Search

Following on from the 2015 Lancet Oncology Commission on expanding global access to radiotherapy, Radiotherapy and theranostics: a Lancet Oncology Commission was created to assess the access and availability of radiotherapy to date and to address the important issue of access to the promising field of theranostics at a global level. A marked disparity in the availability of radiotherapy machines between high-income countries and low-income and middle-income countries (LMICs) has been identified previously and remains a major problem. The availability of a suitably trained and credentialled workforce has also been highlighted as a major limiting factor to effective implementation of radiotherapy, particularly in LMICs. We investigated initiatives that could mitigate these issues in radiotherapy, such as extended treatment hours, hypofractionation protocols, and new technologies. The broad implementation of hypofractionation techniques compared with conventional radiotherapy in prostate cancer and breast cancer was projected to provide radiotherapy for an additional 2·2 million patients (0·8 million patients with prostate cancer and 1·4 million patients with breast cancer) with existing resources, highlighting the importance of implementing new technologies in LMICs. A global survey undertaken for this Commission revealed that use of radiopharmaceutical therapy-other than 131 I-was highly variable in high-income countries and LMICs, with supply chains, workforces, and regulatory issues affecting access and availability. The capacity for radioisotope production was highlighted as a key issue, and training and credentialling of health professionals involved in theranostics is required to ensure equitable access and availability for patient treatment. New initiatives-such as the International Atomic Energy Agency's Rays of Hope programme-and interest by international development banks in investing in radiotherapy should be supported by health-care systems and governments, and extended to accelerate the momentum generated by recognising global disparities in access to radiotherapy. In this Commission, we propose actions and investments that could enhance access to radiotherapy and theranostics worldwide, particularly in LMICs, to realise health and economic benefits and reduce the burden of cancer by accessing these treatments., Competing Interests: Declaration of interests HH serves (unpaid) on an external advisory board of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, on the International Advisory Board of the University of Vienna, on the Scientific Committee of the German Cancer Research Center (DKFZ), on the Board of Trustees of the DKFZ, and on the advisory board of The Lancet Oncology; is remunerated for serving on the Board of Directors of Ion Beam Applications; receives stock options for serving on the Board of Directors of iCAD; and reports research funding to their institution (Memorial Sloan-Kettering Center Support Grant/Core Grant P30 CA008748) from the National Institutes of Health (NIH)–National Cancer Institute (NCI). AA reports funding to their institution from the National Institute for Health and Care Research (NIHR) and the NIH. GB reports research funding to their institution from the Science and Technology Facilities Council UK and reports travel support from International Council Expert Corps. MD reports research funding to their institution from Science and Technology Facilities Council UK and reports travel support from International Council Expert Corps. TE reports honoraria from the University of Washington and the Japanese Society for Radiation Oncology (JASTRO) and reports receiving travel support to attend meetings from JASTRO, the Turkish Society for Radiation Oncology, and the American Society for Radiation Oncology (ASTRO). SGr reports receiving grants from the NCI; reports consulting fees from Lumonus and the Sustainable Dialogue on Peaceful Uses; and has stock options in Harbinger Health. KH reports research funding to their institution from Novartis and Sofie Biosciences; reports consulting fees from Advanced Accelerator Applications, Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curiun, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, Isotopen Technologien Munchen, Janssen, Merck, Molecular Partners, Nvision, POINT Biopharma, Pfizer, Radiopharm Theranostics, Telix, Theragnostics, and Ymabs; reports honoraria for lectures from PeerVoice; serves on paid advisory boards for Fusion and GE Healthcare; reports travel support from Janssen; and has stock options from Sofie Biosciences, Pharma15, Nvision, Convergent, Aktis Oncology, and AdvanCell. MSH reports research funding to their institution from the Prostate Cancer Foundation, the US Department of Defence, Movember, and the Peter MacCallum Foundation; reports clinical trial funding to their institution from Bayer and Isotopia; reports clinical trial support to their institution from the Australian Nuclear Science and Technology Organisation; reports consulting fees from Merck Sharp & Dohme and Novartis; reports speaker fees from Janssen and AstraZeneca; reports fees to their institution for serving on the advisory board on Novartis; reports unremunerated participation in the Scientific Committee at the Australian Friends of Sheba; and is supported by a National Health and Medical Research Council (NHMRC) Investigator grant. DJ reports royalties from Elekta Oncology System, Precision X-ray System, and Modus Medical; reports license of technology to iRT; reports board membership on Break Through Cancer; reports being an advisor to ACS BrightEdge; and is a founder and stockholder in Nanovista. JK reports participation on a data safety monitoring board and advisory board from Novartis (personal fees) and reports lecture honoraria from Monrol. JSL reports research support from Clarity Pharmaceuticals and Avid Radiopharmaceuticals; has acted as an adviser of Alpha-9 Theranostics, Clarity Pharmaceuticals, Earli, Evergreen Theragnostics, Suba Therapeutics, Inhibrx, Precirix, Solve, Goldman Sachs, TPG Capital, Curie Therapeutics, NextTech Invest, and Telix Pharmaceuticals; is secretary/treasurer of the Society of Nuclear Medicine and Molecular Imaging (SNMMI); holds equity in Curie Therapeutics, Summit Biomedical Imaging, Telix Pharmaceuticals, and Evergreen Theragnostics; and is supported by NIH R35 CA232130. YL reports funding to their institution for the European Society for Radiotherapy and Oncology (ESTRO) Chair on Health Economics in Radiation Oncology (HERO)–Value-Based Radiation Oncology, for a proton beam project from the Research Foundation Flanders (FWO)–Applied Biomedical Research with a Primary Finality, and for the ARCHERY trial; reports unpaid positions on advisory boards for the HALT trial and PROSECCA trial; is a member of the ESTRO Scientific Council and the Belgian Board of Oncology; is co-chair of the ESTRO-HERO project; and is principal investigator of the E2-Radiate trial, a joint project of ESTRO, and the European Organisation for Research and Treatment of Cancer (EORTC). JRP reports being an unpaid chair of the American Association of Physicists in Medicine (AAPM) International Council. AAR received consulting fees from Novartis; received honoraria for lectures from the European Society for Medical Oncology, Sociedade Brasileira de Mastologia, and Instituto Oncoclinicas; received financial support for attending meetings from ASTRO, Congresso Gramado, and Congresso Oncolinicas; reports an unpaid leadership position at the Sociedade Brasileira de Radioterapia; and has stock and stock options in Grupo Oncoclinicas. MMS reports research funding to their institution from Aktis, Point Biopharma, and Telix Pharmaceuticals; reports speaker honoraria from Novartis, Ion Beam Applications, and Johnson and Johnson; and holds positions in the Africa Health Research Institute and Adcock. VV holds positions as editor of the Journal of Clinical Oncology/Global Oncology and Translational Oncology and is a member of the board for City Cancer Challenge. RLW reports research funding to their institution from Siemens Healthineers, White Rabbit AI, Fusion, Perspective Therapeutics, Rayze, and Bayer; provides consulting services to Voximetry, Molecular Targeting Technologies (MTT), Perspective, Siemens, Abdera, and Seno; reports speaker payment from Hamad Health Qatar; reports travel support from Rayze and Hamad Health Qatar; has stock options in Voximetry and MTT; is a stockholder in Clarity Pharmaceuticals; participates on advisory boards for Perspective and Fusion; is a member of the SNMMI Mars Shot Board; and was a past president of SNMMI. JSY reports funding to their institution from the NIH, the IVY Foundation, and the Falk Research Medical Trust; reports honoraria from the University of Maryland and the Dana Farber/Harvard Cancer Center; and holds an unpaid position in the Clinical Advisory Council at the American Brain Tumor Association. AMS reports trial funding to their institution from EMD Serono, ITM, Telix Pharmaceuticals, AVID Radiopharmaceuticals, Fusion Pharmaceuticals, and Cyclotek; reports research funding to their institution from Medimmune, Antengene, Humanigen, and Telix Pharmaceuticals; is on advisory boards of Imagion and ImmunOs; reports unpaid board membership of the Australian and New Zealand Society of Nuclear Medicine and the World Federation of Nuclear Medicine and Biology; and is supported by a NHMRC Investigator grant (number 1177837). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: The recent development and approval of new diagnostic imaging and therapy approaches in the field of theranostics have revolutionised nuclear medicine practice. To ensure the provision of these new imaging and therapy approaches in a safe and high-quality manner, training of nuclear medicine physicians and qualified specialists is paramount. This is required for trainees who are learning theranostics practice, and for ensuring minimum standards for knowledge and competency in existing practising specialists., Methods: To address the need for a training curriculum in theranostics that would be utilised at a global level, a Consultancy Meeting was held at the IAEA in May 2023, with participation by experts in radiopharmaceutical therapy and theranostics including representatives of major international organisations relevant to theranostics practice., Results: Through extensive discussions and review of existing curriculum and guidelines, a harmonised training program for theranostics was developed, which aims to ensure safe and high quality theranostics practice in all countries., Conclusion: The guiding principles for theranostics training outlined in this paper have immediate relevance for the safe and effective practice of theranostics., (© 2024. The Author(s).)

Theranostics has become a major area of innovation and progress in cancer care over the last decade. In view of the introduction of approved therapeutics in neuroendocrine tumours and prostate cancer in the last 10 years, the ability to provide access to these treatments has emerged as a key factor in ensuring global benefits from this cancer therapy approach. In this Series paper we explore the issues that affect access to and availability of theranostic radiopharmaceuticals, including supply and regulatory issues that might affect the availability of theranostic treatments for patients with cancer., Competing Interests: Declaration of interests RZ reports direct relations with Global Morpho Pharma, Posifit–Nancyclotep, LemerPax, MEDraysintell, Chrysalium Consulting, and Telix Pharma. NA reports having received a travel grant from the Australian and New Zealand Society of Nuclear Medicine. JSL reports research support from Clarity Pharmaceuticals and AVID Radiopharmaceuticals; has acted as an adviser of Boxer, Clarity Pharmaceuticals, Curie Therapeutics, Earli, Evergreen Theragnostics, NexTech Invest, Telix Pharmaceuticals, Suba Therapeutics, inhibrx, Precirix, Alpha-9 Oncology, and TPG Capital; is a co-inventor on technologies licensed to Diaprost, Elucida Oncology, Theragnostics, CheMatech, and Samus Therapeutics; is the co-founder of pHLIP; holds equity in Summit Biomedical Imaging, Telix Pharmaceuticals, and Evergreen Theragnostics; and is supported by National Institutes of Health R35 CA232130. SEL reports research support from Navidea Biopharmaceuticals, Fusion Pharmaceuticals, Cytosite Biopharma, Viewpoint Molecular Targeting, and Genzyme Corporation; has acted as an adviser for NorthStar Medical Radioisotopes and Trevarx biomedical; and is supported by the US Department of Energy as part of the DOE University Isotope Network under grant DESC0021269. JK reports participation on a data safety monitoring board and advisory board for Novartis (personal fees), and an unrestricted grant from Janssen. AMS reports trial funding from EMD Serono, ITM, Telix Pharmaceuticals, AVID Radiopharmaceuticals, Fusion Pharmaceuticals, and Cyclotek; research funding from Medimmune, AVID Radiopharmaceuticals, Adalta, Antengene, Humanigen, Telix Pharmaceuticals, and Theramyc; is a co-inventor on technologies licensed to Humanigen, AbbVie and Life Science Pharmaceuticals; participates on the advisory boards of Imagion and ImmunOs; and is supported by an Australian National Health and Medical Research Council grant number 1177837. CSC is supported by the US Department of Energy under grants Lab 20-2301, DE-FOA-0003063, and DE-FOA-0002532. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

This paper is the first of a Series on theranostics that summarises the current landscape of the radiopharmaceutical sciences as they pertain to oncology. In this Series paper, we describe exciting developments in radiochemistry and the production of radionuclides, the development and translation of theranostics, and the application of artificial intelligence to our field. These developments are catalysing growth in the use of radiopharmaceuticals to the benefit of patients worldwide. We also highlight some of the key issues to be addressed in the coming years to realise the full potential of radiopharmaceuticals to treat cancer., Competing Interests: Declaration of interests SEL reports research support from Navidea Biopharmaceuticals, Fusion Pharmaceuticals, Cytosite Biopharma, Viewpoint Molecular Targeting, and Genzyme Corporation; has acted as an advisor for NorthStar Medical Radioisotopes and Trevarx Biomedical; and is supported by the Department of Energy as part of the Department of Energy University Isotope Network under grant DESC0021269. PJHS reports research support from Bristol Myers Squibb, Telix Pharmaceuticals, and Radionetics Oncology; has acted as an adviser to Synfast Consulting and Telix Pharmaceuticals; holds equity in Bristol Myers Squibb, Telix Pharmaceuticals, and Novartis; and is supported by National Institutes of Health R01 EB021155. AMS reports trial funding from EMD Serono, ITM, Telix Pharmaceuticals, AVID Radiopharmaceuticals, Fusion Pharmaceuticals, and Cyclotek; research funding from Medimmune, AVID Radiopharmaceuticals, Adalta, Antengene, Humanigen, Telix Pharmaceuticals, and Theramyc; is on the advisory boards of Imagion and ImmunOs; and is supported by Australian National Health and Medical Research Council grant number 1177837. ADW reports his role as the Editor in Chief of Nuclear Medicine and Biology. BMZ holds equity in Summit Biomedical Imaging. RPB is an advisor to 3B Pharmaceuticals (Berlin, Germany), ITM, Full Life Technologies, Sinotau, Jiangsu Huayi Technology, and Telix Pharmaceuticals. APK reports clinical trial funding from Novartis, Bayer, POINT, and Merck; and unpaid consulting for Novartis. JK reports an unrestricted grant from Janssen, and consulting fees from Telix and Novartis. JSL reports research support from Clarity Pharmaceuticals and Avid Radiopharmaceuticals; has acted as an adviser of Alpha-9 Theranostics, Clarity Pharmaceuticals, Earli, Evergreen Theragnostics, Inhibrix, Precirix, and Telix Pharmaceuticals; is a co-inventor on technologies licensed to Diaprost, Elucida Oncology, Theragnostics, CheMatech, Clarity Pharmaceuticals, and Samus Therapeutics; is the co-founder of pHLIP; holds equity in Summit Biomedical Imaging, Telix Pharmaceuticals, Clarity Pharmaceuticals, and Evergreen Theragnostics; and is supported by National Institutes of Health R35 CA232130. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: For cancer patient populations worldwide, the synchronous scale-up of diagnostics and treatments yields meaningful gains in survival and quality of life. Among advanced cancer therapies, radiotherapy (RT) and theranostics are key to achieving practical, high-quality, and personalized precision medicine - targeting disease manifestations of individual patients and broad populations, alike. Aiming to learn from one another across different world regions, the six country vignettes presented here depict both challenges and victories in de novo establishment or improvement of RT and theranostics infrastructure., Methods: The International Atomic Energy Agency (IAEA) convened global RT and theranostics experts from diverse world regions and contexts to identify relevant challenges and report progress in their own six countries: Belgium, Brazil, Costa Rica, Jordan, Mongolia, and South Africa. These accounts are collated, compared, and contrasted herein., Results: Common challenges persist which could be more strategically assessed and addressed. A quantifiable discrepancy entails personnel. The estimated radiation oncologists (ROs), nuclear medicine physicians (NMPs), and medical physicists (MPs for RT and nuclear medicine) per million inhabitants in the six collective countries respectively range between 2.69-38.00 ROs, 1.00-26.00 NMPs, and 0.30-3.45 MPs (Table 1), reflecting country-to-country inequities which largely match World Bank country-income stratifications., Conclusion: Established goals for RT and nuclear medicine advancement worldwide have proven elusive. The pace of progress could be hastened by enhanced approaches such as more sustainably phased implementation; better multinational networking to share lessons learned; routine quality and safety audits; as well as capacity building employing innovative, resource-sparing, cutting-edge technologic approaches. Bodies such as ministries of health, professional societies, and the IAEA shall serve critical roles in convening and coordinating more innovative RT and theranostics translational research, including expanding nuanced global database metrics to inform, reach, and potentiate milestones most meaningfully., Policy Summary: Aligned with WHO 25×25 NCDs target; WHA70.12 and WHA76.5 resolutions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Although the promise of radionuclides for the diagnosis and treatment of disease was recognised soon after the discovery of radioactivity in the late 19th century, the systematic use of radionuclides in medicine only gradually increased over the subsequent hundred years. The past two decades, however, has seen a remarkable surge in the clinical application of diagnostic and therapeutic radiopharmaceuticals, particularly in oncology. This development is an exciting time for the use of theranostics in oncology, but the rapid growth of this area of nuclear medicine has created challenges as well. In particular, the infrastructure for the manufacturing and distribution of radiopharmaceuticals remains in development, and regulatory bodies are still optimising guidelines for this new class of drug. One issue of paramount importance for achieving equitable access to theranostics is building a sufficiently trained workforce in high-income, middle-income, and low-income countries. Here, we discuss the key challenges and opportunities that face the field as it seeks to build its workforce for the 21st century., Competing Interests: Declaration of interests Outside the submitted work: AMS reports trial funding from EMD Serono, ITM, Telix Pharmaceuticals, AVID Radiopharmaceuticals, Fusion Pharmaceuticals, and Cyclotek; research funding from Medimmune, AVID Radiopharmaceuticals, Adalta, Antengene, Humanigen, Telix Pharmaceuticals, and Theramyc; and payment for participation in advisory boards of Imagion and Immunos. BMZ reports research funding from Evergreen Theragnostics, equity in Summit Biomedical Imaging, and has licensed technologies to Clarity Pharmaceuticals. SEL reports research support from Navidea Biopharmaceuticals, Fusion Pharmaceuticals, Cytosite Biopharma, Viewpoint Molecular Targeting, and Genzyme Corporation, and has acted as an advisor for NorthStar Medical Radioisotopes and Trevarx biomedical. PJHS reports research support from Bristol Myers Squibb, Telix Pharmaceuticals, and Radionetics Oncology; has acted as an adviser to Synfast Consulting and Telix Pharmaceuticals; and holds equity in Bristol Myers Squibb, Telix Pharmaceuticals, and Novartis. ADW reports their role as Editor-in-Chief of Nuclear Medicine and Biology. JSL reports research support from Clarity Pharmaceuticals and Avid Radiopharmaceuticals; has acted as an adviser of Alpha-9 Theranostics, Clarity Pharmaceuticals, Earli, Evergreen Theragnostics, Inhibrix, Precirix, and Telix Pharmaceuticals; is a co-inventor on technologies licensed to Diaprost, Elucida Oncology, Theragnostics, CheMatech, Clarity Pharmaceuticals, and Samus Therapeutics; is the co-founder of pHLIP; and holds equity in Summit Biomedical Imaging, Telix Pharmaceuticals, Clarity Pharmaceuticals, and Evergreen Theragnostics. AMS is supported by National Health and Medical Research Council grant number 1177837. SEL is supported by the Department of Energy as part of the DOE University Isotope Network, under grant DESC0021269. PJHS is supported by grant R01 EB021155. JSL is supported by National Institutes of Health grant R35 CA232130. MA-W, AJ, AK, PK, SV, STL, SKL, DP, JZ, JLU, and FG report no competing interests. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

We describe a first suspected case of fibrosing mediastinitis following anti-programmed death (PD)-1 therapy, pembrolizumab. Multimodality imaging, including cardiac magnetic resonance imaging, and a multidisciplinary team approach were integral to the diagnosis. If further substantiated, systematic surveillance after anti-PD-1 therapy for fibrosing mediastinitis may be warranted. ( Level of Difficulty: Intermediate. )., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Purpose: Myocardial perfusion imaging (MPI) has limitations in the presence of balanced multivessel disease (MVD) and left main (LM) coronary artery disease, occasionally resulting in false-normal results despite the high cardiovascular risk associated with this condition. The purpose of this study was to assess the incidence of severe coronary artery disease (CAD) in the presence of a very high Agatston coronary artery calcium (CAC) score (>1,000) in stable symptomatic patients without known CAD but with normal MPI results., Methods: A total of 2,659 prospectively acquired consecutive patients were referred for MPI and evaluation of CAC score by CT. Of this patient population, 8 % (222/2,659) had ischemia without myocardial infarction (MI) on MPIand 11 % (298/2,659) had abnormal MPI (MI and/or ischemia). On presentation 1 % of the patients (26/2,659) were symptomatic, had a CAC score >1,000 and normal MPI results. The definition of normal MPI was strict and included a normal hemodynamic response without ischemic ECG changes and normal imaging, particularly absence of transient ischemic dilation. All of these 26 patients with a CAC score >1,000 and normal MPI findings underwent cardiac catheterization., Results: Of these 26 patients, 58 % (15/26) had severe disease (≥70 % stenosis) leading to revascularization. Of this group, 47 % (7/15) underwent percutaneous intervention, and 53 % (8/15) underwent coronary artery bypass grafting. All of these 15 patients had either MVD (14/15) or LM coronary artery disease (1/15), and represented 0.6 % (15/2,659) of all referred patients (95 % CI 0.3 - 0.9 %). The majority, 90 % (8/9), had severe CAD with typical chest pain., Conclusion: A very high CAC score (>1,000) with normal MPI in a small subset of symptomatically stable patients was associated with a moderate incidence of severe CAD (95 % CI 37 - 77 %). Larger studies and/or a meta-analysis of small studies are needed to more precisely estimate the incidence of CAD in this population. This study also supports the concept that a normal MPI result in patients with severe CAD may be due to balanced MVD.

Introduction: (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) may play an important role in staging patients with potentially resectable esophageal cancer but its impact on clinical management remains unclear., Methods: In a multicenter prospective cohort study of patients with potentially resectable esophageal cancer, we compared stage of disease based on PET/CT with the stage based on conventional staging performed before PET/CT (American Joint Committee on Cancer, 6th edition). The primary outcome was the proportion of patients with a clinically important change in stage, based on PET/CT findings. We used health administrative databases to track health services use and mortality after the index PET/CT scan., Results: Four hundred ninety-one patients who received a PET/CT scan for staging of potentially resectable esophageal cancer were included in the study cohort. PET/CT led to clinically important changes in stage for a total of 188 patients (24.0%): 107 patients (21.8%) were upstaged and 11 patients (2.2%) were downstaged. Results of PET/CT were associated with differences in actual management. At the 6-month follow-up, use of surgery was greater in patients with M0 disease (54.4%) compared with those with M1a (25.0%; p < 0.001) or M1b (7.3%; p < 0.001) disease based on PET/CT. The overall cohort had a median survival of 603 days, and higher stage of disease on PET/CT (i.e., M stage) was associated with shorter survival (p < 0.001)., Conclusions: PET/CT identifies disease not otherwise detected on conventional staging and results in clinically important changes in stage for an appreciable number of patients with potentially resectable esophageal cancer and can make important contributions to the management of these patients.

Lymphatic mapping and sentinel lymphadenectomy (LM/SL) have been successfully used in pre-treatment nodal staging of gynaecological cancers. We hypothesised the added-value of LM/SL plus SPECT/CT in patients with early stage of cervical cancer and vulvar cancer. A prospective, single-center, diagnostic, open label, active control, non-randomized clinical trial has been conducted in 7 patients with FIGO IA-IB1 cervical cancer and 7 patients with FIGO stage I-II-IIIcN0 vulvar cancer. All patients underwent LM/SL plus SPECT/low-dose CT and complete lymph node dissection (CLND) according to the standard of care. In case of negative hematoxylin-eosin staining, serial sections of the SLNs were analysed by immunohistochemistry and high molecular weight cytokeratin. Primary outcome measures were the detection rate, the sensitivity (SV), the negative predictive value (NPV), the diagnostic accuracy (DA) for anatomic localisation of SLNs, and the impact on management of SPECT/CT guided LM/SL versus CLND. The secondary outcome measure was the patient tolerability and operating time of LM/SL guided SPECT/CT versus CLND. http://clinicaltrials.gov/show/NCT00773071 All 14 patients were enrolled into the 1-day research protocol with dual-tracer LM/SL and SPECT/CT. Additional SLNs were detected on SPECT/CT compared to conventional planar imaging. Hot and cold > 1cm SLNs were detected on SPECT/CT. Detection rate, SV, NPV, DA were 100% in both groups; false negative rate was 0%. Rate of SLN metastases was 28.5% in cervical cancer and 42.9% in vulvar cancer. Impact on treatment was 28.5% and 14.3% in cervical cancer and vulvar cancer patients, respectively. SPECT/CT was well tolerated by all patients and operating time for LM/SL was within 30 min. No adverse events were reported with a time frame of 1-to-3 years. In early stage of gynaecological cancers, SPECT/low-dose CT is technically feasible and of clinical added-value for LM/SL.

Mechanical low back pain is a common indication for Nuclear Medicine imaging. Whole-body bone scan is a very sensitive but poorly specific study for the detection of metabolic bone abnormalities. The accurate localisation of metabolically active bone disease is often difficult in 2D imaging but single photon emission computed tomography/computed tomography (SPECT/CT) allows accurate diagnosis and anatomic localisation of osteoblastic and osteolytic lesions in 3D imaging. We present a clinical case of a patient referred for evaluation of chronic lower back pain with no history of trauma, spinal surgery, or cancer. Planar whole-body scan showed heterogeneous tracer uptake in the lumbar spine with intense localisation to the right lateral aspect of L3. Integrated SPECT/CT of the lumbar spine detected active bone metabolism in the right L3/L4 facet joint in the presence of minimal signs of degenerative osteoarthrosis on CT images, while a segment demonstrating more gross degenerative changes was more quiescent with only mild tracer uptake. The usefulness of integrated SPECT/CT for anatomical and functional assessment of back pain opens promising opportunities both for multi-disciplinary clinical assessment and treatment for manual therapists and for research into the effectiveness of manual therapies.

Purpose: The authors performed this retrospective study to investigate the impact of using ventilation scans obtained from single photon emission computed tomography (SPECT) in selecting beam directions in intensity modulated radiation therapy (IMRT) planning in lung cancer radiotherapy to spare dosimetrically well ventilated lung., Methods: For ten consecutive stage III non-small-cell lung cancer patients, the authors obtained both ventilation/perfusion SPECT scans and four-dimensional CT scans for treatment planning purposes. Each ventilation scan was registered with the corresponding planning CT and ventilation volumes corresponding to either > or = 50% (vv50) or > or = 70% (vv70) of the maximum SPECT count were automatically segmented. For each patient, three IMRT plans were generated: One using nine equally spaced beams optimized according to nonfunctional lung based mean lung dose and lung v20; a second using nine equally spaced beams optimized to avoid vv50 and vv70; and a third plan using only three beams with gantry angles chosen based on minimum mean ventilated lung dose calculated for each conformal beam at every 10 degrees gantry angle avoiding vv50 and vv70. Resultant dose volume histogram indices were calculated for each plan and were compared with respect to calculated SPECT-based ventilation parameters in order to quantify the potential utility of ventilation SPECT in this setting., Results: Two patient groups were identified based on (i) the overlap volume between PTV and vv50 and (ii) the average angular mean ventilated lung dose (AAMvLD). The first parameter quantifies the proximity of the PTV to well ventilated lung and the second parameter quantifies the degree of ventilation that surrounds the PTV. For group 1 patients, < or = 5% of the vv50 overlapped with the PTV. For group 2 patients, > 5% of the vv50 overlapped the PTV. Group 1 was further classified into subgroups 1A and 1B: For subgroup 1A, AAMvLD is >18 Gy, implying that the functional lung surrounds the PTV; for subgroup 1B, AAMvLD is <18 Gy, implying that the well ventilated lung does not completely surround PTV. For subgroup 1A, the plans generated using ventilated lung avoidance reduced dose to vv50 and vv70, with below tolerance dose to normal lung and acceptable coverage of the PTV. For subgroup 1B, the dose to the total lung and well ventilated lung are reduced with the beam direction optimization for the three-beam plan. For group 2, there was no significant dosimetric advantage of using SPECT-based ventilation information in IMRT plan optimization., Conclusions: In conclusion, it is feasible to use SPECT ventilation scans to optimize IMRT beam direction and, subsequently, to reduce dose to ventilated lung when overlap of the PTV and the ventilated lung is minimal and that the PTV is not surrounded by the ventilated lung. The potential benefit of ventilation SPECT scanning can be determined by preplanning assessment of overlap volumes and the AAMvLD.

A 70-year-old woman with a high pretest likelihood of coronary artery disease (CAD) underwent a Tc-99m MIBI SPECT-CT study for myocardial perfusion imaging (MPI), which was complemented by a high-resolution volume CT (VCT) study. After attenuation correction, an MPI pattern of ischemia was detected in the lateral wall of the myocardium. The CT calcium score (CTCS) was above the 75th percentile. The CT angiography (CTA) demonstrated a 70% stenosis at the ostial part of the circumflex artery, and incidentally revealed a saccular aneurysm. In today's nuclear cardiology, low-dose SPECT-CT plus high-resolution VCT allows anatofunctional assessment of suspected CAD.

Malignant melanoma of the skin is one of the most lethal cancers. The disease may spread either locally or regionally and to distant sites through predictable or unpredictable metastatic pathways. Accurate staging and restaging of disease are required for appropriate treatment decision making. Routine protocols based on clinical examinations and traditional radiologic evaluations are not cost-effective for the detection of systemic disease. In the last decade, nuclear medicine techniques, such as lymphoscintigraphy-directed lymphatic mapping and sentinel lymphadenectomy and (18)F-FDG PET, have played key roles in nodal and distant staging of melanoma. More recently, anatomic-functional imaging has been improved with the development of integrated PET/CT devices or combined SPECT/CT systems. (18)F-FDG-sensitive intraoperative probes have been specifically designed to detect small nodal and visceral metastases from melanoma and may become important tools for the cancer surgeon. In this article, we review the role of nuclear medicine in the assessment of malignant melanoma.

Unlabelled: Fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) detects recurrence of papillary thyroid carcinoma (PTC) in thyroidectomized patients with elevated thyroglobulin (Tg) levels and negative (131)I-whole-body scans. This paper describes the utility of thyroid-stimulating hormone (TSH)-stimulated fused FDG-PET/computed tomography (CT) scanning on our first 15 patients of this population., Methods: Patients were prepared for PET/CT imaging with thyroid hormone withdrawal (n = 7) or recombinant human TSH (n = 8). All other imaging before the PET/CT did not demonstrate evidence of recurrence., Results: PET/CT scans revealed active foci in 9 patients, 4 prepared with hypothyroidism, and 5 with exogenous TSH. Positive results were demonstrated even in those with relatively low stimulated-TSH Tg values (13 and 14 microg/L). Six patients with positive PET/CT scans were treated surgically, yielding malignant tissue for 5 of those patients., Conclusion: PET/CT scans performed under TSH stimulation are an effective method of detecting of recurrence of PTC and direct surgical interventions, even in those with persistently elevated but relatively low Tg levels.

Purpose: Delayed graft function after live donor transplantation affects 5% to 10% of recipients regardless of procurement technique. This delay in function is associated with an increased risk of rejection and decreased graft survival. In the present study we critically assess allograft recovery to identify the risk factors related to delayed graft function., Materials and Methods: We retrospectively reviewed donor and recipient medical records from 100 consecutive laparoscopic live donor nephrectomies from August 1997 to October 2001. Four criteria were used to classify delayed graft function: I) requirement of dialysis in postoperative week 1, II) creatinine 2.5 mg/dl or greater at postoperative day 5, III) time to half peak activity (mercaptoacetyltriglycine renal scan) at postoperative day 5 greater than 12.2 minutes (normal range 1 to 12.2) and IV) time to peak activity (mercaptoacetyltriglycine renal scan) at day 5 greater than 6.5 minutes (normal range 2.1 to 6.5). Patients could qualify for multiple outcome categories. Patients who did not match any of these criteria were classified as having normal renal function (outcome 0)., Results: The number of patients in the delayed graft function categories were 5 with outcome I, 14 with outcome II, 39 with outcome III and 24 with outcome IV. There were 23 patients represented in more than 1 category and 59 patients were classified as having normal function. Recipient age, donor/recipient gender relationship, unrelated highly mismatched donors and cold/total preservation time were identified as risk factors related to impaired early renal function recovery. None of the variables related to the laparoscopic technique itself represented risk factors for delayed graft function., Conclusions: Female donor kidneys into male recipients and highly HLA mismatched donors represent factors that may be controlled by donor selection when feasible. All attempts should be made to decrease cold ischemia time and, therefore, total preservation time. Prolonged carbon dioxide pneumoperitoneum, warm ischemia time, renal artery length or use of right kidney did not adversely affect the functional outcome of the allografts procured laparoscopically.

Purpose: We conducted a study to evaluate the role of F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in the detection of distant metastases from renal cell carcinoma (RCC)., Materials and Methods: Twenty-four patients with histologically proven clear-cell RCC undergoing surgical evaluation for possible resection of recurrent disease were investigated. All patients had suspected distant metastases based on conventional anatomic imaging techniques (computed tomography and magnetic resonance imaging). A total of 36 distant metastatic sites were identified. Pathology for all sites was obtained by biopsy or after surgical resection., Results: Histologically documented distant metastases from RCC were present in 33 sites (21 patients). Overall sensitivity, specificity, and positive predictive value of FDG-PET for the detection of distant metastases from RCC was 63.6% (21 of 33), 100% (three of three), and 100% (21 of 21), respectively. The mean size of distant metastases in patients with true-positive FDG-PET was 2.2 cm (95% CI, 1.7 to 2.6 cm) compared with 1.0 cm in patients with false-negative FDG-PET (95% CI, 0.7 to 1.4 cm; P =.001)., Conclusion: FDG-PET is not a sensitive imaging modality for the evaluation of metastatic RCC and may not adequately characterize small metastatic lesions. However, positive FDG-PET is predictive for the presence of RCC in lesions imaged, may complement anatomic radiologic imaging modalities, and may alleviate the need for a biopsy in selected situations. A negative FDG-PET, however does not rule out active malignancy.

The goal of cancer therapy is to eliminate the cancer and/or to arrest further growth while decreasing normal tissue toxicity, i.e. to increase the therapeutic ratio. This review focuses on a group of therapeutics that are either (1) directly stimulated by radiation to produce either directly or indirectly cytotoxic agents (i.e. genes under the control of a radiation inducible promoter that produce a cytotoxic protein or an enzyme that converts a prodrug to an active form, respectively); (2) auger-electron emitting radiolabelled oligonucleotides, antibodies, nucleotide analogues, or other small molecules that are internalized; (3) radiation inducible genes that produce a ligand or transporter (or the like) which then can be targeted by cytotoxic agents (e.g. radiolabelled substance). We have termed this group of therapeutics radiogenic therapy., (Copyright 2001 Harcourt Publishers Ltd.)

Radiotherapy prescription can now be customized to target the major mechanism(s) of resistance of individual tumors. In that regard, functional imaging techniques should be exploited to identify the dominant mechanism(s). Tumor biology research has identified several mechanisms of tumor resistance that may be unique to radiation treatments. These fall into 3 broad areas associated with (1) tumor hypoxic fraction, (2) tumor growth rate, (3) and the intrinsic radiosensitivity of tumor clonogens. Imaging research has markers in various stages of development for quantifying relevant information about each of these mechanisms, and those that measure tumor oxygenation and predict for radioresistance are the most advanced. Positron-emission tomography (PET) measurement of oxygen 15 has yielded important information, particularly about brain tissue perfusion, metabolism, and function. Indirect markers of tumor hypoxia have exploited the covalent binding of bioreductive intermediates of azomycin-containing compounds whose uptakes are inversely proportional to intracellular oxygen concentrations. Pilot clinical studies with single-photon emission computed tomography (SPECT) and PET detection of radiolabeled markers to tumor hypoxia have been reported. Recently, other studies have attempted to exploit the reduction properties of both technetium and copper chelates for the selective deposition of radioactive metals in hypoxic tissues. A growing number of potentially useful isotopes are now available for labeling several novel chemicals that could have the appropriate specificity and sensitivity. Preclinical studies with "microSPECT" and "microPET" will be important to define the optimal radiodiagnostic(s) for measuring tissue oxygenation and for determining the time after their administration for optimal hypoxic signal acquisition. Radiolabeled markers of growth kinetics and intrinsic radiosensitivity of cells in solid tumors are also being developed. We conclude that radiation oncology is uniquely positioned to benefit from functional imaging markers that identify important mechanisms of tumor radioresistance, since several strategies for overcoming these individual mechanisms have already been identified., (Copyright 2001 by W.B. Saunders Company)

Study Objectives: We sought to investigate the effect of lung volume reduction surgery (LVRS) on regional lung ventilation., Design: Retrospective analysis of routinely acquired data before and after LVRS., Setting: Large, urban, university medical center., Patients: Twenty-nine patients with severe emphysema., Intervention: Bilateral LVRS., Measurements and Results: (133)Xe washout curves during lung scintigraphy exhibit a biphasic pattern (the first component of the washout curve [m(r)] corresponds to an initial rapid phase in washout that reflects larger airways emptying, and the second component [m(s)] reflects a slower phase of washout that is attributed to gas elimination via smaller airways). We analyzed six standardized regions of the lung (upper, mid, and lower zones of the right and left lung), and calculated m(r) and m(s) for each lung region. The mean (+/- SE) baseline FEV(1) was 0.69+/-0.04 L, total lung capacity (TLC) was 139 +/-4% predicted, and the residual volume (RV)/TLC ratio was 65+/-2%. The mean improvement in FEV(1) 3 months post-LVRS was 38%. Post-LVRS, m(r) and m(s) increased in 79 and 74 lung regions, respectively, and there was no relationship with respect to lung regions that had or had not been operated on. The increase in m(s), however, significantly correlated with the increase in FEV(1) (r = 0.66; p<0.0001) and the decrease in RV/TLC (r = -0.67; p<0.0001). An increase in m(s) also correlated with a decrease in PaCO(2) (r = -0.39; p = 0.03), but m(r) showed no relationship with any parameter., Conclusions: Small airways ventilation in lung regions that had and had not been operated on is associated with a greater improvement in lung mechanics following LVRS.

At the dawn of the 21st century, nuclear oncology is undergoing a formidable and rapid mutagenesis. The progress in radiochemistry, radiopharmacy and, foremost, the advances in molecular oncology are the determinant mutagenic factors. Mutation, amplification, deletion or translocation of deoxyribonucleic acid segments in proto-oncogenes and tumor suppressor genes also called anti-oncogenes account for the uncontrolled cell growth and proliferation resulting in cancer. The astonishing developments in peptide and nucleic acid chemistry have opened the door for the development of new, highly specific probes such as antisense, aptamer and peptidomimetic molecules to image the oncogenes and anti-oncogenes transcriptional (messenger ribonucleic acid) and translational (protein) products involved in carcinogenesis. In this article, I shall review the basic molecular mechanisms of carcinogenesis and describe the molecular probes that are currently being developed.

We report a rapid and simple protocol for measuring the beta-lactamase activity from recombinant Escherichia coli cells transformed with any of the common plasmid vectors that provide ampicillin resistance through constitutive expression and periplasmic localization of the beta-lactamase TEM-1. The hydrolytic enzyme was extracted from the E. coli periplasm and the beta-lactamase activity determined by measuring conversion of ampicillin to aminobenzyl-penicilloic acid using quantitative high-performance liquid chromatography. Under saturating conditions the in vitro assay was linear as a function of both incubation time and enzyme concentration. Application of this assay to investigate TEM-1 expression, from two different protein expression vector systems, demonstrated the potential importance of this assay in studies of recombinant protein expression and translocation., (Copyright 1998 Academic Press.)

Objective: Both in vivo and in vitro red cell labeling methods are available for performing gastrointestinal bleeding studies. While in vitro labeling has been shown to result in higher binding efficiency, no comparison of clinical image quality has been reported between those techniques. This study compares in vivo and in vitro methods using both subjective and objective measurements of image quality., Methods: A consecutive series of gastrointestinal bleeding studies performed on 23 patients using in vivo labeling was compared to a series of 23 studies using in vitro labeling. Images at 30 min postinjection were randomized and analyzed by two observers. Subjective evaluation of image quality, as well as renal activity, was based on a comparison of femoral vein and inferior vena cava activity to adjacent background using numerical scores with a scale of 0-3. Image quality using the subjective scores was further classified as acceptable and poor. Target-to-background measurements of femoral vein to adjacent soft tissue in the thigh and inferior vena cava to adjacent abdominal background also were made., Results: In vitro label subjective image quality was acceptable in 87% and 91% of cases for vascular and renal activity, respectively, but only 35% and 52% for in vivo labeling. In vitro label target-to-background ratios were significantly better than in vivo label for the femoral vein and inferior vena cava, as well as for the subjective assessment of vascular image quality, but not for renal activity., Conclusion: In vitro red cell labeling improves clinical image quality as compared with in vivo labeling. Both subjective and objective measurements of image quality are useful for comparing the results of labeling methods.

Background: The effect of histamine H2 receptor antagonists on gastric emptying is controversial., Aims: To determine the effects of ranitidine, famotidine, and omeprazole on gastric motility and emptying., Patients and Methods: Fifteen normal subjects underwent simultaneous antroduodenal manometry, electrogastrography (EGG), and gastric emptying with dynamic antral scintigraphy (DAS). After 30 minutes of fasting manometry and EGG recording, subjects received either intravenous saline, ranitidine, or famotidine, followed by another 30 minutes recording and then three hours of postprandial recording after ingestion of a radiolabelled meal. Images were obtained every 10-15 minutes for three hours to measure gastric emptying and assess antral contractility. Similar testing was performed after omeprazole 20 mg daily for one week., Results: Fasting antral phase III migrating motor complexes (MMCs) were more common after ranitidine (9/15 subjects, 60%), famotidine (12/15, 80%), and omeprazole (8/12, 67%) compared with placebo (4/14, 29%; p < 0.05). Postprandially, ranitidine, famotidine, and omeprazole slowed gastric emptying, increased the amplitude of DAS contractions, increased the EGG power, and increased the antral manometric motility index., Conclusions: Suppression of gastric acid secretion with therapeutic doses of gastric acid suppressants is associated with delayed gastric emptying but increased antral motility.

We have tried to correlate abnormalities in electrogastrography (EGG) and gastric emptying (GE) with symptom severity in patients with functional dyspepsia. Seventy-two patients with functional dyspepsia underwent EGG, GE, and symptom severity quantitation. EGGs were assessed for dominant frequency (DF), percentage of time of DF in the 2 to 4 cpm range, and postprandial-fasting DF power ratio. Solid-phase GE scintigraphy was assessed for 2-hour percentage retention. Symptoms of upper abdominal discomfort, early satiety, postprandial abdominal distension, nausea, vomiting, and anorexia were graded as none (0), mild (1), moderate (2), and severe (3); the sum represented a total symptom score. The EGG was abnormal in 11 of 22 (50%) patients with delayed GE compared with 11 of 50 (22%) with normal GE (p < 0.025). The total symptom scores were higher in patients with both delayed GE and abnormal EGG compared with patients with normal GE and EGG, normal GE and abnormal EGG, and delayed GE and normal EGG. We conclude that EGG abnormalities are more common in dyspeptic patients with delayed GE. Patients with both delayed GE and abnormal EGG have more severe symptoms. Our results suggest that EGG and GE complement each other in correlating symptoms to gastric dysmotility.

Unlabelled: Accurate measurement of intragastric acidity has both clinical and investigational importance in studying gastric pathophysiology., Objectives: The aims of this study were fourfold: (1) to investigate whether regional differences in intragastric acidity exist; (2) to determine intragastric acidity after a standard antacid was administered in both the fasting and fed states; (3) to monitor gastric emptying of and anatomic distribution of radiolabeled antacid during fasting and postprandial periods; and (4) to determine whether the regional effects of ingested antacid correlated with the anatomic distribution of the antacid., Methods: Eight normal male volunteers were studied after fluoroscopically guided nasogastric placement of a tube assembly containing four pH electrodes, with one electrode in each quartile of the stomach. Simultaneous pH readings were made from the four electrodes while fasting, after administration of fasting antacid (30 ml, 79 mEq buffering capacity), postprandially, and after postprandial antacid ingestion. All subjects repeated the protocol on a separate day, five of them using radiolabeled antacid. Gastric emptying and gastric distribution over time of radiolabeled antacid were determined for comparison to regional intragastric acidity., Results: Intragastric acidity varied regionally over time in response to meals and to fasting and postprandial antacid. In the fasting state, intragastric acidity returned to baseline after antacid ingestion in a proximal to distal (cardia to antrum) sequence, while postprandial antacid resulted in a return to baseline acidity in a distal to proximal (antrum to cardia) sequence. Radiolabeled antacid distribution paralleled intragastric pH and hydrogen ion concentration in the fasting state, with 82% of the antacid localizing in the distal half of the stomach within the first minute after antacid ingestion. Postprandially, the greatest initial and most prolonged antacid buffering effect occurred proximally, correlating with the presence of radiolabeled antacid. Postprandial antacid remained in the stomach for a longer time (T1/2 = 93.1 +/- 23.4 min) compared with fasting antacid (T1/2 = 23.6 +/- 11.1 min)., Conclusions: Measurement of acidity in the four quartiles of the stomach demonstrated regional variation in response to both food and a standard antacid. A single pH electrode does not detect regional intragastric pH differences.

Unlabelled: The lactulose breath test (LBT) and gastroenterocolonic scintigraphy (GECS) can both be used to measure orocecal transit time (OCTT). The aims of this study were (1) to measure OCTT by LBT and GECS and (2) to determine whether lactulose alters orocecal transit., Methods: Eight normal subjects underwent simultaneous breath hydrogen testing, GECS, and duodenal manometry while receiving either 10 g lactulose or placebo with a radiolabeled solid/liquid test meal during two studies. There was a good correlation between OCTT by LBT and GECS when performed simultaneously (r = 0.95; P < 0.001). OCTT by GECS with lactulose was significantly faster (P = 0.004) than by GECS without lactulose, despite no change in gastric emptying of liquids and slowing of gastric emptying of solids (P = 0.02). The postprandial duodenal motility index was greater with lactulose than with placebo (P = 0.031). This study demonstrates that LBT and GECS (without lactulose) are not equivalent measures of OCTT. The standard LBT accelerates OCTT and slows gastric emptying. Therefore, lactulose has a direct accelerating effect on small intestinal transit.

Over the past 2 decades we have witnessed an explosion of new radioisotopic tracers aimed at detecting, staging and eventually treating tumors. In fact, nuclear oncology has evolved into a field on its own. Aside from aspecific radioisotopic tracers such as thallium 201 or gallium 67, clinicians and oncologists can now use specific radiolabeled monoclonal antibodies and metabolic tracers. In the near future, molecular probes based on the sequencing of the human genome with an exquisite specificity should also become available. In this article, we shall review the most recent developments in this new field.

Diurnal variation in insulin sensitivity in patients with NIDDM has long been suspected but has been difficult to document mainly because of the interdependence of changes in glucose and insulin. Stable serum insulin levels during hyperglycemic clamping in patients with NIDDM in the present study provided the opportunity to examine changes in insulin sensitivity unaffected by changes in blood glucose and insulin concentrations. Six patients with NIDDM (four men and two women, BMI 33.9 +/- 2.5) underwent hyperglycemic (11.1 mmol/l, approximately 200 mg/dl) clamping for 72 h. Measured were serum insulin, free fatty acid (FFA), cortisol, and growth hormone concentrations and rates of insulin secretion, insulin clearance, and glucose infusion rate (GIR) needed to maintain hyperglycemia. In addition, five patients (three men and two women, BMI 32.6 +/- 0.6) underwent hyperglycemic clamping for 24 h with hourly determinations of hepatic glucose production (HGP) and glucose disappearance rates (GRd). GIR, reflecting insulin sensitivity, changed rhythmically with a cycle duration of 22.9 +/- 1.4 h and an amplitude of 47.8 +/- 11.2%. GIR was lowest at 8:31 a.m. (+/- 52 min) and highest at 7:04 p.m. (+/- 58 min). Circadian changes in GIR were completely accounted for by changes in HGP, while GRd remained unchanged. Plasma levels of FFAs and cortisol also exhibited circadian fluctuations, and their blood levels correlated negatively with GIR (r = -0.72 and -0.64, respectively). We concluded that insulin sensitivity in patients with NIDDM changed with circadian (approximately 24 h) rhythmicity (decreasing during the night and increasing during the day). These changes were unrelated to blood levels of glucose and insulin, insulin clearance, exercise, food intake, and sleep. They were caused by circadian changes in HGP, which in turn were closely correlated with circadian changes in blood FFA and cortisol levels. We believe that recognition of these circadian changes has implications for the diagnosis and the treatment of patients with NIDDM.

Insulin secretion was studied in healthy volunteers at three different levels of glycemia. Plasma glucose was clamped at approximately 5, approximately 8.8 and approximately 12.6 mM for 68 h. Measured were serum insulin concentration and insulin secretion rates (ISR), the latter by deconvolution of plasma C-peptide concentration. Rhythmic patterns of ISR were identified (with a refined first-order Fourier transform) at all three glucose concentrations tested but were most clearly seen at 12.6 mM. ISR and serum insulin concentration changed in a circadian (approximately 24 h) rhythm, increasing from a nadir between midnight and 6 A.M. and reaching a peak between noon and 6 P.M. At 12.6 mM hyperglycemia, the amplitude of the insulin concentration cycles was greater than that of the ISR cycles (+/- 13.0 vs. +/- 8.7%) due to a decrease in insulin clearance (from 1.55 to 0.5 l/min, P < 0.01). Plasma melatonin levels (a marker of light-dark rhythmicity) changed in the opposite direction, i.e., they peaked when ISR bottomed and bottomed when ISR peaked. We concluded that normal human subjects have a circadian rhythm of insulin secretion, which becomes more apparent with rising ISR, and that circadian changes in ISR, rising during the day and falling during the night, may be one explanation for the well-established observation that glucose tolerance and insulin responses to glucose and meals are higher in the morning than at night.

Gastric emptying scintigraphy was introduced more than 25 years ago by Griffith and still remains the gold standard to assess gastric emptying. Test meals, radiopharmaceutical and acquisition procedures have been refined and optimized over the years and the test procedure is now well standardized. However, in its most common use, gastric emptying scintigraphy provides little information on gastric physiology and pathophysiology. Over the last decade, modeling of the liquid- and solid-emptying curves has provided some insight into the complex gastric physiology. Compartmental analysis of the stomach has also provided information on the pathophysiological mechanisms of delayed gastric emptying. Over the past 5 years, the most dramatic development in gastric emptying scintigraphy has been the introduction of digital antral scintigraphy. Digital antral scintigraphy consists primarily of dynamic imaging of the stomach and a refined Fourier transform processing method. This new procedure allows for the visualization of antral contractions and, like manometry, permits quantitative characterization of the frequency and amplitude of these contractions. Overall, this new procedure provides a unique, noninvasive tool to characterize gastric motility, to define the pathophysiological mechanisms of gastric motor disorders, and to evaluate the effect of new gastrokinetic compounds.

Unlabelled: We evaluated intragastric food distribution and antral motor activity in patients with functional dyspepsia., Methods: A standard gastric emptying test and dynamic imaging of the antrum were used to characterize gastric antral motility disturbances and to correlate them with total and compartmental gastric emptying in 25 dyspeptic patients., Results: We found a 40% prevalence of gastroparesis in functional dyspepsia. Solid gastric emptying delay is indicated by a prolonged lag phase and an increase in frequency and amplitude of gastric contractions, resulting in nonexpulsive antral contractions and/or antropyloric dyscoordination. Food retention in the distal stomach and antral distention appears to account for patients' dyspeptic symptoms., Conclusion: This study demonstrates that scintigraphy not only detects abnormalities of food distribution in the stomach but also provides information on antral motor activity noninvasively. Dynamic antral scintigraphy and compartmental gastric emptying are useful tools to define the pathophysiology of dyspeptic patients with or without gastroparesis.

Based on the specificity of the Watson-Crick base pairing formation, antisense deoxyoligonucleotides have been used to inhibit the expression of oncogenes in various cancer cells. Activation of an oncogene by means of amplification leads to an increased, detectable amount of the mRNA transcript in the cytoplasm. The aim of this study was to demonstrate that cells which are expressing a particular mRNA transcript do preferentially and specifically retain the antisense probe targeting that mRNA. Using a mouse plasmacytoma cell line (MOPC315) which produces high levels of IgA heavy chain mRNA, a control mouse pre B cell line (7OZ/3B), a human mammary cell line (MCF7) which expresses the erbB2 or neu oncogene, MOPC315 cells as neu-negative controls, and antisense DNA oligonucleotides complementary to the 5' region of the mRNAs and the sense sequence, we have shown that there is a preferential, specific retention of the IgA and neu antisense sequence in MOPC315 and MCF7 cells, respectively. We have further demonstrated that this retention is time and concentration dependent with a maximum at 24 h. We conclude that cancer cells which express a particular oncogene are suitable targets for radiolabeled antisense deoxyoligonucleotides directed toward the oncogene transcript. This work and recent developments in the antisense field lead to the expectation of a new class of radiopharmaceuticals with unique specificity.

Neuroendocrine tumors are usually slow-growing tumors that are difficult to locate with standard diagnostic imaging procedures, including enhanced computed tomography and magnetic resonance imaging. The observation that most neuroendocrine tumors have at their surface a high level of somatostatin receptors and the synthesis of octreotide (a long-lasting somatostatin analogue) has led to the development of a new radio-imaging procedure to detect these tumors. This procedure has been applied in numerous patients for the detection of neuroendocrine and other types of tumors. In this review, we summarize the results of the studies published recently in the literature.

In this study, food distribution in the stomach and gastric antral motor activity in patients with longstanding diabetes have been evaluated. With use of a standard gastric emptying test with an acquisition protocol and a refined Fourier algorithm to analyze the data, antral contractions have been characterized and gastric motility parameters were correlated to gastric retention in 20 diabetic patients with or without gastroparesis and in 10 healthy subjects. The results of this study show that, in longstanding diabetes, gastric emptying retardation is accounted for by a retention of food in the proximal stomach, which is reflected by a prolonged lag phase as well as by a reduction in antral motor activity that is determined by a decrease in the amplitude of the antral contractions. This study demonstrates that scintigraphy can noninvasively characterize abnormalities of food distribution in the stomach and provides information similar to that obtained from manometry.

Erythromycin markedly accelerates gastric emptying, possibly because it acts as a motilin agonist. In the present study, the effect of an equipotent dose of motilin was tested. In six patients with severe diabetic gastroparesis, gastric emptying of liquids and solids was examined scintigraphically after motilin or placebo in a double-blind crossover study. Motilin (10 pmol.kg-1.min-1) or saline was infused over a 90-minute period starting 5 minutes before breakfast. Motilin markedly accelerated emptying. For liquids, the half-emptying time was reduced from 51 +/- 6 to 22 +/- 11 minutes (P less than 0.01) and for solids from 111 +/- 4 to 51 +/- 12 minutes (P less than 0.01). The mean increase in plasma motilin levels was 1315 +/- 342 pg/mL, corresponding to an effective infusion rate of about 4 pmol.kg-1.min-1. In the control experiments, basal motilin levels (173 +/- 17 pg/mL) were within the normal range but increased steadily postprandially, reaching 321 +/- 25 pg/mL at the end of the study period, probably reflecting gastric distension. The postprandial increase in pancreatic polypeptide level was blunted compared with accepted normal values but was more pronounced during motilin infusion, i.e., 650 +/- 217 vs. 279 +/- 66 pg/mL (P less than 0.01), probably because of the improved emptying. Our data show that motilin accelerates gastric emptying in diabetic gastroparesis and support the hypothesis that erythromycin's effect is mediated through motilin receptors.

With the use of the radionuclide gastric-emptying test and a new data processing method, the contraction characteristics of the stomach were analyzed. After ingestion of a radiolabeled test meal, dynamic images of the stomach were acquired and analyzed to determine the frequency, amplitude, and rate of gastric contractions in healthy subjects. The frequency of antral contractions was found to be inversely related with food retention in the stomach; in contrast, the amplitude of the contractions decreased progressively during the course of gastric emptying. The peaks of both antral contraction and filling rate and the time of their occurrence remained constant throughout gastric emptying. The observed patterns of phase distribution and sequential phase changes of the food in the stomach confirmed noninvasively what was already known from invasive technique, i.e., that the proximal stomach does not undergo phasic contractions and that, in the distal stomach, smooth muscle contraction originates in midcorpus and propagates aborally to the pylorus. The scintigraphic test can be used to noninvasively and quantitatively characterize gastric motor function and to delineate the spatial sequence of gastric contractions. This technique can be applied to study the pathophysiology of gastric emptying in various motor disorders.

The role of the distal stomach in gastric emptying was studied. Ten patients with proximal gastric vagotomy (PV) and 10 age-matched patients with Roux-en-Y gastro-jejunostomy (R-Y) were compared with 10 healthy controls. Gastric emptying of solids and liquids was determined by the use of Tc-99m SC scrambled eggs and In-111 DTPA. In PV, gastric emptying of both solids and liquids was delayed; the prolongation with solids was mainly accounted for by an abnormal lag phase. In R-Y patients, no lag phase was observed, and the solid emptying curve pattern was characterized by early rapid emptying followed by very slow emptying. Both the solid and liquid phases were prolonged. The lag phase is affected by proximal vagotomy and is mainly determined by the distal stomach, which appears to be essential for normal emptying.

Erythromycin, a macrolide antibiotic, has recently been shown to have a motilin like effect on gastrointestinal muscle strips. In this study, we have evaluated the effect of erythromycin on patients with delayed gastric emptying and healthy subjects using the dual radionuclide technique. Twelve patients with gastroparesis diabeticorum and ten healthy age- and sex-matched controls were studied. Gastric emptying of solids and liquids was determined using 99mTc-SC scrambled egg and 111In-DTPA in water. Following a baseline study and on a separate day, each patient and control received a 15-min i.v. perfusion of erythromycin starting at meal ingestion. Eleven out of the 12 patients were restudied after a 3-wk oral administration. In patients and controls, i.v. erythromycin dramatically accelerated gastric emptying of both solids and liquids which were emptied at the same rate. After chronic oral administration, solid and liquid emptying remained significantly accelerated. Erythromycin appears to be a very powerful gastrokinetic drug. Derived compounds with the gastrokinetic effect and without the antibiotic activity could be useful in dyspeptic patients with delayed gastric emptying.

In a double-blind trial of the European Cooperative Study Group, 721 patients with acute myocardial infarction of less than 5 hours' duration were given either 100 mg recombinant tissue-type plasminogen activator (rt-PA) intravenously over 3 hours or an equivalent placebo infusion. In a subset of 312 patients, infarct size was assessed by the cumulative myocardial release of alpha-hydroxybutyrate dehydrogenase (HBDH) during the first 72 hours and by planar thallium scintigraphy (index of hypoperfusion) performed 10 to 22 days after the acute event. Left ventricular ejection fraction (LVEF) was determined by contrast and nuclear angiography. The median values of HBDH during the first 72 hours were 20% lower and the median values of thallium-201 28% smaller in the rt-PA group in comparison with controls. A significant but limited improvement of angiographic LVEF (2 absolute percentage points) was also shown in the patients treated with rt-PA. A moderate but statistically significant linear association between both measurements of infarct size and LVEF was found.

Erythromycin mimics the effect of the gastrointestinal polypeptide motilin on gastrointestinal motility, probably by binding to motilin receptors and acting as a motilin agonist. Erythromycin may thus have clinical application in patients with disturbances of gastroduodenal motility, such as diabetic gastroparesis. To examine this possibility, we studied the effect of erythromycin on gastric emptying in 10 patients with insulin-dependent diabetes mellitus and gastroparesis. We studied the emptying of liquids and solids simultaneously on separate days after the intravenous administration of erythromycin (200 mg) or placebo, using a double-isotope technique and a double-blind, crossover design. Erythromycin shortened the prolonged gastric-emptying times for both liquids and solids to normal. For example, 120 minutes after the ingestion of a solid meal, mean (+/- SE) retention was 63 +/- 9 percent with placebo and 4 +/- 1 percent with erythromycin, as compared with 9 +/- 3 percent in 10 healthy subjects. The corresponding values 120 minutes after the ingestion of a liquid meal were 32 +/- 4, 9 +/- 3, and 4 +/- 1 percent, respectively. Gastric emptying also improved, but to a lesser degree, in the 10 patients after four weeks of treatment with oral erythromycin (250 mg three times a day). These preliminary results suggest that erythromycin may have therapeutic value in patients with severe diabetic gastroparesis.