Future Perspectives of Artificial Intelligence in Bone Marrow Dosimetry and Individualized Radioligand Therapy.

Radioligand therapy is an emerging and effective treatment option for various types of malignancies, but may be intricately linked to hematological side effects such as anemia, lymphopenia or thrombocytopenia. The safety and efficacy of novel theranostic agents, targeting increasingly complex targets, can be well served by comprehensive dosimetry. However, optimization in patient management and patient selection based on risk-factors predicting adverse events and built upon reliable dose-response relations is still an open demand. In this context, artificial intelligence methods, especially machine learning and deep learning algorithms, may play a crucial role. This review provides an overview of upcoming opportunities for integrating artificial intelligence methods into the field of dosimetry in nuclear medicine by improving bone marrow and blood dosimetry accuracy, enabling early identification of potential hematological risk-factors, and allowing for adaptive treatment planning. It will further exemplify inspirational success stories from neighboring disciplines that may be translated to nuclear medicine practices, and will provide conceptual suggestions for future directions. In the future, we expect artificial intelligence-assisted (predictive) dosimetry combined with clinical parameters to pave the way towards truly personalized theranostics in radioligand therapy.

PSMA-PET follow-up to assess response in patients not receiving PSMA therapy: Is there value beyond localization of disease?

Introduction: Prostate Specific Membrane Antigen Positron Emission Tomography (PSMA-PET) is routinely used for the staging of patients with prostate cancer, but data on response assessment are sparse and primarily stem from metastatic castration-resistant prostate cancer (mCRPC) patients treated with PSMA radioligand therapy. Still, follow-up PSMA-PET is employed in earlier disease stages in case of clinical suspicion of disease persistence, recurrence or progression to decide if localized or systemic treatment is indicated. Therefore, the prognostic value of PSMA-PET derived tumor volumes in earlier disease stages (i.e., hormone-sensitive prostate cancer (HSPC) and non-[177Lu]Lu-PSMA-617 (LuPSMA) therapy castration resistant prostate cancer (CRPC)) are evaluated in this manuscript. Methods: A total number of 73 patients (6 primary staging, 42 HSPC, 25 CRPC) underwent two (i.e., baseline and follow-up, median interval: 379 days) whole-body [68Ga]Ga-PSMA-11 PET/CT scans between Nov 2014 and Dec 2018. Analysis was restricted to non-LuPSMA therapy patients. PSMA-PETs were retrospectively analyzed and primary tumor, lymph node-, visceral-, and bone metastases were segmented. Body weight-adjusted organ-specific and total tumor volumes (PSMAvol: sum of PET volumes of all lesions) were measured for baseline and follow-up. PSMAvol response was calculated as the absolute difference of whole-body tumor volumes. High metastatic burden (>5 metastases), RECIP 1.0 and PSMA-PET Progression Criteria (PPP) were determined. Survival data were sourced from the cancer registry. Results: The average number of tumor lesions per patient on the initial PET examination was 10.3 (SD 28.4). At baseline, PSMAvol was strongly associated with OS (HR 3.92, p <0.001; n = 73). Likewise, response in PSMAvol was significantly associated with OS (HR 10.48, p < 0.005; n = 73). PPP achieved significance as well (HR 2.19, p <0.05, n = 73). Patients with hormone sensitive disease and poor PSMAvol response (upper quartile of PSMAvol change) in follow-up had shorter outcome (p < 0.05; n = 42). PSMAvol in bones was the most relevant parameter for OS prognostication at baseline and for response assessment (HR 31.11 p < 0.001; HR 32.27, p < 0.001; n = 73). Conclusion: PPP and response in PSMAvol were significantly associated with OS in the present heterogeneous cohort. Bone tumor volume was the relevant miTNM region for OS prognostication. Future prospective evaluation of the performance of organ specific PSMAvol in more homogeneous cohorts seems warranted.

Is There a Role of Artificial Intelligence in Preclinical Imaging?

This review provides an overview of the current opportunities for integrating artificial intelligence methods into the field of preclinical imaging research in nuclear medicine. The growing demand for imaging agents and therapeutics that are adapted to specific tumor phenotypes can be excellently served by the evolving multiple capabilities of molecular imaging and theranostics. However, the increasing demand for rapid development of novel, specific radioligands with minimal side effects that excel in diagnostic imaging and achieve significant therapeutic effects requires a challenging preclinical pipeline: from target identification through chemical, physical, and biological development to the conduct of clinical trials, coupled with dosimetry and various pre, interim, and post-treatment staging images to create a translational feedback loop for evaluating the efficacy of diagnostic or therapeutic ligands. In virtually all areas of this pipeline, the use of artificial intelligence and in particular deep-learning systems such as neural networks could not only address the above-mentioned challenges, but also provide insights that would not have been possible without their use. In the future, we expect that not only the clinical aspects of nuclear medicine will be supported by artificial intelligence, but that there will also be a general shift toward artificial intelligence-assisted in silico research that will address the increasingly complex nature of identifying targets for cancer patients and developing radioligands.

Attitude of Veterinarians Toward Self-Informed Animal Owners Affects Shared Decision Making.

The aims of this study were to investigate the role of the veterinarian characteristics (e.g., age, gender, self-estimation, use of the internet), and their attitudes concerning animal owners seeking self-information. A particular focus was laid on any association between shared decision making (SDM), age and gender. In an online survey, 527 German veterinarians were asked about their attitude regarding SDM principles and their experiences with self-informed animal owners. The factors associated with veterinarians' perception of SDM were investigated in a multivariable linear regression model. A recently published structural equation model consolidated the application of SDM, empathic behavior, and veterinarians' evaluation of self-education as latent factors. Interconnected questionnaire items were processed using an exploratory factor analysis to 11 interpretable factors. Veterinarians who assumed therapy failure was associated with themselves had significantly higher rates of SDM (p = 0.002). In contrast, SDM was significantly lower (p = 0.002) if they assumed that therapy failure was due to the animal's owners. SDM was negatively associated with the perceived quality of the pet owners' self-information (p < 0.001) and if skepticism was perceived as the reason for seeking the self-information (p = 0.001). Veterinarians who advised against self-information (p = 0.006) and those who assumed that self-information of animal owners goes along with uncertainty (p = 0.001) had low SDM values (p = 0.006). Asking the animal owner for self-information (p = 0.001), and recommendations of good information sources (p = 0.022) were positively associated with SDM. Looking at the influence of age and gender on the application of SDM, older people and males rated higher. However, the evaluation of the latent factor SDM was based on the self-estimation of the participants. Assuming that younger women were less self-confident, we cannot exclude that young female participants self-evaluated their SDM skills lower than older male participants, although both groups would objectively have the same SDM level. Practitioners who have a positive attitude toward animal owners, who enjoy contact with animal owners and welcome their interest in further (self-)information, show empathic behavior, and have a positive attitude toward SDM are more likely to have better veterinarian-animal owner-relationships.

Age and Hydration of Competing Horses Influence the Outcome of Elite 160 km Endurance Rides.

High elimination rates and the concern for horse welfare are important issues in endurance riding. An improved understanding of the causes of elimination could increase completion rates in this sport. We have identified pre-ride risk factors that allow an assessment of potential elimination before the ride. A longitudinal cohort study was performed among 49 healthy horses competing in the 160 km endurance ride at the 2016 World Championship of Endurance Riding in Samorin/Slovakia. Blood samples were drawn before the ride. For statistical evaluation, horses were categorized in three groups: finishers, lame and metabolically eliminated horses. Risk factors were calculated for each group using multinomial logistic regression. A 1% increase in hematocrit levels was associated with a higher OR for elimination (lameness: OR 1.26, p = 0.017; metabolic: OR 1.34, p = 0.010). Furthermore, increased potassium values correlated negatively with the race outcome. For a 1 mmol/l increase in potassium, the lameness OR was 4.21, p = 0.039 and metabolic OR was 1.15, p = 0.848. Eight-year-old horses had a 100% elimination rate and survival analyses showed a significantly higher hazard for elimination (p = 0.025). We thus conclude that age and hydration affect the outcome of elite endurance rides. Further investigation of age as a risk factor seems to be clinically relevant and adjustments of FEI qualification modes may be appropriate.

Overcoming hypoxia-induced resistance of pancreatic and lung tumor cells by disrupting the PERK-NRF2-HIF-axis.

Hypoxia-induced resistance of tumor cells to therapeutic treatment is an unresolved limitation due to poor vascular accessibility and protective cell adaptations provided by a network, including PERK, NRF2, and HIF signaling. All three pathways have been shown to influence each other, but a detailed picture remains elusive. To explore this crosstalk in the context of tumor therapy, we generated human cancer cell lines of pancreatic and lung origin carrying an inducible shRNA against NRF2 and PERK. We report that PERK-related phosphorylation of NRF2 is only critical in Keap1 wildtype cells to escape its degradation, but shows no direct effect on nuclear import or transcriptional activity of NRF2. We could further show that NRF2 is paramount for proliferation, ROS elimination, and radioprotection under constant hypoxia (1% O2), but is dispensable under normoxic conditions or after reoxygenation. Depletion of NRF2 does not affect apoptosis, cell cycle progression and proliferation factors AKT and c-Myc, but eliminates cellular HIF-1α signaling. Co-IP experiments revealed a protein interaction between NRF2 and HIF-1α and strongly suggest NRF2 as one of the cellular key factor for the HIF pathway. Together these data provide new insights on the complex role of the PERK-NRF2-HIF-axis for cancer growth.

[18F]-Fluorodeoxyglucose Positron Emission Tomography/CT to Assess the Early Metabolic Response in Patients with Hormone Receptor-Positive HER2-Negative Metastasized Breast Cancer Treated with Cyclin-Dependent 4/6 Kinase Inhibitors.

INTRODUCTION: Addition of cyclin-dependent 4/6 kinase (CDK4/6) inhibitors to endocrine therapy is standard of care in the treatment of women with advanced hormone receptor-positive HER2-negative breast cancer. However, the predictive factors for the treatment response to CDK4/6 inhibitor therapy are poorly elucidated. Early changes in the by [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) uptake of tumors receiving different kinds of therapy have proven to reliably predict treatment outcomes in a variety of malignancies. Therefore, the feasibility of early metabolic response assessment to predict the long-term treatment response to CDK4/6 inhibitor therapy was evaluated in the present study. METHODS: Eight patients underwent FDG-PET/CT before and after the initiation of CDK4/6 inhibitor therapy (ribociclib, palbociclib or abemcaciclib). CDK4/6 inhibitor therapy was combined with either aromatase inhibition or fulvestrant. The median interval between the treatment start (including baseline PET) and the follow-up PET examination was 14 days. Conventional radiographic staging was performed 3 months after the start of CDK4/6 inhibitor therapy. The percentual changes in molecular tumor volume, SUVpeak, the summed SUVpeak of up to 5 metastases (PERCIST-5), and total lesion glycolysis (TLG) were calculated for each patient. RESULTS: Three patients showed progressive disease after 3 months of CDK4/6 inhibitor therapy, whereas 5 patients showed disease control (3 stable disease and 2 partial remission). Disease control was maintained in these patients (follow-up range 7-22 months). Patients with disease control had a significantly greater decline in TLG (-55.3 vs. 16.7%; p < 0.05). The same was true for the PERCIST-5 (-21.9 vs. 11.3%, p < 0.05). All patients with progressive TLG showed treatment failure and/or a poor outcome. CONCLUSION: Elevated TLG on early FDG-PET seems to be associated with long-term treatment failure and a poor outcome in patients undergoing CDK4/6 inhibitor therapy for metastatic breast cancer. Early findings indicate a potential prognostic value of early FDG-PET in this setting and warrant a prospective evaluation.

Being Nice Is Not Enough-Exploring Relationship-Centered Veterinary Care With Structural Equation Modeling. A Quantitative Study on German Pet Owners' Perception.

During the last years, the philosophy of relationship-centered care gained increasing attention in veterinary medicine. Relationship-centered care is based on a joint venture between pet owner and veterinarians and therefore offers the opportunity to satisfy the pet owners' need for participation in medical decision-making and to provide the best care for the patient. Although research on relationship-centered care in the veterinary consultation is still limited, the available findings suggest that the characteristics of relationship-centered care reflect the pet owners' expectations on satisfactory veterinary care. In this study a quantitative survey was conducted among German pet owners that collected information regarding their perception of the veterinarians' communication during the last appointments. Questionnaires were available online and paper-based. Data were analyzed using exploratory factor analysis and structural equation modeling using SAS. First aim of the study was to explore structural equation modeling (SEM) as an opportunity to evaluate quantitative data in the field of research on relationship-centered care. Further, SEM was used to evaluate associations between the implementation of different characteristics of relationship-centered care in the veterinary practice (empathic communication, partnership-building) and latent outcome variables regarding the pet owners (pet owners' need for further information, consultation of competing health care providers). N = 1,270 valid questionnaires were completed. Participants owned small companion animals (55.6%), horses (7.6%), or both (36.9%) within the last 2 years. Results of SEM suggest that partnership-centered and empathic communication decreased the pet owners' needs for further information (e.g., from online sources) and their need to consult alternative health providers (e.g., homeopaths). Especially addressing the pet owners' worries and fears, discussing pros and cons of diagnostic and therapeutic options as well as providing the required amount of information were shown to be large influence factors within the model. Therefore, veterinarians are recommended to implement the concept of partnership-centered care in their daily practice, for it may increase pet owners' loyalty and satisfaction. Results may motivate future research in this field. Further development of the proposed model assumptions may enable valuable progress in the field of quantitative research on relationship-centered care.