First report on a prospective trial with yttrium-90-labeled ibritumomab tiuxetan (Zevalin) in primary CNS lymphoma.

Most patients with primary CNS lymphoma (PCNSL) relapse after primary therapy. Standard salvage treatment has not yet been established in PCNSL. Anti-CD20 immunotherapy has expanded treatment options in systemic B-cell lymphoma; however, its use is limited by reconstitution of the blood-brain barrier after tumor shrinkage. The aim of this phase II trial was to evaluate the therapeutic efficacy, toxicity, and biodistribution of yttrium-90 ((90)Y) ibritumomab tiuxetan in PCNSL. Ten patients with relapsed PCNSL were included in a phase II trial and treated with the (90)Y-labeled anti-CD20 antibody ibritumomab tiuxetan. Nine patients actually received the planned radioimmunotherapy. In six patients, biodistribution of the antibody was measured by indium-111 ((111)In) ibritumomab tiuxetan whole-body scans and single-photon-emission CT (SPECT) of the brain. All patients were evaluated for toxicity and response at least 4 weeks after therapy. Four patients responded: one patient had a complete response lasting 30+ months, and three patients had short-lived responses of

Yttrium-90 ibritumomab tiuxetan radioimmunotherapy in primary cutaneous B-cell lymphomas: first results of a prospective, monocentre study.

Radioimmunotherapy with Yttrium-90 ((90)Y) ibritumomab tiuxetan (IT) has been shown to be effective in systemic B-cell lymphomas. We conducted a pilot study to evaluate the outcome and assess complications of (90)Y IT therapy in patients with primary cutaneous B-cell lymphomas (PCBCL). Ten patients, all but one, with relapsed PCBCL were included and treated with rituximab (250 mg m(-2)/body surface) on days 1 and 8 followed by a single dose of (90)Y IT (11-15 MBq kg(-1)). The overall response rate was 100%. The complete response rate was 100%. The median time to relapse was 12 months. Ongoing remissions were achieved in four patients (median follow-up 19 months). Transient and reversible myelosuppression (grade 3-4) was the most frequent adverse event. Radioimmunotherapy with (90)Y IT is an effective treatment in relapsed primary cutaneous follicle centre lymphomas and diffuse large B-cell lymphoma leg-type. Further investigations in controlled randomised clinical trials evaluating the role of (90)Y IT versus rituximab in PCBCL are needed.

Multimodal fusion imaging ensemble for targeted sentinel lymph node management: initial results of an innovative promising approach for anatomically difficult lymphatic drainage in different tumour entities.

PURPOSE: There are situations where exact identification and localisation of sentinel lymph nodes (SLNs) are very difficult using lymphoscintigraphy, a hand-held gamma probe and vital dye, either a priori or a posteriori. We developed a new method using a simultaneous injection of two lymphotropic agents for exact topographical tomographic localisation and biopsy of draining SLNs. The purpose of this prospective pilot study was to investigate the feasibility and efficacy of this method ensemble. METHODS: Fourteen patients with different tumour entities were enrolled. A mixture of (99m)Tc-nanocolloid and a dissolved superparamagnetic iron oxide was injected interstitially. Dynamic, sequential static lymphoscintigraphy and SPECT served as pathfinders. MR imaging was performed 2 h after injection. SPECT, contrast MRI and, if necessary, CT scan data sets were fused and evaluated with special regard to the topographical location of SLNs. The day after injection, nine patients underwent SLN biopsy and, in the presence of SLN metastasis, an elective lymph node dissection. RESULTS: Twenty-five SLNs were localised in the 14 patients examined. A 100% fusion correlation was achieved in all patients. The anatomical sites of SLNs detected during surgery showed 100% agreement with those localised on the multimodal fusion images. SLNs could be excised in 11/14 patients, six of whom had nodal metastasis. CONCLUSION: Our novel approach of multimodal fusion imaging for targeted SLN management in primary tumours with lymphatic drainage to anatomically difficult regions enables SLN biopsy even in patients with lymphatic drainage to obscure regions. Currently, we are testing its validity in larger patient groups and other tumour entities.

Impact of sentinel lymph node biopsy in patients with Merkel cell carcinoma: results of a prospective study and review of the literature.

PURPOSE: Merkel cell carcinoma (MCC) is the most aggressive of the cutaneous malignancies, showing a propensity to spread to regional lymph nodes (LNs). The aim of this prospective study was to examine the feasibility and clinical impact of sentinel lymph node biopsy (SLNB) in this cutaneous malignancy. METHODS: The study population comprised 23 patients with stage I MCC (median age 70 years, range 50-85 years). Lymphoscintigraphic mapping with( 99 m)Tc-nanocolloid was performed in all patients. Sentinel lymph nodes (SLNs) were identified, excised and analysed in serial sections by conventional histopathology and cytokeratin-20 immunohistochemistry. RESULTS: Metastatic disease was determined in the SLNs of 11 patients (47.8%). Elective lymph node dissection (ELND) was performed in eight of these 11 patients, four of whom had additional positive LNs. During follow-up (median 36.1 months, range 3-79 months), seven of the 23 patients (30%) relapsed: four had a local recurrence and three, in-transit metastases. Recurrence developed in two SLN-negative patients with local LN metastases and in one SLN-positive patient with distant metastases. This patient died, representing the only tumour-related death in our sample. Median survival was 49.1 and 35.5 months for SLN-negative and SLN-positive patients, respectively. This difference was not statistically significant (p=0.3452). CONCLUSION: SLNB allows for exact nodal staging in patients with MCC. Whether additional ELND is of further benefit remains unclear.

Radioimmunotherapy using 131I-rituximab in patients with advanced stage B-cell non-Hodgkin's lymphoma: initial experience.

PURPOSE: The aim of this study was to evaluate the safety, toxicity and therapeutic response of non-myeloablative radioimmunotherapy using 131I-rituximab in previously heavily treated patients with B-cell non-Hodgkin's lymphoma (B-NHL). METHODS: Nine patients with relapsed, refractory or transformed B-NHL received ten radioimmunotherapies. Patients had a median of 5 (range 2-7) prior standard therapies. Four patients had received prior high-dose chemotherapy followed by autologous stem cell transplantation, and eight had received prior rituximab therapy. Histopathology consisted of four mantle cell, one follicular and four diffuse large B-cell lymphomas. Rituximab, a monoclonal chimeric anti-CD20 antibody (IDEC-C2B8), was labelled with 131I using the Iodogen method. The administered activity (2,200+/-600 MBq) was based on a dosimetrically calculated 45 cGy total-body radiation dose. All patients received an infusion of 2.5 mg/kg of rituximab prior to administration of the radiopharmaceutical. RESULTS: No acute adverse effects were observed after the administration of 131I-rituximab. Radioimmunotherapy was safe in our patient group and achieved one complete response ongoing at 14 months and two partial responses progressing at 12 and 13 months after treatment. One partial responder was re-treated with radioimmunotherapy and achieved an additional progression-free interval of 7 months. Four non-responders with bulky disease died 4.8+/-2.0 months after therapy. Three patients had an elevated serum lactate dehydrogenase (LDH) level prior to radioimmunotherapy and none of the patients responded. Of two patients who received radioimmunotherapy as an additional treatment after salvage chemotherapy, one continues to be disease-free at 9 months and one relapsed at 5 months' follow-up. Reversible grade 3 or 4 haematological toxicity occurred in seven of nine patients. Median nadirs were 35 days for platelets, 44 days for leucocytes and 57 days for erythrocytes. CONCLUSION: Radioimmunotherapy with 131I-rituximab in previously heavily treated B-NHL patients was safe and well tolerated, and four out of ten therapies induced responses. Radioimmunotherapy was less efficient in patients with bulky disease and elevated LDH. Severe haematological toxicity in seven patients did not cause significant clinical problems. Radioimmunotherapy seems to be an additional therapeutic option in carefully selected therapy-refractory B-NHL patients.

Myocardial viability evaluation using magnetocardiography in patients with coronary artery disease.

OBJECTIVE: Magnetocardiography (MCG) has been used to risk stratify patients in terms of sudden death or to detect ischemia. We evaluated the potential of this technique to assess myocardial viability in coronary artery disease. METHODS: Fifteen patients aged 36-75 (median, 59) years with stable single-vessel disease (> or =70% diameter stenosis) and corresponding regional wall-motion abnormality underwent (1) echocardiography to evaluate wall motion, (2) Tl dipyridamole single-photon emission computed tomography to document perfusion and (3) quantitative F-fluorodeoxyglucose positron emission tomography to assess viability in 16 left-ventricular wall segments. MCG was performed in each patient using a shielded prototype 49-channel low-temperature superconducting quantum interference device (SQUID) system. Multiple time and area parameters were extracted automatically from each baseline-corrected data set. RESULTS: Eleven patients had prior myocardial infarction. In each patient, four to 12 (median, seven) segments were lesion dependent, totalling up to 117 out of 240 segments. A total of 88 segments (75%) were viable and 29 segments (25%) represented scar. Patients were divided into three categories: (a) no scar segments (five patients), (b) scar in one to three segments (six patients) and (c) scar in > or = four segments (four patients). The three MCG parameters with the best selectivity were identified using linear discriminant analysis with forward inclusion (P<0.10). The corresponding Fisher's discriminant functions classified all patients correctly (Wilks' lambda=0.079). CONCLUSION: Selected MCG parameters yielded accurate patient classification with regard to the extension of myocardial scar within the viable tissue in retrospect. These findings indicate that MCG may contribute to the assessment of myocardial viability. Further evaluation in a comprehensive multicenter study is warranted.

Subareolar injection of technetium-99m nanocolloid yields reliable data on the axillary lymph node tumour status in breast cancer patients with previous manipulations on the primary tumour: a prospective study of 117 patients.

According to recently published guidelines, histological clarification by interventional techniques should be undertaken before planning the surgical management of patients with breast carcinoma. In patients with previous manipulations on the primary tumour, peritumoural injection in the context of preoperative scintigraphic detection of the sentinel lymph nodes is not possible. The aim of this prospective study was to clarify whether subareolar injection of nanocolloid can yield reliable data on the axillary lymph node tumour status in breast cancer patients with previous manipulations on the primary tumour. To date, 117 women (age 31-80 years) with breast carcinoma have been enrolled. All of these patients had undergone a biopsy (n=88) or surgery on the primary tumour (n=29) and were without clinical suspicion of lymph node metastases. Subareolar injection of 40 MBq technetium-99m nanocolloid was carried out in at least eight deposits around the areolar margin [one deposit in the middle of each quadrant and one deposit at each quadrant intersection (0.05 ml/deposit)]. Immediately after injection, dynamic and static lymphoscintigraphy of the axillary, thoracic and cervical areas was performed in various views with a gamma camera (LEAP collimator, 256x256 matrix). Lymphatic drainage was directed exclusively to the ipsilateral axilla. Sentinel lymph node biopsy and elective dissection of axillary lymph nodes were performed in all patients. All lymph nodes removed were examined by histology and immunohistochemistry. In 26 patients, lymph node metastases were found in the sentinel lymph nodes. In six of them, non-sentinel lymph nodes also showed tumour involvement. In the remaining 91 patients, lymph node metastases could be found neither in sentinel lymph nodes nor in non-sentinel lymph nodes. In conclusion, subareolar nanocolloid injection can yield reliable information on the axillary lymph node tumour status in patients with previous manipulations on the primary tumour in the breast.

[Testing cross-calibration between positron emission tomographs and their peripheral devices]. / Uberprüfung der Kreuzkalibrierung von Positronen-Emissions-Tomographen zu ihren peripheren Geräten.

The aim of this study was to evaluate the cross-calibration of positron emission tomographs and their peripheral devices prior to a multicenter study. The instrumentation of 22 sites (including 24 dedicated PET scanners), including 21 that could be operated in 2D mode and 20 in 3D mode, was investigated according to standardized acquisition and reconstruction protocols, and the cross-calibration was checked against the dose calibrators (22 instruments) and the sample changer (20 instruments). The deviation of the cross-calibration to the dose calibrators was below 5% for 10 of 21 PET scanners (2D mode) and 6 of 20 (3D mode). For 6 (2D mode) and 6 (3D mode) scanners, the corresponding error was up to 10%. In turn, the deviation between dose calibrator and standard was less than 8% for 19 devices, and even less than 5% for 14 devices. In most of the well counters evaluated, the cross-calibration error was less than 10%. Although required in general, the cross-calibration between positron emission tomographs and their peripheral devices becomes even more critical when pooling data in the framework of quantitative clinical multicenter studies.

Peritumoural versus subareolar administration of technetium-99m nanocolloid for sentinel lymph node detection in breast cancer: preliminary results of a prospective intra-individual comparative study.

The scintigraphic detection of sentinel lymph nodes (SNs) in early-stage breast cancer is a widely accepted diagnostic method. However, which radiotracer administration mode should be used is still controversial. This prospective study aimed to intra-individually compare the detection rates obtained after peritumoural versus subareolar injection with regard to SN number and localisation. Fifty-one women (age, 32-76 years) with breast cancer were investigated on two consecutive days. On day 1, 140-400 MBq technetium-99m nanocolloid was injected along the peripheral tumour margins. Static lymphoscintigrams of the axilla, thorax and neck were taken in various views 1 and 19 h p.i. On day 2, 10 MBq (99m)Tc-nanocolloid was injected subareolarly in the clock position of the tumour and dynamic and static scans were performed immediately. Thereafter, 30 MBq (99m)Tc-nanocolloid was administered peri-subareolarly and lymphoscintigrams were acquired in a dynamic and static manner. In 49/51 women, the different injection techniques disclosed the identical number and location of SNs in the axilla. In seven patients, the peritumoural injection detected additional SNs in the parasternal group. Axillary SNs were detected as early as 2-15 min following subareolar injection, both in the clock position and peri-subareolarly, as compared with about 1 h after peritumoural administration. Sixteen patients showed at least one tumour-positive SN, and nine also had tumour-positive non-SNs. One patient with a tumour-negative SN, visualised concordantly by both subareolar and peritumoural administration, demonstrated two metastatic non-SNs, yielding a false-negative rate of 5.9%. In conclusion, a simple subareolar injection in the clock position is sufficient for SN detection in breast cancer, if it is accepted that parasternal lymph node detection has no therapeutic consequences.

Influence of fast lymphatic drainage on metastatic spread in cutaneous malignant melanoma: a prospective feasibility study.

The concept of sentinel lymph node biopsy in cutaneous malignant melanoma is widely established. Preoperative cutaneous lymphoscintigraphic mapping is a reliable method for identifying the nodal basins at risk of metastases in melanomas. In this prospective study we investigated the correlation between the scintigraphic appearance time and the metastatic involvement of sentinel lymph nodes. In 276 malignant melanoma patients (137 women, 139 men; age 16-93 years), dynamic and static lymphoscintigraphy was performed after strict intracutaneous application of technetium-99m nanocolloid (40-150 MBq; 0.05 ml/deposit) around the tumour or biopsy scar. Analysis of dynamic scans primarily focussed on the appearance time of sentinel lymph nodes. Sentinel lymph node visualisation 20 min as slow drainage. Fast lymphatic drainage was found in 236 patients, of whom 34 (14.4%) had sentinel lymph node metastases. Twenty-two patients showed hybrid (fast and slow) lymphatic drainage, and eight (36.4%) of them had sentinel lymph node metastases. Seven of the latter demonstrated fast lymphatic drainage, while one showed one positive sentinel lymph node with fast and another with slow drainage. The melanomas of 18 patients demonstrated exclusively slow lymphatic drainage, in all cases without sentinel lymph node metastases. This prospective study indicates that the scintigraphic appearance time of sentinel lymph nodes seems to be a clinically relevant factor for prediction of metastatic spread of cutaneous malignant melanoma. Larger numbers of patients need to be examined to truly assess the benefit of the scintigraphic appearance time compared with other predictors of sentinel lymph node tumour positivity.

Myocardial contrast echocardiography for predicting functional recovery after acute myocardial infarction.

UNLABELLED: Myocardial contrast echocardiography (MCE) is a promising diagnostic tool for detecting microvascular integrity. The aim of the study was to investigate the comparative specificity and sensitivity of intravenous MCE, technetium-99m Sestamibi single-photon emission computed tomography (SPECT) and dipyridamole-dobutamine (DIDO) stress echocardiography for predicting functional recovery after coronary revascularization in patients with acute myocardial infarction (AMI). METHODS: In a prospective, observational study, 17 consecutive patients short after AMI who received successful treatment with primary percutaneous coronary angioplasty (PTCA) plus stent-implantation were examined with DIDO (dipyridamole with 0.28 mg/kg over 4 min plus dobutamine up to 10 mcg/kg/min), MCE (10 ml 4 g, 400 mg/ml Levovist intravenously; second harmonic power imaging) within 12-24 h and resting perfusion SPECT within 48-72 h after PTCA. Functional recovery of regional contractile function after 6-month follow-up was the gold standard to assess viability. RESULTS: The rate of agreement between SPECT and MCE was 69% and between SPECT and a positive response to stress echo was 76% for combined DIDO. MCE showed a higher sensitivity (96%) in the identification of viability than SPECT (77%) and combined DIDO alone (79%). Specificity was lower for viability recognition with MCE (58%) compared with SPECT (93%) and DIDO (87%). CONCLUSIONS: The wall motion response during DIDO echocardiography is useful in the prediction of recovery of regional and global ventricular function after revascularization in patients after AMI. Combined intravenous MCE and DIDO is more accurate in the diagnosis of stunned myocardium than Tc-99m-MIBI SPECT alone.

Multicenter comparison of calibration and cross calibration of PET scanners.

UNLABELLED: The purpose of this study was to compare the calibration of PET scanners and their cross calibration to peripheral devices in a multicenter study. METHODS: Twenty-three dedicated PET scanners were investigated, applying standardized protocols. To ensure exact determination of the activity used, dose calibrators were checked using (68)Ge standards. RESULTS: Nine of 19 and 11 of 20 scanners displayed an error of <5% in 3-dimensional and 2-dimensional acquisition modes, respectively. Four and 5 scanners displayed an error of 10% in 3-dimensional and 2-dimensional modes, respectively. All other scanners yielded errors of 5% to <10%. Because of hardware and software problems, the measurements performed on 1 scanner could not be adequately analyzed. CONCLUSION: An investigation of calibration is mandatory. Especially for quantitative analyses in clinical multicenter trials, identification of potentially miscalibrated scanners is necessary.

Use of recovery coefficients as a test of system linearity of response in positron emission tomography (PET).

Quantitative determination of activity concentration has always been regarded as a goal of PET scanner design. Therefore, a linear response with respect to activity concentration is essential. To prove system linearity of response a test is proposed based on the determination of recovery coefficients (RC) for different object geometries. If all degrading effects, especially scatter and attenuation, are corrected to a sufficient degree of accuracy, the system behaves linearly resulting in a theoretical relationship between hot (HSRC) and cold spot recovery coefficients (CSRC). Therefore this relationship, applied to appropriate phantom data containing hot or cold spheres, combined with the constraints on asymptotic behaviour of RC can be used as a test of system linearity of response. After applying the system's standard corrections RC were determined using both 2D and 3D data acquisition modes. For both 2D and 3D data, HSRC directly measured showed an excellent agreement with the HSRC calculated from the CSRC. The analysis was extended to radionuclides of different positron ranges, to the effect of data smoothing, and to that of iterative reconstruction. The agreement between the RC determined under varying border conditions demonstrates the effectiveness of the corrections used in constituting system linearity. Therefore, the method proposed is used as a test of system linearity of response.

Electron beam computed tomography and ventilation perfusion scintigraphy in the diagnosis of pulmonary embolism.

The purpose of this study, performed in patients with suspected pulmonary embolism (PE), was to compare V/Q scans and electron beam computed tomography (CT) scans on a patient-by-patient and segment-by-segment basis. Both a segment-based and a lobe-based analysis was performed in those patients positive for PE. The diagnosis of PE was assumed on the basis of a mismatch at V/Q scanning or a filling defect in a pulmonary vessel at contrast-enhanced electron beam CT. In 37/45 patients (24 female, 21 male, 58+/-16 years) with suspected PE, the diagnosis of PE was confirmed or excluded by both modalities, resulting in a correlation of 82% between electron beam CT and V/Q scanning. In the 28 patients positive for PE according to one or both modalities, 504 segments were evaluated. Of these 504 segments, 248 (nearly 50%) showed perfusion defects on V/Q scans, of which only 90 (36%) displayed emboli at electron beam CT. Overall, a total of only 135 of the 504 segments (27%) were abnormal at electron beam CT. More than 50% of the patients with discrepant results did not show an embolus at electron beam CT. It is concluded that there is a good correlation (82%) between V/Q scanning and electron beam CT on a patient-by-patient basis but a markedly less good correlation (62%) in a segment-based analysis.