Nucl Med Mol Imaging Research Articles

The Immunocytokine L19–IL2 Eradicates Cancer When Used in Combination with CTLA-4 Blockade or with L19-TNF

Systemic high-dose IL2 promotes long-term survival in a subset of metastatic melanoma patients, but this treatment is accompanied by severe toxicities. The immunocytokine L19-IL2, in which IL2 is fused to the human L19 antibody capable of selective accumulation on tumor neovasculature, has recently shown encouraging clinical activity in patients with metastatic melanoma. In this study, we have investigated the therapeutic performance of L19-IL2, administered systemically in combination with a murine anti-CTLA-4 antibody or with a second clinical-stage immunocytokine (L19-TNF) in two syngeneic immunocompetent mouse models of cancer. We observed complete tumor eradications when L19-IL2 was used in combination with CTLA-4 blockade. Interestingly, mice cured from F9 tumors developed new lesions when rechallenged with tumor cells after therapy, whereas mice cured from CT26 tumors were resistant to tumor rechallenge. Similarly, L19-IL2 induced complete remissions when administered in a single intratumoral injection in combination with L19-TNF, whereas the two components did not lead to cures when administered as single agents. These findings provide a rationale for combination trials in melanoma, as the individual therapeutic agents have been extensively studied in clinical trials, and the antigen recognized by the L19 antibody has an identical sequence in mouse and man.

Why do we need accreditation of nuclear medicine departments?

Nuclear medicine is one of the most dynamic areas of medicine with continual technological innovations and developments of new radiotracers. The International Atomic Energy Agency (IAEA) defines nuclear medicine as a medical specialty that uses techniques with high cost-benefit index to obtain functional and anatomical information, constituting a tool for the detection, staging, treatment, prognosis and monitoring of patients [1]. Nuclear medicine has been an independent European medical specialty since 1988. The Section of Nuclear Medicine was created in 1990 within the European Union of Medical Specialists (UEMS), the entity that represents the medical specialties inside the European Union (EU) and that defines the basic principles of training in medical specialties in Europe in order to achieve a comparable level of knowledge and to allow the free movement of specialists among the member countries. The European Board of Nuclear Medicine (EBNM) was established in 1993 with the main objective of ensuring the highest possible levels of quality in the field of nuclear medicine. In 2000 the European Association of Nuclear Medicine (EANM) set up a Task Group on departmental accreditation. In 2003, the UEMS Section and the EBNM merged as the UEMS/EBNM to unify and facilitate their activities and created several committees, including the Committee for Accreditation of Nuclear Medicine Departments (CANMD). This was the EANM Task Group which transferred from the EANM. In practice, the UEMS/EBNM and the CANMD work in cooperation with the EANM. Technological innovations and advances in the field of new radiopharmaceuticals are very important for the continuous development of the nuclear medicine specialty. Any department of nuclear medicine must assure minimum quality requirements according to its available resources. Quality! Never has this word been used so frequently. In fact, in recent times there has been a significant reorganization of the concept of quality. Since 1947, the year the International Standards Organization (ISO) was created, there has been increasing emphasis on the quality of products and services. What before had been performed in a routine local way, nowadays attempts are made to globalize the process through standards and a good quality program and well-defined operating procedures, all of which, in our case, are to be applied to a department of nuclear medicine. Whether a department of nuclear medicine is public or private, it is assumed that it works correctly and assures minimum quality requirements. On this basis, one could ask: “what do I need to get an official accreditation by EANM?—why, in addition to possible certification by ISO and all the daily problems of budget cuts or concern for expenses generated by the cost of new equipment?” It is possible that many European nuclear medicine doctors have received training in concepts such as total quality, standardization, Deming circles, development of quality policies, objectives and indicators, and that they may now be applying those concepts in their daily work, in an effort to improve patient care and the quality of the services provided by their departments of nuclear medicine, in order to stand out from the other competitors and (why not) to survive in these very competitive times marked by the rampant crisis in all sectors. But it is also true that some other nuclear medicine physicians are unaware of these concepts. At CANMD we believe that the accreditation of nuclear medicine services is not the mere collection of a diploma to hang on the wall. To have this official accreditation is relevant and provides multiple benefits that outweigh any sacrifice. Eur J Nucl Med Mol Imaging (2012) 39:1643–1645 DOI 10.1007/s00259-012-2184-y

OT2-05-03: ACRIN 6688 Phase II Study of Fluorine-18 3′-Deoxy-3′ Fluorothymidine (FLT) in Invasive Breast Cancer.

Abstract Background Neoadjuvant chemotherapy (NAC) prior to surgery provides enhanced options for locoregional management and has become an integral component of primary breast cancer management. Initial tumor response in patients receiving NAC is generally determined at therapy completion. This evaluation is determined by either the presence/absence of palpable tumor as a clinical response and/or presence/absence of invasive tumor cells in the breast and nodes as a pathological response. The ability to evaluate the effectiveness of neoadjuvant therapy early during treatment would be of significant importance. FDG PET imaging has been shown to be predictive of subsequent tumor response, but the tendency of FDG to accumulate in inflammatory tissues can complicate image interpretation. MRI changes have also been touted as predictors of response. Preliminary data suggest that early FLT PET is better able to predict response to therapy, as FLT uptake has been shown to correlate with cellular proliferation, and does not significantly accumulate in inflammatory tissue (Kenny et al, Eur J Nucl Med Mol Imaging 2007:1339–1347). The analysis of these data may provide a better understanding of early treatment response and improve the clinical management of breast cancer in the future. Trial design and eligibility: In this phase II multi-institutional study, breast cancer patients with locally advanced disease with a tumor size ≥2cm (measured on imaging or estimated by physical exam) are eligible. Participants will receive standard of care NAC at their respective institutions. Participants will have 3 FLT imaging sessions to evaluate therapy response: at baseline, early-treatment (5-10 days after initiating treatment), and post-treatment prior to surgery. Specific aims: The primary objective is to correlate the percentage change in the standardized uptake value between baseline and early therapy FLT in the primary tumor with pathologic response. Correlatively, FLT PET parameters will be compared with proliferative indices from the initial biopsy and residual tumor surgical samples using Ki-67 staining, mitotic index, and residual cancer burden. Potential safety issues and the physiologic effects associated with FLT administration will also be evaluated. Statistical methods: To evaluate the relationship between an uptake parameter and pathologic complete response, a ROC curve will be estimated and the area under the curve, along with its 95% confidence interval, will be determined. Accrual: Currently, 45/67 patients have accrued to the study. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-05-03.

ACRIN 6688 phase II study of fluorine-18 3′-deoxy-3′ fluorothymidine (FLT) in invasive breast cancer.

TPS125 Background: Neoadjuvant chemotherapy (NAC) prior to surgery provides enhanced options for locoregional management and has become an integral component of primary breast cancer management. Initial tumor response in patients receiving NAC is generally determined at therapy completion. This evaluation is determined by either the presence/absence of palpable tumor as a clinical response and/or presence/absence of invasive tumor cells in the breast and nodes as a pathological response. The ability to evaluate the effectiveness of neoadjuvant therapy early during treatment would be of significant importance. FDG PET imaging has been shown to be predictive of subsequent tumor response, but the tendency of FDG to accumulate in inflammatory tissues can complicate image interpretation. MRI changes have also been touted as predictors of response. Preliminary data suggest that early FLT PET is better able to predict response to therapy, as FLT uptake has been shown to correlate with cellular proliferation, and does not significantly accumulate in inflammatory tissue (Kenny et al, Eur J Nucl Med Mol Imaging 2007:1339-1347). Methods: In this phase II multi-institutional study, breast cancer patients with locally advanced disease with a tumor size ≥2cm (measured on imaging or estimated by physical exam) are eligible. Participants will receive standard of care NAC at their respective institutions. Participants will have 3 FLT imaging sessions to evaluate therapy response: at baseline, early-treatment (5-10 days after initiating treatment), and post-treatment. The primary objective is to correlate the percentage change in the standardized uptake value between baseline and early therapy FLT in the primary tumor with pathologic response. Correlatively, FLT PET parameters will be compared with proliferative indices from the initial biopsy and residual tumor surgical samples using Ki-67 staining, mitotic index, and residual cancer burden. Potential safety issues and the physiologic effects associated with FLT administration will also be evaluated. The analysis of these data may provide a better understanding of early treatment response and improve the clinical management of breast cancer in the future.

Evaluation of Lu-177 RM2 as a targeted radiopharmaceutical in a PC-3 xenograft model of androgen-independent prostate cancer.

e13522 Background: Prostate cancer is the most common cancer in American men (after nonmelanoma skin cancers). In 2010 more than 200,000 cases were diagnosed and more than 30,000 men died of prostate cancer. One in six men will be diagnosed with prostate cancer during his lifetime and one in thirty six men will die of prostate cancer. Human prostate cancer has been shown to widely express the bombesin receptor (BB2R). Lutetium-177 (177 Lu) radiolabeled BB2r agonist analogs are currently being investigated preclinically for their utility as targeted radiation therapy agents. (Maddalena, J Nucl Med, 50:2017, 2009 and Johnson, Can Biother & Radiopharm, 21(2):155, 2006) Recently, Maecke and co-workers identified a high affinity BB2r antagonist (Ga-68 and In-111-RM2) for potential use as a PET/SPECT diagnostic imaging agent. (Mansi, Clin Can Res, 15(16):5240, 2009 and Mansi, Eur J Nucl Med Mol Imaging, May 2010) The purpose of this work was to investigate the biodistribution of Lu-177-RM2 for potential as a radiotherapeutic agent using a PC-3 xenografted SCID mouse model. Methods: Male SCID mice were inoculated subcutaneously with 5 million PC-3 cells/site in 100uL. At 4 weeks post-inoculation, pharmacokinetic studies of 177Lu-VA RM2 were conducted at 1, 4, 24, 48, 72, and 96 hours post-injection. Micro-SPECT/CT imaging studies were done at 24, 48, 72, and 96 hrs. Results: See table; shown in %ID/g. Conclusions: Our study demonstrates that Lu-177-RM2 shows promising pharmacokinetic properties with high affinity for the BB2 receptor and excellent tumor to blood and tumor to organ ratios. The prostate tumor uptake of Lu-177-RM2 is equal or greater than any previously identified BB2r targeting radiotherapeutic agent. Lu-177-RM2 exhibits rapid washout from the pancreas and other non-target organs making it an ideal candidate for tumor targeted therapy research. 1 HR 4 HRS 24 HRS 48 HRS 72 HRS 96 HRS Blood 0.36 +/- 0.15 0.02 +/- 0.01 0.00 +/- 0.00 0.00 +/- 0.00 0.00 +/- 0.00 0.00 +/- 0.00 Pancreas 17.53 +/- 1.97 1.59 +/- 0.7 0.26 +/- 0.03 0.18 +/- 0.04 0.19 +/- 0.03 0.03 +/- 0.00 Tumor 9.25 +/- 3.35 11.46 +/- 5.38 5.56 +/- 1.59 5.28 +/- 1.42 4.03 +/- 0.92 3.14 +/- 0.33

Sodium Iodide Symporter SPECT Imaging of a Patient Treated With Oncolytic Adenovirus Ad5/3-Δ24-hNIS

Sodium Iodide Symporter SPECT Imaging of a Patient Treated With Oncolytic Adenovirus Ad5/3-Δ24-hNIS

Effects of I-131 therapy on gonads and pregnancy outcome in patients with thyroid cancer

We examined the effects of I-131 therapy for thyroid cancer on female and male gonads and pregnancy outcome. After an extensive review of the published literature we concluded that ablative administration of I-131 therapy may result in transient abnormalities of ovarian and testicular function, but subsequent pregnancies are safe without any significant consequences to offspring outcome.

Respective PROGNOSTIC Value of the International Harmonization PROJECT (IHP), Gallamini and London Criteria for Interim FDG PET-CT Performed AFTER 4 Courses of ABVD IN HODGKIN'S LYMPHOMA

AbstractAbstract 3889During the last decade, the role of Interim 2-[18F]fluoro-2-deoxy-D-glucose emission positron tomography (FDG PET-CT) has increased for Hodgkin's lymphoma (HL) evaluation and it is strongly recommended for both staging and post treatment evaluation. Early treatment response assessment is a challenge for risk-adapted therapy and interim PET-CT has emerged as a powerful prognostic tool to predict treatment outcome, a negative exam predicting a favorable disease-free survival while a positive study a worse prognosis. However, FDG PET response criteria are a matter of ongoing debate. So, the aim of our study was to confirm the prognostic value of interim FDG PET-CT performed after 4 courses of chemotherapy (ABVD) but also to compare the respective performances of the different published criteria: International Harmonization Project (IHP), Gallamini criteria, 5-point scale (Gallamini A et al. Haematologica 2006; 91: 475–481; Juweid ME et al. J Clin Oncol 25:571-578, 2007; Barrington SF et al. Eur J Nucl Med Mol Imaging 2009;36(Suppl. 2):S252; Meignan M et al. Leukemia & Lymphoma, August 2009; 50(8): 1257–1260; Gallamini A, et al. Leuk Lymphoma. 2009 Nov;50(11):1761-4.) Design and methods:From 2002 to 2006, newly diagnosed patients with HL who underwent interim PET-CT after 4 courses of ABVD were eligible for the purpose of the present study. Treatment strategy after 4 courses of ABVD was then adapted according to prognostic factors at diagnosis and interim PET-CT result. PET images were interpreted prospectively visually by at least two nuclear medicine physicians with expertise in lymphoma imaging with the criteria used before 2005: negative result was defined as no residual uptake above local background. All other findings were considered as positive. Using these evaluation criteria, interim PET positive patients who were not in CR on CT underwent autologous stem cell transplantation. Interim PET positive patients who reached CR on CT and interim PET negative patients received additional courses of ABVD (patients with advanced HD or bulky disease at diagnosis) or radiotherapy alone (stage I or II without bulky disease). Retrospectively and for the purpose of the present study, interim PET results were interpreted using the more recent criteria (Gallamini criteria, IHP criteria and 5-point scale method) Results:90 patients were included. Median age at diagnosis was 34.4 (16-71). 49% of the patients presented with B-symptoms and 50% had stage III-IV disease. According to initial criteria, 31 patients had a positive interim PET result. Among these patients, 28 underwent ASCT. Fifty-nine patients had a negative interim PET-CT. Six of 31 patients with positive interim PET-CT and 7 of 59 patients with negative interim result presented treatment failure. Thus, the negative predictive value (NPV) and positive predictive value (PPV) for predicting 2 years progression free survival (PFS) was 95% and 16%, respectively. Retrospectively, interim PET-CT was analyzed according to different recent published criteria using mediastinum and liver background as threshold for positivity. With these criteria, NPV remained very high (from 95% to 96%). However, the PPV increased from 25% to 55% according to the threshold used. Taken together, the statistical analysis revealed that Interim PET-CT was significantly correlated with PFS only for two methods: the Gallamini criteria and the 5-point scale method. Conclusion:The first part of our study using the criteria used before 2005 shows the high NPV of interim PET-CT for predicting treatment outcome in HL. However, better prognostic values are obtained by using higher threshold for positivity such as liver background even after 4 cycles of ABVD. Indeed, our analysis underscores the better results reached by the Gallamini criteria and 5-point scale methods. The better method to predict PFS was obtained by the 5-point scale (scores 1, 2, 3 and 4 were classified as negative while only score 5 was classified as positive) showing a PPV and NPV of 55% and 96%, respectively. Disclosures:No relevant conflicts of interest to declare.

Making optimal use of available molybdenum-99

Summary The recent shortage of 99 Mo has created a challenge forradiopharmacy; indeed, it has been extremely stressful attimes. Even if supplies stabilize towards the end of 2010we face several years of uncertainty before more robustsolutions are implemented. However, this has forced us totake a perhaps overdue closer look at how we can makemore efficient use of available 99 Mo to provide as much 99m Tc as possible for the preparation and supply ofradiopharmaceuticals. References 1 Ramamoorthy N. Commentary: supplies of molybdenum-99 – need forsustainable strategies and enhanced international cooperation. Nucl MedCommun 2009; 30:899–905.2 Lewis DM. 99 Mo supply – the times they are a-changing. Eur J Nucl Med MolImaging 2009; 36:1371–1374.3 Ballinger JR. 99 Mo shortage in nuclear medicine: crisis or challenge? J LabelCompd Radiopharm 2010; 53:167–168.4 Bradley E, Adelfang P, Ramamoorthy N, editors. Homogeneous aqueoussolution nuclear reactors for the production of 99 Mo and other short-livedradioistotopes. IAEA-TECDOC-1601. Vienna: International Atomic EnergyAgency; 2008.5 Ruth T. Accelerating production of medical isotopes. Nature 2009;457:536–537.6 Guerin B, Tremblay S, Rodrigue S, Rousseau JA, Dumulon-Perreault V,Lecomte R, et al. Cyclotron production of

The flare phenomenon: still learning after 35 years

These are interesting and challenging times for the isotope bone scan with regard to the identification of metastatic disease, with mounting evidence that the addition of SPECT improves sensitivity and specificity, SPECT/CT is even better, F-fluoride PET/CT better still. In addition there is FDG PET/CT with improved sensitivity for skeletal metastases in certain diseases such as lung cancer [1] and with its ability to identify early marrow involvement, with the lurking threat from whole-body MRI never far away. Nevertheless our conventional, beloved bone scan which has served us so well over the years continues to be widely used due to its well-known advantages of simplicity, relatively low cost, high sensitivity and the ease of evaluating the whole skeleton, and in truth because many clinicians are as yet less knowledgeable about the newer methodologies. However, even with this familiar friend it would appear that we are still learning. The flare phenomenon on a bone scan was first recognised in the mid 1970s and more widely reported upon in the early 1980s with Rossleigh et al. in 1984 [2] the first to identify ‘new’ lesions developing during the flare response (presumably existing small volume disease which was beyond the resolution of the methodology used). The flare phenomenon has always fascinated as conceptually the fact that a worsening scan is good news is counterintuitive. The theory is that if a bone scan is performed early (time interval to be clarified as will be discussed later) following the successful treatment of bone metastases one may witness the skeleton mounting an intense osteoblastic response (reflecting healing), which makes individual lesions appear ‘worse’ (more intense tracer uptake at that site) and additional lesions, not identified on the original study may be visualised with subsequent resolution of the flare by 6 months. To date, in routine practice, this was unlikely to cause problems as bone scans are not generally performed within a few months following change in treatment and the flare response is known about and most nuclear medicine physicians will advise that there should be a significant interval between scans. However, this situation may well change due to the introduction of new, potent therapies and the need for earlier assessment in clinical trials. Monitoring what happens to bone metastases is an important clinical issue in view of the high associated morbidity, but is notoriously difficult to achieve, and it is recognised that individual patients may show a mixed response to treatment, with for example improvement in soft tissue disease but with progression of bone metastases or with some bone lesions responding and others progressing. In recent years there have been major advances in oncology with a variety of new treatments, many of which have significant side effects and which are often extremely costly, and it is important to know as early as possible whether patients are responding. Further patients are often entered into clinical trials with fixed protocols, requiring new baseline bone scans and follow-up studies ‘early’ after instigation of treatment, and therefore optimising such protocols and indeed the correct interpretation of the studies becomes highly relevant. In this volume Cook et al. [3] present interesting new data relating to the flare phenomenon in a prospective study of 99 newly diagnosed patients receiving hormonal treatI. Fogelman (*) King’s College London, Department of Nuclear Medicine, Guy’s Hospital Borough Wing, Great Maze Pond, London SE1 9RT, UK e-mail: ignac.fogelman@kcl.ac.uk DOI 10.1007/s00259-010-1609-8 Eur J Nucl Med Mol Imaging (2011) 38:5–6

Xenon 133 Ventilation Studies as an Alternative for Detecting and Quantifying Fatty Infiltration of the Liver

Xenon 133 Ventilation Studies as an Alternative for Detecting and Quantifying Fatty Infiltration of the Liver

ACR Appropriateness Criteria® on Metastatic Bone Disease

Appropriate imaging modalities for screening, staging, and surveillance of patients with suspected and documented metastatic disease to bone include (99m)Tc bone scanning, MRI, CT, radiography, and 2-[(18)F]fluoro-2-deoxyglucose-PET. Clinical scenarios reviewed include asymptomatic stage 1 breast carcinoma, symptomatic stage 2 breast carcinoma, abnormal bone scan results with breast carcinoma, pathologic fracture with known metastatic breast carcinoma, asymptomatic well-differentiated and poorly differentiated prostate carcinoma, vertebral fracture with history of malignancy, non-small-cell lung carcinoma staging, symptomatic multiple myeloma, osteosarcoma staging and surveillance, and suspected bone metastasis in a pregnant patient. No single imaging modality is consistently best for the assessment of metastatic bone disease across all tumor types and clinical situations. In some cases, no imaging is indicated. The recommendations contained herein are the result of evidence-based consensus by the ACR Appropriateness Criteria((R)) Expert Panel on Musculoskeletal Radiology.

Erratum to: Guidelines for the labelling of leucocytes with 99mTc-HMPAO

Erratum to: Eur J Nucl Med Mol Imaging (2010) 37: 842-848 DOI 10.1007/s00259-010-1394-4 The wrong supplier was named for the Leukokit closed disposable sterile system for WBC separation and labelling. The correct manufacturer of the Leukokit system is GI Pharma (Saluggia, Italy).

High-resolution 18F-FDG PET with MRI for monitoring response to treatment in rheumatoid arthritis

Eur J Nucl Med Mol Imaging (2010) 37:1047 DOI 10.1007/s00259-009-1364-x IMAGE OF THE MONTH High-resolution 18 F-FDG PET with MRI for monitoring response to treatment in rheumatoid arthritis Abhijit J. Chaudhari & Spencer L. Bowen & George W. Burkett & Nathan J. Packard & Felipe Godinez & Anand A. Joshi & Stanley M. Naguwa & David K. Shelton & John C. Hunter & John M. Boone & Michael H. Buonocore & Ramsey D. Badawi Received: 20 November 2009 / Accepted: 10 December 2009 / Published online: 30 January 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Molecular imaging can potentially provide means for mon- itoring response to therapy in rheumatoid arthritis (RA) early in the course of disease [1].Quantitative measurements of RA disease activity made in the wrist by whole-body PET scanners, however, have inadequate accuracy because of limited spatial resolution [2]. A high-resolution PET/CT scanner for imaging extremities has been built at our insti- tution [3]. In conjunction with a clinical MRI scanner, high- resolution PET/MR images can be obtained for the wrist. The CT image is used for PET/MR image coregistration. A 57-year-old female with established RA was stable until a recent clinical flare-up in the right wrist. Clinical exami- nation revealed synovitis, swelling, and diminished range of motion. The patient also had a history of osteoarthritis (OA). An extremity 18 F-FDG PET/CT scan immediately following MRI at baseline was performed on this patient. Tumor necrosis factor alpha (TNF-α) inhibitor (etanercept) therapy was then initiated as a part of the patient’s standard of care. The patient was re-scanned 5 weeks after starting treatment. The figure shows high-resolution 18 F-FDG PET images (pseudocolor) overlaid on pre-contrast MRI images (gray This work was funded by the NIH grants UL1-RR024146, R01CA129561, R01EB002138 and the UC Davis Imaging Research Center. A. J. Chaudhari (*) : S. L. Bowen : G. W. Burkett : N. J. Packard : F. Godinez : D. K. Shelton : J. C. Hunter : J. M. Boone : M. H. Buonocore : R. D. Badawi Department of Radiology, UC Davis Medical Center, Sacramento, CA, USA e-mail: ajchaudhari@ucdavis.edu A. A. Joshi Department of Neurology, UCLA School of Medicine, Los Angeles, CA, USA S. M. Naguwa Department of Internal Medicine, UC Davis Medical Center, Sacramento, CA, USA scale) at baseline (left column) and 5 weeks (right column). Significant reduction in PET signal (suggesting reduced inflammation) in the synovium and at sites of erosions (white arrows) is visible. The green arrow shows inflammation due to OA. Physician examination at 3 months confirmed that this patient responded positively to etanercept. This case illustrates the potential of high-resolution PET with MRI for quantitative visualization of early response to therapy in RA. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which per- mits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Syllabus for postgraduate specialisation in Nuclear Medicine

Nuclear Medicine (NM) became an independent medical specialty in the European Directives in 1988. The minimum duration of the postgraduate specialized training in the European Union is 4 years, but may be extended beyond this period according to the requirements of training in other clinical disciplines. Candidates for specialized training should have a good general background in internal medicine. More detailed knowledge has to be acquired of those conditions which may need to be investigated or treated by NM techniques, as well as of some complementary methods as far as they relate to NM procedures. Training in basic sciences is required, such as pharmacokinetics, radiochemistry, instrumentation, computer science and quality control. The quality of training has to be objectively assessed, using final examination on a national basis covering basic sciences and clinical skills, after satisfactory completion of a minimum number of courses and/or workshops and a formally organized and controlled practical training. Each training programme should contain a standard against which the progress of the trainee can be assessed for each element of the syllabus. The assessment may take the form of an interview, a written paper, an essay, a set of multiple-choice questions, or an oral examination of displayed images of various NM techniques in clinical practice. Continuous assessment is another alternative. Each end of year assessment should carry a score that indicates how the candidate has progressed against the set target. Successful trainees are awarded with a final certificate, degree or diploma that is recognized by the government, local health authority and hospital as an assurance of specialist competence in NM. The clinical training of physicians specializing in NM should include: 1) a minimal theoretical foundation of the general principles of NM with active participation in clinical presentations, seminars and meetings and 2) in vivo diagnostic procedures. Personal responsibility (including indication, performance and interpretation) must be taken for at least 3.000 in vivo NM diagnostic procedures, with a broad-spectrum of the most currently used procedures. The list of the procedures published in the syllabus will be subject to revision. It is recommended that a period of training be spent away from the main department in at least one other recognized centre. In addition the training should cover therapy with unsealed radioactive sources. The trainee must have taken part in a sufficient number of Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-006-0334-9

Can metamizol play a role in nuclear medicine practice?

I read with great interest the letter to the editor by Georgoulias et al., published in the January 2009 issue concerning the drug enhancement of myocardial tracer uptake during myocardial perfusion imaging [1]. The authors also focused on our article “Tc sestamibi myocardial perfusion scintigraphy (MPS) with the novel use of metamizol for the detection of perfusion reversibility” published in the August 2008 issue [2]. Metamizol has been in clinical use for more than three quarters of a century, and recent reports have shown that metamizol also has a relaxing activity in vascular smooth muscle as assessed in in vitro tissue bath techniques and in vivo animal models [3–8]. In our above-mentioned study [2], we aimed to investigate whether the vascular smooth muscle relaxing effect of metamizol has the potential to better define myocardial ischaemia during MPS and we found that metamizol rest MPS displayed the defect reversibility better than baseline rest MPS and that metamizol-induced myocardial sestamibi uptake was significantly higher (p<0.001) than stress/baseline rest MPS examinations. Blood pressure remained unaltered after metamizol induction. So, we concluded that metamizol increases the detection of the viable myocardium regions during MPS and helps to make a confident interpretation for defect reversibility. In their letter to the editor, Georgoulias et al. [1] summarized the use of technetium-labelled tracers (sestamibi and tetrofosmin) for the detection of viable myocardium with one or a combination of the approaches such as determining the severity of resting defects according to the percent of the peak myocardial activity, assessing the radiotracer uptake after nitroglycerin administration and assessing the regional myocardial function and thickening by performing gated SPECT. The authors also shared that they had great experience with gated SPECT on this issue and they emphasized the clinical dilemma in the differentiation of viable myocardium from scar in patients without a history of myocardial infarction who had undergone gated SPECT study. In our study [2], we postulated that since metamizol is no longer detectable in the serum soon after its oral administration, its active metabolite 4-MAA may be responsible from the enhancement of perfusion seen on MPS due to its vasorelaxing effect. 4-MAA has a longer elimination half-life (2.7 h) than nitroglycerin (a few minutes). So, Georgoulias et al. indicated that the investigation of metamizol’s influence on cardiac function would be of interest and proposed that studies are needed to increase the information regarding the use of metamizol in combination with MPS. We are of the same opinion as Georgoulias et al. on this issue. Additionally, in our opinion correlative studies comparing the effects of metamizol and nitroglycerin on the myocardial uptake of the radiopharmaceuticals might be undertaken. Metamizol might have an advantage over nitroglycerin since it causes no significant alteration in blood pressure [2], and we did not observe any complaints such as vertigo, dizziness, nausea or vomiting due to metamizol in our patients. In our above-mentioned study [2], baseline rest MPS showed an average perfusion improvement of 7.8% in the regions where stress perfusion defects were seen. On the other hand, metamizol induction displayed an average perfusion improvement of 18.2% in the same myocardial regions when compared to stress MPS. Consequently, the Eur J Nucl Med Mol Imaging (2009) 36:1191–1192 DOI 10.1007/s00259-009-1149-2

Engineering Clustered Ligand Binding Into Nonviral Vectors: αvβ3 Targeting as an Example

The development of techniques to efficiently deliver genes using nonviral approaches can broaden the application of gene delivery in medical applications without the safety concerns associated with viral vectors. Here, we designed a clustered integrin-binding platform to enhance the efficiency and targetability of nonviral gene transfer to HeLa cells with low and high densities of alpha(v)beta(3) integrin receptors. Arg-Gly-Asp (RGD) nanoclusters were formed using gold nanoparticles functionalized with RGD peptides and used to modify the surface of DNA/poly(ethylene imine) (PEI) polyplexes. DNA/PEI polyplexes with attached RGD nanoclusters resulted in either 5.4- or 35-fold increase in gene transfer efficiency over unmodified polyplexes for HeLa cells with low- or high-integrin surface density, respectively. The transfection efficiency obtained with the commercially available vector jetPEI-RGD was used for comparison as a vector without clustered binding. JetPEI-RGD exhibited a 1.2-fold enhancement compared to unmodified jetPEI in cells with high densities of alpha(v)beta(3) integrin receptors. The data presented here emphasize the importance of the RGD conformational arrangement on the surface of the polyplex to achieve efficient targeting and gene transfer, and provide an approach to introduce clustering to a wide variety of nanoparticles for gene delivery.

Navigating beyond the 6th dimension: a challenge in the era of multi-parametric molecular imaging

This is an exciting time for molecular imaging as we are witnessing a convergence and combination of various imaging modalities driven by an unprecedented multidisciplinary collaboration between scientists. A consequence of this growth is a paradigm shift in health care delivery that is now revolutionizing clinical practice. Within the spectrum of macroscopic medical imaging, sensitivity ranges from the detection of millimolar to submillimolar concentrations of contrast media with computed tomography (CT) and magnetic resonance imaging (MRI), respectively, to picomolar concentrations in positron emission tomography (PET): a 10–10 difference [1]. Despite the remarkable progress and outstanding scientific innovations achieved and the much worthwhile successful research carried out both in academic and corporate settings, there are still plenty of open research questions that offer ample opportunities for the new generation of molecular imaging scientists [2]. There is no shortage of challenges and opportunities nowadays for developing novel molecular imaging probes and technologies and for establishing their role through innovative applications in clinical and research settings. The only limit is the imagination and creativity of the investigators and the challenge is the ability of opinion leaders to attract the best scientists into this discipline. It is the responsibility of scientists involved in today’s molecular imaging research enterprise to debate about essential issues related to the relevance of novel technologies with the aim of focusing the limited resources available for the best benefit of our community. In this respect, the issue of whether the development of molecular imaging technologies should be driven by fundamental molecular biology or design engineering was raised recently [3] and is still a matter of debate [4]. What our community has learned and accepted as a fact dictated by the unremitting modernization of our profession is that medical physicists must either learn to include the biology of molecular imaging in their research programmes or prepare to become irrelevant to the future of this discipline [3]. Among many other issues, the important role of multimodality imaging is growing steadily and gaining acceptance both in the clinical setting [5] and experimental preclinical studies [6]. As diagnostic techniques transition from the systems to the molecular level, the role of multimodality imaging becomes ever more important. Multimodality imaging with high spatial resolution and good sensitivity, allowing one to combine modalities and record either sequentially or simultaneously complementary information gathered from SPECT, PET, CT, MRI, ultrasound (US), optical imaging (OI), fluorescence and bioluminescence imaging, offers many advantages in certain research experiments. MRI, US and CT are favourably suited to assess perfusion, relative blood volume and vessel permeability and as such functional data derived from these imaging modalities may be combined with molecular information provided by SPECT and PET. Optical imaging is a very sensitive biological imaging technique to examine gene expression due to the very low background light levels [7]. Its capability to probe very small signals allows visualization of early expression and signal changes compared to PET imaging. However, PET is a quantitative modality that can provide measurements of metabolic function. While virtually all commercially available clinical and hybrid imaging systems have been configured in the form of SPECT/CT [8] or PET/CT [9], combined PET/MR scanners [10, 11] allowing for simultaneous (as opposed to sequential Eur J Nucl Med Mol Imaging (2009) 36:1025–1028 DOI 10.1007/s00259-009-1095-z

Evaluation of response: is 18F-FDG PET the answer?

A recent paper from the University of Cologne [1] cast some doubts on the usefulness of F-FDG PET in evaluating the response to chemotherapy of patients affected by oesophageal carcinoma. The authors reported on 55 patients recruited from a prospective trial on neoadjuvant radio-chemotherapy. Patients were studied before and at least 3 weeks after the completion of the treatment. Maximum and mean standardized uptake value (SUV) were measured using two different methods and compared with the histopathology assessment of tumour regression. Briefly, the authors reported that: (1) baseline SUV values were higher in responders; (2) after therapy, SUV was lower in responders; and (3) there were no significant differences between the SUV values of responders and those of non-responders. The conclusion of this paper is that F-FDG PET is not a suitable tool for measuring response to radio-chemotherapy in oesophageal carcinoma. Besides several differences in patient populations and technical aspects between studies, these conclusions cast some doubts on the reports by the Munich group, which assessed F-FDG PET as a useful tool in evaluating response in patients with carcinoma of the oesophagogastric junction [2–4]. Levine reported results going in the same direction on patients affected by locally advanced oesophageal cancer [5]. Also, some reviews on the use of F-FDG PET in oesophageal carcinoma [6, 7] concluded enthusiastically on the future use of F-FDG PET not only for staging, but also for prognostic stratification and response evaluation. It must be underlined that other authors [8–10] were already critical of the use of F-FDG PET in making important clinical decisions on patient treatments. Oesophageal carcinoma is only one of the solid tumours and lymphomas that are studied with F-FDG PET in order to assess tumour response to radiation and chemotherapy treatments, which has been recently summarized [11] in a literature review. Above and beyond the general enthusiasm which every new application of nuclear medicine procedures evokes in the nuclear medicine community, we have to be aware that controversial results may emerge in the medium and long term when limited series of patients are studied. Moreover, the large variety of pathologic types of tumours which may be studied must be carefully taken into consideration, as they have different biological behaviour, which ends up in a different capacity to take up a particular biological probe such as F-FDG. The first issued to be faced and solved is the standardization of the technical parameters. We, as nuclear medicine physicians, should do our best to establish some standard parameters to be employed when assessing solid tumours. These parameters are not required to have a general value for all tumour types, but must be determined for as many tumours as possible. This is not an easy task, but the consensus conference on Hodgkin’s lymphoma [12] demonstrated that it is possible, and some efforts have already been made on the technical issues concerning multicentre trials [13]. General issues like ROI drawing and timing of acquisition must be the subject of harmonization proEur J Nucl Med Mol Imaging (2009) 36:733–734 DOI 10.1007/s00259-009-1092-2

V/Q scintigraphy: alive, well and equal to the challenge of CT angiography

It has been almost two decades since the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study was published [1], yet its conclusions remain controversial [2, 3]. Miscalculations in the design of the study, including the prospective parameters, can be attributed to the relatively limited fund of knowledge available to the creators of the PIOPED investigation. Within 3 years, modified criteria were retrospectively developed that, when applied to the PIOPED populations, provided more accurate results [4]. The enormous information that we have gained through the multiple retrospective analyses of the PIOPED data [5–10] are less well recognized than the original publication, although they have led to improvements in both the performance and the interpretation of V/Q scintigraphy. After 20 years, it is time to stop critiquing this invaluable study and move ahead with the greater knowledge and more sophisticated approach that we have developed toward V/Q scintigraphy. One of the major PIOPED critiques deals with the large number (44%) of intermediate/indeterminate interpretations. We believe this is related to the fact that 68% of the study population comprised inpatients who are more likely to have underlying cardiopulmonary disease, such as pneumonia, chronic obstructive lung disease and pleural effusions that will cause “triple matches”, resulting in intermediate or indeterminate interpretations. At Montefiore Medical Center, the great majority of our V/Q studies are performed in relatively young emergency department patients (average age in 2007 was 50.8 years, compared to 56.7 years for CT angiography) without these underlying conditions. We generally screen patients with chest radiography which, when normal or near-normal, can be followed with a very interpretable V/Q study. This was one of the important observations made from retrospective PIOPED analysis and described by the investigators and others [8, 11]. Our number of indeterminate interpretations in more than 2000 studies performed in 2006 and 2007 was 6.5%. Additionally, correlating the indeterminate studies with clinical findings and pretest probability often allows us to skew the interpretation to the low or high portion of the intermediate category making it clinically more useful. Shortly following the original PIOPED study, helical computed tomographic angiography (CTA) was introduced [12]. As additional refinements, including multirow detectors, were developed, CTA overtook V/Q scintigraphy as the most commonly performed imaging modality for suspected pulmonary embolism (PE) [13]. This advanced technology has allowed greater detection of subsegmental PE [14]. Interestingly and importantly, the benefit of diagnosing more PE is uncertain as the risk of recurrent thromboembolism and deaths have not declined [15]. An advantage of CTA is its ability to make alternative diagnoses, e.g., aortic dissection or pneumonia that may explain the patient’s symptoms [14, 16]. Magnetic resonance angiography (MRA) has been studied for nearly two decades, but has not yet found a routine role in the imaging of patients with suspected PE. Eur J Nucl Med Mol Imaging (2009) 36:499–504 DOI 10.1007/s00259-009-1068-2