Society Of Nuclear Medicine Research Articles

Practice guidelines for managing extrahepatic biliary tract cancers.

Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021. Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop. In November 2021, the finalized draft was presented for public scrutiny during a formal hearing. The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.

British Nuclear Medicine Society Spring Meeting 13th - 15th May 2024.

British Nuclear Medicine Society Spring Meeting 13th - 15th May 2024.

Quantitative Brain Amyloid PET.

Since the development of amyloid tracers for PET imaging, there has been interest in quantifying amyloid burden in the brains of patients with Alzheimer disease. Quantitative amyloid PET imaging is poised to become a valuable approach in disease staging, theranostics, monitoring, and as an outcome measure for interventional studies. Yet, there are significant challenges and hurdles to overcome before it can be implemented into widespread clinical practice. On November 17, 2022, the U.S. Food and Drug Administration, Society of Nuclear Medicine and Molecular Imaging, and Medical Imaging and Technology Alliance cosponsored a public workshop comprising experts from academia, industry, and government agencies to discuss the role of quantitative brain amyloid PET imaging in staging, prognosis, and longitudinal assessment of Alzheimer disease. The workshop discussed a range of topics, including available radiopharmaceuticals for amyloid imaging; the methodology, metrics, and analytic validity of quantitative amyloid PET imaging; its use in disease staging, prognosis, and monitoring of progression; and challenges facing the field. This report provides a high-level summary of the presentations and the discussion.

The MIRD Schema for Radiopharmaceutical Dosimetry: A Review.

Internal dosimetry evaluates the amount and spatial and temporal distributions of radiation energy deposited in tissue from radionuclides within the body. Historically, nuclear medicine had been largely a diagnostic specialty, and the implicitly performed risk-benefit analyses have been straightforward, with relatively low administered activities yielding important diagnostic information whose benefit far outweighs any potential risk associated with the attendant normal-tissue radiation doses. Although dose estimates based on anatomic models and population-average kinetics in this setting may deviate rather significantly from the actual normal-organ doses for individual patients, the large benefit-to-risk ratios are very forgiving of any such inaccuracies. It is in this context that the MIRD schema was originally developed and has been largely applied. The MIRD schema, created and maintained by the MIRD committee of the Society of Nuclear Medicine and Molecular Imaging, comprises the notation, terminology, mathematic formulas, and reference data for calculating tissue radiation doses from radiopharmaceuticals administered to patients. However, with the ongoing development of new radiopharmaceuticals and the increasing therapeutic application of such agents, internal dosimetry in nuclear medicine and the MIRD schema continue to evolve-from population-average and organ-level to patient-specific and suborgan to voxel-level to cell-level dose estimation. This article will review the basic MIRD schema, relevant quantities and units, reference anatomic models, and its adaptation to small-scale and patient-specific dosimetry.

Modulation Imaging Contrast Agent for Cancer

Molecular imaging, also known as molecular imaging, is a medical technique used to visualize and analyze biological molecules in the human or animal body. According to the Society of Nuclear Medicine and Molecular Imaging's website, "Molecular Imaging" is a type of medical imaging that provides a detailed picture of what is happening in the body at the molecular and cellular levels. This definition refers to the significant advancements researchers have made over the past two decades in applying the principles of molecular imaging in various areas, from basic and translational science to advanced patient diagnosis and therapy. Essentially, molecular imaging allows us to visualize biochemical processes and target localization patterns that are invisible at the level of anatomical imaging. The goal of molecular imaging is to obtain information about molecular activity and function in living tissue. The technologies commonly used in imaging modulation are Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), and Magnetic Resonance Imaging (MRI).

Challenges, limitations, and pitfalls of PET and advanced MRI in patients with brain tumors: A report of the PET/RANO group.

Brain tumor diagnostics have significantly evolved with the use of positron emission tomography (PET) and advanced magnetic resonance imaging (MRI) techniques. In addition to anatomical MRI, these modalities may provide valuable information for several clinical applications such as differential diagnosis, delineation of tumor extent, prognostication, differentiation between tumor relapse and treatment-related changes, and the evaluation of response to anticancer therapy. In particular, joint recommendations of the Response Assessment in Neuro-Oncology (RANO) Group, the European Association of Neuro-oncology, and major European and American Nuclear Medicine societies highlighted that the additional clinical value of radiolabeled amino acids compared to anatomical MRI alone is outstanding and that its widespread clinical use should be supported. For advanced MRI and its steadily increasing use in clinical practice, the Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition provided more recently an updated acquisition protocol for the widely used dynamic susceptibility contrast perfusion MRI. Besides amino acid PET and perfusion MRI, other PET tracers and advanced MRI techniques (e.g. MR spectroscopy) are of considerable clinical interest and are increasingly integrated into everyday clinical practice. Nevertheless, these modalities have shortcomings which should be considered in clinical routine. This comprehensive review provides an overview of potential challenges, limitations, and pitfalls associated with PET imaging and advanced MRI techniques in patients with gliomas or brain metastases. Despite these issues, PET imaging and advanced MRI techniques continue to play an indispensable role in brain tumor management. Acknowledging and mitigating these challenges through interdisciplinary collaboration, standardized protocols, and continuous innovation will further enhance the utility of these modalities in guiding optimal patient care.

Implementation of PSMA PET/CT and alignment of ordering to SNMMI appropriate use criteria in a large network system.

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) provides appropriate use criteria (AUC) for prostate-specific membrane antigen positron emission tomography/computed tomography(PSMA PET/CT) which include guidance on imaging in newly diagnosed prostate cancer and in patients with biochemically recurrent (BCR) disease. This study aims to examine trends in PSMA implementation and the prevalence and outcomes of scans ordered in scenarios deemed rarely appropriate or not meeting SNMMI AUC. We retrospectively identified patients who were diagnosed with presumptive National Comprehensive Cancer Network unfavorable intermediate, high, or very high risk prostate cancer, patients who underwent staging for BCR, and all patients staged with PSMA between July 2021 and March 2023. Positivity was validated by adherence to a predetermined reference standard. The frequency of PSMA use increased in initial staging from 24% to 80% and work-up of BCR from 91% to 99% over our study period. In addition, 5% (17/340) of PSMA scans ordered for initial staging did not meet AUC and 3% (15/557) of posttreatment scans were deemed rarely appropriate. Initial staging orders not meeting SNMMI AUC resulted in no positivity (0/17), while rarely appropriate posttreatment scans were falsely positive in 75% (3/4) of cases. Urologists (53%, 17/32) comprised the largest ordering specialty in rarely appropriate use. The frequency of PSMA use rose across the study period. A significant minority of patients received PSMA PET/CT in rarely appropriate scenarios yielding no positivity in initial staging and significant false positivity post-therapy. Further education of providers and electronic medical record-based interventions could help limit the rarely appropriate use of PET imaging.

Nuclear Medicine Imaging Tools in Fever of Unknown Origin: Time for a Revisit and Appropriate Use Criteria.

Fever of unknown origin (FUO) is a clinical conundrum for patients and clinicians alike, and imaging studies are often performed as part of the diagnostic workup of these patients. Recently, the Society of Nuclear Medicine and Molecular Imaging convened and approved a guideline on the use of nuclear medicine tools for FUO. The guidelines support the use of 2-18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in adults and children with FUO. 18F-FDG PET/CT allows detection and localization of foci of hypermetabolic lesions with high sensitivity because of the 18F-FDG uptake in glycolytically active cells that may represent inflammation, infection, or neoplasia. Clinicians should consider and insurers should cover 18F-FDG PET/CT when evaluating patients with FUO, particularly when other clinical clues and preliminary studies are unrevealing.

The British nuclear medicine research strategy - the framework.

The British Nuclear Medicine Society (BNMS) has developed a Research Strategy framework led by the Research Champions of the BNMS and overseen by the BNMS Research and Innovation Committee. The objectives of the Research Strategy are to improve translation of cutting-edge nuclear medicine research from bench to bedside, the implementation of state-of-the-art multimodality technologies and to enhance multicentre radionuclide research in the UK. It strives to involve patients and the public in radionuclide research and to contribute to and work with the multi-professional national and international organisations involved in research with an ultimate aim to improve nuclear medicine services, and patients' outcomes and care.

An Evaluation of Gastric Emptying Scintigraphy Protocols in Health Care Institutions When Compared with the Society of Nuclear Medicine and Molecular Imaging Procedure Guidelines.

This study aimed to analyze the compliance of health care institutions with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) procedure guidelines for gastric emptying scintigraphy (GES). Methods: A 19-question survey on demographics and the GES protocol was conducted using a Google form. The demographic questions covered position, number of technologists in the department, location, type of health care institution, and number of GES studies per month. The protocol questions included patient preparation, meal preparation, withholding of scheduled medications, radiopharmaceutical type, and radiopharmaceutical dose. The survey was sent to 7 nuclear medicine Facebook groups and a list of clinical affiliates provided by the Indiana University School of Medicine Nuclear Medicine Program. Descriptive statistics were compiled for most questions. A Fisher exact test with a significance level of 0.05 was used to compare the type of health care institution with compliance with the SNMMI GES protocol regarding radiolabeling time, meal preparation, and meal components, as well as to compare the type of health care institution with the number of GES studies performed per institution. Results: In total, 240 people responded to the survey. Most were nonsupervisory nuclear medicine technologists (72%) in nonacademic institutions (72%) and groups with 4 or more technologists (62%). Of the respondents, 72% followed the SNMMI guideline of adding the radiopharmaceutical before cooking, but only 37% followed the meal component guideline. There was no significant association between the type of institution or the number of GES studies and compliance with radiolabeling time or with meal preparation or components. Most respondents asked patients to withhold medications per SNMMI guidelines and used the recommended radiopharmaceutical (99mTc-sulfur colloid, 95%) at the recommended dose (18.5-37 MBq, 84%). Conclusion: Although most respondents followed most aspects of the SNMMI guidelines for GES, more than half did not use the recommended meal of liquid egg whites. Compliance did not vary between academic and nonacademic institutions or between groups performing a large or a small number of GES studies.

The Efficacy of Radiolabeling the Albumin in Egg Whites with 99mTc-Sulfur Colloid.

In 2009, the Society of Nuclear Medicine and Molecular Imaging published a standardized protocol guideline for gastric emptying scintigraphy that contains specific instructions on the exact meal and preparation procedure. Previous research has shown that the standardized meal and proper preparation of the meal for gastric emptying scintigraphy are not being adopted by some facilities. This research explores the differences of radiolabeling in the method of preparation of 99mTc-sulfur colloid (SC)-radiolabeled eggs. Methods: Liquid egg whites were mixed with 99mTc-SC before cooking in conjunction with the standardized protocol. A second sample set was prepared by adding the 99mTc-SC to eggs after they were cooked. Each sample set was placed in a solution of HCl and pepsin to simulate gestation. Radiolabeling efficacy was tested on each sample set at 2 and 4 h after gestating in HCl and pepsin. Results: 99mTc-SC added to the liquid egg whites before microwave cooking yielded radiolabeling efficacy of 70% 99mTc-SC after 2 and 4 h of simulated gastric fluid gestation. In contrast, radiolabeling after cooking the egg whites yielded 50% radiolabeling after simulated gestation. Conclusion: The results from this experiment showed that the method of mixing the 99mTc-SC with liquid egg whites before microwave cooking has higher binding efficacy than when adding 99mTc-SC onto already cooked egg whites. These results highlight the importance of following the standardized protocol for the meal preparation of a gastric emptying study.

Real-world applicability of differentiated thyroid cancer guidelines.

Thyroid cancer (TC) is the most common endocrine malignancy with constantly growing incidence. Radioiodine ablation is a safe and effective method for managing TC. Recently various Guidelines (GL) have been published on whom should be ablated, when and under which circumstances. Our study compares 6 GL with a given patient cohort. Additionally, we evaluated each GL's quality via an independent tool. We compared six Guidelines (GL) for TC ablation on a cohort of 336 patients, implementing GL retrospectively: 2009 and 2016 American Thyroid Association (ATA), European Thyroid Association's (ETA) Consensus Statement, UK's National Institute for Health and Care Excellence (NICE), German position paper from Surgery and Nuclear Medicine (German) and European Association of Nuclear Medicine and Society of Nuclear Medicine and Molecular Image (EANM/SNMMI). Quality assessment was conducted using the Appraisal of Guidelines, Research and Evaluation instrument II (AGREE II). Results showed significant variability among GL. American Thyroid Association 2016, a clear improvement of the ATA 2009, presents a large grey area of "probable ablation candidates". European Thyroid Association and NICE agree that only a small portion of our ablated patients would benefit from it and the AGREE II tool shows a lack of applicability, but very good scores elsewhere. German and EANM/SNMMI GL agree that most of our clinical decisions to ablate were correct and their AGREE II scores are the highest in all six domains. Considering that dynamic risk classification plays a major role in determining the most appropriate treatment, it appears that the guidelines should be updated in order to support individualized patient management. However, it is the experience of the individual physician that will determine the final decision.

Formulating a national position statement and guide on modern theranostics in the Philippines.

Barriers to the establishment of advanced technologies in developing countries were overcome when modern theranostics pertaining to the use of Ga-68 and Lu-177 PSMA and DOTATATE were first offered to patients in the Philippines in early 2018. However, significant growth was not experienced at St. Luke's Medical Center for five years and lutetium was not yet distributed to other institutions by a radiopharmaceutical supplier. Due to the relative novelty and rapid expansion of theranostics worldwide, position statements were released by the Australasian Association of Nuclear Medicine Specialists, European Association of Nuclear Medicine, Society of Nuclear Medicine and Molecular Imaging, and International Atomic Energy Agency primarily to uphold patient safety and ensure a level of standard among its practitioners. Subsequently in the latter half of 2022, these were adopted and modified according to what is feasible and applicable locally within the Philippine Society of Nuclear Medicine, considering the current status and future possibilities. Different representatives were involved, and several groups were mobilized for successful implementation. A liability clause was incorporated to discourage unprofessional acts.

Inter-scanner Aβ-PET harmonization using barrel phantom spatial resolution matching.

The standardized uptake value ratio (SUVR) is used to measure amyloid beta-positron emission tomography (Aβ-PET) uptake in the brainDifferences in PET scanner technologies and image reconstruction techniques can lead to variability in PET images across scanners. This poses a challenge for Aβ-PET studies conducted in multiple centers. The aim of harmonization is to achieve consistent Aβ-PET measurements across different scanners. In this study, we proposean Aβ-PET harmonization methodof matching spatial resolution, as measured viaabarrel phantom, across PET scanners. Our approach wasvalidated using paired subject data, for whichpatients were imaged on multiple scanners. In this study, three different PET scanners were evaluated: the Siemens Biograph Vision 600, Siemens Biograph molecular computed tomography (mCT), and Philips Gemini TF64. A total of five, eight, and five subjects were each scanned twice with [18F]-NAV4694 across Vision-mCT, mCT-Philips, and Vision-Philips scanner pairs. The Vision and mCT scans were reconstructed using various iterations, subsets, and post-reconstruction Gaussian smoothing, whereas only one reconstruction configuration was used for the Philips scans. The full-width at half-maximum (FWHM) of each reconstruction configuration was calculated using [18F]-filled barrel phantom scans with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) phantom analysis toolkit. Regional SUVRs were calculated from 72 brain regions using the automated anatomical labelling atlas 3 (AAL3) atlas for each subject and reconstruction configuration. Statistical similarity between SUVRs was assessed using paired (within subject) t-tests for each pair of reconstructions across scanners; the higher the p-value, the greater the similarity between the SUVRs. Vision-mCT harmonization: Vision reconstruction with FWHM=4.10mm and mCT reconstruction with FWHM=4.30mm gave the maximal statistical similarity (maximum p-value) between regional SUVRs. Philips-mCT harmonization: The FWHM of the Philips reconstruction was 8.2mm and the mCT reconstruction with the FWHM of 9.35mm, which gave the maximal statistical similarity between regional SUVRs. Philips-Vision harmonization: The Vision reconstruction with an FWHM of 9.1mm gave the maximal statistical similarity between regional SUVRs when compared with the Philips reconstruction of 8.2mm and were selected as the harmonized for each scanner pair. Based on data obtained from three sets of participants, each scanned on a pair of PET scanners, it has been verified that using reconstruction configurations that produce matched-barrel, phantom spatial resolutions results in maximally harmonized Aβ-PET quantitation between scanner pairs. This finding is encouraging for the use of PET scanners in multi-center trials or updates during longitudinal studies. Question: Does the process of matching the barrel phantom-derived spatial resolution between scanners harmonize amyloid beta-standardized uptake value ratio (Aβ-SUVR) quantitation? Pertinent findings: It has been validated that reconstruction pairs with matched barrel phantom-derived spatial resolution maximize the similarity between subjects paired Aβ-PET (positron emission tomography) SUVR values recorded on two scanners. Implications for patient care: Harmonization between scanners in multi-center trials and PET camera updates in longitudinal studies can be achieved using a simple and efficient phantom measurement procedure, beneficial for the validity of Aβ-PET quantitation measurements.

Thai national guideline for nuclear medicine investigation in movement disorders: Nuclear medicine society of Thailand, the neurological society of Thailand, and Thai medical physicist society collaboration.

Movement disorders are chronic neurological syndromes with both treatable and non-treatable causes. The top causes of movement disorders are Parkinson's disease and related disorders. Functional imaging investigations with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) images play vital roles in diagnosis and differential diagnosis to guide disease management. Since there have been new advanced imaging technologies and radiopharmaceuticals development, there is a need for up-to-date consensus guidelines. Thus, the Nuclear Medicine Society of Thailand, the Neurological Society of Thailand, and the Thai Medical Physicist Society collaborated to establish the guideline for Nuclear Medicine investigations in movement disorder for practical use in patient care. We have extensively reviewed the current practice guidelines from other related societies and good quality papers as well as our own experience in Nuclear Medicine practice in movement disorders. We also adjust for the most suitability for application in Thailand and other developing countries.

The 20th Biennial congress of the South African Society of Nuclear Medicine conference report

This conference report encompasses abstracts and posters presented at the 20th Biennial Congress of the South African Society of Nuclear Medicine on ‘Going Back to our Roots', 24–27 August 2023, at the Boardwalk Hotel Conference Centre, Gqeberha, South Africa.

An International Survey Investigating the Incidence and Management of Brown Fat Uptake on 18F-FDG PET/CT at Children's Hospitals and Interventions for Mitigation.

Brown fat can present challenges in patients with cancer who undergo 18F-FDG PET scans. Uptake of 18F-FDG by brown fat can obscure or appear similar to active oncologic lesions, causing clinical challenges in PET interpretation. Small, retrospective studies have reported environmental and pharmacologic interventions for suppressing brown fat uptake on PET; however, there is no clear consensus on best practices. We sought to characterize practice patterns for strategies to mitigate brown fat uptake of 18F-FDG during PET scanning. Methods: A survey was developed and distributed via e-mail LISTSERV to members of the Children's Oncology Group diagnostic imaging committee, the Society for Nuclear Medicine and Molecular Imaging pediatric imaging council, and the Society of Chiefs of Radiology at Children's Hospitals between April 2022 and February 2023. Responses were stored anonymously in REDCap, aggregated, and summarized using descriptive statistics. Results: Fifty-five complete responses were submitted: 51 (93%) faculty and fellow-level physicians, 2 (4%) technologists, and 2 (4%) respondents not reporting their rank. There were 43 unique institutions represented, including 5 (12%) outside the United States. Thirty-eight of 41 (93%) institutions that responded on environmental interventions reported using warm blankets in the infusion and scanning rooms. Less than a third (n = 13, 30%) of institutions reported use of a pharmacologic intervention, with propranolol (n = 5, 38%) being most common, followed by fentanyl (n = 4, 31%), diazepam (n = 2, 15%), and diazepam plus propranolol (n = 2, 15%). Selection criteria for pharmacologic intervention varied, with the most common criterion being brown fat uptake on a prior scan (n = 6, 45%). Conclusion: Clinical practices to mitigate brown fat uptake on pediatric 18F-FDG PET vary widely. Simple environmental interventions including warm blankets or increasing the temperature of the injection and scanning rooms were not universally reported. Less than a third of institutions use pharmacologic agents for brown fat mitigation.

Updated Appropriate Use Criteria for Amyloid and Tau PET

AbstractBackgroundThe Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging convened a Workgroup to update previous Appropriate Use Criteria (AUC) for amyloid PET (Johnson 2013) and develop the first AUC for tau PET. The AUC represent general guidelines and should not be considered a substitute for clinical judgment exercised in the care of individual patients.MethodThe Workgroup included 14 researchers with multidisciplinary expertise. Meetings were held between June 2020 and August 2021. Key research questions were identified using the PICOTS framework, triggering an independent systematic literature review. Using established methods (Fitch 2001), the Workgroup identified 17 clinical scenarios in which amyloid/tau PET may be considered. Appropriateness of amyloid and tau PET as independent, stand‐alone modalities were ranked for each scenario using a 9‐point scale (Table 1). Consensus was achieved using a modified Delphi process. Online surveys were completed iteratively by Workgroup members, followed by discussion, until all votes for each scenario fell within one of the following categories: Appropriate/Uncertain/Rarely Appropriate.ResultAs an over‐arching principle, amyloid/tau PET should be considered in patients who: (1) have undergone a comprehensive assessment by a dementia expert; (2) Alzheimer’s disease (AD) is a diagnostic possibility but uncertainty remains; and (3) knowledge of amyloid/tau PET results is expected to help establish diagnosis and guide patient management. Consensus ratings for clinical scenarios are shown in Table 2. More evidence was available to inform recommendations for amyloid than tau PET. Amyloid PET was considered “Appropriate” to inform diagnosis of MCI or dementia due to suspected AD; clarify diagnosis when CSF biomarkers are equivocal; to inform prognosis in MCI; and to determine eligibility for amyloid‐targeting therapies. Tau PET was considered “Appropriate” to clarify diagnosis in patients with MCI/dementia under age 65 or those with atypical presentations; and to inform prognosis in MCI or dementia due to suspected AD.ConclusionThe updated AUC highlight a growing role for amyloid PET and an emerging role for tau PET in the clinical evaluation of cognitively impaired patients. AUC are expected to further evolve based on data from ongoing studies of clinical utility and a rapidly developing therapeutic landscape.

55th Annual Conference of Society of Nuclear Medicine, India

55th Annual Conference of Society of Nuclear Medicine, India

Guideline for Radioiodine Therapy for Benign Thyroid Diseases(6/2022 - AWMF No. 031-003)

This version of the guideline for radioiodine therapy of benign thyroid disorders is an update of the version, which was published by the German Society of Nuclear Medicine (Deutsche Gesellschaft für Nuklearmedizin, DGN) in co-ordination with the German Society of Endocrinology (Deutsche Gesellschaft für Endokrinologie, DGE, Sektion Schilddrüse) and the German Society of General- and Visceral-Surgery (Deutsche Gesellschaft für Allgemein- und Viszeralchirurgie, DGAV) in 2015. This guideline was harmonized with the recommendations of the European Association of Nuclear Medicine (EANM). According to the German "Directive on Radiation Protection in Medicine" the physician specialised in nuclear medicine ("Fachkunde in der Therapie mit offenen radioaktiven Stoffen") is responsible for the justification to treat with radioiodine. Therefore, relevant medical indications for radioiodine therapy and alternative therapeutic options are discussed within the guideline. This procedure guideline is developed in the consensus of an expert group. This fulfils the level S1 (first step) within the German classification of Clinical Practice Guidelines.