Type and course of symptoms demonstrated in the terminal and dying phases by people with dementia in nursing homes.

BACKGROUND: In all, 39 % of people living in Swiss nursing homes suffer from dementia. Detailed data about type and course of symptoms displayed by these patients in their terminal phase are lacking. METHODS: This descriptive, retrospective study analysed 65 nursing documents from deceased people with dementia in four nursing homes in the canton of Zurich, Switzerland. RESULTS: Difficulties with mobility (81 %), pain (71 %) and sleep disturbance (63 %) were the most frequent of the 10 identified symptoms. Towards the end of life, difficulties with mobility, sleep disturbance, agitation and other neuropsychiatric symptoms, such as episodes of depression, decreased (decrescent pattern), while pain, feeding problems, breathing abnormalities, apathy and anxiety increased (crescent pattern). Courses of pain were documented in 17 % of the nursing records. In addition, 76 % of the residents had been visited on a daily basis by next of kin in their last 7 days, compared with only one third of residents previously. Furthermore, daily communication between healthcare professionals and next of kin tripled during this period. CONCLUSION: The documented prevalence of a high and increasing level of pain towards the end of life, combined with the lack of documented courses of pain, shows potential for improvement in pain relief and pain identification for patients with dementia in their terminal phase. The increasing number of visits by next of kin and the increasingly intensive contact between healthcare professionals and next of kin in the last 7 days are a strong indicator that the end of life can be predicted relatively well by the involved participants and appropriate reactions follow.

A new diagnostic algorithm for Burkitt and diffuse large B-cell lymphomas based on the expression of CSE1L and STAT3 and on MYC rearrangement predicts outcome.

BACKGROUND: Aggressive mature B-cell non-Hodgkin's lymphomas (BCL) sharing features of Burkitt's lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) (intermediate BL/DLBCL) but deviating with respect to one or more characteristics are increasingly recognized. The limited knowledge about these biologically heterogeneous lymphomas hampers their assignment to a known entity, raising incertitude about optimal treatment approaches. We therefore searched for discriminative, prognostic, and predictive factors for their better characterization. PATIENTS AND METHODS: We analyzed 242 cytogenetically defined aggressive mature BCL for differential protein expression. Marker selection was based on recent gene-expression profile studies. Predictive models for diagnosis were established and validated by a different set of lymphomas. RESULTS: CSE1L- and inhibitor of DNA binding-3 (ID3)-overexpression was associated with the diagnosis of BL and signal transduction and transcription-3 (STAT3) with DLBCL (P<0.001 for all markers). All three markers were associated with patient outcome in DLBCL. A new algorithm discriminating BL from DLBCL emerged, including the expression of CSE1L, STAT3, and MYC translocation. This 'new classifier' enabled the identification of patients with intermediate BL/DLBCL who benefited from intensive chemotherapy regimens. CONCLUSION: The proposed algorithm, which is based on markers with reliable staining properties for routine diagnostics, represents a novel valid tool in separating BL from DLBCL. Most interestingly, it allows segregating intermediate BL/DLBCL into groups with different treatment requirements.

[Assisted suicide - medical, legal, and ethical aspects]. / Beihilfe zum Suizid - medizinische, rechtliche und ethische Aspekte.

Unlike in most European countries, assisted suicide is not illegal in Switzerland. The number of assisted suicides procured by right-to-die organisations such as Exit or Dignitas has sharply increased in the last twenty years. Central part of the doctor's involvement is the prescription of a lethal dose of sodium pentobarbital. In doing so, the doctor has to apply to the rules of medical due care. A proper examination of the patient is required, who must be informed about his diagnosis, about the expected prognosis, and about different treatment options. Verification of the patient's decisional capacity is crucial. In general, a staff member of the organisation but not the doctor is present during suicide. Following death, the assisted suicide has to be reported to the police as an extraordinary death case.

Suicide assisted by two Swiss right-to-die organisations.

BACKGROUND: In Switzerland, non-medical right-to-die organisations such as Exit Deutsche Schweiz and Dignitas offer suicide assistance to members suffering from incurable diseases. OBJECTIVES: First, to determine whether differences exist between the members who received assistance in suicide from Exit Deutsche Schweiz and Dignitas. Second, to investigate whether the practices of Exit Deutsche Schweiz have changed since the 1990s. METHODS: This study analysed all cases of assisted suicide facilitated by Exit Deutsche Schweiz (E) and Dignitas (D) between 2001 and 2004 and investigated by the University of Zurich's Institute of Legal Medicine (E: n = 147; D: n = 274, total: 421). Furthermore, data from the Exit Deutsche Schweiz study which investigated all cases of assisted suicide during the period 1990-2000 (n = 149) were compared with the data of the present study. RESULTS: More women than men were assisted in both organisations (D: 64%; E: 65%). Dignitas provided more assistance to non-residents (D: 91%; E: 3%; p = 0.000), younger persons (mean age in years (SD): D: 64.5 (14.1); E: 76.6 (13.3); p = 0.001), and people suffering from fatal diseases such as multiple sclerosis and amyotrophic lateral sclerosis (D: 79%; E: 67%; p = 0.013). Lethal medications were more often taken orally in cases assisted by Dignitas (D: 91%; E: 76%; p = 0.000). The number of women and the proportion of older people suffering from non-fatal diseases among suicides assisted by Exit Deutsche Schweiz has increased since the 1990s (women: 52% to 65%, p = 0.031; mean age in years (SD): 69.3 (17.0) to 76.9 (13.3), p = 0.000), non-fatal diseases: 22% to 34%, p = 0.026). CONCLUSIONS: Weariness of life rather than a fatal or hopeless medical condition may be a more common reason for older members of Exit Deutsche Schweiz to commit suicide. The strong over-representation of women in both Exit Deutsche Schweiz and Dignitas suicides is an important phenomenon so far largely overlooked and in need of further study.

A role for doctors in assisted dying? An analysis of legal regulations and medical professional positions in six European countries.

OBJECTIVES: To analyse legislation and medical professional positions concerning the doctor's role in assisted dying in western Europe, and to discuss their implications for doctors. METHOD: This paper is based on country-specific reports by experts from European countries where assisted dying is legalised (Belgium, The Netherlands), or openly practiced (Switzerland), or where it is illegal (Germany, Norway, UK). RESULTS: Laws on assisted dying in The Netherlands and Belgium are restricted to doctors. In principle, assisted suicide (but not euthanasia) is not illegal in either Germany or Switzerland, but a doctor's participation in Germany would violate the code of professional medical conduct and might contravene of a doctor's legal duty to save life. The Assisted Dying for the Terminally Ill Bill proposed in the UK in 2005 focused on doctors, whereas the Proposal on Assisted Dying of the Norwegian Penal Code Commission minority in 2002 did not. Professional medical organisations in all these countries except The Netherlands maintain the position that medical assistance in dying conflicts with the basic role of doctors. However, in Belgium and Switzerland, and for a time in the UK, these organisations dropped their opposition to new legislation. Today, they regard the issue as primarily a matter for society and politics. This "neutral" stance differs from the official position of the Royal Dutch Medical Association which has played a key role in developing the Dutch practice of euthanasia as a "medical end-of-life decision" since the 1970s. CONCLUSION: A society moving towards an open approach to assisted dying should carefully identify tasks to assign exclusively to medical doctors, and distinguish those possibly better performed by other professions.

[Forgoing life-sustaining measures in patients at the end of life in the German-speaking part of Switzerland: results of a death certificate study]. / Begrenzung lebenserhaltender Massnahmen bei Patienten am Lebensende in der deutschsprachigen Schweiz -- Resultate einer Todesfallstudie.

BACKGROUND AND OBJECTIVE: There have not been any comprehensive data from German-speaking countries on the medical practice of withholding or withdrawing treatment at the end of life. This study from the German-speaking part of Switzerland provides the first in-depth analysis in this field. This study is based on data from this region and is a contribution to a large empirical research project on medical end-of-life decisions in 6 European countries (EURELD). METHODS: Continuous random samples (n = 4991) were taken from all deaths in the German-speaking part of Switzerland that had been reported to the Swiss Federal Office of Statistics between June and October 2001. Doctors who had been attending the deceased person were asked to complete mailed questionnaires, their replies being kept strictly anonymous. RESULTS: The response rate was 67 %. Medications were withheld or withdrawn in 48 % of all treatments forgone: among these, antibiotics accounted for 17 %. Other potentially life-sustaining medical measures forgone included artificial hydration (12 %), surgery (7 %), artificial feeding (6 %), chemotherapy (6 %), diagnostic tests (4 %), hospital admissions (3 %), renal dialysis (2 %), blood product infusions (2 %), intubation (2 %), ventilation (2 %), resuscitation (2 %), and radiotherapy (1 %). 43 % of all treatments were forgone in patients who died in hospital, 42 % in nursing homes, and 15 % at home. In almost three-quarters (73 %) of the treatments forgone, a primary-care doctor had ordered the treatment to be withheld or withdrawn. On average, forgoing treatment led to a life-shortening effect of more than one month in 8 % of all cases. The proportion was higher for renal dialysis (25 %), blood products infusion (18 %), and diagnostic tests (16 %). CONCLUSIONS: Forgoing life-sustaining medical treatment comprises a wide range of decisions taken in many different clinical settings. In most cases the likely lifespan is only slightly shortened.

[Place of death: "Where do people die in Switzerland nowadays?"]. / Der Sterbeort: "Wo sterben die Menschen heute in der Schweiz?"

BACKGROUND: Official information on the place of death has not been collected by the Swiss Federal Office of Statistics since 1987. Thus, no statements can be made for the developments in Switzerland. METHODS: Physicians from the German speaking part of Switzerland who had filled in a death certificate between June 1 and October 30, 2001 were sent a questionnaire about circumstances of the specific death case. The frequencies of the place of death (at home, in hospital, in home for elderly, in nursing home, other place) were compared with the official data of the years 1969 until 1986. Using logistic regressions predictors for the place of death were estimated. RESULTS: In 2001 in the German speaking part of Switzerland death occurred most frequently in hospital (37.2% of all death cases) followed by a home for elderly (33.5%) and dying at home (22.7%). Relevant predictors for the place of death were cause of death, sex, marital status and partly religion. Whereas between 1969 and 1986 a development towards dying in institutions was found, between 1986 and 2001 the place of death shifted within the institutions from hospitals to homes for elderly. CONCLUSION: The relevance of the home for elderly as the place of death will further grow in the future. To allow people to fulfill the tasks of caring for their relatives at home the ambulant emergency services will have to be augmented and relatives have to be motivated and supported.

Assisted suicide bordering on active euthanasia.

A 44-year-old woman was almost completely paralysed after a severe brainstem haemorrhage. Even after several years of efforts at rehabilitation, she remained completely dependent on the help of others. However, a special device enabled her to administer (after careful preparation) liquids through the PEG catheter despite her poorly coordinated movements. Four years after the stroke, the woman joined a right-to-die society with the wish to bring her life to an end. A doctor working with this organisation prescribed her a lethal dose of pentobarbital. In the presence of her husband and her companion from the organisation, the woman administered herself the lethal substance by means of the device. On the basis of the fact that she herself had switched the device on this death was classed as (assisted) suicide.

[How stable is the attitude of aged people towards life-extending measures? Results of a 3-year follow-up in nursing home residents]. / Wie stabil ist die Einstellung Betagter zu lebensverlängernden Massnahmen? Resultate einer 3-Jahres-Katamnese von Pflegeheimbewohnern.

OBJECTIVE: To explore the stability of attitude towards life-extending measures in aged people. METHOD: Face-to-face interviews of nursing home residents at an interval of 3 years (prospective longitudinal survey). RESULTS: During the first interview period in 1997 (n=50), 19 nursing home residents (38%) had advocated treatment with antibiotics in a hypothetical scenario of acute life-threatening pneumonia. 15 individuals (30%) had refused such treatment, while statements from a further 16 (32%) had been ambivalent. Three years later, 19 individuals could be re-interviewed (28 had died in the meantime, 3 suffered from advanced dementia). 16 of these expressed the same or a similar attitude towards the above scenario as they did three years earlier (correspondence 84.2%, p<0.01). CONCLUSION: The results indicate a high stability of attitude towards life-extending measures in aged people. This finding may have implications for the meaning of advance directives in geriatric long-term care.

Open regulation and practice in assisted dying.

The Netherlands, Oregon and Switzerland are the only areas in the world where assistance in dying has legally been practised in recent years. This article provides a detailed comparison of the history of the origins, legislation, monitoring systems and the extent of assistance in dying in these three places. It shows that the actual practice in Switzerland which, unlike Oregon, also allows assistance in suicide by means of infusions or gastric tubes, can today be technically quite similar to the permitted practice of active euthanasia on request in the Netherlands. Considering the preconditions restricting these practices, Swiss regulations are the most open, in that the law requires neither a medical second opinion (as in both the Netherlands and Oregon) nor the existence of a terminal illness (as in Oregon) as prerequisite to assistance in dying. In 2001, the proportion of assisted deaths (as reported to the authorities) in all deaths was almost ten times higher in the Netherlands (1.5% of all deaths) then in Oregon (<0.1% of all deaths) or Switzerland (0.2% of all deaths). The analysis of the different normative concepts underlying legislation reveals that in the Netherlands the basis for non-prosecution lies in the conflict of the physician's duties to respect life versus relief of suffering, while in the USA and in Switzerland the right-to-die concept plays a major role. These two concepts allow appreciation of distinctions between the roles of the physician in end-of-life practices and between assisted suicide and voluntary active euthanasia.

Differential toxicity of anticancer drugs on late (GM-CFC) and early (LTC-IC) hemopoietic progenitors in vitro.

The clinical hematological toxicity of cytotoxic drugs can be acute, with a nadir of neutrophil count after 2 weeks and recovery the following week, or subacute, with a nadir of neutrophil count after 3 weeks and recovery in the following 2-3 weeks. The explanation usually given for this difference is that drugs in the first group are more toxic to mature hemopoietic precursors, while drugs of the second type are more toxic to undifferentiated cells. In an attempt to verify this hypothesis, we compared in vitro the effect of toxic doses of etoposide and tallimustine as representatives of drugs with acute toxicity, and of BCNU, melphalan, and carzelesin as representatives of drugs with subacute toxicity. Their effects were studied separately on more differentiated and earlier progenitors represented by granulocyte-macrophage colony-forming cells (GM-CFC) and long-term culture-initiating cells (LTC-IC), respectively. Etoposide, melphalan, BCNU, and carzelesin showed higher toxicity in differentiated than in early precursors: the concentration of drug inhibiting 70% (ID70) of GM-CFC inhibited only by 10-40% the growth of LTC-IC. Tallimustine, in contrast, inhibited both GM-CFC and LTC-IC at comparable levels. These results do not correspond to the clinical pattern of myelotoxicity observed for those drugs. We conclude that the differential effects of antitumor drugs on later (GM-CFC) or earlier (LTC-IC) hemopoietic precursors may not represent a valid model for the pattern of myelotoxicity observed in humans.

Hematotoxicity on human bone marrow- and umbilical cord blood-derived progenitor cells and in vitro therapeutic index of methoxymorpholinyldoxorubicin and its metabolites.

PURPOSE: MMDX [3'-deamino-3'-[2(S)-methoxy-4-morpholinyl] doxorubicin], an anthracycline derivative active in vitro and in vivo against multidrug-resistant tumors, is currently under investigation in phase I clinical trials. In vivo it is metabolically activated, resulting in more cytotoxic compounds. We determined in vitro the toxic concentration of a 1-h period of exposure to doxorubicin (DX), MMDX, and bioactivated MMDX on hematopoietic progenitors and tumor cell lines. METHODS: DX and MMDX were tested on both bone marrow- (BM) and cord blood (hCB)-derived clonogenic cells, whereas the metabolites were tested on hCB only. All substances were tested on seven tumor cell lines. RESULTS: BM cells proved to be twice as sensitive as hCB cells to cytotoxics, and MMDX was twice as toxic as DX against hCB cells; MMDX activated with normal rat-liver microsomes and with dexamethasone-induced rat microsomes were, respectively, 70 and 230 times more toxic than MMDX. A comparison of the cytotoxic concentrations on hematopoietic progenitors and tumor cells, revealed that DX and MMDX had 5-fold stronger activity on tumor cell lines than on granulocyte/macrophage colony-forming cells (GM-CFCs), whereas bioactivated MMDX showed comparable cytotoxicity against tumor cells and hematopoietic progenitors. CONCLUSIONS: MMDX metabolites are very potent but display a lower degree of tumor selectivity than MMDX. Strategies to reduce MMDX metabolization should be developed to optimize the therapeutic index of this new anthracycline.

Immunoglobulin heavy chain diversity genes rearrangement pattern indicates that MALT-type gastric lymphoma B cells have undergone an antigen selection process.

Gastric MALT lymphoma usually develops from chronic gastritis, the vast majority of which (>90%) is associated with Helicobacter pylori infection. We sequenced the third complementarity determining region (CDR3) of immunoglobulin heavy chain genes in 19 gastric MALT lymphoma clones to determine the pattern of variable (V), diversity (D) and joining (J) gene utilization during immunoglobulin gene rearrangement. DNA was extracted from paraffin-embedded sections and the rearranged CDR3 regions were amplified using a semi-nested polymerase chain reaction (with primers complementary to the conserved framework-three segment of the variable region [FR3A] and J regions). The DNA used for cloning and sequencing was obtained after purification of monoclonal bands excised from polyacrylamide gels. The N-D-N region specific to each clone was compared with known germline D sequences. Similarly to that observed in normal and leukaemic B cells, our series of gastric MALT lymphomas showed apparent preferential utilization of genes from the DXP family. In two cases no similarity between the CDR3 nucleotide sequences of the neoplastic clones and the known germline D sequences could be found. In 10/19 analysed alleles the lymphoma B-cell clones appeared to contain two D gene segments (D-D recombination), a rare occurrence in normal individuals but one which has been described as a significant event in the determination of idiotype expression and antigen-binding affinity. Remarkably, despite the use of different D and J segments, the resultant amino acid sequences matched in two patients, suggesting the presence of a common selecting antigen. The observed pattern of D gene rearrangement suggests that MALT lymphoma B-cell clones have undergone antigen selection, which seems to indicate that the antigen stimulation plays a pivotal role in the development of the lymphoma.

Clinical relevance of bcl-2(MBR)/J(H) rearrangement detected by polymerase chain reaction in the peripheral blood of patients with follicular lymphoma.

We evaluated the prognostic role of peripheral blood polymerase chain reaction (PCR) assay for detection of the bcl-2(MBR)/J(H) rearrangement in 59 patients with follicular lymphoma (FL) treated at our centre since 1989. Thirty-five (59%) patients were bcl-2/J(H) positive and 24 (41%) were negative in the peripheral blood at diagnosis. Peripheral blood bcl-2/J(H) rearrangement detection at diagnosis had no relation to overall survival (OS) and time to progression (TTP). Peripheral blood PCR assay was performed post treatment in 17 patients who were bcl-2/J(H) positive at diagnosis. Fourteen of the patients (82%, 95% CI 56-96%) became bcl-2/J(H) negative. Nine of these patients were further analysed during follow-up and, after several months, circulating cells carrying the bcl-2/J(H) rearrangement reappeared in five of the nine patients. Peripheral blood clearance of bcl-2/J(H)-positive cells was correlated with better overall survival (log-rank P < 0.05) but not with TTP. Our data confirmed that bcl-2(MBR)/J(H) rearrangement detection by PCR at diagnosis is not a prognostic factor in follicular lymphoma. In our series, clearance of circulating bcl-2/J(H)-positive cells appeared to correlate with better overall survival. Post-treatment examination of the peripheral blood by PCR may have clinical relevance for prediction of the survival pattern of the patients.

Estimation of the haematological toxicity of minor groove alkylators using tests on human cord blood cells.

We evaluated the myelotoxicity and the anti-tumor potential of tallimustine, three of its analogues and carzelesin, with melphalan as reference substance. Tallimustine was tested by clonogenic assays on both human bone marrow (BM) and cord blood (hCB) cells, the other compounds on hCB only. The degree of inhibition of the haemopoietic progenitors GM-CFC, CFC-E and BFU-E was evaluated after exposure to different concentrations. The same schedules were tested on five tumour cell lines. We found that the dose-response curves for tallimustine on BM and hCB cells were similar. Carzelesin was shown to be the most potent of the substances tested and to be the one with the best in vitro therapeutic index; of the distamycin analogues, the one bearing an alpha-bromoacrylic group (FCE 25450) had the best index. For melphalan, tallimustine and carzelesin, the concentration inhibiting the growth of 70% of progenitor cells in vitro (ID70) was similar to the concentrations found in the serum of patients treated at the maximum tolerated dose (MTD). We conclude that hCB cells may be used instead of BM cells for in vitro myelotoxicity tests. Therapeutic indexes can be extrapolated from this model and could help in selecting the most promising analogue for further clinical development. The in vitro-active concentrations are similar to myelotoxic concentrations in patients, suggesting a predictive value for the assay.

Clinical significance of bcl-2 (MBR)/JH rearrangement in the peripheral blood of patients with diffuse large B-cell lymphomas.

BACKGROUND: Approximately one-fourth of diffuse large B-cell lymphomas (DLCL) carry the bcl-2(MBR)/JH rearrangement caused by the t(14;18) translocation. The clinical significance of this rearrangement in patients with DLCL remains controversial. By polymerase chain reaction (PCR) we prospectively evaluated the prognostic relevance of the bcl-2 (MBR)/JH rearrangement present in circulating B-cells at the time of diagnosis. MATERIALS AND METHODS: The bcl-2 (MBR)/JH rearrangement was analysed by a nested-PCR method in peripheral blood samples of 51 HIV-negative patients with previously untreated DLCL. RESULTS: The bcl-2 (MBR)/JH rearrangement was detected in 16 cases (31%). Peripheral blood bcl-2 (MBR)/JH rearrangement detection by PCR at diagnosis was correlated with poor overall survival, lymphoma-specific survival and time to progression (log-rank P < 0.05). There was no statistically significant difference between the clinical characteristics at presentation of bcl-2/JH-positive and negative patients. CONCLUSIONS: The peripheral blood is a readily accessible tissue for this type of analysis, and this study indicates that detection of the t(14;18) translocation at presentation in the blood of patients with DLCL may presage a poor prognosis.