Jukka Schildt

Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma

The main objective of the MCL3 study was to improve outcome for patients not in complete remission (CR) before transplant by adding (90)Y-ibritumomab-tiuxetan (Zevalin) to the high-dose regimen. One hundred sixty untreated, stage II-IV mantle cell lymphoma patients <66 years received rituximab (R)-maxi-CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) alternating with R-high-dose cytarabine (6 cycles total), followed by high-dose BEAM/C (bis-chloroethylnitrosourea, etoposide, cytarabine, and melphalan or cyclophosphamide) and autologous stem cell transplantation from 2005 to 2009. Zevalin (0.4 mCi/kg) was given to responders not in CR before transplant. Overall response rate pretransplant was 97%. The outcome did not differ from that of the historic control: the MCL2 trial with similar treatment except for Zevalin. Overall survival (OS), event-free survival (EFS), and progression-free survival (PFS) at 4 years were 78%, 62%, and 71%, respectively. For responding non-CR patients who received Zevalin, duration of response was shorter than for the CR group. Inferior PFS, EFS, and OS were predicted by positron emission tomography (PET) positivity pretransplant and detectable minimal residual disease (MRD) after transplant. In conclusion, positive PET and MRD were strong predictors of outcome. Intensification with Zevalin may be too late to improve the outcome of patients not in CR before transplant. This trial was registered at www.clinicaltrials.gov as #NCT00514475.

Complementary Roles of 18F-DOPA PET/CT and 18F-FDG PET/CT in Medullary Thyroid Cancer

Serum calcitonin and carcinoembryonic antigen (CEA) are markers of recurrent or persistent disease in medullary thyroid cancer (MTC). However, conventional imaging often fails to localize metastatic disease. Our aim was to compare fluorine-labeled dihydroxyphenylalanine (18F-DOPA) and 18F-FDG PET/CT with multidetector CT (MDCT) and MRI in recurrent or persistent MTC. Methods: Nineteen MTC patients with increased calcitonin or CEA on follow-up (mean ± SD, 93 ± 91 mo; range, 4–300 mo) after primary therapy were prospectively imaged with 4 techniques: 18F-DOPA PET/CT, 18F-FDG PET/CT, MDCT, and MRI. Images were analyzed for pathologic lesions, which were surgically removed when possible. The correlation between the detection rate for each method and the calcitonin and CEA concentrations and histopathologic findings was investigated. Results: On the basis of histology and follow-up, one or more imaging methods accurately localized metastatic disease in 12 (63%) of 19 patients. The corresponding figures for 18F-DOPA PET/CT, 18F-FDG PET/CT, MDCT, and MRI were 11 (58%) of 19, 10 (53%) of 19, 9 (47%) of 19, and 10 (59%) of 17, respectively. Calcitonin and CEA correlated with 18F-DOPA PET/CT (P = 0.0007 and P = 0.0263, respectively) and 18F-FDG PET/CT findings (both P < 0.0001). In patients with an unstable calcitonin doubling time (n = 8), 18F-DOPA and 18F-FDG PET/CT were equally sensitive. In contrast, for patients with an unstable CEA doubling time (n = 4), 18F-FDG PET/CT was more accurate. Conclusion: For most MTC patients with occult disease, 18F-DOPA PET/CT accurately detects metastases. In patients with an unstable calcitonin level, 18F-DOPA PET/CT and 18F-FDG PET/CT are complementary. For patients with an unstable CEA doubling time, 18F-FDG PET/CT may be more feasible. MRI is sensitive but has the highest rate of false-positive results.

Planar Scintigraphy with 123I/99mTc-Sestamibi, 99mTc-Sestamibi SPECT/CT, 11C-Methionine PET/CT, or Selective Venous Sampling Before Reoperation of Primary Hyperparathyroidism?

All patients with primary hyperparathyroidism should undergo localization studies before reoperation, but it is not known which method is most accurate. The purpose of this prospective study was to compare the performance of planar scintigraphy with 123I/99mTc-sestamibi, 99mTc-sestamibi SPECT (SPECT/CT), 11C-methionine PET/CT, and selective venous sampling (SVS) in persistent primary hyperparathyroidism. Methods: Twenty-one patients referred for reoperation of persistent hyperparathyroidism were included and investigated with 123I/99mTc-sestamibi, SPECT/CT (n = 19), 11C-methionine PET/CT, and SVS (n = 18) before reoperation. All patients had been operated on 1–2 times previously because of hyperparathyroidism. The results of the localization studies were compared with operative findings, histology, and biochemical cure. Results: Eighteen (86%) of 21 patients were biochemically cured. Nineteen parathyroid glands (9 adenomas, 1 atypical adenoma, and 9 hyperplastic glands) were removed from 17 patients, and 1 patient who was biochemically cured had an unclear histology result. The accuracy for localizing a pathologic parathyroid gland to the correct side of the neck was 59% (95% confidence interval [CI], 36%–79%) for 123I/99mTc-sestamibi, 19% (95% CI, 5%–42%) for SPECT/CT, 65% (95% CI, 43%–84%) for 11C-methionine PET/CT, and 40% (95% CI, 19%–65%) for SVS (P < 0.01 for 123I/99mTc-sestamibi vs. SPECT/CT). The corresponding accuracy for the correct quadrant or more specific site was 48% (95% CI, 27%–69%) for 123I/99mTc-sestamibi, 14% (95% CI, 3%–36%) for SPECT/CT, 61% (95% CI, 39%–80%) for 11C-methionine PET/CT, and 25% (95% CI, 9%–49%) for SVS (P < 0.02 for 123I/99mTc-sestamibi vs. SPECT/CT). In the 3 patients not cured, preoperative 123I/99mTc-sestamibi and SPECT/CT remained negative, SVS was false predictive in all, and 11C-methionine PET/CT in 1. 11C-methionine PET/CT accurately revealed the pathologic gland in 4 of 8 (50%) patients with a negative 123I/99mTc-sestamibi scan result, all of whom were biochemically cured after reoperation. Conclusion: Planar scintigraphy with 123I/99mTc-sestamibi performs well in complicated primary hyperparathyroidism and is recommended as first-line imaging before reoperation. 11C-methionine PET/CT provides valuable additional information if 123I/99mTc-sestamibi scan results remain negative. 99mTc-sestamibi SPECT/CT and SVS provide no additional information, compared with the combined results of 123I/99mTc-sestamibi and 11C-methionine PET/CT imaging.

Autologous bone marrow mononuclear cell transplantation in ischemic heart failure: A prospective, controlled, randomized, double-blind study of cell transplantation combined with coronary bypass

BACKGROUND Bone marrow mononuclear cell (BMMC) transplantation for heart failure has shown inconsistent therapeutic efficacy. METHODS We enrolled 104 ischemic heart failure patients scheduled for coronary artery bypass surgery (CABG). After 4- to 12-week pharmacotherapy optimization, 39 patients with left ventricular ejection fraction (LVEF) of ≤45% received injections of BMMC or vehicle intra-operatively into the myocardial infarction border area in a randomized, double-blind manner. RESULTS The median number of cells injected was 8.4 × 10(8) (interquartile range [IQR]: 5.2 × 10(8) to 13.5 × 10(8)). We measured LV function and myocardial scar size by magnetic resonance imaging (MRI), and viability by positron emission tomography (PET) and single-photon emission computed tomography (SPECT), pre-operatively and after 1-year follow-up. LVEF, the pre-defined primary end-point measure, improved by a median of 5.6% in the control group (IQR 0.2 to 10.1) and by 4.8% in the BMMC group (IQR -0.5 to 8.2) (p = 0.59). Wall thickening in injected segments rose by a median of 4.5% among controls (IQR -18.1 to 23.9) and by 5.5% in the BMMC group (IQR -6.6 to 26.5) (p = 0.68). Changes in viability by PET and SPECT did not differ between groups. Myocardial scar size by MRI in injected segments rose by a median of 5.1% among controls (IQR -3.3 to 10.8), but fell by 13.1% in the BMMC group (IQR -21.4 to -6.5) (p = 0.0002). CONCLUSIONS BMMC therapy combined with CABG failed to improve LV systolic function, or viability, despite reducing myocardial scar size.

Comparison of Five Parathyroid Scintigraphic Protocols

Objectives. We compared five parathyroid scintigraphy protocols in patients with primary (pHPT) and secondary hyperparathyroidism (sHPT) and studied the interobserver agreement. The dual-tracer method (99mTc-sestamibi/123I) was used with three acquisition techniques (parallel-hole planar, pinhole planar, and SPECT/CT). The single-tracer method (99mTc-sestamibi) was used with two acquisition techniques (double-phase parallel-hole planar, and SPECT/CT). Thus five protocols were used, resulting in five sets of images. Materials and Methods. Image sets of 51 patients were retrospectively graded by four experienced nuclear medicine physicians. The final study group consisted of 24 patients (21 pHPT, 3 sHPT) who had been operated upon. Surgical and histopathologic findings were used as the standard of comparison. Results. Thirty abnormal parathyroid glands were found in 24 patients. The sensitivities of the dual-tracer method (76.7–80.0%) were similar (P = 1.0). The sensitivities of the single-tracer method (13.3–31.6%) were similar (P = 0.625). All differences in sensitivity between these two methods were statistically significant (P < 0.012). The interobserver agreement was good. Conclusion. This study indicates that any dual-tracer protocol with 99mTc-sestamibi and 123I is superior for enlarged parathyroid gland localization when compared with single-tracer protocols using 99mTc-sestamibi alone. The parathyroid scintigraphy was found to be independent of the reporter.

F-18-fluorodeoxyglucose positron emission tomography-guided sampling of mediastinal lymph nodes in the diagnosis of cardiac sarcoidosis.

Histologic proof of granulomatous inflammation is prerequisite for the diagnosis of cardiac sarcoidosis (CS). Because of the limited sensitivity of endomyocardial biopsy (EMB), confirmation of sarcoidosis often has to be acquired from extracardiac biopsies. We set out to review our experience of F-18-fluorodeoxyglucose positron emission tomography (F-18-FDG PET) in guiding extracardiac tissue biopsies in suspected CS. We included in this work 68 consecutive patients with proved CS who had undergone cardiac F-18-FDG PET with (n = 57) or without whole-body imaging as part of initial diagnostic evaluation. Their hospital charts, imaging studies, and diagnostic biopsies were reviewed in retrospect. Whole-body PET images showed extracardiac foci of abnormally high F-18-FDG uptake in 39 of 57 patients, of whom 38 had involvement of mediastinal lymph nodes (MLN). Parallel F-18-FDG uptake was found in other lymph nodes (n = 10), lungs (n = 9), liver (n = 3), spleen (n = 2), and thyroid gland (n = 1). Adding the mediastinal findings at cardiac PET without whole-body imaging, abnormal F-18-FDG uptake in MLN was found in totally 43 of the 68 patients with CS (63%). Histology of systemic sarcoidosis was known at presentation of cardiac symptoms in 8 patients. Of the 60 patients with missing histology, 24 patients underwent mediastinoscopy for sampling of PET-positive MLN, most often (n = 20) after nondiagnostic EMB; microscopy revealed diagnostic noncaseating granulomatous inflammation in 24 of the 24 cases (sensitivity 100%). In the remaining 36 patients, sarcoidosis histology was confirmed by EMB (n = 30), by biopsy of lungs (n = 2) or peripheral lymph nodes (n = 2), or at autopsy (n = 1) or post-transplantation (n = 1). In conclusion, MLN accumulate F-18-FDG at PET in most patients with CS and provide a highly productive source for diagnostic biopsies either primarily or subsequent to nondiagnostic EMB.

Combining FDG-PET and 99mTc-SPECT to predict functional outcome after coronary artery bypass surgery.

AIMS Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are suggested to improve clinical decision-making in ischaemic cardiomyopathy. Here, we present a unique cohort of patients who underwent nuclear medicine studies and cardiac magnetic resonance imaging (MRI) both before and 1 year after coronary artery bypass (CABG) surgery to assess benefit from surgery. METHODS AND RESULTS Before CABG, we applied three quantitative techniques using (18)F-fluorodeoxyglucose-PET and (99m)technetium-tetrofosmin-SPECT with a software tool to measure defects with hypoperfused but viable and non-viable myocardium in 15 patients. One method used solely PET, two others combined PET and SPECT at different thresholds. As a reference, we used change in left-ventricular (LV) function and volume by MRI. Preoperatively, ischaemic but viable areas detected by the method with a 10% threshold combining PET-SPECT and the PET-only method correlated significantly with preoperative regional wall thickening (WT; P = 0.03 and P = 0.005, respectively). When compared with global functional outcome (change in LV ejection fraction) and LV remodelling (change in end-diastolic volume) 1 year postoperatively, no correlation appeared with preoperative PET- or PET-SPECT-derived viable or non-viable tissue. Neither was any correlation observable between local change in WT and local preoperative defect size evaluated by any of these three methods. CONCLUSION Preoperatively, PET and PET-SPECT with 10% threshold detected dysfunctional myocardium, but all analysis methods failed to predict 1-year functional outcome assessed by MRI. In patients with three-vessel disease and heart failure, SPECT perfusion and PET viability study results show substantial heterogeneity; this should be considered when selecting patients for revascularization.

99mTechnetium Sestamibi-123Iodine Scintigraphy Is More Accurate Than 99mTechnetium Sestamibi Alone before Surgery for Primary Hyperparathyroidism

Objectives. Studies comparing outcome of single-99mTc-methoxyisobutylisonitrile (99mTc-sestamibi) and dual-tracer 99mTc-sestamibi scintigraphy in combination with 123I before primary surgery of primary hyperparathyroidism (PHPT) are scarce. Methods. We compared 99mTc-sestamibi/123I and 99mTc-sestamibi in a single-centre retrospective series of 269 PHPT patients. The results were related to laboratory, surgical and histological findings. Results. 99mTc-sestamibi/123I and 99mTc-sestamibi were positive in 206 (76.6%) and 111 (41.3%) of 269 patients, respectively (P < 0.001). Accuracies for 99mTc-sestamibi/123I and 99mTc-sestamibi were 63.4% and 34.9%, respectively (96% CI, P < 0.001). Prevalence of multiglandular disease was 15.2%. In multiglandular disease, 99mTc-sestamibi/123I and 99mTc-sestamibi revealed 43.8 and 22.1% of pathological glands, respectively (P < 0.001). Cure rate was similar for patients with (191/206; 92.7%) and without (59 of 63; 93.7%) a positive 99mTc-sestamibi/123I finding. Duration of targeted surgery (one or two quadrants) was 21 and 15 minutes shorter than bilateral neck exploration, respectively (both P < 0.001). Higher serum calcium (P = 0.014) and PTH (P = 0.055) concentrations and larger tumours (P < 0.001) characterized the 206 patients with a positive preoperative scan who were cured by removal of a single adenoma. Conclusions. 99mTc-sestamibi/123I scintigraphy is more accurate than 99mTc-sestamibi before surgery of PHPT. However, outcome of surgery is not determined by scintigraphy alone.

Heterogeneity of myocardial 2-[18F]fluoro-2-deoxy-D-glucose uptake is a typical feature in cardiac sarcoidosis: a study of 231 patients

Aims The goal of the investigation was to evaluate whether a semi-quantitative method reflecting myocardial 2-[18F]fluoro-2-deoxy-D-glucose (FDG) uptake heterogeneity has added value in addition to visual analysis in the diagnosis of cardiac sarcoidosis (CS). Methods and results This retrospective analysis included 271 consecutive patients suspected of CS attending cardiac positron emission tomography combined with computed tomography (PET-CT) at our institution between 2007 and 2013. Visual analysis of PET-CT and semi-quantitative analysis of heterogeneity [coefficient of variation (CoV)] of myocardial FDG uptake were performed. The presence of CS and initial symptoms were verified from patient data. The criteria for CS included histological verification from the myocardium or from an extracardiac site. Thirty cancer patients without cardiac disease were included as controls. CS was diagnosed in 48/231 (20.8%) of analysed patients. Of these, 13 (27.1%) had no extracardial signs of the disease and 30 (62.5%) had FDG positive mediastinal lymph nodes. Visual analysis of PET-CT identified 48.9% of the CS patients. We found a cut-off value of 0.184 for CoV to have the best accuracy to detect CS from a patient population with suspected CS (75.0% sensitivity and 51.4% specificity). Compared to controls, CoV identified CS patients with a good accuracy (68.8% sensitivity and 93.3% specificity). CS patients with FDG positive mediastinal lymph nodes had higher CoV than CS patients without lymph node involvement (0.282 vs. 0.208, P = 0.016). CS patients with more severe initial symptoms had a higher CoV than patients with more benign symptoms (0.283 vs. 0.195, P = 0.01). Conclusion CoV provides a good addition to visual analysis of cardiac FDG PET-CT in diagnosis of CS. As a semi-quantitative measure, it reduces intra-observer variability. It also seems to indicate more severe disease, but to confirm this, prospective studies are needed.

Seasonal Temperature Changes Do Not Affect Cardiac Glucose Metabolism.

FDG-PET/CT is widely used to diagnose cardiac inflammation such as cardiac sarcoidosis. Physiological myocardial FDG uptake often creates a problem when assessing the possible pathological glucose metabolism of the heart. Several factors, such as fasting, blood glucose, and hormone levels, influence normal myocardial glucose metabolism. The effect of outdoor temperature on myocardial FDG uptake has not been reported before. We retrospectively reviewed 29 cancer patients who underwent PET scans in warm summer months and again in cold winter months. We obtained myocardial, liver, and mediastinal standardized uptake values (SUVs) as well as quantitative cardiac heterogeneity and the myocardial FDG uptake pattern. We also compared age and body mass index to other variables. The mean myocardial FDG uptake showed no significant difference between summer and winter months. Average outdoor temperature did not correlate significantly with myocardial SUVmax in either summer or winter. The heterogeneity of myocardial FDG uptake did not differ significantly between seasons. Outdoor temperature seems to have no significant effect on myocardial FDG uptake or heterogeneity. Therefore, warming the patients prior to attending cardiac PET studies in order to reduce physiological myocardial FDG uptake seems to be unnecessary.