Cognitive dysfunction and chemotherapy: neuropsychological findings in perspective

Currently, the interest in cognitive functioning following chemotherapy is rapidly expanding as is reflected in a growing number of published studies on this topic. Although most studies are indicative of cognitive deficits after chemotherapy, definite conclusions on the role of chemotherapy on cognitive function can often not be drawn due to methodological problems. On the basis of the studies on cognitive functioning after chemotherapy that are conducted in The Netherlands Cancer Institute, the current article describes a number of such methodological topics that obscure straightforward interpretation of neuropsychological findings in toxicity research. Measurement issues that diverge from usual assessment issues encountered in psychosocial oncology will be described, and factors that might play a role in the cause of cognitive impairment will be evaluated. Also, future developments necessary to gain more insight into the prevalence, the pattern, and the impact of cognitive problems following chemotherapy are discussed     

The first two patients with dura mater associated Creutzfeldt-Jakob disease in the Netherlands

Creutzfeldt-Jakob disease (CJD) can be transmitted through human growth hormone or gonadotrophin administration, dura mater or cornea transplantation, depth EEG monitoring and the use of contaminated neurosurgical instruments. We describe the first two dura mater associated CJD cases in the Netherlands. Ten and fourteen years before the onset of symptoms both patients received a Lyodura implantation. Findings are discussed in light of the growing epidemic of CJD among dura mater recipients. Received: 5 December 2000, Received in revised form: 5 March 2001, Accepted: 4 April 2001     

Neuromotor function and school performance in 7-year-old children born as high-risk preterm infants

Neuromotor behavior was studied in 63 children at a mean age of 7 years. They were born at a gestational age less than 32 weeks and/or birthweight under 1500 g and were categorized according to their medical history in conformance with the Neonatal Medical Index (from category I to V, from few to serious complications). We included only children considered at high risk as categorized in III to V. The neuromotor behavior study focuses on different subcategories, such as hand function, quality of walking, posture, passive muscle tone, coordination, and diadochokinesia. Hand preference and/or lateralization, the presence of associated movements, and/or asymmetry were noted, as was school performance. Then gender, gestational age, birthweight, and dysmaturity were investigated as confounding factors. The outcome at 7 years was correlated with the Neonatal Medical Index and the neonatal brain ultrasonography classification. None of the children scored 100% on the combined subcategories. Nineteen children (30%) had an overall score between 75 and 99%. Significant relationships between all different subcategories were found. Lack of hand preference, poor lateralization, and male gender were related to poor overall outcome. Poor motor control was correlated to special schooling and education below age level. The Neonatal Medical Index proved to have a significant influence on total outcome and the subcategories at the age of 7 years, with the worst outcome in children formerly classified in category V. Neuromotor behavior at 7 years of age was not related to birthweight, gestational age, dysmaturity, and neonatal brain ultrasonography classification only.     

Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drug therapy: a randomized, prospective, multicenter study

Uncertainty exists regarding the necessity of continuing triple therapy consisting of mycophenolate mofetil (MMF), cyclosporine (CsA), and prednisone (Pred) after kidney transplantation (RTx). At 6 mo after RTx, 212 patients were randomized to stop CsA (n = 63), stop Pred (n = 76), or continue triple drug therapy (n = 73). The MMF dose was 1000 mg twice daily, target CsA trough levels were 150 ng/ml, and Pred dose was 0.10 mg/kg per d. Follow-up was until 24 mo after RTx. Biopsy-proven acute rejection occurred in 14 (22%) of 63 patients after CsA withdrawal compared with 3 (4%) of 76 in the Pred withdrawal group (P = 0.001) and 1 (1.4%) of 73 in the control group (P = 0.0001). Biopsy-proven chronic rejection was present in one patient in the control group, in nine patients after CsA withdrawal (P = 0.006 versus control group); and in four patients after discontinuation of Pred (NS). Graft loss occurred in two versus one patient after CsA or Pred withdrawal, respectively, and in two patients in the control group (NS). Patients who successfully withdrew CsA had a significantly lower serum creatinine during follow-up. Pred withdrawal resulted in a reduction in mean arterial pressure, and the total cholesterol/HDL ratio increased. In conclusion, rapid CsA withdrawal at 6 mo after RTx results in a significantly increased incidence of biopsy-proven acute and chronic rejection. Pred withdrawal was safe and resulted in a reduction in mean arterial pressure. However, patient and graft survival and renal function 2 yr after RTx were not different among groups.     

Increased arterial stiffness in young adults with end-stage renal disease since childhood

Increased arterial stiffness is a risk factor for mortality in adults over 40 yr of age with end-stage renal disease (ESRD). As no data exist on vascular changes in young adults with ESRD since childhood, a long-term outcome study was performed. All living Dutch adult patients with onset of ESRD between 1972 and 1992 at age 0 to 14 yr were invited for carotid artery and cardiac ultrasound and BP measurements. Data on clinical characteristics were collected by review of all medical charts. Carotid ultrasound data were compared with those of 48 age-matched and gender-matched healthy controls. Carotid artery and cardiac ultrasound was performed in 130 out of 187 eligible patients. Mean age was 29.0 (20.7 to 40.6) yr. Compared with controls, patients had a similar intima media thickness but a reduced mean arterial wall distensibility DC (40.0 versus 45.0 kPa(-1). 10(-3); 95% CI, -9.1 to -0.8; P < 0.001), an increased stiffness parameter beta (4.2 versus 3.8; 95% CI, 0.05 to 0.68; P = 0.02), an increased elastic incremental modulus E(inc) (0.35 versus 0.27 kPa. 10(3); 95% CI, 0.02 to 0.12; P < 0.001). Multiple regression analyses in all subjects revealed that ESRD was associated with an increase in beta and E(inc). Arterial wall properties of patients currently on dialysis and transplanted patients were comparable. In all patients, current systolic hypertension was associated with increased E(inc) and decreased DC. In conclusion, carotid arterial wall stiffness is increased in young adult patients with pediatric ESRD. Hypertension is a main determinant and might be a target for treatment of these potentially lethal arterial wall changes.     

The evaluation of the introduction of a quality management system: a process-oriented case study in a large rehabilitation hospital

OBJECTIVES: So far, there is limited proof concerning the effects of the introduction of quality management systems (QMS) on organisational level. This study concerns the introduction of a QMS in a large rehabilitation hospital. METHODS: Using an observational framework, a process-analysis is performed. The effects were analysed with repeated analyses using the Dutch version of the EFQM-model. RESULTS: The introduction of a QMS can be seen as a change process; the pre-change diagnosis proved to be essential. Although many change-related aspects are vital, training and communication, in particular, seemed to be underestimated. Outcomes are a positive correlation between participation in quality activities and work satisfaction and a repeatedly favourable EFQM-score (compared to national levels). CONCLUSIONS: Through a process-analysis, information could be generated to guide organisations in introducing a QMS. An outcome analysis revealed positive effects both in the EFQM-score and the staff's work satisfaction.     

The influence of recombinant human insulin-like growth factor-I (rhIGF-I) on cell growth and cytotoxicity of drugs in childhood rhabdomyosarcoma cell lines and xenograft models

Purpose: Recombinant human insulin-like growth factor I (rhIGF-I) has been reported to ameliorate vincristine-induced neuropathy, the dose-limiting side effect of this antimitotic anticancer drug. However, rhIGF-I also might have adverse effects, as has been shown in vitro, where it stimulates growth of cancer cells and protects them from cytotoxicity of anticancer drugs. The influence of rhIGF-I on the cytotoxicity of vincristine has not yet been studied. Furthermore, studies performed have been done under serum-free conditions, which are far from physiological. Methods: We studied the influence of rhIGF-I on the growth of two rhabdomyosarcoma cell lines (Rh30 and Rh1) and on the antitumor effects of vincristine, cisplatin, etoposide, doxorubicin, and topotecan under serum-free and serum-containing conditions. To extend the in vitro data, we grew Rh30 cells as xenografts in mice and determined the effects of vincristine, rhIGF-I or their combination on tumor growth. Results: In vitro, both cell lines demonstrated a functional type I IGF receptor, as shown by the rapid activation of ribosomal p70 S6 kinase after stimulation with rhIGF-I. Under serum-free conditions, rhIGF-I stimulated growth of both cell lines. Exposure to cytotoxic drugs with and without rhIGF-I resulted in higher cell numbers in cultures exposed to rhIGF-I. However, relative to the appropriate control, fractional growth inhibition and or cell kill of the cytotoxic drugs was identical with and without rhIGF-I. Under serum-containing conditions, rhIGF-I had no effect on cell growth or drug cytotoxicity. In vivo we did not find a significant influence of rhIGF-I on HxRh30 cell growth, or on the antitumor activity of vincristine. Conclusions: These studies show that rhIGF-I has no adverse effects on human rhabdomyosarcoma growth or on the antitumor effect of cytotoxic drugs under serum-containing conditions in vitro or in tumor-bearing mice. Potentially, therefore, rhIGF-I may ameliorate vincristine-induced neuropathy without adversely influencing tumor growth or vincristine cytotoxicity in children. Received: 12 February 1999 / Accepted: 21 June 1999     

Toxicity of lead acetate to female rabbits after chronic subcutaneous administration. 1. Biochemical and clinical effects

The effect of chronic subcutaneous administration of lead acetate was studied in female rabbits. The low-dose group (15 animals) received three times a week 0.10–0.20 g/kg body weight and the high-dose group (15 animals) 0.80–1.20 g/kg. The control group received the vehicle only. Concentrations of lead in blood in the low-dose group increased to ca. 400 g/l after 70 days and in the high-dose group to ca. 900 g/l after 110 days. After 7.5 months eight animals of each group were sacrificed. The remaining rabbits were kept for an additional 4 months without treatment. Blood lead concentrations decreased with a half-time of 60–70 days. During exposure the gain in body weight was lower in the high-dose group than in the control group and the low-dose group. The high-dose group developed slight anaemia and low MCV, MCH and MCHC, and basophilic stippling of erythrocytes. These effects disappeared during recovery. ALAD activity in erythrocytes was very low during exposure in both exposed groups and did not reach control values during recovery. During exposure the concentrations of ZPP and ALA-U increased, but only ALA-U returned to normal during recovery. No other effects of lead on the composition of the urine were observed. No effects were observed on plasma urea and creatinine concentrations. In the highdose group the concentration of ALAD in the liver decreased by 30%. During recovery this effect was no longer present. No effects were seen in cytochrome P-450 content or cytochrome P-450-dependent enzyme activities. Lead was mainly stored in bones, but some also in serveral soft tissues. After recovery the concentrations in soft tissues decreased to a variable degree. In the high-dose group the relative weights of heart and liver increased. These effects disappeared during recovery. At 400 g lead/l blood no adverse effects were observed that did occur at the high dose level.Part 2, dealing with the histopathology and (electron) microscopy of the kidneys is in preparation     

Carbon-11 labelled tyrosine to study tumor metabolism by positron emission tomography (PET)

To measure the rate of protein synthesis in human neoplasms by positron emission tomography, we prepared no carrier added DL-(1-¹¹C)-tyrosine by ¹¹C-carboxylation of the appropriate -lithioisocyanide followed by hydrolysis of the isocyanide function and removal of the protecting methoxy group. The purification, resolution and solvent switch to saline was performed by high performance liquid chromatography (HPLC). DL-(1-¹¹C)-Tyrosine in 0.1 N NaH₂PO₄ buffer was prepared with a radiochemical yield of 8%–16% (EOS, 35 min). The enantiomeric separation and solvent switch to saline were achieved in 5 min and 10 min respectively. Consequently L-(1-¹¹C)-tyrosine in physiological saline was obtained in 2%–4% radiochemical yield. Tumor accumulation in rats with the experimental WALKER 256 carcinosarcoma was observed for both the L- and D-isomer. Using positron emission tomography a tumor/muscle ratio of two was observed for the L-isomer 15 min after injection. The corresponding figure for the D-isomer was 2.5. The first clinical results with DL-(1-¹¹C)-tyrosine show accumulation of radioactivity in meningioma, a primary breast carcinoma and in liver metastases of a colonic carcinoma.