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Eighty-six patients between 15 and 60 yr with primary acute myelogenous leukemia in health regions I, III, IV and V in Norway were treated according to a common protocol from 21 January 1990 until 1 September 1995 (until 1 January 1993 for health region IV). Seventy-one percent of the patients reached complete remission (CR) and went on to receive consolidation treatment. In addition to chemotherapy, 18 patients under the age of 52, i.e. 28% of all patients in this age group, received allogeneic bone marrow transplantation. A follow-up analysis was performed by 1 September 1996. The median overall survival was 15 months, estimated 3-yr survival 30% and estimated survival at 5 yr was 26%. The median duration of 1st CR was 19 months, and the leukemia-free survival at 3 yr was 29%. At follow-up 26/86 patients were alive, 18 in 1st CR (4 after BMT) and 8 in 2nd CR (5 after BMT in 2nd, 1 after BMT in early 1st relapse). These results are comparable to many previously published studies, but may be inferior to the results obtained with more intensive consolidation treatment, including high dose Ara C.

63 evaluable patients with myelodysplastic syndromes (MDS) and 15 with acute myelogenous leukemia (AML) were randomized between low-dose ara-C (arm A) and low dose ara-C in combination with 13-cis-retinoic acid (13-CRA) and 1 alpha-hydroxy-vitamin D3 (1 alpha D3) (arm B). 69 patients were evaluable and 18 (26.1%) responded to therapy. The addition of 13-CRA and 1 alpha D3 had no positive influence on survival of the patients, remission rates or duration of remissions. 12/27 patients in arm A and 6/29 patients in arm B progressed from MDS to AML during the course of the study (p = 0.0527). Arm B gave significantly more side-effects than arm A (p = 0.005). Therapeutic effects of 13-CRA and 1 alpha D3 on MDS is not supported by this study. However, an inhibiting effect on AML development in some MDS subgroups cannot be excluded.

Studies of blood lymphocytes from 4 patients with pure red cell aplasia were performed with lymphocyte surface markers, and with various in vitro tests for lymphocyte functions. Pathologically low B-lymphocyte values were found. In contrast, no marked deviation from normals were seen for T-lymphocytes and Fc-receptor-bearing lymphocytes thought largely to represent non-B, non-T-lymphocytes. In 3 patients normal lymphocyte transformation was found with unspecific and specific mitogens, while the DNA-synthesis induced by unspecific mitogens was subnormal in the fourth patients. The lymphocyte-mediated PHA-induced cytotoxicity against target cells in vitro was subnormal in 2 patients, while no depression was seen in antibody-dependent cytotoxicity mediated in vitro by lymphocytes (K-cells). It is concluded that considerable immunological abnormalities are associated with pure red cell aplasia, and the possible significance of this is discussed.

Strong lupus anticoagulant activity was detected in the plasma of a 73-yr-old woman with Waldenström's macroglobulinaemia. Purified patient IgM caused significant prolongation of the APTT in concentrations as low as 30 micrograms/ml, and its activity was inhibited by intact or (more effectively) by frozen-thawed blood platelets. Employing varying concentrations of cephalin in the APTT assay, it was demonstrated that the macroglobulin had a direct cephalin-neutralizing effect. When tested in an ELISA system using phospholipid-coated microtiter wells, the IgM was shown to possess antibody activity against cephalin. With purified phospholipids as antigens, the protein was found to display antibody activity against phosphatidyl serine and phosphatidyl ethanolamine, which are main constituents of cephalin. These observations were confirmed in absorption experiments.

To cite this article: Liestol S, Sandset PM, Mowinckel M-C, Wisloff F. Activated protein C resistance determined with a thrombin generation-based test is associated with thrombotic events in patients with lupus anticoagulants. J Thromb Haemost 2007; 5: 2204–10. Summary. Background: Several studies suggest that antiphospholipid antibodies interfere with the activity of activated protein C (APC). This acquired form of APC resistance has been proposed as a possible pathogenic mechanism underlying hypercoagulability associated with the antiphospholipid syndrome (APS). Objectives: We wanted to investigate the inhibitory effect of recombinant APC (rAPC) on ex vivo thrombin generation in plasma and the modification of this effect by the presence of lupus anticoagulants (LA). Patients/ Methods: We analyzed plasmas from 81 patients with LA (52 patients fulfilling the criteria for the APS) and 91 controls. Percent inhibition of the endogenous thrombin potential (ETP) as a parameter of APC sensitivity was determined in plasmas using a thrombin generation-based APC resistance test probed with rAPC. All results were normalized using pooled normal plasma (PNP) as a reference. Results: Normalized percent inhibition of ETP by APC was lower in patients with LA [61.4%, 95% confidence interval (CI) 45.8–74.5%] compared to controls (107.8%, 95% CI: 107.1–109.3%). In patients with LA and APS, median inhibition was lower than in patients with LA without APS (44.6%, 95% CI: 30.1–55.7% vs. 78.8%, 95% CI: 73.9–95.8%). This difference also persisted when patients on warfarin therapy were excluded from the APS subgroup. Conclusions: APC resistance can be demonstrated with a thrombin generation-based test in a majority of patients with the LA laboratory phenotype. A history of thrombotic events in patients with LA is associated with a stronger resistance to the anticoagulant effect of APC.

Aim To test the reliability, validity and sensitivity of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-MY24 questionnaire, designed to assess the quality of life of myeloma patients with the QLQ-C30. Methods The study was carried out through the EORTC Quality of Life Group using clinical trials in seven countries. All trials used the QLQ-C30 and QLQ-MY24 at baseline and a follow-up timepoint. Results Two hundred and forty patients participated. The questionnaires were acceptable to patients. The hypothesised scale structure (disease symptoms, side-effects, body image and future perspective) was confirmed by multi-trait scaling, internal consistency and correlation analysis. Most scales demonstrated sensitivity to change and discriminated between clinically different patients. The social support scale (4 items) was removed due to observed ceiling effects. Conclusion The final questionnaire contains 20 items, QLQ-MY20, and is a reliable and valid instrument recommended for use with the QLQ-C30 in myeloma patients.

Bone disease is an important feature of multiple myeloma, and hypercalcaemia is a frequent complication of this disease. We examined the association between serum calcium and quality of life (QOL) scores of 686 multiple myeloma patients at the time of diagnosis. Data from two Nordic studies using the EORTC QLQ-C30 questionnaire were analysed by means of linear regression analysis and a curve fitting program. Serum calcium was independently related to appetite loss, nausea/vomiting and physical functioning (P < 0.001) and to cognitive functioning (P = 0.001), i.e. scores reflecting symptoms that are well known in non-malignant hypercalcaemia. In addition, we found a highly significant independent relationship between serum calcium and the scores for fatigue and pain (P < 0.001). Serum calcium appeared to be as strong a predictor for fatigue as the concentration of haemoglobin. A cubic model (y = a + bx3) fitted the data slightly better than the simple linear model (y = a + bx) and suggested worsening QOL scores at levels of serum calcium above 2.5-3.0 mmol/L. Hypercalcaemia in patients with multiple myeloma seems to be associated with the same symptoms as in non-malignant hypercalcaemia. In addition, an increased level of serum calcium may aggravate the pain and fatigue caused by the skeletal disease itself.

In 2001, guidelines for the diagnosis and management of myeloma were published by the Guidelines Working Group of the UK Myeloma Forum (UKMF) on behalf of the British Committee for Standards in Haematology (BCSH) (UK Myeloma Forum; British Committee for Standards in Haematology, 2001). That same year, the second edition of guidelines prepared by the Nordic Myeloma Study Group (NMSG) in 1995 was issued (in the Scandinavian languages; http:// www.myeloma-nordic.org). As both sets of guidelines were intended to be evidence based, it was reassuring to note that the recommendations were similar. Subsequently, informal contact between members of the two groups led to the decision to prepare these common, updated guidelines. These revised and updated guidelines include new sections on imaging and the management of skeletal disease, cover new developments in disease classification and staging and the use of new therapeutic approaches, such as thalidomide, bortezomib and reduced-intensity allogeneic transplantation. The guidelines are presented in specific sections as follows

Earlier studies showing a negative impact of anaemia on quality of life (QOL) lack adequate adjustment for confounding factors such as disease stage and tumour response. We examined the impact of haemoglobin concentration on QOL scores of 745 multiple myeloma patients followed from diagnosis, adjusting for objective disease parameters. Data from two Nordic studies with the EORTC QLQ-C30 questionnaire were analysed using linear regression analysis. Haemoglobin was independently related only to fatigue at baseline (P = 0.001) and at 12 months (P = 0.010). In multivariate analysis, extent of skeletal disease was at least as strong a predictor for fatigue at diagnosis as haemoglobin and was also related to other important QOL scores such as physical functioning, role functioning, global QOL and pain (P < 0.001). At 12 months' follow-up, response to therapy was related to physical functioning (P < 0.001) and pain (P = 0.001). In conclusion, haemoglobin and extent of skeletal disease were both predictors for fatigue in patients with newly diagnosed multiple myeloma, but extent of skeletal disease was also associated with other important QOL scores. During follow-up, response to therapy emerged as an important predictor variable. When examining the effect of haemoglobin on QOL, it is essential to adjust for disease parameters and response to therapy in order not to overestimate the impact of haemoglobin on QOL. Our findings imply that uncontrolled studies on the effect of erythropoietin (EPO) in cancer patients may be making exaggerated claims for the effect of EPO on QOL.

The accomplishments of the Nordic Myeloma Study Group (NMSG) during its first 15 yr are briefly surveyed, together with a discussion of principles guiding the group's clinical trials and of problems that need to be addressed in coming years. The group has so far carried out 12 clinical trials, comprising more than 2500 patients, spanning from minor phase II to large randomised phase III trials. At the time of writing, two randomised trials are running (comparing two doses of i.v. pamidronate, and melphalan-prednisone (MP) vs. MP-thalidomide to elderly patients). The group has strived for a simple organisation with much responsibility delegated to regional coordinators (Denmark 3, Norway 5, Sweden 5). With regard to trial design, the group has considered it important that studies are based on sound scientific questions, are simple to handle for the participants, population based, investigator initiated, include quality of life and health resources assessment as end-points, and can be used as basis for diverse scientific spin-off projects. Like other clinical trial groups, NMSG faces a number of challenges in coming years. The financial situation for independent investigator-initiated trials is far from satisfactory, especially with regard to the resource-consuming implementation of more stringent good clinical practice rules and ethical committee demands. NMSG has also encountered increasing difficulties in recruiting patients to recent trials, partly because of problems related to participating physicians (lack of support, laborious paper work, insufficient credit for participation). Solutions to these problems have to be found if industry-independent clinical trial groups are to survive.

Introduction Current consensus recommendations suggest that patients with antiphospholipid antibodies (APLA) are at high risk of recurrent arterial or venous thromboembolism (VTE) despite warfarin administered to achieve an international normalized ratio (INR) of 2.0 to 3.0. These recommendations have been called into question by three recently reported studies. Methods We sought to determine the current “best practice” for the prevention of recurrent TE in patients with APLA and TE. Data was derived from a MEDLINE search and review of recent conference abstracts. The literature search was confined to studies of treatment to prevent recurrent thrombosis in patients with APLA. Results The overall proportion of patients suffering recurrent TE when allocated to moderated-intensity warfarin (target INR of 2.0 to 3.0) was 5/113 (4.4%), and it was 11/110 (10.0%) when such patients were randomized to high-intensity warfarin (target INR of 3.0 to 4.0). APLA-positive patients with noncardioembolic/nonatheroembolic stroke appear to have similar risks of recurrent TE whether they are treated with warfarin or aspirin. Discussion Patients with APLA and TE have an acceptable rate of recurrent TE if they are treated with usual-intensity warfarin. Patients with APLA and stroke are probably best treated with aspirin, while those with other forms of arterial TE are likely best treated with moderate-intensity warfarin plus aspirin.

Sixty-five patients who were primary or secondary refractory to melphalan/prednisone or other type of chemotherapy, or relapsed within 6 months after high dose chemotherapy with stem cell support, were given thalidomide at a dose of 200 mg/d escalating to 800 mg. The patients were followed for a median of 2 years and 22 weeks. Response was evaluated according to M-protein reduction combined with improvement of haemoglobin (Hb) concentration, renal function and pain. Altogether, 14% of patients had a minor response, 14% partial response and 6% complete response. Median survival was 12 months and 29% were alive at last contact. Decline of M protein started early and a minimum 25% reduction of M protein was detected in 14 of 20 responders (70%) after 3 weeks, and in 20 of 22 responders (91%) after 5 weeks of treatment. Reduction of M protein continued for 3 months and further decline was observed in only four patients. The Hb concentration showed a different time course, with a significant increase after 3 months and further increases continued for up to 12 months. Blood concentration levels of thalidomide from 40 patients were used to evaluate the pharmacokinetics of the drug. Rate of absorption, rate of elimination, volume of distribution, clearance and elimination half-life were calculated to be 0.200/h, 0.140/h, 0.886 l/kg, 0.126 l/h/kg and 4.98 h respectively. We found no relationship between thalidomide concentration and effect after 12 weeks.

Objectives: Without clear guidelines, clinicians and health care providers are often uncertain how to interpret (quality of life) QOL scores. To facilitate the interpretation, QOL scores of multiple myeloma patients at diagnosis were compared with the scores of a reference population, and the clinical significance of QOL score differences and of changes in scores over time was assessed. Methods: Data from two prospective Nordic Myeloma Study Group trials (221 patients 60 yr treated with melphalan and prednisone) were analysed. The EORTC QLQ-C30 questionnaire was used. The results were compared with the scores of an age- and gender-adjusted Norwegian reference population (n = 3000), using a regressional approach. The magnitude of the observed differences and of score changes during follow-up was estimated as effect size [score difference (SD)] and according to a subjective rating system as small, moderate or large. Results: At diagnosis, the most distressing problems were pain and fatigue, reduced physical functioning, limitations in role functioning and reduced overall QOL. These differences from the reference population were statistically significant (P

Introduction Current consensus recommendations suggest that patients with antiphospholipid antibodies (APLA) are at high risk of recurrent arterial or venous thromboembolism (VTE) despite warfarin administered to achieve an international normalized ratio (INR) of 2.0 to 3.0. These recommendations have been called into question by three recently reported studies. Methods We sought to determine the current "best practice" for the prevention of recurrent TE in patients with APLA and TE. Data was derived from a MEDLINE search and review of recent conference abstracts. The literature search was confined to studies of treatment to prevent recurrent thrombosis in patients with APLA. Results The overall proportion of patients suffering recurrent TE when allocated to moderated-intensity warfarin (target INR of 2.0 to 3.0) was 5/113 (4.4%), and it was 11/110 (10.0%) when such patients were randomized to high-intensity warfarin (target INR of 3.0 to 4.0). APLA-positive patients with noncardioembolic/nonatheroembolic stroke appear to have similar risks of recurrent TE whether they are treated with warfarin or aspirin. Discussion Patients with APLA and TE have an acceptable rate of recurrent TE if they are treated with usual-intensity warfarin. Patients with APLA and stroke are probably best treated with aspirin, while those with other forms of arterial TE are likely best treated with moderate-intensity warfarin plus aspirin.

We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S-Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony-stimulating factor (G-CSF) + Epo. S-Epo 500 U/l and >/= 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G-CSF + Epo. The overall response rate was 42% with 28.3% achieving a complete and 13.2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0.001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0.01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48-74%) to treatment with G-CSF + Epo. The majority of these patients have shown complete and durable responses.

The lupus ratio (LR) test is a normalized ratio of the clotting times obtained with low and high phospholipid (PL) concentrations, where the test plasma is mixed 1:1 with normal pooled plasma (NP). As an integrated, automated, and computer-assisted assay, this principle has been applied to the dilute activated partial thromboplastin time (dAPTT) and dilute Russell viper venom time (dRVVT) test systems. In this study, we used recombinant thromboplastin to develop an automated LR test based on the dilute prothrombin time (dPT). Using plasma samples from a selected group of patients (N=92) with a well-defined lupus anticoagulant (LA) status, the dPT-based LR test showed fair agreement with the dAPTT-based LR test (kappa=.60, P

We evaluated the costs and the cost utility of high-dose melphalan and autologous stem cell support followed by interferon maintenance relative to conventional treatment with melphalan and prednisone, in patients less than 60 yr of age with multiple myeloma. From March 1994 to July 1997, 274 patients with newly diagnosed, symptomatic multiple myeloma were enrolled in a prospective, non-randomized, population-based, multicenter study to evaluate the treatment with high-dose melphalan and autologous blood stem cell support. Health-related quality-of-life was measured prior to treatment and during follow-up, using the EORTC QLQ-C30 questionnaire. Resource consumption was also recorded prospectively. The intensive treatment yielded a significant increase in median survival time from 44 to 62 months compared to conventionally treated patients. The corresponding gain in quality-adjusted life years (QALY) was found to be 1.2. Cost per QALY gained by the treatment with high-dose melphalan and autologous blood stem cell support was estimated at NOK 249,000 (USD 27,000).

In a population-based study, the Nordic Myeloma Study Group found a survival advantage for high-dose melphalan with autologous blood stem-cell support compared to conventional chemotherapy in myeloma patients under 60 yr of age (risk ratio: 1.62; confidence interval [CI] 1.22-2.15; p = 0.001). A study of health-related quality of life (HRQoL) was integrated in the trial, using the EORTC QLQ-C30 questionnaire. Of the 274 patients receiving intensive therapy 221 (81%) were compared to 113 (94%) of 120 patients receiving conventional melphalan-prednisone treatment. Prior to treatment, there were no statistically significant differences in any HRQoL score between the two groups. One month after the start of induction chemotherapy, the patients on intensive treatment had more sleep disturbance than the control patients. At 6 mo, corresponding to a mean of 52 d after high-dose melphalan, the patients on intensive treatment had moderately lower scores for global QoL and role and social functioning and there was also a significantly higher score for appetite loss. At 12 and 24 mo, the HRQoL was similar to that of the control patients. At 36 mo, there was a trend toward less fatigue, pain, nausea, and appetite loss in the intensive-treatment group. Thus, the 18 mo of prolonged survival seem to be associated with a good health-related quality of life. Despite the moderate HRQoL reduction associated with the early intensive chemotherapy phase, this treatment modality must be regarded as an important step forward in the care of multiple myeloma.

The effect of interferon on the health-related quality of life in multiple myeloma was assessed in two trials carried out by the Nordic Myeloma Study (Group (NMSG). In both trials, the EORTC QLQ-C30 questionnaire, supplemented with 11 items relating to interferon toxicity, was used. The first was a randomized controlled trial (NMSG 4/90) evaluating the addition of interferon alpha-2b to melphalan and prednisone during induction, maintenance and relapse. During the first 12 months, patients on interferon reported more chills, fever, fatigue, pain, nausea/vomiting, appetite loss and dry skin than the control patients, and a slight reduction of global health and quality of life. From 12 months onward there were no significant differences in any score between the two groups. In a later trial (NMSG 5/94) evaluating the effect of high-dose chemotherapy with stem cell support in patients under 60 years of age with newly diagnosed myeloma, interferon was used as maintenance. During the maintenance phase, symptom and toxicity scores were not significantly different from those in control patients under 60 years of age in the previous trial. Thus, interferon appeared to be well tolerated after high-dose chemotherapy with stem cell support.

A review of current treatment options in multiple myeloma is presented, including data on health-related quality of life and pharmacoeconomics. For induction chemotherapy, no combination of cytostatic drugs has been shown to be consistently superior to the simple cyclic oral treatment with melphalan and prednisone that has been available for 30 years. The total resource consumption and direct costs per patient treated with melphalan and prednisone is approximately $US10,000 (1995 values). As median survival is prolonged from less than a year in untreated patients to 30 to 36 months, this treatment must be considered cost effective. Interferon-alpha has a modest effect on progression-free and overall survival when added to chemotherapy regimens. However, the high cost and toxicity of this drug results in an unfavourable cost-utility ratio, estimated to be between $US50,000 to $US100,000 per quality-adjusted life-year gained. Clinical trials suggest that high dose chemotherapy followed by autologous stem cell support administered to patients who have achieved disease stabilisation or objective response to conventional induction chemotherapy, prolongs median survival by about 1.5 years. Preliminary cost-utility analyses suggest a cost per life-year gained of $US30,000 to $US40,000. Further potential improvements of this therapeutic modality are under way. Several bisphosphonates have been tested for the ability to prevent the skeletal complications of multiple myeloma. Monthly infusions of pamidronate have been shown in 1 randomised trial to significantly reduce the rate of skeletal complications. Unfortunately, the rapid and widespread acceptance of this therapy seems to preclude further prospective, placebo-controlled trials with cost-utility evaluation.

We have analysed the prognostic information for survival of presenting features in an unselected series of 394 myeloma patients. 15 variables with significant prognostic information were identified, among these were some not previously or only recently reported: serum levels of hepatocyte growth factor (HGF), interleukin-6 (IL-6), C-terminal cross-linked telopeptide of collagen I (ICTP) and soluble interleukin-6 receptor (sIL-6R). In a multivariate Cox analysis six variables were significantly and independently associated with poor survival: high age, low W.H.O.-performance status (PS), high serum levels of calcium, β-2-microglobulin (β-2M), IL-6 and sIL-6R. A risk score formed to predict survival for each percentile of the patient population allowed an efficient separation of prognostic groups. The discriminating power of the model compared favourably with three other previously published staging systems applied to the study population. Exclusion of IL-6 and sIL-6R from the model only marginally decreased the efficacy of the separation. The predictive value of some variables (sIL-6R, β-2M and W.H.O.-PS) decreased significantly over time. We conclude that formation of a risk score based on independent variables is an efficient way to separate prognostic groups, that the contribution of new and not easily available parameters should be thoroughly evaluated before inclusion in prognostic models for clinical use and that the predictive value of parameters may decrease over time.

This study was conducted to investigate whether antiphospholipid antibodies (APA) can interfere with the phospholipid-dependent inhibition of coagulation exerted by tissue factor pathway inhibitor (TFPI). Eleven patients with APA and eleven healthy controls matched for age and gender were enrolled. Blood samples were drawn before and 5 minutes after an intravenous injection of unfractionated heparin 5000 IE, which is known to cause TFPI release in healthy individuals. The preheparin samples showed significantly higher TFPI free antigen levels in the APA positive patients than in the controls (21.7 vs. 14.2 ng/ml, p = 0.03). TFPI activity as measured in a chromogenic substrate assay also was higher in patients, but this difference was not statistically significant (1.13 vs. 1.01 U/ml, p = 0.2). The TFPI levels showed a considerable rise in both patients and controls after heparin injection. In both assays, the postheparin levels were significantly higher in patients than in controls (TFPI antigen: 179 vs. 153 ng/ml, p = 0.05; TFPI activity: 3.26 vs. 2.51 U/ml, p = 0.03). A modified diluted prothrombin time assay (dPT) was used to measure TFPI anticoagulant activity. In this assay, samples from the patients with the strongest effect of lupus anticoagulants (LAs) on preheparin coagulation times showed little or no increase after heparin injection. This result may reflect an inhibition of TFPI anticoagulant activity by strong LAs. In conclusion, we have found that patients with APA have higher TFPI amidolytic activity/antigen level both before and after heparin stimulation of TFPI release. These observations do not explain the higher thrombotic risk in these patients but may reflect an upregulated tissue factor activity, which has been demonstrated in these patients. TFPI anticoagulant activity, however, as measured in a dPT assay, may be inhibited by strong LAs.

A multiple myeloma-specific quality-of-life questionnaire module has been designed in collaboration with the EORTC Quality-of-Life Study Group to be used in clinical trials with the EORTC QLQ-C30, a general cancer questionnaire. Strict methodology was employed to ensure thorough and appropriate development of the module. An extensive literature review was performed to identify health-related quality-of-life issues relevant to patients with multiple myeloma. Semi-structured interviews were then carried out in several European countries with health-care providers experienced in the treatment of patients with multiple myeloma, and with a group of patients with multiple myeloma, to identify the issues which were most important to patients. A questionnaire was devised from the list of issues, using a 1-week time-frame and response categories consistent with the EORTC QLQ-C30. The provisional questionnaire and the EORTC QLQ-C30 were administered to patients with multiple myeloma in each participating country with further semi-structured interviews to refine the content and design of the questionnaire. A review of the results obtained in each stage of development resulted in a 24-item myeloma-specific module, the EORTC QLQ-MY24, which assesses disease-specific symptoms and their impact on everyday life, treatment side-effects, social support, and future perspective. The module is currently undergoing further international field-testing to assess its psychometric properties.

Background. Preeclampsia is a major contributor to perinatal disease and fetal growth retardation (FGR). It has been suggested that increased intravascular coagulation, fibrin deposition in spiral arteries and hypoperfusion of the placenta are involved in these pregnancy complications. Methods. Multiple variables of the hemostatic system and lipid metabolism, as well as clinical features, were entered into univariate and multivariate models in order to examine the association with preeclampsia and FGR. Results. Two hundred women with preeclampsia and 97 normotensive pregnant women were examined. Plasma levels of the thrombin-antithrombin complex (TAT), tissue factor pathway inhibitor free antigen (TFPI-Fag), protein S free antigen, plasminogen activator inhibitor type-1 (PAI-1) activity and serum levels of triglycerides were significantly increased, whereas plasma levels of antithrombin (AT), fibrinogen, C4b-binding protein (C4b-BP), PAI-2 antigen and serum HDL-cholesterol levels were decreased in the presence of preeclampsia. In the multivariate regression analysis, high TFPI-Fag plasma levels were associated with the presence of preeclampsia. The presence of FGR was in the univariate analysis associated with decreased PAI-I activity and lower concentrations of fibrin, fibrinogen, factor VII antigen and PAI-2 antigen, as well as with evidence of macroscopic placental infarction. In a multivariate regression model, low maternal weight, placental infarction and low PAI-2 levels were predictors for low birth weight. In a logistic regression model, with the presence or absence of FGR as the dependent variable, male sex of the infant, placental infarction, low PAI-I activity and factor VII antigen or PAI-2 antigen levels were independent predictors. Conclusions. Our results are consistent with activated coagulation in the placental vessels in preeclampsia. A low concentration of PAI-2 antigen in plasma emerged as the most consistent risk factor for preeclampsia and FGR.

Compliance is of extreme importance in assessing quality of life since lost data never can be retrieved. In order to assess this issue in various studies, a cross-sectional study in cured cancer patients, three prospective trials and a normative study were explored. In the cross-sectional study 82 per cent of the patients completed the questionnaires after one reminder. More females than males answered the questionnaires. The compliance rate varied from 99 per cent to 62 per cent in the prospective studies depending upon time after inclusion. It seems that compliance decreases during follow up, primarily because of disease progression. In one of the prospective studies low compliance rate (approximately 30 per cent) was found in the questionnaire assessing religious issues. In the normative study 68 per cent of the population completed the questionnaire. No gender differences were found, but younger males and elderly women were poor compliers. In conclusion, our data support that most patients complete quality of life questionnaires. It seems that patients with inferior education, reduced physical function and with progressive/terminal disease are low compliers. Introduction of the first quality of life questionnaires to the patients is of great importance. Detailed information about the study should be given and the importance of completing the questionnaires should be underlined.

Objective: To examine the association between antiphospholipid anti-bodies and preeclampsia/fetal growth retardation.Methods: In this prospective, observational study, six tests for antiphospholipid antibodies (IgG and IgM anticardiolipin and anticephalin antibody enzyme-linked immunosorbent assays, activated partial thromboplastin time and Russell's viper venom time-based clotting tests) were performed on plasma from 200 unselected women with preeclampsia (145 cases of mild and 55 cases of severe preeclampsia) and 97 normotensive pregnant women of matched gestational age.Main Outcome Measures: Prevalence of antiphospholipid antibodies in preeclamptic women and controls, and the association between these autoantibodies and fetal growth retardation.Results: The IgG anticephalin antibody test and the activated partial thromboplastin time-based test for lupus anticoagulants were both positive in a significantly higher proportion of preeclamptic women (10.5% and 11.5%, respectively) than in controls (3.1% for...

This study evaluated the cost utility of adding interferon-alpha 2b to conventional treatment in patients with multiple myeloma. It also provides a methodology for transforming complex quality-of-life profiles into a single index value on the conventional 0 to 1 quality-adjusted life-year scale (QALY). From 1990 to 1992, 583 patients with newly diagnosed, symptomatic multiple myeloma were enrolled in a randomised, multicentre, phase III study to evaluate the addition of interferon-alpha 2b to treatment with melphalan and prednisone. Addition of interferon-alpha 2b yielded a 12% increase in median survival time, at the expense of a slight reduction in quality of life during the first year of treatment. The gain in survival time was not large enough to reach statistical significance. Patients receiving interferon-alpha 2b also had a 5- to 6-month prolongation of the plateau phase. Cost per QALY gained by adding interferon-alpha 2b was conservatively estimated at $US110,000. Potentially better cost effectiveness may be found in different treatment regimens or in certain patient subgroups.

Measurement of health-related quality of life was integrated into a randomized trial (NMSG 4/90) comparing melphalan/prednisone to melphalan/prednisone + interferon alpha-2b in newly diagnosed multiple myeloma. One of the aims of the study was to assess the prognostic significance of quality-of-life scores, using the EORTC QLQ-C30 questionnaire. Univariate analysis showed a highly significant association with survival from the start of therapy for physical functioning as well as role and cognitive functioning, global quality of life, fatigue and pain. In multivariate analysis, physical functioning and W.H.O. performance status were independent prognostic factors (P values = 0.001 for both) when analysed in a Cox regression model with the somatic variables beta-2 microglobulin, skeletal disease and age. The best prediction for survival from the start of therapy was obtained by combining the beta-2 microglobulin and physical functioning scores in a variable consisting of three risk factor levels with an estimated median survival of 17, 29 and 49 months, respectively. At a 12 months landmark analysis, the relative risk for patients with physical functioning score 0-20 v 80-100 was 5.63 (99% CI 2.76-11.49), whereas the relative risk for patients without an objective response to chemotherapy compared to those with at least a minor response was 2.32 (99% CI 1.44-3.74). Quality-of-life assessment may be an independent and valuable addition to the known prognostic factors in multiple myeloma.

Objectives: The aims of this study were to (i) compare the responsiveness of the EORTC QLQ-C30 cancer-specific questionnaire and the generic questionnaires EQ-5D and 15D used for economic evaluation of healthcare interventions and (ii) determine the minimal important differences (MIDs) in these questionnaires. The MID is the smallest change in a quality-of-life score considered important to patients. Methods: Between 2006 and 2008, 239 patients with multiple myeloma completed the questionnaires at inclusion (T1) and after 3 months (T2). At T2, patients were asked whether they had noticed any change in their quality of life. Responsiveness and MIDs were determined by mean score changes (T2–T1) for patients who, in the interview, stated they had improved, deteriorated, or were unchanged. Responsiveness was also assessed using standardized response means. Wilcoxon tests for pair differences were used to evaluate the statistical significance of the changes. Results: Patients who improved had significantly (P

Udgivelsesdato: 2010-Oct BACKGROUND: Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma. METHODS: This double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials.gov, number NCT00376883. FINDINGS: From January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62·9-70·0) in the 90 mg group and 68 points (64·6-71·4) in the 30 mg group (95% CI of difference -6·6 to 3·3; p=0·52). Median time to first skeletal-related event in patients who had such an event was 9·2 months (8·1-10·7) in the 90 mg group and 10·2 months (7·3-14·0) in the 30 mg group (p=0·63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group. INTERPRETATION: Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma. FUNDING: Nordic Cancer Union and Novartis Healthcare.

In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.gov as #NCT00218855.

Background We previously reported that changes of 6-17 percent in the EORTC QLQ-C30 scores are regarded important by patients with multiple myeloma and thus may be considered as Minimal Important Differences (MIDs). However, patients' internal standard of measurement may have changed over time (response shift, RS). In the present work, we evaluated whether myeloma patients experience RS and if this could affect the MID-estimates. Methods Between 2006 and 2008, 239 patients with multiple myeloma completed the EORTC QLQ-C30 at baseline (T1) and after three months (T2). At T2, patients were asked if they had noticed any change in the domains pain, fatigue, physical function and global quality of life. They were also asked to give a retrospective judgment of their baseline values on all the four domains. Results We found clear evidence of RS in myeloma patients. However, there were differences in both magnitude and direction between patients who stated that they improved and those who deteriorated. Deteriorating patients retrospectively reported better health-related quality of life at T1 for the domains pain, fatigue and physical function. In these patients, MIDs adjusted for RS were observed to increase up to 12 percentage points. In contrast, for patients stating that they improved, we only found evidence of statistically significant RS in the domain global quality of life. Conclusions MIDs estimated from pre-test/post-test data appeared to be robust against RS in patients reporting improvement over 3-months. This could indicate that RS has a minimal impact on the results in patients who respond to treatment, and that RS may not have an important impact on interpretation of changes reported in clinical trials where an improvement occurs. Although the effect sizes of the RSs were small, RS in deteriorating patients may have an important impact on the interpretation of changes reported in clinical trials. Trial registration The study is registered at clinicaltrials.gov, identifier NCT00290095.

Objective: To determine the clinical significance of changes in quality-of-life scores in patients with multiple myeloma (MM), we have estimated the minimal important difference (MID) for the health-related quality-of-life instrument, the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30. The MID is the smallest change in a quality-of-life score considered important to patients. Methods: Between 2006 and 2008, 239 patients with MM completed the EORTC QLQ-C30 at inclusion (T1) and after 3 months (T2). At T2, a structured quality-of-life interview was also performed. MIDs were calculated by using mean score changes (T2–T1) for patients who in the interview stated they had improved, deteriorated or were unchanged. MIDs were also estimated by the receiver-operating characteristic (ROC) curve method as well as by calculation effect sizes using standard deviations of baseline scores. Results: MIDs varied slightly depending on the method used. Patients stating in the interview that they had ‘improved’ or ‘deteriorated’ had a corresponding change in EORTC QLQ-C30 score ranging from 6 to15 (improvement) and from 9 to17 (deterioration) (scale range 0–100). The ROC analysis indicated that changes in score from 7 to17 represent clinically important changes to patients. The effect size method suggested 5–6 to be a small and 11–15 to be a medium change. Conclusion: Calculation of MIDs as mean score changes or by ROC analysis suggested that a change in the EORTC QLQ-C30 score in the range of approximately 6–17 is considered important by patients with MM. These MIDs are closer to a medium effect size than to a small effect size. Our findings imply that mean score changes smaller than 6 are unlikely to be important to the patients, even if these changes are statistically significant.

The effect of different methods of plasma preparation on the results of 1) a clotting assay for lupus anticoagulant (LA) detection (the dilute activated partial thromboplastin time, dAPTT), and of 2) an ELISA test for anticephalin antibody (aCEPHA) detection, was evaluated. It is well known that platelet disintegration resulting from freeze-thawing of plasma samples may release procoagulant phospholipid--"LA-bypassing" activity. Even with fresh plasma, the dAPTT of LA positive samples was sensitive to the presence of residual blood platelets. This effect was accentuated by freezing and thawing: with test plasma that had been prepared by a centrifugation force of 3,000 g or less for 15 min at 4 degrees C, freeze-thawing caused a significant shortening of the dAPTT. This phenomenon could not be demonstrated with filtered test plasma, which was platelet free. Surprisingly, ultracentrifugation also led to a substantial shortening of the dAPTT compared to filtered plasma, and should not be recommended as a method of plasma preparation for LA detection. The ELISA test was less sensitive to residual platelets than the dAPTT. Thus, plasma prepared by a centrifugation force of at least 1,500 g may be stored at -20 degrees C before performance of the ELISA test. For the dAPTT, filtering of test plasma and control plasma after centrifugation is recommended for maximum sensitivity, regardless of whether they are to be examined in the fresh state or after freezing and thawing.

Objectives: Patients with multiple myeloma (MM) often have pronounced symptoms and substantially reduced quality of life. The aims of treatment are to control disease, maximise quality of life and prolong survival. Hence, health-related quality of life (HRQOL) should be an important end-point in randomised controlled trials (RCTs) in addition to traditional endpoints. We wanted to evaluate whether trials reporting HRQOL outcomes have influenced clinical decision making and whether HRQOL was assessed robustly according to predefined criteria. Methods: A systematic review identified RCTs in MM with HRQOL assessment as a study end-point. The methodological quality of these studies was assessed according to a checklist developed for evaluating HRQOL outcomes in clinical trials. The impact of the HRQOL results on clinical decision making was assessed, using published clinical guidelines as a reference. Results: Fifteen publications presenting RCTs with HRQOL as a study end-point were identified. In 13 trials, the author stated that HRQOL results should influence clinical decision making. We found, however, that the HRQOL data only had a limited impact on published treatment guidelines for bisphosphonates, high-dose treatment, interferon, erythropoiesis-stimulating agents and novel agents. Conclusion: The present review indicates that the there are still few RCTs in MM including HRQOL as a study end-point. Systematic incorporation of HRQOL measures into clinical trials allows for a comparison of treatment arms that includes the patients’ perspective. Before the full impact on clinical decisions can be realised, the quality and methodology of collecting HRQOL data must be further improved and the results rendered more comprehensible to clinicians.

The last 15 years several studies have evaluated the quality of the Norwegian Cancer Registry. A pilot study from 1981 showed that the registration quality of non-solid tumours was significantly weaker than that for solid tumours. We wanted to study the registration quality of multiple myeloma in the Norwegian Cancer Registry during the 1990s.In the 1990s, the majority of younger Norwegian patients with multiple myeloma diagnosed in certain time periods were included in clinical studies. 348 patients were included, whereas 440 patients were registered in the Norwegian Cancer Registry during the same time period. We compared the patients included in studies with those in the Registry. When a discrepancy was found the diagnostic data and the registration process were looked into.Registration of multiple myeloma in the Norwegian Cancer Registry in the 1990s had a completeness of 92.7 % and an accuracy of 92.5 %.The quality of multiple myeloma registration in the Norwegian Cancer Registry has improved from the 1970s (the data had a completeness of 77-82%) to the 1990s, but is still not as good as the registration of solid tumours. Increased awareness of this problem at pathological and haematological departments can probably improve the quality of registration further.

Intensive chemotherapy is mandatory in curative treatment of acute myeloid leukemia (AML), but whether the nutritional status deteriorates during treatment, is unknown. We therefore prospectively examined anthropometric and biochemical nutritional markers during intensive chemotherapy in 26 Russian and 19 Norwegian AML patients during 9 months from diagnosis. Although the body mass index remained unchanged in both cohorts, hand grip strength and triceps skinfold thickness declined (P0.05) during treatment before normalisation at study end. We detected a similar significant, temporary decrease in albumin, transferrin, testosterone and gonadotrophins in both cohorts. Although the fat-soluble vitamins D and E also displayed such a pattern, vitamin A dropped and remained low throughout the study in both cohorts. The Russian patients reported lower global quality of life, more symptoms and more financial concern than the Norwegians. Our data suggest a catabolic metabolism during intensive chemotherapy for AML, leading to impaired nutritional status, hypofunction of the pituitary-gonadal axis and decreased health-related quality of life.

Lupus anticoagulants (LA) are IgG or IgM antibodies which prolong phospholipid-dependent coagulation tests. For the detection and quantitation of such antibodies, we have developed an ELISA with cephalin as the coating antigen. The sensitivity of this assay was compared to the activated partial thromboplastin time (APTT). LA was defined as greater than or equal to 5 sec prolongation of the APTT with standard cephalin dilution, or greater than or equal to 10 sec prolongation with a high cephalin dilution, on a 1:1 mixture of patient and control plasma. Plasma samples from 158 healthy individuals were tested for anticephalin antibodies. The 97.5 percentile was chosen as the upper reference limit and allocated a value of 1 ELISA unit. A "four-parameter logistic" model was used for transformation of the absorbances to ELISA units. Of 314 plasma samples referred for LA screening, positive results were found in 62 by both APTT and ELISA. Twenty-three samples were ELISA positive and APTT negative; this finding may be explained by greater sensitivity of the ELISA, which gave positive results in a four-fold greater dilution than the APTT. Prolongation of the APTT without antibody activity was found in 8 samples of which 2 had an inhibitor of factor VIII:C, the remaining 6 probably had true LA. In conclusion, our computer-assisted ELISA is a sensitive and reliable test method for quantitation of anticephalin antibodies. This assay has a high concordance with LA as detected with the APTT.