Functional motor compensation in amyotrophic lateral sclerosis.

The present study investigated the fMRI correlates of functional compensation/neural reorganization of the motor system in patients with amyotrophic lateral sclerosis (ALS). The hypothesis was that ALS patients would recruit additional brain regions compared with controls in a motor task and that activity in these regions would vary as a function of task difficulty. Patients and controls executed a motor task with two sequences (a simple and a more difficult one) of consecutive button presses. Patients and controls both activated brain regions known to be involved in motor execution and control. Activity in ipsilateral motor areas as well as difficulty-related activity in the left cerebellum could only be observed in patients. The behavioral data indicated that the motor task was much more difficult for patients than for controls. At nearly equal difficulty the observed patterns of hemodynamic activity in controls were very similar to those observed in ALS. The findings suggest that functional compensation in ALS relies on existing resources and mechanisms that are not primarily developed as a consequence of the lesion.

Substantial impact of FDG PET imaging on the therapy decision in patients with early-stage Hodgkin's lymphoma.

This prospective study assessed the impact of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the staging and possible consequential changes of treatment regimen in patients with Hodgkin's lymphoma (HL). A total of 88 consecutive patients with histologically verified Hodgkin's lymphoma underwent a PET scan in addition to conventional staging procedures. Treatment was based on the conventional staging only, and the results of the FDG-PET did not affect the treatment strategy. The evaluation focused on the suggested change in clinical stage according to the Ann Arbor classification and on the suggested change in treatment strategy rather than on a lesion-by-lesion analysis. Using all the methods performed as the standard of reference, (18)F-FDG-PET staging was concordant with conventional staging in 70 out of 88 patients (80%). (18)F-fluorodeoxyglucose positron emission tomography suggested a change to a different clinical stage in 18 patients (20%). Management would have been changed in 16 patients (18%): intensification of treatment in nine patients (10%) and minimisation of treatment in seven patients (8%). In the 44 patients with early disease (stage IA-IIB), treatment would have been intensified in nine out of 44 patients (20%). (18)F-fluorodeoxyglucose positron emission tomography is a relevant noninvasive method that supplements conventional staging procedures and should therefore be used routinely to stage Hodgkin's lymphoma, particularly in patients with an early stage.

Comparison of GP IIB/IIIA inhibitors and their activity as measured by aggregometry, flow cytometry, single platelet counting, and the rapid platelet function analyzer.

BACKGROUND: GP IIb/IIIa inhibitors have primarily been used short-term e.g., during PTCA. They failed to show clinical benefit during long-term therapy. One reason might be the absence of a method to monitor inhibitor activity. This study compared platelet aggregometry, the rapid platelet function analyzer (RPFA) test, single platelet counting, and flow cytometric determination of receptor occupancy to measure GP IIb/IIIa-receptor inhibitor activity. METHODS: Increasing doses of abciximab, tirofiban, and eptifibatide were added to whole blood in vitro. Whole blood was used for the RPFA, for single platelet counting and flow cytometry. Platelet rich plasma was prepared for aggregometry. RESULTS: The correlation between aggregometry and RPFA results was linear for abciximab and eptifibatide. Tirofiban was a stronger inhibitor with the RPFA (IC(50) 7.7nM) than with aggregometry (IC(50) 19.6nM). The single platelet counting technique showed that even supratherapeutic concentrations of all three inhibitors could not completely suppress microaggregation. Abciximab concentrations that were equipotent to tirofiban with aggregometry were less potent with regards to the inhibition of microaggregation. This difference was more pronounced with TRAP induced microaggregation than with ADP. The flow cytometric receptor occupancy test showed that occupancy was 95% with 5 microg/ml abciximab and almost 97% with 10 microg/ml. Tirofiban reached a maximum receptor occupancy of 56%, eptifibatide 64%. CONCLUSIONS: While aggregometry is time consuming the RPFA provides results fast and with little variability. There is still a discrepancy between aggregometry and RPFA results for tirofiban. The single platelet counting technique detects the inhibition of microaggregation the relevance of which for the clinical outcome is not known. The flow cytometric receptor occupancy assay is best suited for abciximab.

[The value of positron emission tomography (PET) in the treatment of patients with cancer of unknown primary (CUP)]. / Bedeutung der Positronenemissionstomographie (PET) für die Behandlung von Patienten mit unbekanntem Primärtumor (CUP).

BACKGROUND: In patients with cancer of unknown primary median survival for localized disease is 20, for disseminated disease 7 months. After diagnostic procedures including MRI or endoscopy, the primary tumor is detected in less than 25%. In the study presented here the value of PET for detection of the primary tumor and a possible dissemination has been investigated and related to therapeutic regimens. PATIENTS AND METHODS: Between May 1998 and February 2001 a total of 52 patients with CUP syndrome, 18 females and 34 males, have been included. At first diagnosis, stage of disease was localized in 43 patients (35 lymphonodal, eight visceral), and disseminated in nine patients (Table 1). After a median of seven (range three to eleven) diagnostic procedures without detection of the primary tumor (Table 2) PET with fluorine-18-fluorodeoxyglucose was performed. RESULTS: Due to the PET result a primary tumor was suggested in 31/52 patients (60%), and confirmed in 21/52 patients (40%). In 16/43 patients (37%) with initially (before PET) localized disease dissemination was detected by PET only, despite various preceding diagnostic procedures (Figure 1). Overall, in 33/52 patients (63%) the PET result had major impact on selection of an individual treatment (Table 3), in case of initially localized disease in 30/43 patients (70%). CONCLUSION: In patients with CUP the PET result is not only of great value for detection of the primary tumor, but in case of initially localized disease also for diagnosis of a possible dissemination. The PET result often has relevant influence on therapeutic management.

[1-(11)C]Acetate as a quantitative perfusion tracer in myocardial PET.

UNLABELLED: Our objective was to investigate the properties of [1-(11)C]acetate as a quantitative perfusion tracer for myocardial PET studies. METHODS: We determined the flow dependence of the effective acetate extraction by a comparison with [(13)N]ammonia in 24 patients at rest (n = 8) and under pharmacologic vasodilation (n = 16). Furthermore, we compared the statistical quality of the perfusion values derived with both tracers. Quantification was based on an irreversible 2-compartment model for [(13)N]ammonia and a reversible 1-compartment model for [1-(11)C]acetate. Area-conserving polar maps were used to determine the correlation between the unidirectional uptake parameters of both tracers on a pixel-by-pixel basis for the whole left ventricular myocardium. RESULTS: A fit of a generalized Renkin-Crone formula to the data yielded the unidirectional acetate extraction fraction E(f) = 1 - 0.64e(-1.20/f). An extraction correction based on this formula led to good quantitative agreement of perfusion values derived with [(13)N]ammonia and [1-(11)C]acetate over the whole observed flow range (average difference of flow values, 3%; correlation coefficient, 0.96). This agreement proved the applicability of acetate as a quantitative perfusion tracer even under stress conditions. An analysis of the statistical properties of the parameter estimates showed, moreover, that statistical errors were reduced by a factor of nearly 2 in comparison with ammonia. CONCLUSION: [1-(11)C]acetate allows accurate quantification of myocardial perfusion with PET at rest as well as under stress conditions. The use of acetate leads to distinctly improved statistical accuracy for the perfusion estimates in comparison with ammonia. This accuracy facilitates the generation of reliable parametric polar maps, which are especially useful for clinical application of myocardial perfusion quantification.

[18F-FDG positron-emission-tomography in cervical carcinoma: preliminary findings]. / 18F-FDG-Positronen-Emissions-Tomographie bei Zervixkarzinom: Erste Ergebnisse.

18F-Fluorodesoxyglucose-Positron-Emission-Tomography (18F-FDG-PET) is a novel imaging modality for malignancies. This study was initiated to define the efficiency of PET in detecting and characterizing metabolically the primaries and in preoperatively assessing of lymphonodal metastases of cervical cancer. 15 patients with histologically proven cervical carcinoma were studied with 18F-FDG-PET regarding 18F-FDG-uptake of primary tumor and evidence as well as extent of lymphonodal metastases. 18F-FDG-PET and histopathological results were compared after radical hysterectomy with pelvic and supplementary in 7 cases paraaortal lymphadenectomy. All primary tumours showed 18F-FDG accumulation and had a mean maximal standardized uptake value (SUV) of 8.0 +/- 5.3. 3/6 lymph node metastases were obtained with 18F-FDG-PET. Micrometastases (size of metastasis < or = 0.2 cm) were present in 2 patients with false negative PET results. Regarding the subgroup with paraaortal lymph node dissection, PET detected one patient with metastases, the other one had micrometastasis, while metastasis was not observed by PET. The accuracy of PET is 73% for assessment of pelvic lymph nodes and 86% for assessment of paraaortal lymph nodes. In conclusion 18F-FDG accumulates reliably in primaries of cervical cancer. Regarding assessment of lymph node metastases PET seems to be of potential use, offering metabolic information independent of the size of metastatic lymph nodes. An improvement of accuracy can be expected if combined evaluation of morphologic and metabolic images is performed.

Localised disease in cancer of unknown primary (CUP): the value of positron emission tomography (PET) for individual therapeutic management.

BACKGROUND: Two to four percent of cancer patients present with CUP syndrome. Median survival for localised disease is 20 and for disseminated disease, seven months. For localised disease, curative treatment is more likely and individual therapeutic strategies become more important. After conservative diagnostic procedures including MRI, the primary is detected in less than 25%. The diagnostic value of PET and its influence on therapeutic strategies was evaluated. PATIENTS AND METHODS: Forty-two patients with localised CUP were investigated from 5 of 98 to 10 of 2000. The presenting site was lymph node metastasis in 34 and visceral metastasis in 8 patients. After a median of 7 (3-11) diagnostic procedures without detection of the primary, but evidence of localised disease, PET was performed with fluorine-18-fluorodeoxyglucose. RESULTS: In 26 of 42 patients (62%), a primary was suggested by PET and confirmed in 18 (43%). In 5 of 18 patients beyond localised disease, additional dissemination, not detected by previous diagnostic measures, was diagnosed by PET. Overall, dissemination was only detected only by PET in 16 of 42 patients (38%). In29 of 42 patients (69%), the PET result influenced selection of the definitive treatment. CONCLUSION: In CUP patients, PET has a certain impact on detection of the primary as well as of the disseminated disease. and may also have a certain impact on therapeutic management.

Effect of glycoprotein IIb/IIIa inhibitors on CD62p expression, platelet aggregates, and microparticles in vitro.

Flow cytometry can detect platelet activation (CD62p), aggregate formation, microparticle formation, and glycoprotein IIb/IIIa (GP IIb/IIIa) receptor occupancy in one sample at the level of single particles. We studied the effect of GP IIb/IIIa inhibitors on platelet activation with flow cytometry in vitro. Citrated whole blood was incubated with increasing concentrations of three different GP IIb/IIIa inhibitors (c7E3, DMP728, XJ757), then thrombin or adenosine diphosphate (ADP) was added, and after 1 minute the sample was fixed. Samples with thrombin but without c7E3 had a decrease in platelet count, from a mean of 260,000 platelets/microl to 56,000 platelets/microL, and aggregates increased. Samples with concentrations of c7E3 that resulted in 80% or more receptor blockade had no decrease in platelet count, and no aggregates were formed, but the number of CD62p-positive single platelets increased from 1200 to 7400 platelets/microL. The two other inhibitors (DMP 725, XJ757) or ADP instead of thrombin gave similar results. Microparticle formation did not change with platelet activation in the presence of a GP IIb/IIIa inhibitor. With small inhibitor doses resulting in <80% receptor blockade, the number of aggregates did not change or was even higher than that in samples without inhibitor. GP IIb/IIIa inhibitors do prevent aggregate formation but they do not prevent activation of platelets. With GP IIb/IIIa inhibition, more activated single platelets remain in the blood. One may expect an increasing number of circulating, activated platelets with the use of GP IIb/IIIa inhibitors.

[Occult tumor cells of malignant melanoma and consequences for surgical treatment]. / Okkulte Tumorzellen des malignen Melanoms und Konsequenzen für das chirurgische Vorgehen.

UNLABELLED: Immediate and complete surgical excision is the standard mode of treatment for primary malignant melanoma. There is still a controversy about the adequate resection margins. In this study we looked for microscopic satellites in order to estimate the extent of local therapy. METHOD: 19 patients with malignant melanoma of the trunk or extremities, treated by wide excision, were included. Clinical courses were documented. Postoperative follow-up was 1.4 years in the mean. In primary tumours and cutaneous excisions we looked for microscopic satellites with routine histology and immunohistochemistry (APAAP-technique, monoclonal antibody HMB-45). RESULTS: Using APAAP-technique in combination with routine histology, we could show that microscopic satellites only occurred in specimens of melanomas of more than 5 mm thickness. In the two cases where evident microscopic satellites were present a systemic dissemination obviously evolved already before the first surgical treatment. Therefore, in those cases wide resection margins do not provide an increasing chance of survival. CONCLUSION: The idea to remove microscopic satellites by wide surgical excisions and thus to reduce the risk for systemic dissemination and local recurrence cannot be supported.

Quantitative assessment of platelets, platelet microparticles, and platelet aggregates with flow cytometry.

With fluorescent beads it has become possible to determine absolute numbers of cells in a given sample instead of relative percentages on a standard flow cytometer. This study assesses the ability to count platelets, microparticles, and aggregates with a flow cytometer. Whole blood was stimulated with 0.1 U thrombin per milliliter. Platelet and microparticle counts decreased, while the number of aggregates increased. Unactivated whole blood was diluted with buffer and showed a corresponding decrease in the concentration of platelets, microparticles, and aggregates. The platelet count on the flow cytometer was always in good correlation with counts on an automated blood analyzer. Only the cytometer, and not the automated analyzer, was able to detect and count microparticles and aggregates. In highly diluted samples of unactivated whole blood there was a spurious relative increase in CD62p-positive platelets because of a surplus of anti-CD62p antibodies and a relative increase in microparticles. Flow cytometry is a valuable method for counting platelets, aggregates, and microparticles in unstimulated and activated blood samples. If the platelet count changes and drops to less than 50% of the count for which the amount of antibody and the cytometer settings have initially been adjusted, care has to be taken to avoid misinterpretation.

Relative and absolute changes of activated platelets, microparticles and platelet aggregates after activation in vitro.

Standard flow cytometers provide relative numbers of activated platelets, microparticles, and platelet aggregates. With fluorescent beads it is now possible to determine absolute numbers. Whole blood and platelet-rich plasma were incubated with agonists (ADP, collagen, thrombin). CD62p expression, microparticle and platelet aggregate formation were measured. Flow-Count Fluorospheres((R)) were added to calculate absolute concentrations. After activation there was an increase in the percentage of CD62p-positive platelets. However, the total number of platelets decreased and therefore the absolute number of CD62p-positive platelets did not increase but decreased. The number of CD62p-positive platelets decreased not as much as the number of CD62p-negative platelets, which explains why the relative percentage of CD62p-positive platelets increased. A similar increase in percent and decrease in absolute counts was found for microparticles. Platelet aggregates increased both in relative and absolute numbers. These results suggest that the detection of activated platelets by flow cytometry has to be complemented by the determination of the absolute concentrations to avoid misinterpretation.