Case Report: Imaging immune checkpoint inhibitor-induced yin-yang effects in the brain.

Background: Treatment with immune checkpoint inhibitors (ICI) can induce durable responses in cancer patients, but it is commonly associated with serious immune-related side effects. Both effects are suggested to be mediated by CD8+ T-cell infiltration. Whole body CD8+ T-cell distribution can be visualized by PET imaging of a 89Zr-labeled anti-humanCD8a minibody, currently investigated in a phase 2b trial. Main body: An adult patient diagnosed with metastatic melanoma developed ICI-related hypophysitis after two courses of combined immunotherapy (ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) at 3 weeks interval). On a [89Zr]Zr-crefmirlimab berdoxam PET/CT scan, made 8 days before clinical symptoms occurred, increased CD8+ T-cell infiltration in the pituitary gland was detected. Simultaneously, tracer uptake in a cerebral metastasis was increased, indicating ICI-induced tumor infiltration by CD8+ T-cells. Conclusions: The observations in this case report underscore the role of CD8+ T-cell in non-tumor tissues in ICI-related toxicity. In addition, it illustrates a potential role for molecular imaging by PET/CT for investigation and monitoring of ICI-induced effects.

Clinically unsuspected orthopedic implants during S. aureus bacteremia do not require additional diagnostic work-up.

PURPOSE: To assess the likelihood of occult infection in patients with clinically unsuspected orthopedic implants during Staphylococcus aureus bacteremia (SAB). METHODS: In a retrospective study in two Dutch hospitals, we included all patients with SAB between 2013 and 2020 with one or more orthopedic implants in whom [18F]FDG-PET/CT was performed. The primary outcome was the percentage of patients who had an orthopedic implant-related infection by S. aureus. We also compared clinical parameters in patients with clinically suspected and unsuspected implants. RESULTS: Fifty-five of 191 (29%) orthopedic implants in 118 SAB patients included had clinical signs of infection. Of all 136 unsuspected implants, 5 (3%, all arthroplasties), showed increased [18F]FDG uptake around the prosthesis on [18F]FDG-PET/CT. The clinical course of these patients without clinically overt infection or relapse of bacteremia during follow-up of a median of 48 months (range 0-48), however, argued against prosthetic joint infection. CONCLUSION: Although orthopedic implants are evidently a risk factor for metastatic infection during SAB, the absence of clinical symptoms obviate the need of additional investigations or prolonged antibiotic treatment.

The impact of implementing an endocarditis team in comparison to the classic heart team in a tertiary referral centre.

BACKGROUND: Infective endocarditis (IE) is a complex disease for which the European Society of Cardiology guideline recommends a dedicated multidisciplinary endocarditis team (ET) approach since 2015. It is currently unknown whether this ET approach is beneficial compared to a classic heart team approach including bedside consultation by an infectious disease specialist in Western Europe. METHODS: This retrospective single centre, observational cohort study was conducted at the Radboudumc, a tertiary referral centre in the Netherlands. Consecutive patients treated for IE were included from September 2017 to September 2018 before implementation of a dedicated ET and from May 2019 to May 2020 afterwards. RESULTS: In total, 90 IE patients (45 patients before and 45 patients after the implementation of the ET) were included. No significant differences were found in diagnostic workup, surgical treatment (surgery performed 69% vs. 71%, p = 0.82), time to surgery because of an urgent indication (median 4 vs. 6 days, p = 0.82), in-hospital complications (53% vs. 67%, p = 0.20), and 6-month mortality (11% vs. 13%, p = 0.75) between IE patients treated before and after the implementation of the ET. CONCLUSION: Formalization of the recommended multidisciplinary endocarditis team might not significantly improve the complication rate nor the short term outcome.

Quantitative CT perfusion imaging in patients with pancreatic cancer: a systematic review.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death with a 5-year survival rate of 10%. Quantitative CT perfusion (CTP) can provide additional diagnostic information compared to the limited accuracy of the current standard, contrast-enhanced CT (CECT). This systematic review evaluates CTP for diagnosis, grading, and treatment assessment of PDAC. The secondary goal is to provide an overview of scan protocols and perfusion models used for CTP in PDAC. The search strategy combined synonyms for 'CTP' and 'PDAC.' Pubmed, Embase, and Web of Science were systematically searched from January 2000 to December 2020 for studies using CTP to evaluate PDAC. The risk of bias was assessed using QUADAS-2. 607 abstracts were screened, of which 29 were selected for full-text eligibility. 21 studies were included in the final analysis with a total of 760 patients. All studies comparing PDAC with non-tumorous parenchyma found significant CTP-based differences in blood flow (BF) and blood volume (BV). Two studies found significant differences between pathological grades. Two other studies showed that BF could predict neoadjuvant treatment response. A wide variety in kinetic models and acquisition protocol was found among included studies. Quantitative CTP shows a potential benefit in PDAC diagnosis and can serve as a tool for pathological grading and treatment assessment; however, clinical evidence is still limited. To improve clinical use, standardized acquisition and reconstruction parameters are necessary for interchangeability of the perfusion parameters.

[18F]FDG PET/CT in the staging of inflammatory breast cancer: A systematic review.

Up to 78 % of patients with inflammatory breast cancer (IBC) present with axillary lymph node involvement and up to 40 % with distant metastases. Previous studies indicate that 2-deoxy-2-(18F)fluoro-d-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) might be used for initial staging in patients with inflammatory breast cancer (IBC). In other cancer types, [18F]FDG PET/CT has been demonstrated to be a sensitive technique, providing complementary information on locoregional and distant disease to conventional imaging modalities. This systematic review showed that 18F]FDG PET/CT detects additional locoregional lymph node metastases and distant metastases in 10.3 % of patients, that were not detected with standard staging imaging. Compared with conventional imaging procedures, [18F]FDG PET/CT had better diagnostic performance for detection of locoregional and distant metastases and should standardly be used in the diagnostic work-up of IBC patients.

Imaging angiogenesis in patients with head and neck squamous cell carcinomas by [68Ga]Ga-DOTA-E-[c(RGDfK)]2 PET/CT.

PURPOSE: Angiogenesis plays an important role in the growth and metastatic spread of solid tumours and is characterised by the expression of integrins on the cell surface of endothelial cells. Radiolabelled RGD peptides specifically target angiogenesis-related αvß3 integrins, expressed on the activated endothelial cells of sprouting blood vessels. Here, we validated the feasibility of 68Ga[Ga]-DOTA-E-[c(RGDfK)]2 (68Ga-RGD) PET/CT to visualise angiogenesis in patients with oral squamous cell carcinoma (OSCC). METHODS: Ten patients with OSCC and scheduled for surgical resection including elective neck dissection received an intravenously administration of 68Ga-RGD (42 ± 8 µg; 214 ± 9 MBq). All patients subsequently underwent dynamic (n = 5) or static PET/CT imaging (n = 5) for 60 min or for 4 min/bed position at 30, 60 and 90 min after injection, respectively. Quantitative tracer uptake in tumour lesions was expressed as standardised uptake values (SUV). Additionally, tumour tissue was immunohistochemically stained for αvß3 integrin to assess the expression pattern. RESULTS: 68Ga-RGD tumour accumulation was observed in all patients. At 60 min post injection, tumour SUVmax ranged between 4.0 and 12.7. Tracer accumulation in tumour tissue plateaued at 10 min after injection. Uptake in background tissue did not change over time, resulting in tumour-to-muscle tissue of 6.4 ± 0.7 at 60 min post injection. CONCLUSIONS: 68Ga-RGD PET/CT of αvß3 integrin expression in OSCC patients is feasible with adequate tumour-to-background ratios. It will provide more insight in angiogenesis as a hallmark of the head and neck squamous cell carcinomas' tumour microenvironment. TRIAL REGISTRATION: https://eudract.ema.europa.eu no. 2015-000917-31.

The value of FDG-PET CT scans to evaluate bone marrow in haemato-oncological conditions.

In the past decade, 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (18F-FDG PET-CT) scans have been increasingly implemented in the diagnostic process of several haemato-oncological conditions. Accurate assessment of bone marrow activity observed on 18F-FDG PET-CT is crucial for a correct diagnostic conclusion, subsequent treatment decision, and follow-up strategies. By systematically considering the arguments of the level of 18F-FDG uptake, distribution pattern, coinciding changes of the bone structure, and the clinical context, interpretation and validity may improve. This review aims to give a comprehensive overview of the different patterns of 18F-FDG uptake on PET/CT in common benign, clonal, and malignant haematological conditions, accompanied by illustrative cases.

Imaging of cellular therapies.

Cellular therapy promises to revolutionize medicine, by restoring tissue and organ function, and combating key disorders including cancer. As with all major developments, new tools must be introduced to allow optimization. For cell therapy, the key tool is in vivo imaging for real time assessment of parameters such as cell localization, numbers and viability. Such data is critical to modulate and tailor the therapy for each patient. In this review, we discuss recent work in the field of imaging cell therapies in the clinic, including preclinical work where clinical examples are not yet available. Clinical trials in which transferred cells were imaged using magnetic resonance imaging (MRI), nuclear scintigraphy, single photon emission computed tomography (SPECT), and positron emission tomography (PET) are evaluated from an imaging perspective. Preclinical cell tracking studies that focus on fluorescence and bioluminescence imaging are excluded, as these modalities are generally not applicable to clinical cell tracking. In this review, we assess the advantages and drawbacks of the various imaging techniques available, focusing on immune cells, particularly dendritic cells. Both strategies of prelabeling cells before transplant and the use of an injectable label to target cells in situ are covered. Finally, we discuss future developments, including the emergence of multimodal imaging technology for cell tracking from the preclinical to the clinical realm.

Dendritic cell vaccination and immune monitoring.

We exploited dendritic cells (DC) to vaccinate melanoma patients. We recently demonstrated a statistical significant correlation between favorable clinical outcome and the presence of vaccine-related tumor antigen-specific T cells in delayed type hypersensitivity (DTH) skin biopsies. However, favorable clinical outcome is only observed in a minority of the treated patients. Therefore, it is obvious that current DC-based protocols need to be improved. For this reason, we study in small proof of principle trials the fate, interactions and effectiveness of the injected DC.

Dendritic cell vaccines in melanoma: from promise to proof?

Dendritic cells (DC) are the directors of the immune system, capable of inducing tumour antigen-specific T- and B-cell responses. As such, they are currently applied in clinical studies in cancer patients. Early small clinical trials showed promising results, with frequent induction of anti-cancer immune reactivity and clinical responses. In recent years, additional trials have been carried out in melanoma patients, and although immunological responses are often reported, objective clinical responses remain anecdotal with objective response rates not exceeding 5-10%. Thus, DC vaccination research has now entered a stage in between 'proof of principle' and 'proof of efficacy' trials. Crucial questions to answer at this moment are why the clinical responses remain scarce and what can be done to improve the efficacy of vaccination. The answers to these questions probably lie in the preparation and administration of the DC vaccines. Predominantly, cytokine-matured DC are used in clinical studies, while from preclinical studies it is evident that DC that are activated by pathogen-associated molecules are much more potent T cell activators. For sake of easy accessibility monocyte-derived DC are often used, but are these cells also the most potent type of DC? Other yet unsettled issues include the optimal antigen-loading strategy and route of administration. In addition, trials are needed to investigate the value of manipulating tolerizing mechanisms, such as depletion of regulatory T cells or blockade of the inhibitory T cell molecule CTLA-4. These issues need to be addressed in well-designed comparative clinical studies with biological endpoints in order to determine the optimal vaccine characteristics. DC vaccination can then be put to the ultimate test of randomized clinical trials. Here, we review the immunobiology of DC with emphasis on the different aspects that are most relevant for the induction of anti-tumour responses in vivo. The different variables in preparing and administering DC vaccines are discussed in this context and the immunological and clinical results of studies with DC vaccines in melanoma patients are summarized.