Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQoL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial.

Thalidomide with melphalan/prednisone (MPT) was defined as standard treatment in elderly patients with multiple myeloma (MM) based on five randomized trials. In one of these trials, HOVON49, a prospective health-related quality-of-life (HRQoL) study was initiated in order to assess the impact of thalidomide on QoL. Patients aged >65 years with newly diagnosed MM were randomized to receive melphalan plus prednisone (MP) or MPT, followed by thalidomide maintenance in the MPT arm. Two hundred eighty-four patients were included in this side study (MP, n=149; MPT n=135). HRQoL was assessed with the EORTC Core QoL Questionnaire (QLQ-C30) and the myeloma-specific module (QLQ-MY24) at baseline and at predetermined intervals during treatment. The QLQ-C30 subscales physical function (P=0.044) and constipation (P<0.001) showed an improvement during induction in favour of the MP arm. During thalidomide maintenance, the scores for the QLQ-MY24 paraesthesia became significantly higher in the MPT arm (P<0.001). The QLQ-C30 subscales pain (P=0.12), insomnia (P=0.068), appetite loss (P=0.074) and the QLQ-MY24 item sick (P=0.086) scored marginally better during thalidomide maintenance. The overall QoL-scale QLQ-C30-HRQoL showed a significant time trend towards more favourable mean values during protocol treatment without differences between MP and MPT. For the QLQ-C30 subscales emotional function and future perspectives, difference in favour of the MPT arm from the start of treatment was observed (P=0.018 and P=0.045, respectively) with no significant 'time × arm' interaction, indicating a persistent better patient perspective with MPT treatment. This study shows that the higher frequency of toxicity associated with MPT does not translate into a negative effect on HRQoL and that MPT holds a better patient perspective.

No firm association between N-terminal pro-brain natriuretic peptide and percentage of pulmonary vascular obstruction in patients with acute pulmonary embolism.

INTRODUCTION: High concentrations of N-terminal-pro-brain natriuretic peptide (NT-proBNP) are found in patients with right ventricular overload. Right ventricular overload may be the result of large perfusion defects in patients with pulmonary embolism (PE). NT-proBNP levels are associated with poorer outcome in patients with acute PE. Likewise, the percentage of pulmonary vascular obstruction (PVO) has shown to be a prognostic parameter for outcome in PE-patients. We postulated that NT-proBNP is associated with the amount of perfusion defects, expressed as the PVO, on perfusion scintigraphy. METHODS: We included 85 consecutive patients in whom the diagnosis PE was confirmed by ventilation-perfusion scintigraphy. PVO was calculated in all patients. NT-proBNP concentrations were measured at presentation. We plotted the logarithm of NT-proBNP versus the PVO. The strength of the estimated association between NT-proBNP and the PVO was expressed by R2. RESULTS: Eighteen percent of the variation in PVO could be explained by NT-proBNP. A positive association becomes apparent for NT-proBNP values above 200 pg/mL, with an increase in PVO of 6.3% (95% Confidence Interval 2.0 to 10.6), with every doubling of NT-proBNP. CONCLUSION: There is an association between NT-proBNP concentrations and PVO, although this relation is quite weak. Some patients with low NT-proBNP values can have a high PVO, which might be relevant for outcome. Therefore, we advise caution in risk stratification and not to focus on NT-proBNP, without involving the clinical condition.

Is extensive screening for cancer in idiopathic venous thromboembolism warranted?

BACKGROUND: Patients with a first episode of idiopathic venous thromboembolism (IVTE) have an estimated 10% incidence of cancer within 12 months after diagnosis. However, the utility of screening for cancer in this population is controversial. METHODS: In this prospective concurrently controlled cohort study, limited and extensive cancer screening strategies were compared. All 630 patients underwent baseline screening consisting of history, physical examination, basic laboratory tests and chest X-ray. In the extensive screening group abdominal and chest CT scan and mammography were added. Outcomes were incidence and curability of cancer, and cancer-related and overall mortality. RESULTS: In 12 of the 342 (3.5%) patients in the extensive screening group malignancy was diagnosed at baseline compared with 2.4% (seven of 288 patients) in the limited screening group. Extensive screening detected six additional cancers (2.0%; 95% CI, 0.74-4.3), of which three were potentially curable. During a median 2.5 years of follow-up, cancer was diagnosed in 3.7% and 5.0% in the extensive and limited screening groups, respectively. In the extensive screening group 26 patients (7.6%) died compared with 24 (8.3%) in the limited screening group; adjusted hazard ratio 1.22 (95% CI, 0.69-2.22). Of these deaths 17 (5.0%) in the extensive screening group and 8 (2.8%) in the limited screening group were cancer related; adjusted hazard ratio 1.79 (95% CI, 0.74-4.35). CONCLUSIONS: The low yield of extensive screening and lack of survival benefit do not support routine screening for cancer with abdominal and chest CT scan and mammography in patients with a first episode of IVTE.

Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.

BACKGROUND: Low NT-proBNP levels are associated with an uncomplicated course in patients with pulmonary embolism (PE). The aim of this multicenter management study was to investigate the safety of home treatment of patients with PE with low (< 500 pg mL(-1)) NT-proBNP. METHODS AND RESULTS: Hemodynamically stable outpatients with acute PE and NT-proBNP level < 500 pg mL(-1) were included. Patients were discharged immediately from the emergency room or within a maximum of 24 h after admission. The primary study objective was the absence of mortality during the first 10 days of treatment. Secondary objectives were the incidence of re-admission due to PE or its treatment and the patient's satisfaction during the first 10 days of treatment as well as the incidence of serious adverse events during the 3-month follow-up period. Of 351 patients, 152 (43%) fulfilled the inclusion criteria and were treated as outpatients. No deaths, major bleedings or recurrent venous thromboembolism occurred in the first 10 days of treatment or in the follow-up period of 3 months in these patients. Seven patients required readmission in the first 10 days: three because of complaints that could be related to PE and four due to an illness unrelated to PE. The HADS-A anxiety score did not change significantly between day 0 and day 10. The PSQ-18 showed a high score for satisfaction with home treatment. CONCLUSION: Out of hospital treatment is safe in hemodynamically stable patients with PE with low (< 500 pg mL(-1)) NT-proBNP levels. Approximately 45% of patients with PE can be treated in an outpatient setting. Patients do not consider out of hospital treatment as inconvenient and have no increase in anxiety scores. CLINICAL TRIAL REGISTRATION INFORMATION: http://clinicaltrials.gov/ct2/show/NCT00455819.

Homocysteine in inflammatory bowel disease: a risk factor for thromboembolic complications?

OBJECTIVE: Patients with inflammatory bowel disease (IBD) are at increased risk for thromboembolic events. Hyperhomocysteinemia, which is an established risk factor for arterial as well as venous thrombosis, may be more prevalent in IBD because of vitamin deficiencies. METHODS: In this retrospective study, we studied the concentrations of total homocysteine (tHcy), cobalamin, folate, and pyridoxine in 231 consecutive patients with IBD, of whom 16 patients had a history of venous thrombosis, and nine a history of arterial thrombosis. Age- and gender-matched healthy volunteers served as controls (n = 102). RESULTS: Homocysteine concentrations in patients were higher (12.3 micromol/L [range 4.6-51.3] vs 11.1 micromol/L [range 3.9-27.6], p = 0.001) and hyperhomocysteinemia tended to be more prevalent in patients than in the controls (11.1% vs 5%, p = 0.07). Folate, cobalamin, creatinine, and pyridoxine concentrations were correlated with tHcy. Folate deficiency was infrequently encountered in IBD patients (4.3%). The tHcy concentration in patients with a history of venous or arterial thrombosis was not higher than in patients without a history of thrombosis (12.7 micromol/L [range 4.6-40.1] and 15.2 micromol/L (range 10.5-26.8) vs 12.3 micromol/L [range 10.5-26.8], not significant). Hyperhomocysteinemia was found in 18.8% of the patients with venous thrombosis, 11.1% of the patients with arterial thrombosis, and 10.5% of the patients without thrombosis (not significant). CONCLUSIONS: Hyperhomocysteinemia is a common phenomenon in IBD and correlates with serum folate, cobalamin, creatinine, and pyridoxine concentrations. No correlation between tHcy and a history of venous or arterial thromboembolic complications is found. Hyperhomocysteinemia does not seem to be a major contributory factor in the development of venous or arterial thrombosis in IBD patients.

The effect of different treatment regimens in reducing fasting and postmethionine-load homocysteine concentrations.

OBJECTIVES: To determine the homocysteine-lowering effect of different treatment regimens on both fasting and postmethionine-load plasma total homocysteine (tHcy) concentrations. DESIGN: Descriptive study of consecutive hyperhomocysteinaemic subjects per treatment regimen. Homocysteine was measured in the fasting state and 6 h after methionine loading, both before and after 8 weeks of vitamin therapy. Hyperhomocysteinaemia was defined as a fasting tHcy and/or increase in tHcy (postmethionine-load minus fasting tHcy concentration) exceeding the 95th percentile of local controls. SETTING: Outpatient clinic of internal medicine of a large non-academic teaching hospital. SUBJECTS: One hundred and seventeen hyperhomocysteinaemic subjects (vascular patients and first-degree relatives). INTERVENTIONS: There were four regimens: pyridoxine, 200 mg; folic acid, 5 mg; combination of folic acid 0.5 mg and pyridoxine 100 mg; and folic acid, 0.5 mg daily. RESULTS: All regimens, except pyridoxine 200 mg, significantly reduced fasting tHcy without differences in the percentage reduction (32-38%). All regimens produced a significant reduction in the increase in tHcy and postmethionine-load tHcy. The reduction in postmethionine-load tHcy was smaller for pyridoxine 200 mg than for combination therapy. No differences were found in the percentage reduction (for both increase in tHcy and postmethionine-load tHcy) between folic acid 5 mg and folic acid 0.5 mg. CONCLUSIONS: Monotherapy folic acid (0.5 mg daily) is the lowest effective therapy for reducing both fasting and postmethionine-load tHcy concentrations, with the same results as high-dose folic acid (5 mg daily). Pyridoxine has no additional value.

Hyperhomocysteinaemia as a cardiovascular risk factor: an update.

There is overwhelming epidemiological evidence that hyperhomocysteinaemia is an independent and graded cardiovascular risk factor, although a cause-and-effect relationship is still unproven. Acquired causes of hyperhomocysteinaemia include B-vitamin deficiencies and renal insufficiency. The most important inherited cause is a point mutation in methylenetetrahydrofolate reductase gene, which is, remarkably, not associated with an increased cardiovascular risk. A methionine loading test identifies substantially more subjects with hyperhomocysteinaemia compared with a fasting homocysteine determination alone. Repeated blood sampling is necessary due to an intra-individual variability in homocysteine concentrations up to 25%. A conservative reference value for fasting homocysteine is 15 micromol/l, although there seems to be no definite threshold in the presumed linear relation between homocysteine concentration and cardiovascular risk. The pathophysiological mechanism of homocysteine-induced cardiovascular disease is still not elucidated. The concept of endothelial dysfunction, demonstrated by impaired endothelium-dependent vasodilation, by oxidant damage has been confirmed in hyperhomocysteinaemic healthy adults. Folic acid supplementation (0.5 mg daily) can be considered the optimum homocysteine lowering therapy, with the exception of renal failure patients. Ongoing large prospective, randomised controlled clinical trials are investigating the potential beneficial effect of homocysteine lowering therapy on cardiovascular morbidity and mortality in subjects with hyperhomocysteinaemia.

Combination of low-dose folic acid and pyridoxine for treatment of hyperhomocysteinaemia in patients with premature arterial disease and their relatives.

Hyperhomocysteinaemia is an independent risk factor for atherosclerotic disease and venous thrombosis. The optimal homocysteine-lowering vitamin dose and target total homocysteine (tHcy) concentration are currently unknown. We prospectively studied the homocysteine-lowering effect after 8 weeks low-dose combination of folic acid (0.5 mg) and pyridoxine (100 mg) in 49 hyperhomocysteinaemic persons (33 patients with documented premature arterial disease and 16 of their first-degree relatives). Hyperhomocysteinaemia was in both sexes defined as fasting tHcy concentration > 12 micromol/l and/or post-methionine load tHcy concentration > 38 micromol/l. Low-dose vitamin therapy significantly reduced fasting tHcy concentration (median 13.9 to 9.3 micromol/l, reduction 32% (95% CI: 27-37%)) and post-load tHcy concentration (median 55.2 to 36.5 micromol/l, reduction 30% (95% CI: 25-35%)). Fasting tHcy reduction was similar in women and men, as well as in patients and relatives. Post-load tHcy reduction was significantly less in men compared to women (P = 0.04) and in relatives compared to patients (P = 0.03). Although low-dose combination of folic acid and pyridoxine results in a substantial reduction of tHcy concentrations (30-32%) in subjects with hyperhomocysteinaemia, the normalisation percentage to predefined criteria was less impressive (49%).

Donor leukocyte infusions inducing remissions repeatedly in a patient with recurrent multiple myeloma after allogeneic bone marrow transplantation.

We describe a patient with recurrent relapses after allogeneic BMT for multiple myeloma who repeatedly went into CR after donor leukocyte infusions (DLI). The first bone marrow relapse, 24 months after allogeneic BMT, was treated successfully with the infusion of 1.2 x 10(8) donor T cells. The second extramedullary relapse, 18 months later with a pleural mass and midthoracic spine process, responded again to DLI, however, only after three courses were given, each with escalating doses of T cells. The pleural mass was treated successfully with radiation therapy after the second DLI but reappeared 3 months later and responded again to the final DLI course with 5 x 10(8) T cells/kg. Nevertheless, graft-versus-host disease (GVHD) did not occur. Retrospective analysis of minimal residual disease in bone marrow aspirates during CR periods using a sensitive quantitative tumor-specific PCR showed that BM tumor cell infiltration persisted. The possible clinical implications of this case report, like maintenance DLI and the aim for molecular remissions, are discussed.

Methionine loading test is necessary for detection of hyperhomocysteinemia.

Hyperhomocysteinemia, defined as an elevated concentration of homocysteine in the fasting state or after methionine loading, is an independent risk factor for premature atherosclerosis and venous thrombosis. The role of the methionine loading test (MLT) is, however, controversial. To determine the additional value of the MLT for diagnosis of hyperhomocysteinemia, we prospectively studied 281 patients with premature arterial disease and 148 of their first-degree relatives in the outpatient clinic of a general hospital. Total plasma homocysteine (fasting and 6 hours after methionine loading), folic acid, cobalamin, pyridoxine, and creatinine concentrations were measured. Hyperhomocysteinemia was defined as a fasting homocysteine concentration and/or an increase in homocysteine concentration after methionine loading exceeding the 95th percentile of a healthy control group. Hyperhomocysteinemia was found in 141 (33%) of the 429 subjects: 15% were diagnosed by fasting homocysteine concentration and 18% by MLT. Seventy-eight (55%) of the 141 hyperhomocysteinemic persons were diagnosed only by the MLT. Folic acid was lower in the group with an elevated fasting homocysteine concentration than in those with only an abnormal MLT result (11 versus 15 nmol/L, p = 0.002). Folic acid was significantly negatively correlated, and creatinine significantly positively correlated, with both fasting homocysteine concentration and increase in homocysteine concentration. Negative correlations of cobalamin and pyridoxine with fasting homocysteine concentration were found. In conclusion, the MLT is necessary for diagnosis of hyperhomocysteinemia, because a considerable number of hyperhomocysteinemic persons (55%) remain undiagnosed with the determination of a fasting homocysteine concentration alone.

Intermediate-dose melphalan (IDM) combined with G-CSF (filgrastim) is an effective and safe induction therapy for autologous stem cell transplantation in multiple myeloma.

Twenty-one previously untreated multiple myeloma (MM) patients and 10 previously treated patients with refractory or relapsed disease received two or three cycles of intermediate-dose melphalan (70 mg/m2) (IDM), administered intravenously every 6 weeks. Seven previously untreated patients received three and all other patients received two courses of IDM. The objective of the study was to reduce the toxicity of high-dose melphalan (140 mg/m2) (HDM) while maintaining its cytotoxic efficacy and secondly to ensure the possibility of collecting sufficient numbers of peripheral blood stem cells (PBSC) for transplantation. 18 (85%) previously untreated patients responded, of whom four achieved CR (18%). In addition five out of 10 previously treated patients with refractory or relapsed disease responded although bone marrow toxicity in this category was a major drawback. Toxicity was moderate, consisting of alopecia and moderate bone marrow suppression: the granulocyte count dropped below 0.5 x 10(9)/l and platelets below 25 x 10(9)/l for a median of 8 and 6 d, respectively. No serious infections occurred and the majority of patients attended the out-patient clinic. In 12/14 previously untreated patients sufficient peripheral blood CD34+ cells for harvest were present in the repopulation phase after the first IDM. In nine patients peripheral blood stem cells were collected and eight patients have undergone successful transplantation. Repeated IDM followed by filgrastim is highly effective in untreated MM and may be safely administered to reduce tumour load prior to PBSC collection. Autologous stem cells harvested after repeated IDM have a full long-term repopulating capacity.

Radiation therapy for aggressive fibromatosis. The Experience at the University of Florida.

Twenty-nine patients (thirty sites) who had histologically confirmed aggressive fibromatosis were treated with radical courses of radiation at the University of Florida between March 1975 and February 1986. The minimum length of follow-up was two years; 76 per cent of the patients were followed for more than five years. Twenty-seven sites received doses of at least 5000 centigrays (one centigray equals one rad). Twelve patients were treated twice a day. Fourteen sites were treated with radiation postoperatively for known or presumed microscopic quantities of residual aggressive fibromatosis; in eleven, the disease was locally controlled. Sixteen sites were treated postoperatively for known grossly apparent residual disease; in fourteen, the disease was locally controlled. Over-all, aggressive fibromatosis was controlled in twenty-five (83 per cent) of the thirty sites. The six-year actuarial rate of local control was 79 per cent. The five local recurrences occurred at four, eleven, thirty-four, sixty-one, and sixty-eight months after the initiation of radiation therapy. Two of the five failures occurred in the high-dose radiation field in patients who were treated for grossly apparent disease. The remaining three failures occurred at the margin of the irradiated field in patients who were treated for assumed microscopic quantities of residual disease. There was no apparent difference in local control between patients who were treated for primary (previously untreated) aggressive fibromatosis and those who were treated after one or more recurrences. Comparison of the results of radiation therapy with published data on operative treatment shows that local control substantially improves with postoperative radiation therapy when operative margins are less than wide.(ABSTRACT TRUNCATED AT 250 WORDS)

Preoperative irradiation for soft tissue sarcomas of the trunk and extremities in adults.

Between May 1978 and January 1987, 58 adult patients with previously untreated sarcomas of the trunk and extremities were treated with preoperative irradiation and surgery at the University of Florida. All patients had a minimum of 2 years of follow-up; 24 had a minimum of 5 years of follow-up. The preoperative dose was usually 5040 cGy, with 120-125 cGy per fraction delivered twice daily. Operations were performed 2 to 6 weeks after radiation therapy. Eight patients received adjuvant chemotherapy. The tumors were high grade in 52 (90%), measured greater than 10 cm in 45 (78%), and were extracompartmental in 49 (84%). The surgical margins were wide in 17, marginal in 31, and intralesional in 10 patients. A functional extremity was preserved in 47 of 54 patients who would have required an amputation had they been treated by operation alone. Five of 58 patients (9%) developed local failure; in three, the failure occurred outside of the irradiated volume. Survival rates (product-limit method) at 5 years according to grade and size of lesion were as follows: low grade, 100%; high grade, 10 cm or less in largest diameter, 68%; high grade, 11-20 cm, 39%. Data are insufficient for a 5-year analysis of high-grade lesions greater than 20 cm; to date, there are no 5-year survivors in these patients. Moderate and severe wound complications occurred in 16%. There were four pathological fractures in 52 long bones at risk.