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OBJECTIVE: To describe the attitudes towards truth-telling of both terminal patients and professional caregivers, and to determine their perceived barriers to full information exchange. METHODS: In-depth interviews with 17 terminal patients selected through GPs and staff members of Flemish palliative care centres, and 3 focus groups with different professional caregivers. Analysis was based on grounded theory. RESULTS: There was considerable variability in the preferences of patients regarding when and how they wanted to be informed of their diagnosis, prognosis, expected disease course and end-of-life decisions. Major ambivalence was observed regarding the degree to which patients wanted to hear 'the whole truth'. Patients and caregivers agreed that truth-telling should be a 'dosed and gradual' process. Several barriers to more complete and timely truth-telling were identified. CONCLUSION: The preferences of both patients and caregivers for step-by-step--and hence slow and limited--information prevents terminal patients from reaching the level of information needed for informed end-of-life decision-making. PRACTICE IMPLICATIONS: The preference of patients and caregivers to 'dose' the truth may entail some risks, such as a 'Catch 22' situation in which both patients and caregivers wait for a signal from each other before starting a dialogue about impending death. [ABSTRACT FROM AUTHOR]

BACKGROUND: Communication with patients on end-of-life decisions is a delicate topic for which there is little guidance.AIM: To describe the development of a guideline for GPs on end-of-life communication with patients who wish to die at home, in a context where patient autonomy and euthanasia are legally regulated. DESIGN OF STUDY: A three-phase process (generation, elaboration and validation). In the generation phase, literature findings were structured and then prioritised in a focus group with GPs of a palliative care consultation network. In the elaboration phase, qualitative data on patients' and caregivers' perspectives were gathered through a focus group with next-of-kin, in-depth interviews with terminal patients, and four quality circle sessions with representatives of all constituencies. In the validation phase, the acceptability of the draft guideline was reviewed in bipolar focus groups (GPs-nurses and GPs-specialists). Finally, comments were solicited from experts by mail. SETTING: Primary home care in Belgium. SUBJECTS: Participants in this study were terminal patients (n = 17), next-of-kin of terminal patients (n = 17), GPs (n = 25), specialists (n = 3), nurses (n = 8), other caregivers (n = 2) and experts (n = 41). RESULTS: Caregivers and patients expressed a need for a comprehensive guideline on communication in end-of-life decisions. Four major communication themes were prioritised: truth telling; exploration of the patient's wishes regarding the end of life; dealing with disproportionate interventions; and dealing with requests for euthanasia in the terminal phase of life. Additional themes required special attention in the guideline: continuity of care by the GP; communication on foregoing food and fluid; and technical aspects of euthanasia. CONCLUSION: It was feasible to develop a guideline by combining the three cornerstones of evidence-based medicine: literature search, patient values and professional experience. [ABSTRACT FROM AUTHOR]

CONTEXT: Death is often preceded by medical decisions that potentially shorten life (end-of-life decisions [ELDs]), for example, the decision to withhold or withdraw treatment. Respect for patient autonomy requires physicians to involve their patients in this decision making. OBJECTIVES: The objective of this study was to examine the involvement of advanced lung cancer patients and their families in ELD making and compare their actual involvement with their previously stated preferences for involvement. METHODS: Patients with Stage IIIb/IV non-small cell lung cancer were recruited by physicians in 13 hospitals and regularly interviewed between diagnosis and death. When the patient died, the specialist and general practitioner were asked to fill in a questionnaire. RESULTS: Eighty-five patients who died within 18 months of diagnosis were studied. An ELD was made in 52 cases (61%). According to the treating physician, half of the competent patients were not involved in the ELD making, one-quarter shared the decision with the physician, and one-quarter made the decision themselves. In the incompetent patients, family was involved in half of cases. Half of the competent patients were involved less than they had previously preferred, and 7% were more involved. Almost all of the incompetent patients had previously stated that they wanted their family involved in case of incompetence, but half did not achieve this. CONCLUSION: In half of the cases, advanced lung cancer patients-or their families in cases of incompetence-were not involved in ELD making, despite the wishes of most of them. Physicians should openly discuss ELDs and involvement preferences with their advanced lung cancer patients.Copyright © 2012 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

Purpose: To assess neurocognitive function (NCF), psychosocial outcome, health-related quality of life (HRQoL), and long-term effects of immune-related adverse events (irAE) on metastatic melanoma survivors treated with ipilimumab (IPI)., Methods: Melanoma survivors were identified within two study populations ( N = 104), at a single-center university hospital, and defined as patients who were disease-free for at least 2 years after initiating IPI. Data were collected using 4 patient-reported outcome measures, computerized NCF testing, and a semistructured interview at the start and 1-year follow-up., Results: Out of 18 eligible survivors, 17 were recruited (5F/12M); median age is 57 years (range 33-86); and median time since initiating IPI was 5.6 years (range 2.1-9.3). The clinical interview revealed that survivors suffered from cancer-related emotional distress such as fear of recurrence ( N = 8), existential problems ( N = 2), survivor guilt ( N = 2), and posttraumatic stress disorder ( N = 6). The mean EORTC QLQ-C30 Global Score was not significantly different from the European mean of the healthy population. Nine survivors reported anxiety and/or depression (Hospitalization Depression Scale) during the survey. Seven survivors (41%) reported fatigue (Fatigue Severity Scale). Seven patients (41%) had impairment in NCF; only three out of seven survivors had impairment in subjective cognition (Cognitive Failure Questionnaire). Anxiety, depression, fatigue, and neurocognitive symptoms remained stable at the 1-year follow-up. All cases of skin toxicity ( N = 8), hepatitis ( N = 1), colitis ( N = 3), and sarcoidosis ( N = 1) resolved without impact on HRQoL. Three survivors experienced hypophysitis; all suffered from persistent fatigue and cognitive complaints 5 years after onset. One survivor who experienced a Guillain-Barré-like syndrome suffered from persisting depression, fatigue, and impairment in NCF., Conclusion: A majority of melanoma survivors treated with IPI continue to suffer from emotional distress and impairment in NCF. Timely detection in order to offer tailored care is imperative, with special attention for survivors with a history of neuroendocrine or neurological irAE. The trial is registered with B.U.N. 143201421920., Competing Interests: AR reports personal fees from Bristol-Myers Squibb and Merck Sharp & Dohme, outside the submitted work. GA and JKS report travel accommodations—Merck Sharp & Dohme, Pfizer, and Astellas—outside the submitted work. AS and PM report to be full-time employees of Cogstate Ltd, the company that provided the computerized cognitive tests in this study. BN reports grants and personal fees from Novartis, personal fees from Bristol-Myers Squibb, personal fees from Merck Sharp & Dohme, grants and personal fees from Pfizer, personal fees from AstraZeneca, and grants and personal fees from Roche, outside the submitted work. CL, JL, MD, JC, and PT report no conflict of interest., (Copyright © 2020 Anne Rogiers et al.)

The Belgian model of 'integral' end-of-life care consists of universal access to palliative care (PC) and legally regulated euthanasia. As a first worldwide, the Flemish PC organisation has embedded euthanasia in its practice. However, some critics have declared the Belgian-model concepts of 'integral PC' and 'palliative futility' to fundamentally contradict the essence of PC. This article analyses the various essentialistic arguments for the incompatibility of euthanasia and PC. The empirical evidence from the euthanasia-permissive Benelux countries shows that since legalisation, carefulness (of decision making) at the end of life has improved and there have been no significant adverse 'slippery slope' effects. It is problematic that some critics disregard the empirical evidence as epistemologically irrelevant in a normative ethical debate. Next, rejecting euthanasia because its prevention was a founding principle of PC ignores historical developments. Further, critics' ethical positions depart from the PC tenet of patient centeredness by prioritising caregivers' values over patients' values. Also, many critics' canonical adherence to the WHO definition of PC, which has intention as the ethical criterion is objectionable. A rejection of the Belgian model on doctrinal grounds also has nefarious practical consequences such as the marginalisation of PC in euthanasia-permissive countries, the continuation of clandestine practices and problematic palliative sedation until death. In conclusion, major flaws of essentialistic arguments against the Belgian model include the disregard of empirical evidence, appeals to canonical and questionable definitions, prioritisation of caregiver perspectives over those of patients and rejection of a plurality of respectable views on decision making at the end of life., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: In 2002, physician-assisted dying was legally regulated in the Netherlands and Belgium, followed in 2009 by Luxembourg. An internationally frequently expressed concern is that such legislation could stunt the development of palliative care (PC) and erode its culture. To study this, we describe changes in PC development 2005-2012 in the permissive Benelux countries and compare them with non-permissive countries., Methods: Focusing on the seven European countries with the highest development of PC, which include the three euthanasia-permissive and four non-permissive countries, we compared the structural service indicators for 2005 and 2012 from successive editions of the European Atlas of Palliative Care. As an indicator for output delivery of services to patients, we collected the amounts of governmental funding of PC 2002-2011 in Belgium, the only country where we could find these data., Results: The rate of increase in the number of structural PC provisions among the compared countries was the highest in the Netherlands and Luxembourg, while Belgium stayed on a par with the UK, the benchmark country. Belgian government expenditure for PC doubled between 2002 and 2011. Basic PC expanded much more than endowment-restricted specialised PC., Conclusions: The hypothesis that legal regulation of physician-assisted dying slows development of PC is not supported by the Benelux experience. On the contrary, regulation appears to have promoted the expansion of PC. Continued monitoring of both permissive and non-permissive countries, preferably also including indicators of quantity and quality of delivered care, is needed to evaluate longer-term effects., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: "Life-ending acts without explicit patient request," as identified in robust international studies, are central in current debates on physician-assisted dying. Despite their contentiousness, little attention has been paid to their actual characteristics and to what extent they truly represent nonvoluntary termination of life., Methods: We analyzed the 66 cases of life-ending acts without explicit patient request identified in a large-scale survey of physicians certifying a representative sample of deaths (n = 6927) in Flanders, Belgium, in 2007. The characteristics we studied included physicians' labelling of the act, treatment course and doses used, and patient involvement in the decision., Results: In most cases (87.9%), physicians labelled their acts in terms of symptom treatment rather than in terms of ending life. By comparing drug combinations and doses of opioids used, we found that the life-ending acts were similar to intensified pain and symptom treatment and were distinct from euthanasia. In 45 cases, there was at least 1 characteristic inconsistent with the common understanding of the practice: either patients had previously expressed a wish for ending life (16/66, 24.4%), physicians reported that the administered doses had not been higher than necessary to relieve suffering (22/66, 33.3%), or both (7/66, 10.6%)., Interpretation: Most of the cases we studied did not fit the label of "nonvoluntary life-ending" for at least 1 of the following reasons: the drugs were administered with a focus on symptom control; a hastened death was highly unlikely; or the act was taken in accordance with the patient's previously expressed wishes. Thus, we recommend a more nuanced view of life-ending acts without explicit patient request in the debate on physician-assisted dying.

Purpose: The objective is to explore changes over time in the information and participation preferences of newly diagnosed stage IIIb/IV non-small-cell lung cancer patients., Methods: Patients were recruited by physicians in 13 hospitals and interviewed every 2 months until the fourth and every 4 months until the sixth interview., Results: Sixty-seven patients were interviewed three times. Over a period of 4 months from diagnosis, half of patients changed their information preferences for palliative care and end-of-life decisions with a possible or certain life-shortening effect (ELDs, e.g., non-treatment decisions) in both directions, from not wanting to wanting the information, but also--and as much--from wanting to no longer wanting it. The latter were more likely to be in a better physical condition. Preferences for participation in medical decision making also changed: 50% to 78%, depending on the type of decision (general, treatment, transfer or ELD), changed their preference towards wanting more or less participation. Pain seemed to be a trigger for patients wanting more involvement, which contrasts with studies suggesting that patients who are more ill tend to give up more control., Conclusions: Doctors should regularly ask their advanced lung cancer patients how much information and participation they want because preferences do change in unexpected ways.

This study explores expressed wishes and requests for euthanasia (i.e. administration of lethal drugs at the explicit request of the patient), and incidence of end-of-life decisions with possible life-shortening effects (ELDs) in advanced lung cancer patients in Flanders, Belgium. We performed a prospective, longitudinal, observational study of a consecutive sample of advanced lung cancer patients and selected those who died within 18 months of diagnosis. Immediately after death, the pulmonologist/oncologist and general practitioner (GP) of the patient filled in a questionnaire. Information was available for 105 out of 115 deaths. According to the specialist or GP, one in five patients had expressed a wish for euthanasia; and three in four of these had made an explicit and repeated request. One in two of these received euthanasia. Of the patients who had expressed a wish for euthanasia but had not made an explicit and repeated request, none received euthanasia. Patients with a palliative treatment goal at inclusion were more likely to receive euthanasia. Death was preceded by an ELD in 62.9% of patients. To conclude, advanced lung cancer patients who expressed a euthanasia wish were often determined. Euthanasia was performed significantly more among patients whose treatment goal after diagnosis was exclusively palliative.

Objective: To review the empirical claims made in: Pereira J. Legalizing euthanasia or assisted suicide: the illusion of safeguards and controls. Curr Oncol 2011;18:e38-45., Design: We collected all of the empirical claims made by Jose Pereira in "Legalizing euthanasia or assisted suicide: the illusion of safeguards and controls." We then collected all reference sources provided for those claims. We compared the claims with the sources (where sources were provided) and evaluated the level of support, if any, the sources provide for the claims. We also reviewed other available literature to assess the veracity of the empirical claims made in the paper. We then wrote the present paper using examples from the review., Results: Pereira makes a number of factual statements without providing any sources. Pereira also makes a number of factual statements with sources, where the sources do not, in fact, provide support for the statements he made. Pereira also makes a number of false statements about the law and practice in jurisdictions that have legalized euthanasia or assisted suicide., Conclusions: Pereira's conclusions are not supported by the evidence he provided. His paper should not be given any credence in the public policy debate about the legal status of assisted suicide and euthanasia in Canada and around the world.

The use of quality of life (QOL) outcomes in clinical trials is increasing as a number of practical, ethical, methodological, and regulatory reasons for their use have become apparent. It is important, then, that QOL measurements and differences between QOL scores be readily interpretable. We study interpretation in two contexts: when determining QOL and when basing decisions on QOL differences. We consider both clinical situations involving individual patients and research contexts, e.g., randomized clinical trials, involving groups of patients. We note the ethical importance of such understanding: proper interpretation and communication facilitate health care decision making. Communication that facilitates interpretation is of moral significance since better communication can attenuate ethical problems and inform choices. Much of what is communication worthy about QOL assessments is determined by the particular QOL instrument used in the assessment and how it is administered. In practice, these choices will be driven by the purpose of the assessment, but, it is argued, to maximize understanding, we should combine the information garnered from traditional standardized QOL instruments, from individualized QOL assessments, and from a recently proposed dialogic paradigm, where QOL is determined by shared conversation regarding the interpretation of texts. And, while some studies can surely succeed using abbreviated methods of administration (e.g., postal surveys may suffice for certain purposes), we will focus on methods of administration involving interviewer-respondent interaction. We suggest that during the QOL elicitation process, interviewer and respondent should engage in a two-way conversation in order to achieve a shared understanding of the "answers" to QOL "questions" and, finally, to reach a shared interpretation of the individual's QOL.

Objectives Locked-in syndrome (LIS) consists of anarthria and quadriplegia while consciousness is preserved. Classically, vertical eye movements or blinking allow coded communication. Given appropriate medical care, patients can survive for decades. We studied the self-reported quality of life in chronic LIS patients. Design 168 LIS members of the French Association for LIS were invited to answer a questionnaire on medical history, current status and end-of-life issues. They self-assessed their global subjective well-being with the Anamnestic Comparative Self-Assessment (ACSA) scale, whose +5 and -5 anchors were their memories of the best period in their life before LIS and their worst period ever, respectively. Results 91 patients (54%) responded and 26 were excluded because of missing data on quality of life. 47 patients professed happiness (median ACSA +3) and 18 unhappiness (median ACSA -4). Variables associated with unhappiness included anxiety and dissatisfaction with mobility in the community, recreational activities and recovery of speech production. A longer time in LIS was correlated with happiness. 58% declared they did not wish to be resuscitated in case of cardiac arrest and 7% expressed a wish for euthanasia. Conclusions Our data stress the need for extra palliative efforts directed at mobility and recreational activities in LIS and the importance of anxiolytic therapy. Recently affected LIS patients who wish to die should be assured that there is a high chance they will regain a happy meaningful life. End-of-life decisions, including euthanasia, should not be avoided, but a moratorium to allow a steady state to be reached should be proposed.

Objective: To explore the preferences of competent patients with advanced lung cancer regarding involvement of family and/or others in their medical decision-making, and their future preferences in case of loss of competence., Methods: Over 1 year, physicians in 13 hospitals in Flanders, Belgium, recruited patients with initial non-small–cell lung cancer, stage IIIb or IV. The patients were interviewed with a structured questionnaire every 2 months until the fourth interview and every 4 months until the sixth interview., Results: At inclusion, 128 patients were interviewed at least once; 13 were interviewed 6 consecutive times. Sixty-nine percent of patients wanted family members to be involved in medical decision-making and this percentage did not change significantly over time. One third of these patients did not achieve this preference. Ninety-four percent of patients wanted family involvement if they lost competence, 23% of these preferring primary physician control over decision-making, 41% shared physician and family control, and 36% primary family control. This degree of preferred family involvement expressed when competent did not change significantly over time at population level, but did at individual level; almost half the patients changed their minds either way at some point during the observation period., Conclusions: The majority of patients with lung cancer wanted family involvement in decision-making, and almost all did so in case of future loss of competence. However, as half of the patients changed their minds over time about the degree of family involvement they wanted if they lost competence, physicians should regularly rediscuss a patient's preferences.

Purpose: To evaluate whether the WHOQOL-BREF measures the QOL construct in the same way across nations., Methods: Students from Flanders, Belgium and Iran completed the WHOQOL-BREF as part of a larger Quality of Life questionnaire. Their responses were compared using a multi-group confirmatory factor analysis., Results: In general, the QOL construct appears rather similar in both cultures; however, participants from both countries seem to respond differently to particular items of the WHOQOL-BREF. Especially for the physical and psychological domain, this is problematic, because none of their indicators works in the same way across samples., Conclusions: Notwithstanding some limitations of this study, it must be concluded that the WHOQOL-BREF should only be used with great caution in cross-national comparisons., (© Springer Science+Business Media B.V. 2010)

The Locked-In Syndrome (LIS) is classically caused by an anterior pontine vascular lesion and characterized by quadriplegia and anarthria with preserved consciousness and intellectual functioning. We here review the definition, etiologies, diagnosis and prognosis of LIS patients and briefly discuss the few studies on their quality of life and the challenging end-of-life decisions that can be encountered. Some clinicians may consider that LIS is worse than being in a vegetative or in a minimally conscious state. However, preliminary data from chronic LIS survivors show a surprisingly preserved self-scored quality of life and requests of treatment withdrawal or euthanasia, though not absent, are infrequent.

Objectives: Exploring terminal patients' perceptions of GPs' role in delivering continuous end-of-life care and identifying barriers to this., Design: Qualitative interview study with patients (two consecutive interviews)., Setting: Primary care Belgium., Participants: Seventeen terminally ill cancer patients, informed about diagnosis and prognosis., Results: Terminal patients attribute a pivotal role to GPs in different aspects of two types of continuity. Relational continuity: having an ongoing relationship with the same GP, of which important aspects are eg, keeping in touch after referral and feeling responsible for the patient. Informational continuity: use of information on past events and personal circumstances to provide individualised care, of which important aspects are eg, exchange of information between GPs, specialists and care facilities. Patients also identify barriers to continuity eg, lack of time and of GPs' initiative., Conclusions: At the end of life when physicians can no longer rely on biomedical models of diagnosis-therapy-cure, patients' perspectives are of utmost importance. This qualitative study made it possible to gain insights into terminal patients' perceptions of continuous primary end-of-life care. It clarifies the concept and identifies barriers to it.

Purpose: Incidence studies reported more end-of-life decisions with possible/certain life-shortening effect (ELDs) among cancer patients than among noncancer patients. These studies did not correct for the different proportions of sudden/unexpected deaths of cancer versus noncancer patients, which could have biased the results. We investigated incidences and characteristics of ELDs among nonsudden cancer and noncancer deaths., Methods: We sampled 5,005 certificates of all deaths in 2001 (Flanders, Belgium) stratified for ELD likelihood. Questionnaires were mailed to the certifying physicians. Data were corrected for stratification and nonresponse., Results: The response rate was 59%. Among 2,128 nonsudden deaths included, ELDs occurred in 74% of cancer versus 50% of noncancer patients (P < .001). Symptom alleviation with possible life-shortening effect occurred more frequently among cancer patients (P < .001); nontreatment decisions occurred less frequently (P < .001). The higher incidence of lethal drug use among cancer patients did not hold after correcting for patient age. Half of the cancer patients who died after an ELD were incompetent to make decisions compared with 76% of noncancer patients (P < .001). Discussion with patients and relatives was similar in both groups. In one fifth of all patients the ELD was not discussed., Conclusion: ELDs are common in nonsudden deaths. The different incidences for symptom alleviation with possible life-shortening effect and nontreatment decisions among cancer versus noncancer patients may be related to differences in dying trajectories and in timely recognition of patient needs. The end-of-life decision-making process is similar for both groups: consultation of patients and relatives can be improved in a significant minority of patients.

Purpose: Our aim was to describe and assess the medicinal products and doses used for euthanasia in a series of cases, identified within an epidemiological death certificate study in Belgium, where euthanasia was until recently legally forbidden and where guidelines for euthanasia are not available., Methods: In a random sample of the deaths in 1998 in Belgium, the physicians who signed the death certificates were identified and sent an anonymous mail questionnaire. The questionnaires of the deaths classified as euthanasia cases were reviewed by a multi-disciplinary panel., Results: A total of 22 among 1925 questionnaires pertained to voluntary euthanasia. In 17 cases, detailed information on the euthanatics (medicinal substances used for euthanasia) used was provided. Opioids were used in 13 cases (in 7 as a single drug). Time between last dose and expiry ranged from 4 to 900 min. The panel judged that only in 4 cases effective euthanatics were used., Conclusions: In the end-of-life decision cases perceived by Belgian physicians as euthanasia, pharmacological practices were disparate, although dominated by the use of morphine, in the very late phase of dying, in doses which were unlikely to be lethal. Most physicians clandestinely engaging in euthanasia in Belgium seemed unaware of procedures for guaranteeing a quick, mild and certain death. Information on the pharmacological aspects of euthanasia should be included in the medical curriculum and continuing medical education, at least in countries with a legal framework permitting euthanasia under specified conditions.

Recently, laws on euthanasia have been adopted in the Netherlands and Belgium. In both countries the legality of euthanasia is conditioned by adherence to strict conditions and by confirmation after a notification procedure. Although both laws are rather similar, the Belgian law is more fastidious on the requirements of prudent practice. The Belgian law does and the Dutch law does not distinguish between terminal conditions and non-terminal or slowly evolutive chronic conditions. In Belgium, the law only applies to adults, whereas in the Netherlands, minors over 12 years of age may under certain conditions receive euthanasia. However, the Belgian National Medical Disciplinary Board has recently mitigated differences by drafting guidelines which reflect a broad interpretation of the law. A major difference between the two countries is that in the Dutch society the norm setting on euthanasia developed more through jurisprudence and endorsement by the Medical Association than through legislation. We anticipate that the implementation of the new law and the notification procedure may be more difficult in Belgium than in the Netherlands. In order to promote the quality of the euthanasia practice, the euthanasia notification procedure in the Netherlands is followed by systematic feedback to the physicians. The strict anonymity of the Belgian notification procedure will be broken only when the control commission finds some anomaly or deficiency in the declaration. Therefore, unless the Evaluation and Control Commission makes ample use of its prerogative to contact the physician, the Belgian physicians may be less supported by the notification procedure to improve their knowledge and skills in euthanasia.

In January 1999, 500 tons of feed contaminated with approximately 50 kg of polychlorinated biphenyls (PCBs) and 1 g of dioxins were distributed to animal farms in Belgium, and to a lesser extent in the Netherlands, France, and Germany. This study was based on 20,491 samples collected in the database of the Belgian federal ministries from animal feed, cattle, pork, poultry, eggs, milk, and various fat-containing food items analyzed for their PCB and/or dioxin content. Dioxin measurements showed a clear predominance of polychlorinated dibenzofuran over polychlorinated dibenzodioxin congeners, a dioxin/PCB ratio of approximately 1:50,000 and a PCB fingerprint resembling that of an Aroclor mixture, thus confirming contamination by transformer oil rather than by other environmental sources. In this case the PCBs contribute significantly more to toxic equivalents (TEQ) than dioxins. The respective means +/- SDs and the maximum concentrations of dioxin (expressed in TEQ) and PCB observed per gram of fat in contaminated food were 170.3 +/- 487.7 pg, 2613.4 pg, 240.7 +/- 2036.9 ng, and 51059.0 ng in chicken; 1.9 +/- 0.8 pg, 4.3 pg, 34.2 +/- 30.5 ng, and 314.0 ng in milk; and 32.0 +/- 104.4 pg, 713.3 pg, 392.7 +/- 2883.5 ng, and 46000.0 ng in eggs. Assuming that as a consequence of this incident between 10 and 15 kg PCBs and from 200 to 300 mg dioxins were ingested by 10 million Belgians, the mean intake per kilogram of body weight is calculated to maximally 25,000 ng PCBs and 500 pg international TEQ dioxins. Estimates of the total number of cancers resulting from this incident range between 40 and 8,000. Neurotoxic and behavioral effects in neonates are also to be expected but cannot be quantified. Because food items differed widely (more than 50-fold) in the ratio of PCBs to dioxins, other significant sources of contamination and a high background contamination are likely to contribute substantially to the exposure of the Belgian population.

Objective: The aim of this study was to determine the sensitivity of cytopathologic examination for the detection of vaginal or cervical clear cell adenocarcinoma (CCA)., Methods: Systematic collection in the Dutch automated nationwide pathology archive of all cytology and histology data of women with CCA, born in The Netherlands after 1947 was performed. All cytologic examinations within 2 years prior to histological diagnosis of CCA were included., Results: Ninety patients with CCA have been registered. Forty-nine of these patients had cytologic examinations prior to histology. Eighty-five percent of cervical CCAs were preceded by a positive cervical smear. One hundred percent of vaginal CCAs were preceded by a positive vaginal smear. Cervical smears are relatively insensitive to detect vaginal CCA. Vaginal smears were often omitted. Only 2 apparently false-negative smears were found. The mean numbers of smears in diethylstilbestrol (DES)-exposed and nonexposed women were minimally different: 1.0 and 0.8, respectively. This suggests an only modest impact of the awareness of DES as a risk factor. FIGO tumor stage I was preceded more frequently by cytology than the higher tumor stages., Conclusion: The majority of CCA cases can be detected at an early stage by yearly clinical and cytological examinations, which must comprise cervical as well as vaginal sampling. Since CCA may also occur in postmenopausal women, for the purpose of secondary prevention of CCA regular cytologic examinations of DES-exposed women must be continued after menopause., (Copyright 1999 Academic Press.)

Medical, scientific and societal progress has been such that, in a universalist humanist perspective such as the WHO's, it has become an ethical imperative for the primary endpoints in evidence based health care research to be expressed in e.g. Quality Adjusted Life Years (QALYs). The classical endpoints of discrete health-related functions and duration of survival are increasingly perceived as unacceptably reductionistic. The major problem in 'felicitometrics' is the measurement of the 'quality' term in QALYs. That the mental, physical and social domains, each containing many dimensions and items, all contribute to QOL is uncontroversial. What is controversial, is the weight of the different dimensions in overall QOL. It has been shown to be very different between different patient populations. In human individuals, assuredly complex systems, the many dimensions and items of QOL observably interact, probably sometimes in chaotic ways. In these conditions, the weights of isolated items in individuals become for all practical purposes meaningless. Therefore, the much used multi-item questionnaires at best describe, but do not evaluate QOL, neither in individuals, nor in populations. For example, allergic patients treated with cetirizine scored better than those on placebo on all dimensions of the SF-36, a standard QOL questionnaire. Here there is no serious doubt that the treatment improved QOL, because it is highly unlikely that any important dimension on which the patient groups would have scored otherwise is missing in the SF-36. However, whether piracetam treatment of acute stroke, which improved the surrogate endpoints neurological and functional scores, also improved QOL is plausible, but will be proven only when comprehensive QOL measurement will have been done. And suppose in randomised populations of end-stage metastatic solid cancer patients, one would compare palliative last-line chemotherapy with only palliative care, and one would, as can be expected, find no significant differences in average survival, and chemotherapy superior for the mental domain, but inferior for the physical comfort domain: we would not know which treatment, on aggregate, would be the better. The problem is that QOL is an individual and emergent construct, the resultant of a great many interactions, and of a different order than its contributing components. Overall QOL can therefore best be captured only as the Gestalt of a global self-assessment. Just as people in everyday life, while acting under uncertainty, make global assessments all the time, so they can seriously answer the serious question: 'How have you been?' A solemn, practical, non peer-relativistic, non-cultural, experiential, and well tolerated way to obtain such responses is Anamnestic Comparative Self Assessment (ACSA), in which the subjects' memories of the best and the worst times in their life experience define their individual scale of QOL. ACSA is thus both exquisitely idiosyncratic, and yet can in a universalist humanistic perspective be considered generic. Using both a multi-item questionnaire and a global assessment allows by one logistic regression, to estimate the weights of the dimensions and items in populations, and thus identify those whose improvement would most contribute to the QOL of the greatest number. A combined approach to measurement of QOL is necessary to maximise the utility of QOL interventions.

Recent studies have suggested that the progression of experimental chronic renal disease may be prevented by early use of antihypertensive drugs. It is unclear, however, whether such therapies may also affect established and progressive renal disease. In the present study we compared the effects of captopril (CEI) and diltiazem (CCB), started either at week 10 or at week 24 on the evolution of adriamycin nephropathy (AN). Rats were studied at weeks 7, 16, 24, 32, and 38 of the disease. None of the treatments influenced the development of nephrotic range proteinuria. The use of CCB from week 10 was even associated with increased proteinuria. The moderate hypertension of ADR rats was reduced to the same degree with both drugs. Inulin clearance (GFR) was significantly reduced in all ADR rats. However, in ADR rats treated with CEI from week 10 and in those treated with CCB from week 24, the GFR was relatively higher. Glomerular injury, evaluated by semiquantitative methods, was not ameliorated by CEI treatment. Earlier CCB treatment (week 10) worsened glomerular lesions, whilst CCB treatment initiated at week 24 reduced significantly the degree of mesangial expansion and focal glomerular sclerosis. We conclude that, in addition to their common antihypertensive action, the specific effect of drug therapy seems to be crucially time dependent.

A case of advanced, reversible renal failure due to psychogenic urinary retention occurring in a 17 year old female, is reported. The diagnosis of psychogenic urinary retention was made on the basis of existent florid psychopathology and the concomitant exclusion of an organic cause. Family psychodynamics are discussed. Psychosocial intervention led to a resumption of normal micturition, the disappearance of the urinary retention with resultant improvement of renal function.

The mode of action of 5-fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd) on L1210 leukaemia has been studied. It is shown that FUra and FdUrd follow different routes of metabolism and have different targets with respect to their cytotoxic activity. FUra is converted to 5-fluorouridine-5'triphosphate ( FUTP ), which is incorporated into nascent RNA. FdUrd is converted to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which inhibits the de novo synthesis of 2'-deoxythymidine-5'-monophosphate (dTMP). Conversion of FUra to FdUMP does occur, but this phenomenon does not contribute to the final cytotoxic effect. No conversion of FdUrd to FUra has been detected.

A 56-year-old man had fever, precordial pain, and a mediastinal mass. The mass disappeared two months later and the patient remained asymptomatic for 2 1/2 years. At that time a full-blown nephrotic syndrome developed, with minimal-change glomerulopathy. The chest x-ray film showed the reappearance of a giant mediastinal mass. On biopsy of the mass, malignant thymoma was diagnosed. Association between minimal-change disease and Hodgkin's disease is well known, while the association with malignant thymoma has not been previously reported. The relationship between malignant thymoma and minimal-change disease is discussed, and a possible pathogenic mechanism involving cell-mediated immunity is proposed.

The modes of action of 5-fluoro-2'-deoxyuridine (FdUrd) and 5-fluoro-2'-deoxycytidine (FdCyd) were studied in PHA-stimulated lymphocytes from normal volunteer donors and a fragile X patient. In both cell types, FdUrd and FdCyd inhibited cell proliferation at concentrations of 3 x 10(-8) M. Thymidylate synthetase was identified as the decisive target for the action of both FdUrd and FdCyd, as judged from the following observations: First, addition of thymidine to the culture medium was able to counteract both FdUrd and FdCyd toxicities, whereas addition of dCyd had no observable effect. Second, inhibition of the in situ thymidylate synthetase activity measured as an increase in the level of [3H]-dThd incorporation coincided with the inhibition of cell proliferation. Third, the inhibition of the thymidylate synthetase-dependent incorporation of [3H]-dUrd into newly synthesized DNA coincided with the inhibition of cell proliferation. The effects of FdUrd and FdCyd on the in vitro expression of fragile site Xq27 of fragile X chromosomes was shown to be based on the depletion of the intracellular pool of thymidine-5'-monophosphate (dTMP), as judged from the following observations: First, both the FdUrd- and FdCyd-dependent induction of site Xq27 coincided with the antiproliferative effects of the respective fluoropyrimidines. Second, addition of thymidine (dThd) to the culture medium both prevented the expression of site Xq27 and neutralized the cytotoxicity of FdUrd and of FdCyd. On the basis of these findings, we provide further evidence for the concept that the fragile X site is located in an AT-rich region.

The response of human lymphocytes to phytohemagglutinin (PHA) stimulation was assessed in detailed kinetic studies, in order to define conditions permitting and regulating proliferation. By utilizing live and dead cell counts, cell cycle characterizations, and calculations of rates of entry into S phase and mitosis, it was demonstrated that dilute culture conditions (2 X 10(5) cells/ml) enable lymphocytes to proliferate for a period of 5 or 6 days. Although cell division occurs in concentrated cultures (2 X 10(6) cells/ml), net proliferation is not demonstrable due to extensive cell death and earlier decay in the proliferative response. It is projected that without cell death the cell count would rise more than 6-fold in a dilute culture and 2-fold in a concentrated culture under these growth conditions. The kinetic analyses did not demonstrate separate PHA dose thresholds for blastogenesis and entry into S phase. High doses of PHA stimulated a suboptimal response by causing excessive cell death without reducing initial entry into the cell cycle. These results provide a kinetic explanation for the frequent observation of little net proliferation despite substantial 3H-thymidine incorporation in PHA-stimulated lymphocyte cultures. Cell death is identified as a parameter that must be considered in the interpretation of in vitro lymphocyte stimulation studies, and methods for quantifying the role of cell death are demonstrated.

A mathematical model is presented for the analysis of transition between cycling and non-cycling compartments by cells responding to a growth stimulus. The cellular age distribution as a function of time is derived from sequential [3H]thymidine pulse labeling indices. Rates of entry into and exit from the cycling compartment are determined on the basis of labeling indices obtained after instantaneous and long duration [3H]thymidine pulses. Analysis of an experiment involving sequential measurements over the whole lifespan of a human lymphocyte culture stimulated by phytohemagglutinin is presented as an example of the application of this method.

The steroid hormones estradiol, progesterone and testosterone, in addition to cortisol, inhibited stimulation of human peripheral blood lymphocytes by phytohaemagglutinin (PHA) and Con A. This effect upon lymphocyte transformation was assayed by three methods: quantitation of [3H]thymidine incorporation into acid precipitable material, microscopic assessment of blastic transformation and determination of the labelling index. Addition of steroid hormones at the initiation of culture resulted in a marked inhibition in all three parameters, which was observed with lower concentrations of cortisol than the other hormones. The inhibition was not attributable to cell death and could be partially reversed by removing hormones from the incubation medium after culture for 48-72 hr. Late addition of steroid hormones, 52 hr after addition of mitogen and 18 hr prior to pulse-labelling with [3H]thymidine, also resulted in reduced [3H]thymidine incorporation, accompanied by a nearly 50% reduction in the labelling indices and only a minimal decrease in the per cent transformed cells. Inhibition of lympohcyte stimulation by steroid hormones operates by the following cytokinetic mechanisms: (1) suppressed recruitment of cells from G3 to G1 phase of the cell cycle, as indicated by the diminished per cent blasts; (2) inhibition of progression from G1 phase into S phase, as evidenced by the reduced ratio [labelling index/blasts]; and, in the case of estradiol and progesterone, (3) reduced rate of DNA replication or altered intracellular [3H]thymidine specific activity as shown by the decreased ([3H]thymidine incorporation/labelling index) ratio. Late addition of steroid hormones to stimulated cultures reduced the per cent of cells in S phase, but did not revert previously transformed cycling lymphocytes to the G3 state.

Eleven cases of renal vein thrombosis (RVT) are reported, 9 of which presented with nephrotic syndrome (NS) and 2 with acute renal failure (ARF). Hematuria, enlarged kidneys, assymetric peripheral edema and collateral vein dilatations were the classic symptoms. Phlebography was employed in 101 suspected cases and permitted definitive diagnosis in 11 percent. Phlebography was performed in 13 percent of the NS cases and 11 percent of the ARF cases, but in none of the other cases. Fifteen kidney biopsies (KB) were performed in 8 patients, 6 with NS and 2 with ARF. In the 6 cases of NS, 4 presented a pattern of membranous glomerulonephritis and 2 had mild thickening of the basement membrane. This was confirmed by electromicroscopy in 5. In the 2 with ARF capillary dilatations, polynuclear infiltrates and interstitial edema was found. Repetitive KB, performed in 3 cases, revealed the same histological pattern in 2, while in the other case granular membranous deposits were found on the second biopsy that were not apparent in the first. This last patient was free from clinical manifestations at the time of this last biopsy. Immunofluorescent studies (iF) were performed on 7 KB of 5 patients, 4 with NS and 1 with ARF. Three of the 4 with NS presented a pattern of membranous deposits. On i.F one patient was found to have IgG and C3 deposits, one IgG and fibrinogen and one no detectable IgG, IgA, IgM, IgE, C3 or fibrinogen. The fourth with minimal histological changes was also negative for i.F, as was the case of ARF. Sequential treatment by heparin and antivitamin K was administered in 8 patients. Recovery occurred in 3 and stabilization in 4, while in 1 case this treatment was without effect.