Recent advances and impending challenges for the radiopharmaceutical sciences in oncology.

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.

Production and regulatory issues for theranostics.

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.

Trends in nuclear medicine and the radiopharmaceutical sciences in oncology: workforce challenges and training in the age of theranostics.

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.

Guardians of precision: advancing radiation protection, safety, and quality systems in nuclear medicine.

BACKGROUND: In the rapidly evolving field of nuclear medicine, the paramount importance of radiation protection, safety, and quality systems cannot be overstated. This document provides a comprehensive analysis of the intricate regulatory frameworks and guidelines, meticulously crafted and updated by national and international regulatory bodies to ensure the utmost safety and efficiency in the practice of nuclear medicine. METHODS: We explore the dynamic nature of these regulations, emphasizing their adaptability in accommodating technological advancements and the integration of nuclear medicine with other medical and scientific disciplines. RESULTS: Audits, both internal and external, are spotlighted for their pivotal role in assessing and ensuring compliance with established standards, promoting a culture of continuous improvement and excellence. We delve into the significant contributions of entities like the International Atomic Energy Agency (IAEA) and relevant professional societies in offering universally applicable guidelines that amalgamate the latest in scientific research, ethical considerations, and practical applicability. CONCLUSIONS: The document underscores the essence of international collaborations in pooling expertise, resources, and insights, fostering a global community of practice where knowledge and innovations are shared. Readers will gain an in-depth understanding of the practical applications, challenges, and opportunities presented by these regulatory frameworks and audit processes. The ultimate goal is to inspire and inform ongoing efforts to enhance safety, quality, and effectiveness in nuclear medicine globally.

Guiding principles on the education and practice of theranostics.

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.

[The role of molecular imaging (PET-CT) in the diagnostic and treatment pf prostate cancer]. / Die Rolle der molekularen Bildgebung (PET-CT) in der Diagnostik und Therapie des Prostatakarzinoms.

Prostate cancer is the most frequent cancer type in men in industrialized countries. In case of biochemical recurrent disease of prostate cancer is molecular imaging with PET-CT or PET-MRI a very promising modality for the detection of local recurrence, lymph node involvement or distant metastasis. Of the so far implemented radiopharmaceuticals the radioactive labeled PSMA ligands (i. e. Ga-68 PSMA) have prevailed. There are also in the meanwhile treatment approaches with PSMA ligands (i. e. Lu-177 PSMA) in case of metastatic disease.

Acoustic Structure Quantification Analysis of the Thyroid in Patients with Diffuse Autoimmune Thyroid Disease.

The aim of this study was to assess whether acoustic structure quantification (ASQ) can differentiate normal from pathological thyroid parenchyma in patients with diffuse autoimmune thyroid disease (AITD). We evaluated 83 subjects (72 [87%] women and 11 [13%] men) aged 19 to 94 years with a mean age of 53 years. We performed a prospective study (from March 2011 to November 2014) that included 43 (52%) patients with chronic autoimmune thyroiditis (CAT), 22 (26%) patients with Graves' disease (GD), and 18 (22%) healthy volunteers. The ASQ values were significantly lower in normal subjects than in subjects with CAT and GD (p < 0.001). In contrast, the differences between the GD and the CAT patients (p = 0.23) were not statistically significant. The optimal cutoff ASQ value for which the sum of sensitivity and specificity was the highest for the prediction of diffuse thyroid pathology was 103 (95% confidence interval = [0.79, 0.95]). At this cutoff value, the sensitivity was 83% and the specificity was 89%. Our findings suggest that ASQ is a useful method for the assessment of the thyroid in patients with AITD.

Oncocytic adenomas of thyroid-mimicking benign or metastatic disease on 18F-FDG-PET scan.

BACKGROUND: The literature is sparse concerning 18F-fluorodeoxyglucose (18F-FDG) accumulation in the Hürthle cell neoplasm (HCN) of the thyroid. Given the difficulty of accurately diagnosing HCN, even with ultrasound (US) and fine needle aspiration biopsy (FNAB), the ability to accurately characterize these lesions by 18F-FDG positron emission tomography (PET) would be of value. PURPOSE: To describe six cases of oncocytic proliferation in the thyroid gland that mimics the presence of metastatic disease and was detected incidentally by an 18F-FDG PET scan. MATERIAL AND METHODS: We conducted whole-body 18F-FDG PET examinations for cancer staging in 1862 oncological patients from 2012 to 2013. Among them, six subjects (4 women, 2 men; age range, 45-85 years) with focal-enhanced 18F-FDG accumulation in the thyroid gland were selected from the study population. This study group was further investigated using 99 m-Tc-pertechnetate scintigraphy, US, and FNAB. Two experienced nuclear physicians reviewed the images. Gray-scale US and color Doppler (CD) sonographic examinations of the thyroid were undertaken for all subjects using a sonographic device Logiq 5 Expert (GE Medical Systems, Osaka, Japan) equipped with a 7-12 MHz linear array transducer. RESULTS: In all six cases, abnormal 18F-FDG uptake was found locally in the thyroid. The average SUVmax of the HCN was 5.8 (range, 2.6-16). In all six cases, 99 m-Tc-pertechnetate scintigraphy showed a cold spot. Compared with normal parenchymal vascularity, five of the six masses were shown to be hypervascular by CD ultrasonography. CONCLUSION: On PET scans, oncocytic proliferations of the thyroid may mimic metastases of other malignancies. The focal-enhanced uptake of 18F-FDG PET may be associated with a focal increase in the metabolic activity of the thyroid parenchyma due to the presence of oncocytes. Our study emphasizes the importance of obtaining cytological evidence before making a diagnosis of metastatic disease.

[Acute spinal cord compression under systemic therapy - radiotherapy or surgery?] / Akuter Querschnitt unter Systemtherapie ­ Radiotherapie oder OP?

Vertebral bodies are one of the most common metastasis sites found in advanced prostate cancer and have a significant impact on patients' quality of life. Spinal metastases frequently cause severe back pain and in some occasions can lead to secondary complications, with serious neurological deficits and loss of function. The main treatment goals include adequate pain management, controlling tumour growth and restoring spinal stability. Publications on the role of surgery - both conventional and stereotactic radiotherapy, and either as an individual modality or in combination - have been inconclusive. The NOMS score has proven to be useful in making treatment decisions. Existing data show better outcomes in patients with surgical therapy, both when performed in isolation and also combined with radiotherapy, in which some of the cohorts studied including patients with primary cancer other than prostate cancer. Comparative studies that specifically investigate the superiority of specific therapy modalities for metastatic prostate carcinoma are scarce. Similarly, there are limited data on microsurgical interventions for spinal metastases. Radiotherapy alone is crucial in the setting of palliation, especially for pain relief, and its effectiveness has been shown in many studies. The patient's life expectancy plays a crucial role in deciding the most appropriate treatment approach. Given the complexity of the patient population, a multimodal therapy approach is necessary. Current trends in therapy favour greater use of surgical interventions, particularly in the early detection of spinal metastases.

Predictors for quality of life, pain and functional outcomes after surgical treatment of metastatic disease in the spine.

BACKGROUND: While predictors for postoperative survival in spine tumour patients have been identified, there is limited evidence for predictors of postoperative Quality of Life (QoL), pain and functional outcome. METHODS: One hundred and fifty-three consecutive patients, who had undergone surgery for symptomatic spinal metastases between June 2016 and April 2019, were interviewed preoperatively and during follow-ups at three, six and 12 months using the EQ-5D-3L, COMI, and ODI questionnaires. Differences in means exceeding the specific Minimal Clinically Important Difference (MCID) values were considered clinically significant. RESULTS: Thirty-three percent of the patients were reported dead after 12 months. Only one metastasis compared to multiple metastases has 7.9 the Odds for an improved EQ-5D-3L score at three months. No neoadjuvant metastatic irradiation has 6.8 the Odds for the improvement at that time against performed radiation. A preoperative ODI score between 50.1 and 100 has 22.0 times the odds compared to the range from 0 to 50 for an improved EQ-5D-3L after three months, and 12.5 times the odds in favour of improved COMI after three months, and 13.6 times the odds for improvement of ODI at the three-month follow-up. A preoperative COMI score ranging from 5.0 to 10 has 21 times the odds of a COMI between 0 and 5 for an improved EQ-5D-3L score and 11 times the odds for an improved ODI after 12 months. Other predictors showed no statistically significant improvement. CONCLUSION: An improvement in QoL, pain and spinal function after 12 months can be predicted by a subjective preoperative poor health condition. Impaired spinal function before surgery, a singular metastasis and no previous irradiation is predictive of improved spinal function and quality of life three months after surgery.

Fibroblast Activation Protein Inhibitor (FAPI) PET Imaging in Sarcomas: A New Frontier in Nuclear Medicine.

The field of nuclear medicine has witnessed significant advancements in recent years, particularly in the area of PET imaging. One such development is the use of Fibroblast Activation Protein Inhibitors (FAPI) as a novel radiotracer. FAPI PET imaging has shown promising results in various malignancies, including sarcomas, which are a diverse group of cancers originating from mesenchymal cells. This paper aims to explore the potential of FAPI PET imaging in the diagnosis, staging, and treatment monitoring of sarcomas. Several studies have demonstrated the potential of FAPI PET in sarcomas. Furthermore, FAPI PET imaging has shown potential in assessing treatment response, with changes in FAPI uptake correlating with treatment outcomes. However, there are challenges to be addressed. The heterogeneity of sarcomas, both inter- and intra-tumoral, may affect the uniformity of Fibroblast Activation Protein (FAP) expression and thus the effectiveness of FAPI PET imaging. Additionally, the optimal timing and dosage of FAPI for PET imaging in sarcomas need further investigation. In conclusion, the introduction of FAPI PET imaging represents a significant advancement in the field of nuclear medicine and oncology. The ability to target FAP, a protein overexpressed in the majority of sarcomas, offers new possibilities for the diagnosis and treatment of these complex and diverse tumors. Its potential applications in diagnosis, staging, and theranostics are vast, and on-going research continues to explore and address its limitations. As we continue to deepen our understanding of this novel imaging technique, it is hoped that FAPI PET imaging will play an increasingly important role in the fight against cancer. However, as with any new technology, further research is needed to fully understand the potential and limitations of FAPI PET imaging in the clinical setting.

Preoperative Performance Status Threshold for Favorable Surgical Outcome in Metastatic Spine Disease.

BACKGROUND AND OBJECTIVES: Surgical treatment is an integral component of multimodality management of metastatic spine disease but must be balanced against the risk of surgery-related morbidity and mortality, making tailored surgical counseling a clinical challenge. The aim of this study was to investigate the potential predictive value of the preoperative performance status for surgical outcome in patients with spinal metastases. METHODS: Performance status was determined using the Karnofsky Performance Scale (KPS), and surgical outcome was classified as "favorable" or "unfavorable" based on postoperative changes in neurological function and perioperative complications. The correlation between preoperative performance status and surgical outcome was assessed to determine a KPS-related performance threshold. RESULTS: A total of 463 patients were included. The mean age was 63 years (range: 22-87), and the mean preoperative KPS was 70 (range: 30-100). Analysis of clinical outcome in relation to the preoperative performance status revealed a KPS threshold between 40% and 50% with a relative risk of an unfavorable outcome of 65.7% in KPS ≤40% compared with the relative chance for a favorable outcome of 77.1% in KPS ≥50%. Accordingly, we found significantly higher rates of preserved or restored ambulatory function in KPS ≥50% (85.7%) than in KPS ≤40% (48.6%; P < .001) as opposed to a significantly higher risk of perioperative mortality in KPS ≤40% (11.4%) than in KPS ≥50% (2.1%, P = .012). CONCLUSION: Our results underline the predictive value of the KPS in metastatic spine patients for counseling and decision-making. The study suggests an overall clinical benefit of surgical treatment of spinal metastases in patients with a preoperative KPS score ≥50%, while a high risk of unfavorable outcome outweighing the potential clinical benefit from surgery is encountered in patients with a KPS score ≤40%.

PET/CT in leukemia: utility and future directions.

2-Deoxy-2-[ 18 F]fluoro- d -glucose PET/computed tomography ([ 18 F]FDG PET/CT) has proven to be a sensitive method for the detection and evaluation of hematologic malignancies, especially lymphoma. The increasing incidence and mortality rates of leukemia have raised significant concerns. Through the utilization of whole-body imaging, [ 18 F]FDG PET/CT provides a thorough assessment of the entire bone marrow, complementing the limited insights provided by biopsy samples. In this regard, [ 18 F]FDG PET/CT has the ability to assess diverse types of leukemia The utilization of [ 18 F]FDG PET/CT has been found to be effective in evaluating leukemia spread beyond the bone marrow, tracking disease relapse, identifying Richter's transformation, and assessing the inflammatory activity associated with acute graft versus host disease. However, its role in various clinical scenarios in leukemia remains unacknowledged. Despite their less common use, some novel PET/CT radiotracers are being researched for potential use in specific scenarios in leukemia patients. Therefore, the objectives of this review are to provide a thorough assessment of the current applications of [ 18 F]FDG PET/CT in the staging and monitoring of leukemia patients, as well as the potential for an expanding role of PET/CT in leukemia patients.

Quality Assurance Considerations in Radiopharmaceutical Therapy Dosimetry Using PLANETDose: An International Atomic Energy Agency Study.

Implementation of radiopharmaceutical therapy dosimetry varies depending on the clinical application, dosimetry protocol, software, and ultimately the operator. Assessing clinical dosimetry accuracy and precision is therefore a challenging task. This work emphasizes some pitfalls encountered during a structured analysis, performed on a single-patient dataset consisting of SPECT/CT images by various participants using a standard protocol and clinically approved commercial software. Methods: The clinical dataset consisted of the dosimetric study of a patient administered with [177Lu]Lu-DOTATATE at Tygerberg Hospital, South Africa, as a part of International Atomic Energy Agency-coordinated research project E23005. SPECT/CT images were acquired at 5 time points postinjection. Patient and calibration images were reconstructed on a workstation, and a calibration factor of 122.6 Bq/count was derived independently and provided to the participants. A standard dosimetric protocol was defined, and PLANETDose (version 3.1.1) software was installed at 9 centers to perform the dosimetry of 3 treatment cycles. The protocol included rigid image registration, segmentation (semimanual for organs, activity threshold for tumors), and dose voxel kernel convolution of activity followed by absorbed dose (AD) rate integration to obtain the ADs. Iterations of the protocol were performed by participants individually and within collective training, the results of which were analyzed for dosimetric variability, as well as for quality assurance and error analysis. Intermediary checkpoints were developed to understand possible sources of variation and to differentiate user error from legitimate user variability. Results: Initial dosimetric results for organs (liver and kidneys) and lesions showed considerable interoperator variability. Not only was the generation of intermediate checkpoints such as total counts, volumes, and activity required, but also activity-to-count ratio, activity concentration, and AD rate-to-activity concentration ratio to determine the source of variability. Conclusion: When the same patient dataset was analyzed using the same dosimetry procedure and software, significant disparities were observed in the results despite multiple sessions of training and feedback. Variations due to human error could be minimized or avoided by performing intensive training sessions, establishing intermediate checkpoints, conducting sanity checks, and cross-validating results across physicists or with standardized datasets. This finding promotes the development of quality assurance in clinical dosimetry.

Strengthening education and training programmes for medical physics in Asia and the Pacific: the IAEA non-agreement technical cooperation (TC) regional RAS6088 project.

This article documents the work conducted in implementing the IAEA non-agreement TC regional RAS6088 project "Strengthening Education and Training Programmes for Medical Physics". Necessary information on the project was collected from the project counterparts via emails for a period of one month, starting from 21st September 2023, and verified at the Final Regional Coordination Meeting in Bangkok, Thailand from 30th October 2023 to 3rd November 2023. Sixty-three participants were trained in 5 Regional Training Courses (RTCs), with 48%, 32% and 20% in radiation therapy, diagnostic radiology, and nuclear medicine, respectively. One RTC was successfully organised to introduce molecular biology as an academic module to participants. Three participating Member States, namely United Arab Emirates (UAE), Nepal and Afghanistan have initiated processes to start the postgraduate master medical physics education programmes by coursework, adopting the IAEA TCS56 Guidelines. UAE has succeeded in completing the process while Nepal and Afghanistan have yet to initiate the programme. The postgraduate master medical physics programmes by coursework were strengthened in Indonesia, Jordan, Malaysia, Pakistan, Syria, and Thailand, along with the national registration of medical physicists. In particular, Thailand has revised 6 postgraduate master medical physics programmes by coursework during the tenure of this project. Home Based Assignment and RTCs have resulted in two publications. In conclusion, the RAS6088 project was found to have achieved its planned outcomes despite challenges faced due to the COVID-19 pandemic. It is proposed that a follow up project be implemented to increase the number of Member States who are better prepared to improve medical physics education and training in the region.

Case Report: Desmoid tumor response to magnetic resonance-guided high intensity focused ultrasound over 4 years.

Desmoid tumors are a rare form of cancer, which show locally aggressive invasion of surrounding tissues and may occur anywhere in the body. Treatment options comprise conservative watch and wait strategies as tumors may show spontaneous regression as well as surgical resection, radiation therapy, nonsteroidal anti-inflammatory drugs (NSAID), chemotherapy, or local thermoablative approaches for progressive disease. The latter comprises cryotherapy, radiofrequency, microwave ablation, or thermal ablation with high intensity focused ultrasound (HIFU) as the only entirely non-invasive option. This report presents a case where a desmoid tumor at the left dorsal humerus was 2 times surgically resected and, after recurrence, thermally ablated with HIFU under magnetic resonance image-guidance (MR-HIFU). In our report, we analyze tumor volume and/or pain score during standard of care (2 years) and after HIFU treatment over a 4-year follow-up period. Results showed MR-HIFU treatment led to complete tumor remission and pain response.

Molecular In-Depth Characterization of Chondrosarcoma for Current and Future Targeted Therapies.

Chondrosarcoma (CHS) are heterogenous, but as a whole, represent the second most common primary malignant bone tumor entity. Although knowledge on tumor biology has grown exponentially during the past few decades, surgical resection remains the gold standard for the treatment of these tumors, while radiation and differentiated chemotherapy do not result in sufficient cancer control. An in-depth molecular characterization of CHS reveals significant differences compared to tumors of epithelial origin. Genetically, CHS are heterogenous, but there is no characteristic mutation defining CHS, and yet, IDH1 and IDH2 mutations are frequent. Hypovascularization, extracellular matrix composition of collagen, proteoglycans, and hyaluronan create a mechanical barrier for tumor suppressive immune cells. Comparatively low proliferation rates, MDR-1 expression and an acidic tumor microenvironment further limit therapeutic options in CHS. Future advances in CHS therapy depend on the further characterization of CHS, especially the tumor immune microenvironment, for improved and better targeted therapies.

Local Recurrence and Development of Spinal Cord Syndrome during Follow-Up after Surgical Treatment of Metastatic Spine Disease.

BACKGROUND: Surgical decompression (SD), with or without posterior stabilization followed by radiotherapy, is an established treatment for patients with metastatic spinal disease with epidural spinal cord compression (ESCC). This study aims to identify risk factors for occurrence of neurological compromise resulting from local recurrence. METHODS: All patients who received surgical treatment for metastatic spinal disease at our center between 2011 and 2022 were included in this study. Cases were evaluated for tumor entity, surgical technique for decompression (decompression, hemilaminectomy, laminectomy, corpectomy) neurological deficits, grade of ESCC, time interval to radiotherapy, and perioperative complications. RESULTS: A total of 747 patients were included in the final analysis, with a follow-up of 296.8 days (95% CI (263.5, 330.1)). During the follow-up period, 7.5% of the patients developed spinal cord/cauda syndrome (SCS). Multivariate analysis revealed prolonged time (>35 d) to radiation therapy as a solitary risk factor (p < 0.001) for occurrence of SCS during follow-up. CONCLUSION: Surgical treatment of spinal metastatic disease improves patients' quality of life and Frankel grade, but radiation therapy needs to be scheduled within a time frame of a few weeks in order to reduce the risk of tumor-induced neurological compromise.

Role of Decompressive Surgery in Neurologically Intact Patients with Low to Intermediate Intraspinal Metastatic Tumor Burden.

BACKGROUND: Surgical decompression (SD) followed by radiotherapy (RT) is superior to RT alone in patients with metastatic spinal disease with epidural spinal cord compression (ESCC) and neurological deficit. For patients without neurological deficit and low- to intermediate-grade intraspinal tumor burden, data on whether SD is beneficial are scarce. This study aims to investigate the neurological outcome of patients without neurological deficit, with a low- to intermediate-ESCC, who were treated with or without SD. METHODS: This single-center, multidepartment retrospective analysis includes patients treated for spinal epidural metastases from 2011 to 2021. Neurological status was assessed by Frankel grade, and intraspinal tumor burden was categorized according to the ESCC scale. Spinal instrumentation surgery was only considered as SD if targeted decompression was performed. RESULTS: ESCC scale was determined in 519 patients. Of these, 190 (36.6%) presented with no neurological deficit and a low- to intermediate-grade ESCC (1b, 1c, or 2). Of these, 147 (77.4% were treated with decompression and 43 (22.65%) without. At last follow-up, there was no difference in neurological outcome between the two groups. CONCLUSIONS: Indication for decompressive surgery in neurologically intact patients with low-grade ESCC needs to be set cautiously. So far, it is unclear which patients benefit from additional decompressive surgery, warranting further prospective, randomized trials for this significant cohort of patients.

Manufacturing of Textured Bulk Fe-SmCo5 Magnets by Severe Plastic Deformation.

Exchange-coupling between soft- and hard-magnetic phases plays an important role in the engineering of novel magnetic materials. To achieve exchange coupling, a two-phase microstructure is necessary. This interface effect is further enhanced if both phase dimensions are reduced to the nanometer scale. At the same time, it is challenging to obtain large sample dimensions. In this study, powder blends and ball-milled powder blends of Fe-SmCo5 are consolidated and are deformed by high-pressure torsion (HPT), as this technique allows us to produce bulk magnetic materials of reasonable sizes. Additionally, the effect of severe deformation by ball-milling and severe plastic deformation by HPT on exchange coupling in Fe-SmCo5 composites is investigated. Due to the applied shear deformation, it is possible to obtain a texture in both phases, resulting in an anisotropic magnetic behavior and an improved magnetic performance.