referred to our hospital because of low HDL cholesterol levels have a functional ABCA1 gene mutation. It is furthermore demonstrated that in vitro studies are needed to assess functionality of ABCA1 missense mutations.

Plasma levels of lecithin:cholesterol acyltransferase and risk of future coronary artery disease in apparently healthy men and women: a prospective case-control analysis nested in the EPIC-Norfolk population study.

LCAT plays a key role in the maturation of HDL, as evidenced by low HDL-cholesterol levels in carriers of deleterious mutations in LCAT. However, the role of LCAT in atherosclerosis is unclear. We set out to study this in a prospective study. Plasma LCAT levels, which strongly correlate with LCAT activity, were measured in baseline nonfasting samples of 933 apparently healthy men and women who developed coronary artery disease (CAD) and 1,852 matched controls who remained free of CAD during 6 year follow-up. LCAT levels did not differ between cases and controls but were higher in women than men. Stratification into LCAT quartiles revealed a positive association with plasma LDL-cholesterol and triglyceride levels in the unexpected absence of an association with HDL-cholesterol. In mixed-gender analyses, the odds ratio (OR) for future CAD in the highest LCAT quartile versus the lowest was 1.00 [confidence interval (CI): 0.76-1.29, P for linearity = 0.902], although opposite trends were observed in men and women. In fact, high LCAT levels were associated with an increased CAD risk in women (unadjusted OR 1.45, CI: 0.94-2.22, P for linearity = 0.036). In contrast to our studies in carriers of LCAT mutations, the current data show that low LCAT plasma levels are not associated with increased atherosclerosis in the general population.

Combination statin-fibrate therapy: safety aspects.

Patients with type 2 diabetes or metabolic syndrome remain at high residual risk of cardiovascular events even after intensive statin therapy. While treatment guidelines recommend the addition of a fibrate to statin therapy in this setting, concerns about the potential for myopathy may limit the use of this combination in clinical practice. These concerns are certainly justified for gemfibrozil, which interferes with statin glucuronidation, leading to elevation in statin plasma concentrations and an increased risk of myotoxicity in combination with a range of commonly prescribed statins. However, the available evidence refutes suggestions that this is a class effect for fibrates. Fenofibrate does not adversely influence the metabolism or pharmacokinetics of any of the commonly prescribed statins. This in turn translates to a reduced potential for myotoxicity in combination with a statin. Data are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study to evaluate the efficacy and safety of fenofibrate plus simvastatin combination therapy in type 2 diabetes patients.

Role of nitric oxide in gastric motor and sensory functions in healthy subjects.

BACKGROUND AND AIMS: Impaired accommodation and hypersensitivity to distension of the proximal stomach are considered to be important factors in the pathogenesis of dyspeptic complaints. As fundus relaxing agents may be effective in the treatment of these symptoms, insight into the mediators involved in fundic accommodation and associated perceptual responses is important. Therefore, we studied the effect of nitric oxide (NO) synthase inhibition by N(G)-monomethyl-L-arginine (L-NMMA) on fundic tone, postprandial sensations, and gastric perception in healthy volunteers. SUBJECTS AND METHODS: Eighteen healthy volunteers participated in a double blind, placebo controlled, randomised study. They underwent a gastric barostat study to evaluate the effect of L-NMMA on meal and distension induced sensations and on fundic relaxation in response to oral meal intake, intraduodenal lipid, and glucagon administration. RESULTS: Compared with placebo, L-NMMA decreased fundic volume after oral meal intake (438 (55) v 304 (67) ml; n=8; p<0.05) and during intraduodenal lipid infusion (384 (37) v 257 (43) ml; n=10; p<0.05) but not after glucagon injection (570 (62) v 540 (52) ml; n=4; p=0.4). In addition, basal fundic volume was significantly reduced by L-NMMA. Scores for nausea and satiation were decreased by L-NMMA after oral meal intake but not during intraduodenal lipid infusion. Perception scores to gastric distension were not altered by L-NMMA. CONCLUSIONS: NO is involved in maintaining basal fundic tone and in meal induced fundic relaxation in humans, but not in visceral perception.

Perspectives of new reproductive and diagnostic techniques among biologists and physicians, social scientists and ethicists.

The introduction and acceptance of new techniques in the field of reproductive medicine and antenatal genetic diagnosis is a complicated process in which biomedical professionals, and also social scientists and ethicists, play an important role. In this study the attitudes, expectancies and opinions of a panel of biological and medical professionals working in the field of this new technology are compared with those of a panel of concerned social scientists, psychologists, ethicists and leading members of patient groups. Various aspects of the new techniques are investigated: the present and future feasibility, the potential importance, the ethical evaluation and the social acceptance. The social-ethical panel appears to be much more reluctant regarding the importance, ethical values and social acceptability of new techniques than the biomedical panel, in particular, for preimplantation genetic diagnosis and fetal cell sorting large differences exist.

Preimplantation genetic diagnosis as an alternative to amniocentesis and chorionic villus sampling: psychosocial and ethical aspects.

Social and ethical considerations play an increasing role in decisions about the use of diagnostic technologies. In this article expert opinions of a medical-biological and a social-ethical panel on psychosocial, ethical and social aspects of preimplantation genetic diagnosis (PGD) are discussed. PGD is a new diagnostic technology for identifying chromosomal or single gene defects, which is now available as a medical treatment in several western countries. In contrast to traditional technologies like amniocentesis and chorionic villus sampling PGD offers the possibility for diagnosis before pregnancy. The panels expected PGD to be chosen only in serious situations. IVF was considered to be a barrier for PGD but less so in more serious situations. Destruction of pre-embryos was thought more acceptable than selective abortion, but only marginally. Finally a substantial decrease was expected in the acceptance of handicapped people in society as a consequence of the possibilities of technologies like PGD. Although PGD offers new possibilities for couples at risk of having a child with a genetic defect, it is important that couples are counseled in a way that emphasizes both the advantages and disadvantages of the technology. The general public should be informed about possibilities and impossibilities of preventive diagnosis and the right of future parents not to use genetic diagnosis.

Clozapine versus placebo in Huntington's disease: a double blind randomised comparative study.

OBJECTIVES: To establish the effect of the atypical neuroleptic clozapine on chorea, voluntary motor performance, and functional disability in patients with Huntington's disease. METHODS: Thirty three patients with Huntington's disease participated in a double blind randomised trial. A maximum of 150 mg/day clozapine or placebo equivalent was given for a period of 31 days. Assessments were performed in the week before and at the last day of the trial. Chorea was scored using the abnormal involuntary movement scale (AIMS), the chorea score of the unified Huntington's disease rating scale (UHDRS), and judgement of video recordings. Voluntary motor performance was assessed using the UHDRS motor scale. Patients and their partners completed a questionnaire regarding functional disability. Twelve patients already used other neuroleptic medication, which was kept unchanged during the trial period. Results of neuroleptic naive and neuroleptic treated patients were analysed separately. RESULTS: Clozapine tended to reduce chorea in neuroleptic naive patients only (AIMS); improvement seemed more pronounced in patients receiving higher doses of clozapine. Other measures of chorea (UHDRS chorea score, video ratings) showed no improvement. Clozapine had no beneficial effect on chorea in patients already receiving neuroleptic medication. Voluntary motor performance did not improve with clozapine. Neuroleptic naive patients reported aggravation of functional disability, possibly reflecting the frequent occurrence of side effects. Adverse reactions forced trial termination in six patients and dose reduction in another eight, and consisted mainly of drowsiness, fatigue, anticholinergic symptoms, and walking difficulties. CONCLUSIONS: Clozapine has little beneficial effect in patients with Huntington's disease, although individual patients may tolerate doses high enough to reduce chorea. Because adverse reactions are often encountered, clozapine should be used with restraint in this patient group.

Surfactant treatment of respiratory failure induced by hydrochloric acid aspiration in rats.

BACKGROUND: The surfactant system seems to be involved in the pathophysiology of respiratory failure caused by hydrochloric acid (HCl) aspiration. This study was an investigation of the effect of different treatment strategies using an exogenous surfactant preparation on lung function of rats suffering from respiratory failure after intratracheal HCl instillation. METHODS: In rats anesthetized with halothane, nitrous oxide, and oxygen, tracheotomy was performed and the lungs were mechanically ventilated. Respiratory failure was induced by intratracheal instillation of HCl (0.1 N, 3 ml/kg). After the PaO2 decreased to < 200 mmHg, the animals were randomly divided into five groups. Group I received no treatment; group II received a natural surfactant preparation intratracheally (200 mg/kg); group III underwent bronchoalveolar lavage (BAL) with saline, followed by surfactant treatment (200 mg/kg); and groups IV and V underwent BAL with saline and a diluted surfactant suspension (3.3 mg/ml in 30 ml/kg), respectively. Groups IV and V received a second and third BAL 60 and 120 min after the first lavage. Blood gas analysis and protein measurements in BAL fluids were performed. RESULTS: Gas exchange improved in Groups III and V only. Protein concentrations were high in all BAL fluids. In the rats receiving BAL three times (groups IV and V), a decrease in protein concentration was observed. CONCLUSIONS: From these results, it was concluded that plasma-derived proteins (which are known to inhibit surfactant function) are washed out of the alveoli by BAL, resulting in improved efficacy of surfactant treatment.