ROC study and SUV threshold using quantitative multi-modal SPECT for bone imaging.

BACKGROUND: We investigated the clinical performance of a quantitative multi-modal SPECT/CT reconstruction platform for yielding radioactivity concentrations of bone imaging with 99mTc-methylene diphosphonate (MDP) or 99mTc-dicarboxypropane diphosphonate (DPD). The novel reconstruction incorporates CT-derived tissue information while preserving the delineation of tissue boundaries. We assessed image-based reader concordance and confidence, and determined lesion classification and SUV thresholds from ROC analysis. METHODS: Seventy-two cancer patients were scanned at three US and two German clinical sites, each contributing two experienced board-certified nuclear medicine physicians as readers. We compared four variants of the reconstructed data resulting from the Flash3D (F3D) and the xSPECT Bone™ (xB) iterative reconstruction methods and presented images to the readers with and without a fused CT, resulting in four combinations. We used an all-or-none approach for inclusion, compiling results only when a reader completed all reads in a subset. After the final read, we conducted a "surrogate truth" reading, presenting all data to each reader. For any remaining discordant lesions, we conducted a consensus read. We next undertook ROC analysis to determine SUV thresholds for differentiating benign and lesional uptake. RESULTS: On a five-point rating scale of image quality, xB was deemed better by almost two points in resolution and one point better in overall acceptance compared to F3D. The absolute agreement of the rendered decision between the nine readers was significantly higher with CT information either inside the reconstruction (xB, xBCT) or simply through image fusion (F3DCT): 0.70 (xBCT), 0.67 (F3DCT), 0.64 (xB), and 0.46 (F3D). The confidence level to characterize the lesion was significantly higher (3.03x w/o CT, 1.32x w/CT) for xB than for F3D. There was high correlation between xB and F3D scores for lesion detection and classification, but lesion detection confidence was 41% higher w/o CT, and 21% higher w/CT for xB compared to F3D. Without CT, xB had 6.6% higher sensitivity, 7.1% higher specificity, and 6.9% greater AUC compared to F3D, and similarly with CT-fusion. The overall SUV-criterion (SUVc) of xB (12) exceeded that for xSPECT Quant™ (xQ; 9), an approach not using the tissue delineation of xB. SUV critical numbers depended on lesion volume and location. For non-joint lesions > 6 ml, the AUC for xQ and xB was 94%, with SUVc > 9.28 (xQ) or > 9.68 (xB); for non-joint lesions ≤ 6 ml, AUCs were 81% (xQ) and 88% (xB), and SUVc > 8.2 (xQ) or > 9.1 (xB). For joint lesions, the AUC was 80% (xQ) and 83% (xB), with SUVc > 8.61 (xQ) or > 13.4 (xB). CONCLUSION: The incorporation of high-resolution CT-based tissue delineation in SPECT reconstruction (xSPECT Bone) provides better resolution and detects smaller lesions (6 ml), and the CT component facilitates lesion characterization. Our approach increases confidence, concordance, and accuracy for readers with a wide range of experience. The xB method retained high reading accuracy, despite the unfamiliar image presentation, having greatest impact for smaller lesions, and better localization of foci relative to bone anatomy. The quantitative assessment yielded an SUV-threshold for sensitively distinguishing benign and malignant lesions. Ongoing efforts shall establish clinically usable protocols and SUV thresholds for decision-making based on quantitative SPECT.

Improvement of peripheral and cardiopulmonary performance after a short-term exercise program with additive prostaglandin E1.

In patients with intermittent claudication, the walking distance can be increased, both by means of several months of intensive training and administration of IV prostaglandin E1 (PGE1) for 4 weeks. The aim of this study was, therefore, to investigate whether the combination of intensive training and PGE1 infusions during pedalergometry can increase peripheral and cardiopulmonary performance after 2 weeks. Ten patients with intermittent claudication received a once-daily intravenous infusion of 60 microg PGE1 over 2 hours during pedalergometry. In addition, a physical training program was carried out mornings and afternoons, as well as progressive treadmill training. Walking distance (3 km/h, 12%) and cardiopulmonary performance were determined at the beginning and end of the 2-week treatment. Results were compared with those of a historical control group having received a similar training program without PGE1. The initial walking distance increased from 71 to 166 m (134%). At the same time, peak work load increased by 108%, and the physical work capacity by 100%. Cardiopulmonary function improvement was reflected in all the parameters investigated (peak VO2; peak VO2/peak work load ratio; slope of deltaVO2/deltat; RER). Compared with the historical control group, the difference between the two groups with regard to the increase in walking distance was significant in favor of the combined training program with PGE1. The combination of short-term intensive training and PGE1 infusions during pedal ergometry significantly improves both the peripheral as well as the highly restricted functional capacity in patients with intermittent claudication.

Randomized reliability study evaluating constant-load and graded-exercise treadmill test for intermittent claudication.

The aim of this randomized study was to compare the reliability of the treadmill test at constant-load (C-test, 3 km/hr; fixed grade of 12%) recommended in Germany with that of the graded-exercise test (G-test, 3 km/hr; increase in grade of 3.5% every 3 minutes) propagated in the United States. In 50 patients with an absolute claudication distance (ACD) in the C-test of between 50 and 400 m, the two treadmill tests were carried out in randomized order on one and the same day, and repeated on 3 days within 1 week. For the initial claudication distance (ICD), the intraclass correlation was 0.88 in the C-test and 0.87 in the G-test. For the ACD the coefficients were identical at 0.91. The within-subject variation (CVwithin) in the C-test and G-test was 25% and 27% for the ICD and for the ACD 24% and 21%, respectively. The between-subject variation was very similar with 72% and 73% (ICD) and with 78% and 68% (ACD). However, in ACDs below 100 m and between 100 to 150 m, the C-test showed significantly smaller coefficients of variation than the G-test: 13% vs 81% and 14% vs 50%, respectively. In conclusion, the results showed that both C-test and G-test are equally well reproducible.

[Methods and results of controlled walking training in patients with peripheral arterial occlusive disease]. / Methoden und Ergebnisse eines kontrollierten Gehtrainings bei Patienten mit paVK.

To establish the effect of exercise training in patients with PAOD Stage II according to Fontaine, 125 publications between 1966 and 1998 were systematically reviewed. The best results occurred with the following method: duration greater than 30 minutes per session, frequency of at least three sessions per week, intermittent walking to near-maximal pain and program length of greater than six months. A methodological study of six randomized clinical trials was performed. The claudication distance was assessed with a treadmill test at a constant-load of 0.82-1.06 Watt/kg. Improvement in initial/absolute claudication distance (ICD/ACD) ranged from +28% to +213%. The average increase was +150% in ICD, and +200% in ACD. Exercise rehabilitation significantly improved patient's quality-of-life as well. However, the benefit of exercise training however was only moderate (6-32%). Exercise training is a very effective therapeutic measure. However, for further use better guidelines and prospective cost-effectiveness studies including evaluation of rehabilitation programs with regard to improvements in functional capacity, modification of risk factors, long-term compliance, quality-of-life and medical costs incurred are needed.

Treadmill testing for evaluation of claudication: comparison of constant-load and graded-exercise tests.

OBJECTIVES: To compare the correlation and practicability of single-stage vs. graded treadmill protocols in the assessment of the absolute claudication distance (ACD). DESIGN: Randomized open study. MATERIAL AND METHODS: In 52 patients with peripheral arterial occlusive disease, the ACD on treadmill at 3 km/h and 12% grade (constant-load test = C-test) ranged form 50 to 400 m. The C-test and the graded-exercise test (walking on the treadmill at 3 km/h and 0% gradient for 3 min, with subsequent increase in gradient of 3.5% every 3 min = G-test) were carried out at random on the same day under standardized conditions. RESULTS: The ACD was higher in the G-test than in the C-test (360.4 +/- 208.8m vs. 166.5 +/- 93.6m; p < 0.001). The coefficients of variation were very similar (57.9% and 56.2%, respectively). In the subgroup of patients with an ACD of between 100 m and 150 m, a large difference was found both for the coefficient of variation (58.6% G-test, 9.6% C-test) and for the standard deviation (339.8 +/- 199.0m and 133.1 +/- 12.8m, respectively). CONCLUSIONS: For the assessment of the ACD in patients with severe claudication the C-test would seem to be more suitable than the G-test.

[Functional evaluation of intermittent claudication]. / Funktionelle Beurteilung der Claudicatio intermittens.

Despite new technologies and therapeutical developments in angiology, the functional evaluation of intermittent claudication still remains unsatisfying. The Fontaine-Classification from 1954, which is currently used as stage IIa and IIb, is not generally accepted. In the clinical routine, the estimate taken for decision strategy, even for the interventional and surgical procedures, is often that claimed by the patient in his case history. Due to lack of standardization the results of therapeutical studies are not comparable. Recommendations for treadmill exercise testing are confusing. Globally, both the constant-load-test at 3 km/h and 12% grade and the graded-exercise-test (3,2 km/h with an increase in grade of 3,5% every 3 minutes) show similar results. However, in patients with absolute claudication distance between 50-150 m, the constant-load-test is superior. The problem in measurement of the treadmill walking distance could probably be solved by the quantification of exercise capability and evaluation of physical capacity in patients with intermittent claudication in the same manner, as usual in cardiology and sports medicine.

Improvement in the quality of life after i.v. PGE1 therapy for intermittent claudication.

BACKGROUND: Increasingly and justifiably, clinical studies are now being expected to investigate the influence of therapeutic measures also on the quality of life of the patient. PATIENTS AND METHODS: Since no data on the variability of changes in the quality of life of the patient following PGE1 treatment are so far available, the initial investigation was designed as an uncontrolled pilot study. 104 patients (median age 64.5 years) with a maximum of walking distance on the treadmill (3 km/12%) of 50-250 m were included and given a daily intravenous infusion of 60 micrograms PGE1 (Prostavasin) over a period of 4 weeks excluding weekends. This was followed by a treatment-free follow-up period of 3 months. Changes in the quality of life were recorded with both the newly developed disease-specific questionnaire PAVK-86, and the generic questionnaire SF 36; in addition, the pain-free and maximum walking distances on the treadmill were also established prior to and immediately following treatment, as also at the end of the follow-up period. RESULTS: The quality of life was significantly improved in all dimensions (functional status, complaints, pain, mood, anxiety, social life, treatment expectations) in addition to a marked increase in the median pain-free walking distance from 77 to 108 m (p < 0.001) and the maximum walking distance from 118 to 171 m (p < 0.001). At the end of the 3-month observation period, the improvement was essentially still demonstrable. CONCLUSION: The study has shown for the first time that treatment with intravenous PGE1 brings about not only the already known increase in the walking distance, but also a clinically relevant and significant improvement in the patient's quality of life.

[Development of an illness-specific instrument for assessment of quality of life in patients with arterial occlusive disease (Peripheral Arterial Occlusive Disease 86 Questionnaire)]. / Entwicklung eines krankheitsspezifischen Instruments zur Erfassung der Lebensqualität von Patienten mit arterieller Verschlusskrankheit (PAVK-86 Fragebogen.

Impairment in health-related quality of life in patients with peripheral arterial occlusive disease (PAOD) are well-known to clinicians, but due to the lack of disease specific assessment instruments, have not been systematically investigated. We describe the development and psychometric testing of a 86-items patient-based questionnaire for the assessment of the quality of life in PAOD containing 7 dimensions: functional status, pain, symptoms, mood, disease related anxiety, social life and treatment evaluation. The questionnaire was included along with standard questionnaires in a prospective study with 308 patients suffering from PAOD in Fontaine stages I to IV before and one week into treatment. Psychometric testing pertained to reliability (internal consistency, retest), validity (convergent, discriminant) and sensitivity (treatment-related change over time). In addition patient acceptance of the questionnaire was assessed. Psychometric testing yield exellent results regarding scale structure and reliability of the newly developed questionnaire. Validity was reflected in high correlations with standard generic questionnaires and in discriminating in quality of life between patients according to disease severity. The sensitivity was reflected in improved quality of life ratings in patients with improved treadmill performance. Patients needed 20 minutes for responding and rated the questionnaire to be easily understandable and not exhausting. These results show that the newly developed PAVK-86 questionnaire is a reliable, valid and sensitive instrument for the assessment of quality of life in patients with arterial occlusive disease which can be used in clinical studies, epidemiological research and quality assurance programs.

[Quality of life in peripheral arterial occlusive disease. Multicenter study of quality of life characteristics with a newly developed disease-specific questionnaire]. / Lebensqualität bei peripher-arterieller Verschlusskrankheit. Multizentrische Untersuchung zur Lebensqualitätscharakteristik mit einem neu entwickelten krankheitsspezifischen Fragebogen (PAVK 86).

AIM: Owing to a lack of disease-specific measuring instruments, no systematic investigations of the impairment of the quality of life in patients with peripheral arterial occlusive disease (PAOD) have so far been possible. The aim of the present study, therefore, was to develop an appropriate questionnaire and to submit it to a psychometric test in a sufficiently large number of patients. PATIENTS AND METHOD: A disease-specific questionnaire comprising 86 individual items was developed (PAVK 86) and was tested in a longitudinal study involving 308 patients with confirmed peripheral arterial occlusive disease, Fontaines's stages I to IV. At the same time, three established generic questionnaires were also employed (SF 36, NHP, Every Day Life). RESULTS: Analysis showed that, in comparison with a normal population, the quality of life in patients with PAOD is considerably impaired, in particular by pain, anxiety, general complaints and reduced physical mobility and performance, and is comparable with that of patients suffering from renal carcinoma. In Fontaine's stage III and IV, the quality of life is significantly more greatly impaired than in patients with stage II disease. No differences in quality of life were to be found between Fontaine's stages III and IV. The psychometric test revealed that the PAVK 86 questionnaire is a sensitive, reliable, valid and practicable measuring instrument. CONCLUSION: The PAVK 86 questionnaire is suitable for determining the course and outcome of therapeutic measures on the quality of life of PAOD patients, and can therefore be included in clinical studies. In addition, its use in combination with established generic questionnaires also permits a comparison with age-matched healthy control groups, and is thus also of importance for the assessment of aspects of health economics.

[The effectiveness of standardized exercise training in intermittent claudication]. / Wirksamkeit eines standardisierten Bewegungstrainings bei Claudicatio intermittens.

In stage II peripheral arterial occlusive disease (PAOD) physical training is generally the therapy of choice if no reopening procedures are indicated. The aim of this pilot study was to ascertain the increase in claudication distance due to the exclusive implementation of an intensive exercise programme under standardized conditions, for a planned double blind placebo controlled study regarding the efficacy of pharmacotherapy in addition to physical training. 23 in-patients (median age 62 years) with an absolute claudication distance on treadmill of between 50 m and 200 m (12% inclination, 3 km/h walking speed) participated 5 days a week in the following intensive standardized physical training programme: in the morning and afternoon supervised gymnastics for about 30 minutes, followed by 2 cycles of treadmill exercise each amounting to 66% of the absolute claudication distance. After a training programme of 4 weeks the mean initial claudication distance rose significantly from 83 m to 134 m (61%), as did the mean absolute claudication distance from 127 m to 222 m (75%). If an increase in claudication distance of at least 60% is taken as criterion of efficacy, 48% of the patients can be defined as responders. After completion of personal inquiries 62% of the patients were willing to participate in a similar training programme again.

Treatment of patients with peripheral arterial occlusive disease Fontaine stage IV with intravenous iloprost and PGE1: a randomized open controlled study.

In a randomized open controlled study the clinical effects and tolerability of prostaglandin E1 (PGE1) and the stable prostacyclin (PGI2) analogue, iloprost in the management of diabetic and non-diabetic patients with advanced peripheral arterial occlusive disease (PAOD Fontaine stage IV) were compared. 267 patients were enrolled in this multicentre study and treated for 21-28 days, either by daily infusions of 6 h with iloprost or 2 x 2 h with PGE1. At the end of treatment patients were assessed for evidence of improvement of trophic lesions, relief of rest pain and change of global clinical status. 228 patients were considered as evaluable for efficacy analysis, which revealed 52.7% responders in the iloprost group and 43.1% for PGE1 (p = 0.148). Whereas iloprost showed similar effects in diabetics and non-diabetics (53.3% and 51.4% response rates, respectively), the diabetics treated with PGE1 had a considerably poorer outcome (36.6% versus 53.3%). At 6 months follow-up 62.2% of patients in both groups were alive with a viable limb. Slightly more iloprost patients underwent major amputation (32.1% versus 27.2%), but the number of deaths was reduced by 50% in the iloprost group compared to the PGE1 group (7.5% versus 14.6%, p = 0.10). Side-effects such as headache, flushing and gastrointestinal symptoms were significantly more common in the iloprost group (73.9%) than in the PGE1 group (31.0%), particularly during the first 3 days of dose titration. No specific toxic or unexpected reactions were reported in either group.

Mechanisms for the elevation of blood pressure in human renal disease. Preliminary report.

Detailed hemodynamic studies were carried out in 99 subjects with chronic nonuremic renal disease and 17 healthy subjects. The earliest hemodynamic abnormality found in normotensive renal patients was a raised circulating blood volume and an increased cardiac output. The blood pressure remained normal as long as the peripheral vascular bed (arteriolar and venous) adjusted to these conditions. When this adjustment ceased, hypertension developed and the blood volume normalized. It is suggested that a disturbed volume-homeostatic function of the kidney, leading to a rise of the circulating blood volume, is the proper starter of hemodynamic events leading eventually to hypertension in chronic parenchymatous renal disease.