Emergency Department visits due to intoxications in a Dutch university hospital: Occurrence, characteristics and health care costs.

BACKGROUND: Intoxications with alcohol and drugs are common in the Emergency Department. This study aimed to describe the occurrence and characteristics of intoxications (alcohol, Drugs of Abuse (DOA), pharmaceutical and chemical) presented to the Emergency Department and the health care costs of these intoxications. METHODS: This was a retrospective medical record study of all patients (≥ 16 years) who presented to the Emergency Department of an inner-city academic hospital in the Netherlands due to single or multiple intoxication(s) as the primary or secondary reason in the year 2016. An intoxication was reported as present if the attending physician described the intoxication in the patient's medical record. RESULTS: A total of 783 patients were included, accounting for 3.2% of the adult Emergency Department population (age ≥ 16 year). In 30% more than one substance was used. Intoxications with alcohol, Drugs of Abuse and pharmaceuticals was reported in respectively 62%, 29% and 21% of the intoxicated patients. The mean costs per patient presenting with an intoxication to the Emergency Department was € 1,490. The mean costs per patient were highest for pharmaceutical intoxications (€ 2,980), followed by Drugs of Abuse (€ 1,140) and alcohol (€ 1,070). CONCLUSIONS: Intoxications among patients aged 16 years and older are frequently seen at the Emergency Department and are frequently caused by multiple substances. Alcohol is the most common intoxication. Substantial healthcare costs are involved. Therefore, this study suggests that further research into hazardous alcohol consumption and DOA abuse is warranted.

The Stability of Comorbid Psychiatric Disorders: A 7 Year Follow Up of Children with Pervasive Developmental Disorder-Not Otherwise Specified.

The current study was a 7-year follow-up of 74 6-12 year old children with Pervasive Developmental Disorder-Not Otherwise Specified. We examined the rates and 7 year stability of comorbid psychiatric diagnoses as ascertained with the Diagnostic Interview Schedule for Children: Parent version at ages 6-12 and again at ages 12-20. Also, we examined childhood factors that predicted the stability of comorbid psychiatric disorders. The rate of comorbid psychiatric disorders dropped significantly from childhood (81 %) to adolescence (61 %). Higher levels of parent reported stereotyped behaviors and reduced social interest in childhood significantly predicted the stability of psychiatric comorbidity. Re-evaluation of psychiatric comorbidity should be considered in clinical practice, since several individuals shifted in comorbid diagnoses.

ASD Symptom Severity in Adolescence of Individuals Diagnosed with PDD-NOS in Childhood: Stability and the Relation with Psychiatric Comorbidity and Societal Participation.

The current 7-year follow-up study investigated: (1) the stability of ASD severity, and (2) associations of ASD severity in adolescence with (a) childhood and concurrent psychiatric comorbidity, and (b) concurrent societal functioning. The Autism Diagnostic Observation Schedule (ADOS) and the Diagnostic Interview Schedule for Children were administered in childhood (ages 6-12) and in adolescence (ages 12-20) to 72 individuals with a pervasive developmental disorder-not otherwise specified (PDD-NOS). ADOS calibrated severity scores showed a large stability (r = .51). Psychiatric comorbidity in childhood and adolescence were not associated with ASD severity in adolescence. Mental health care use (87 %) and special education needs were high (71 %). Reevaluation of ASD severity and psychiatric comorbidity later in life seem useful when PDD-NOS is diagnosed in childhood.

Pathology practice patterns affect lymph node evaluation and outcome of colon cancer: a population-based study.

BACKGROUND: A large variation in the number of nodes examined between patients, hospitals, and regions has been reported for patients with colon cancer. We studied determinants of this variation and its relation to survival in the south of The Netherlands. PATIENTS AND METHODS: All patients who underwent resection for stage I-III colon carcinoma diagnosed from 1999 to 2002 in the Eindhoven Cancer Registry area were included (n = 2168). Determinants of lymph node evaluation and their relationship to survival were assessed, including variation between the six departments of pathology. RESULTS: A median number of six lymph nodes per specimen had been examined. The median number for each department of pathology ranged from three to eight (P < 0.0001). After correction for relevant factors, this variation remained, resulting in differences in the proportion of N+ tumours between departments from 29% to 41% (P < 0.0001). The number of nodes examined was positively associated with survival. Survival for node-negative patients differed between the departments of pathology (up to hazard ratio 1.5; P = 0.02). CONCLUSION: There was a large variation in lymph node evaluation between the departments of pathology, leading to differences in stage distribution and survival. Intervention strategies should be directed at nodal assessment.

Greater influence of age than co-morbidity on primary treatment and complications of prostate cancer patients: an in-depth population-based study.

We investigated the influence of age and co-morbidity on treatment, the occurrence of serious non-urological complications of treatment and prognosis for prostate cancer patients diagnosed and treated in community hospitals. Additional information from a random sample of 505 prostate cancer patients (aged 40 years or older) from the Eindhoven Cancer Registry diagnosed between 1995 and 1999 was collected. In all, 43% of the prostate cancer patients aged 40-69 years and 64% of those aged 70 or older suffered from one or more serious concomitant disease that barely affected primary treatment choice. However, compared to patients without co-morbidity, patients with cardiovascular diseases underwent radical prostatectomy less often (P=0.01). In all, 38% of the patients undergoing radical prostatectomy suffered from complications during the first year after diagnosis versus about 20% of those receiving radiotherapy. The number of complications did not seem to be affected by co-morbidity. After adjustment for age, stage, grade, prostate-specific antigen level and treatment, the cumulative risk of death was almost two times higher for patients with two or more concomitant diseases than for patients without co-morbidity. After adjustment for age, prostate cancer patients with co-morbidity were not treated differently, did not suffer from more complications but had a worse prognosis, compared to those without co-morbidity.

Mixed adherence to clinical practice guidelines for colorectal cancer in the Southern Netherlands in 2002.

AIMS: Population-based cancer registries can provide excellent data for insight in disease management practice. This study examines the extent to which the consensus-based national clinical guidelines (version 2000-2001) for colorectal cancer (CRC) had been implemented in the diagnostic and treatment approach in the Southern Netherlands in 2002. METHODS: Data were gathered from the medical records for a random sample from the Eindhoven Cancer Registry of 308 patients with colorectal cancer. Adherence to clinical guidelines was determined for diagnostic assessment, pathology, and treatment during the first year after diagnosis. RESULTS: Surgical procedures and referral for pre-operative radiotherapy were carried out largely conform the recommendations. The number of performed colonoscopies among colon cancer patients amounted to 60%; contrast enemas after incomplete colonoscopy were performed in only 27% of patients. The median number of examined lymph nodes was only six for patients with colon and five for patients with rectal cancer; the administration of adjuvant chemotherapy for patients with stage III colon cancer decreased from 95% of patients younger than 70 years to 48% of patients over 70. CONCLUSIONS: Adherence to clinical guidelines was not optimal. Feedback to surgeons and pathologists should improve adherence, especially with respect to nodal retrieval and assessment.

[The correlation of age and comorbidity with therapy and survival in cancer patients in North-Brabant and North-Limburg, 1995-2001]. / Samenhang van leeftijd en comorbiditeit met therapie en overleving bij patiënten met kanker in Noord-Brabant en Noord-Limburg, 1995-2001.

The proportion of elderly cancer patients has increased considerably. This means that more patients are being diagnosed with one or more serious concomitant condition which may complicate the treatment of cancer. Little is known about treatment outcomes, as elderly patients with comorbidity are often excluded from clinical trials. The Eindhoven Cancer Registry has been registering serious co-morbidity in North-Brabant and North-Limburg in the Netherlands since 1993. Using data from patients diagnosed with cancer in 1995-2001, the correlation between age and comorbidity and choice of therapy and survival rates was described. Very elderly patients or patients with co-morbidity often were not treated in accordance with the guidelines. Elderly patients with localized lung cancer or prostate cancer underwent less surgery as often and elderly patients with colorectal cancer, breast cancer or ovarian cancer received less adjuvant chemotherapy or radiotherapy than younger patients. The prognosis was often worse for elderly patients than for younger patients, and the presence of co-morbidity decreased survival in most types of tumour. The question remains whether the prognosis for elderly patients with cancer would improve if more of them were treated in accordance with the guidelines, or if this will only lead to more complications.

Co-morbidity leads to altered treatment and worse survival of elderly patients with colorectal cancer.

BACKGROUND: The aim of this study was to evaluate the effects of co-morbidity on the treatment and prognosis of elderly patients with colorectal cancer. METHODS: The independent influence of age and co-morbidity on treatment and survival was analysed for 6931 patients with colorectal cancer aged 50 years or more diagnosed between 1995 and 2001 in the southern part of the Netherlands. RESULTS: Co-morbidity had no influence on resection rate. The use of adjuvant chemotherapy in patients with stage III colonic cancer was influenced by co-morbidity, especially a previous malignancy (odds ratio (OR) 0.2 (95 per cent confidence interval (c.i.) 0.1 to 0.6); P = 0.002) or chronic obstructive pulmonary disease (COPD) (OR 0.3 (95 per cent c.i. 0.1 to 0.9); P = 0.043). Co-morbidity also influenced use of adjuvant radiotherapy in patients with rectal cancer, especially the presence of hypertension in combination with diabetes (OR 0.5 (95 per cent c.i. 0.2 to 0.9); P = 0.031). Co-morbidity influenced survival (hazard ratio up to 1.6), when adjusted for age, sex, tumour stage and treatment. The greatest influence on survival of patients with colonic cancer was previous malignancy, cardiovascular disease and COPD, and that of patients with rectal cancer was COPD, hypertension, and hypertension in combination with diabetes. CONCLUSION: Elderly patients with co-morbidity were treated less aggressively and had a worse survival than those with no concomitant disease.

[Surgery and follow-up 131I therapy in patients with differentiated thyroid carcinoma in the south-east of the Netherlands, 1983-1996, compliance with the 1987 consensus guidelines: additional data]. / Chirurgie en 131I-nabehandeling bij patiënten met gedifferentieerde schildklierkanker in Zuidoost-Nederland, 1983-1996, vergeleken met de consensusrichtlijnen uit 1987: aanvullende gegevens.

In a previous study using data from the regional cancer registry of the Comprehensive Cancer Centre South, Eindhoven, The Netherlands, we concluded that in the majority of cases surgical treatment was in accordance with the consensus recommendations, but that about 40% of patients with differentiated thyroid cancer from a number of regional hospitals had not been referred for 131I therapy. However, in a subsequent study using patient data from these hospitals, it became clear that almost all patients had in fact been referred for therapy but to centres outside the 131I therapy region. The conclusion of the study should therefore be altered: the great majority of patients with differentiated thyroid cancer in the south-east of The Netherlands (1983-96) were referred for 131I treatment and therefore the primary surgical and the follow-up treatment complied with the 1987 consensus guidelines.

Phase I and pharmacokinetic study of XR11576, an oral topoisomerase I and II inhibitor, administered on days 1-5 of a 3-weekly cycle in patients with advanced solid tumours.

XR11576 is an oral topoisomerase I and II inhibitor. The objectives of this phase I study were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to describe the pharmacokinetics (PKs) of XR11576 when administered orally on days 1-5 every 3 weeks to patients with advanced solid tumours. Patients were treated with escalating doses of XR11576 at doses ranging from 30 to 180 mg day(-1). For PK analysis, plasma sampling was performed during the first and second courses of treatment and XR11576 concentrations were assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. In all, 21 patients received a total of 47 courses. The MTD was reached at 180 mg day(-1), with diarrhoea and fatigue as DLT. Nausea and vomiting, although not qualifying for DLT, was ubiquitous. Only in combination with an extensive prophylactic antiemetic regimen consisting of a combination of both dexamethasone and a 5HT3 antagonist was treatment with XR11576 at 120 mg day(-1) tolerable. The systemic exposure of XR11576 increased more than proportionally with increasing dose, with a large interpatient variability. No objective responses were seen; four patients experienced stable disease for periods of 12-30 weeks. In this study, the DLTs of XR11576 were diarrhoea and fatigue. The recommended dose for phase II studies of XR11576 is 120 mg administered orally, on days 1-5 every 21 days. Alternative regimens are currently being explored.

Anaemia prior to operation is related with poorer long-term survival in patients with operable rectal cancer.

PURPOSE: Local hypoxia has been linked to a higher risk of metastasis in patients with cancer of the uterine cervix and a haemoglobin concentration of 7.45 mmol/l or less. It is unknown whether the same holds true for rectal cancer. We evaluated the independent impact of pre-operative anaemia on survival in patients with rectal cancer. PATIENTS AND METHODS: A random set of 144 patients diagnosed with Dukes' A, B or C rectal cancer in the period 1995-1999 and registered in the database of the Eindhoven Cancer Registry was included in a survival analysis. Parameters tested were gender, age, pre-operative haemoglobin concentration, tumour stage and therapy. The ones that showed a relation with survival (log-rank test, p<0.1) were entered in a multivariate analysis. RESULTS: For patients without pre-operative anaemia, the hazard ratio of death was 0.35 (95% confidence interval 0.19-0.65, p=0.001), which indicates a three times higher mortality risk. For patients with a higher tumour stage (Dukes' B vs. Dukes' A or Dukes' C vs. Dukes' B) the hazard ratio of death was 1.52 (95% CI 1.04-2.23, p=0.03). For older patients (64-73 years vs. <64 years or >73 years vs. 64-73 years) the hazard ratio of death was 1.85 (95% CI 1.29-2.63, p=0.001). CONCLUSION: Long-term survival was significantly affected in rectal cancer patients with pre-operative anaemia. Further study on the relation between anaemia, tumour oxygenation and prognosis is needed, as it may have implications for future therapy.

Comorbidity has negligible impact on treatment and complications but influences survival in breast cancer patients.

In the present study, we investigated whether age and serious comorbid conditions influence treatment decisions, complications and survival in breast cancer patients. The Eindhoven Cancer Registry records patient, tumour and therapy characteristics of all patients diagnosed with cancer in the southern part of the Netherlands. Additional information on severity of comorbidity and serious complications was collected for a random sample of 527 breast cancer patients (aged 40 years and older). More than 70% of the patients >or=80 exhibited high severity of comorbidity compared to 6% of those aged 40-49 years. Treatment was not influenced by severity of comorbidity. Less than 30% of the breast cancer patients had complications after diagnosis. The number of complications was not related to age or severity of comorbidity. The hazard ratio (HR) of dying for patients with low/moderate severity of comorbidity was 2.4 for those aged 40-69 years and 1.6 for those aged >or=70 years, after adjustment for age, nodal status and treatment. For patients with high severity of comorbidity, the risk of dying was almost three times higher. Older breast cancer patients with serious comorbidity were not treated differently and did not have more complications compared to those without comorbidity, but they exhibited a worse prognosis.

Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor.

The aims of this study were to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of irinotecan given with oral R115777 (tipifarnib), a farnesyl protein transferase inhibitor. Patients were treated with escalating doses of irinotecan with interval-modulated dosing of R115777 (continuously or on days 1-14, and repeated every 21 days). In total, 35 patients were entered onto the trial for a median duration of treatment of 43 days (range, 5-224 days). Neutropenia and thrombocytopenia were the dose-limiting toxicities; other side effects were mostly mild. The MTD was established at R115777 300 mg b.i.d. for 14 consecutive days with irinotecan 350 mg x m(-2) given every 3 weeks starting on day 1. Three patients had a partial response and 14 had stable disease. In the continuous schedule, the area under the curves of irinotecan and its active metabolite SN-38 were 20.0% (P=0.004) and 38.0% (P<0.001) increased by R115777, respectively. Intermittent dosing of R115777 at a dose of 300 mg b.i.d. for 14 days every 3 weeks is the recommended dose of R115777 in combination with the recommended single-agent irinotecan dose of 350 mg x m(-2).

Variable FMR1 gene methylation of large expansions leads to variable phenotype in three males from one fragile X family.

The fragile X syndrome is caused by an expanded CGG repeat (> 200 units, full mutation) at the 5' end of the FMR1 gene, which is associated with methylation of a CpG island upstream of the FMR1 gene and down regulation of the transcription. We describe three related males with full mutations in the FMR1 gene, as defined by size, but with different percentages of unmethylated alleles (+/-90%, 35%, and 15%, respectively) as studied in leucocytes. Normal mental status was observed in the male who showed 90% lack of methylation, whereas his two cousins were retarded. The mentally normal male did show some minor facial features of the fragile X syndrome; the FMR protein was detectable in 75% of his leucocytes. In all three cases, the proportion of unmethylated FMR1 genes corresponded to the percentage of leucocytes showing FMR1 protein production. Our results indicated a direct relationship between methylation and the ability to produce FMR protein. These cases will be discussed in relation to the phenotypic effects of incompletely methylated full mutations in the FMR1 gene as observed by others.

FMRP is associated to the ribosomes via RNA.

The FMR1 transcript is alternatively spliced and generates different splice variants coding for FMR1 proteins (FMRP) with a predicted molecular mass of 70-80 kDa. FMRP is widely expressed and localized in the cytoplasm. To study a possible interaction with other cellular components, FMRP was isolated and characterized under non-denaturing conditions. Under physiological salt conditions FMRP appears to have a molecular mass of > 600 kDa, indicating a binding to other cellular components. This interaction is disrupted in the presence of high salt concentrations. The dissociation conditions to free FMRP from the complex are similar to the dissociation of FMRP from RNA as shown before. The binding of FMRP from the complex is also disrupted by RNAse treatment. That the association of FMRP to a high molecular weight complex possibly occurs via RNA, is further supported by the observation that the binding of FMRP, containing an lle304Asn substitution, to the high molecular weight complex is reduced. An equal reduced binding of mutated FMRP to RNA in vitro was observed before under the same conditions. The reduced binding of FMRP with the lle304Asn substitution further indicates that the interaction to the complex indeed occurs via FMRP and not via other RNA binding proteins. In a reconstitution experiment where the low molecular mass FMRP (70-80 kDa) is mixed with a reticulocyte lysate (enriched in ribosomes) it was shown that FMRP can associate to ribosomes and that this binding most likely occurs via RNA.

Normal phenotype in two brothers with a full FMR1 mutation.

The fragile X syndrome is associated with an expanding CGG repeat in the 5' untranslated region of the first exon of the FMR1 gene. Subsequent methylation of the promoter region inhibits expression of the FMR1 gene. In two clinically normal brothers large, expanded CGG repeats and cytogenetically visible fragile sites were found. The FMR1 promoter was unmethylated and both RNA and protein could be detected. This indicates that inactivation of the FMR1 gene and not repeat expansion itself results in the fragile X phenotype. We conclude that repeat expansion does not necessarily induce methylation and that methylation is no absolute requirement for the induction of fragile sites.

Characterization of FMR1 proteins isolated from different tissues.

FMR1 protein expression was studied in different tissues. In human, monkey and murine tissues, high molecular mass FMR1 proteins (67-80 kDa) are found, as shown in lymphoblastoid cells lines. The identity of these proteins was confirmed by their absence in tissues from patients with the fragile X syndrome and a FMR1 knock-out mouse. An Ile367Asn substitution in the FMR1 protein did not alter the translation, processing and localization of FMR1 proteins in lymphoblastoid cells from a patient carrying this mutation. All the high molecular mass FMR1 proteins isolated from normal lymphoblastoid cells and cells from the patient with the Ile367Asn substitution were able to bind RNA. However, the FMR1 proteins of the patient had reduced affinity for RNA binding at high salt concentrations. In some human, monkey and murine tissues low molecular mass FMR1 proteins (39-41 kDa) were found, which had the same N terminus as the 67-90 kDa isoforms, but differ in their C terminus and are therefore most likely the result of carboxy-terminal proteolytic cleavage. These low molecular mass FMR1 proteins did not bind RNA, in contrast with the high molecular mass FMR1 proteins. The significance of these low molecular mass proteins remains to be studied.

Characterization and localization of the FMR-1 gene product associated with fragile X syndrome.

The fragile X syndrome is the most frequent form of inherited mental retardation after Down's syndrome, having an incidence of one in 1,250 males. The fragile X syndrome results from amplification of the CGG repeat found in the FMR-1 gene. This CGG repeat shows length variation in normal individuals and is increased significantly in both carriers and patients; it is located 250 base pairs distal to a CpG island which is hypermethylated in fragile X patients. The methylation probably results in downregulation of FMR-1 gene expression. No information can be deduced about the function of the FMR-1 protein from its predicted sequence. Here we investigate the nature and function of the protein encoded by the FMR-1 gene using polyclonal antibodies raised against the predicted amino-acid sequences. Four different protein products, possibly resulting from alternative splicing, have been identified by immunoblotting in lymphoblastoid cell lines of healthy individuals. All these proteins were missing in cell lines from patients not expressing FMR-1 messenger RNA. The intracellular localization of the FMR-1 gene products was investigated by transient expression in COS-1 cells and found to be cytoplasmic. Localization was also predominantly cytoplasmic in the epithelium of the oesophagus, but in some cells was obviously nuclear.