Lung cancer multi-omics digital human avatars for integrating precision medicine into clinical practice: the LANTERN study.

BACKGROUND: The current management of lung cancer patients has reached a high level of complexity. Indeed, besides the traditional clinical variables (e.g., age, sex, TNM stage), new omics data have recently been introduced in clinical practice, thereby making more complex the decision-making process. With the advent of Artificial intelligence (AI) techniques, various omics datasets may be used to create more accurate predictive models paving the way for a better care in lung cancer patients. METHODS: The LANTERN study is a multi-center observational clinical trial involving a multidisciplinary consortium of five institutions from different European countries. The aim of this trial is to develop accurate several predictive models for lung cancer patients, through the creation of Digital Human Avatars (DHA), defined as digital representations of patients using various omics-based variables and integrating well-established clinical factors with genomic data, quantitative imaging data etc. A total of 600 lung cancer patients will be prospectively enrolled by the recruiting centers and multi-omics data will be collected. Data will then be modelled and parameterized in an experimental context of cutting-edge big data analysis. All data variables will be recorded according to a shared common ontology based on variable-specific domains in order to enhance their direct actionability. An exploratory analysis will then initiate the biomarker identification process. The second phase of the project will focus on creating multiple multivariate models trained though advanced machine learning (ML) and AI techniques for the specific areas of interest. Finally, the developed models will be validated in order to test their robustness, transferability and generalizability, leading to the development of the DHA. All the potential clinical and scientific stakeholders will be involved in the DHA development process. The main goals aim of LANTERN project are: i) To develop predictive models for lung cancer diagnosis and histological characterization; (ii) to set up personalized predictive models for individual-specific treatments; iii) to enable feedback data loops for preventive healthcare strategies and quality of life management. DISCUSSION: The LANTERN project will develop a predictive platform based on integration of multi-omics data. This will enhance the generation of important and valuable information assets, in order to identify new biomarkers that can be used for early detection, improved tumor diagnosis and personalization of treatment protocols. ETHICS COMMITTEE APPROVAL NUMBER: 5420 - 0002485/23 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Università Cattolica del Sacro Cuore Ethics Committee. TRIAL REGISTRATION: clinicaltrial.gov - NCT05802771.

Innovations in imaging modalities: a comparative review of MRI, long-axial field-of-view PET, and full-ring CZT-SPECT in detecting bone metastases.

The accurate diagnosis of bone metastasis, a condition in which cancer cells have spread to the bone, is essential for optimal patient care and outcome. This review provides a detailed overview of the current medical imaging techniques used to detect and diagnose this critical condition focusing on three cardinal imaging modalities: positron emission tomography (PET), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Each of these techniques has unique advantages: PET/CT combines functional imaging with anatomical imaging, allowing precise localization of metabolic abnormalities; the SPECT/CT offers a wider range of radiopharmaceuticals for visualizing specific receptors and metabolic pathways; MRI stands out for its unparalleled ability to produce high-resolution images of bone marrow structures. However, as this paper shows, each modality has its own limitations. The comprehensive analysis does not stop at the technical aspects, but ventures into the wider implications of these techniques in a clinical setting. By understanding the synergies and shortcomings of these modalities, healthcare professionals can make diagnostic and therapeutic decisions. Furthermore, at a time when medical technology is evolving at a breakneck pace, this review casts a speculative eye towards future advances in the field of bone metastasis imaging, bridging the current state with future possibilities. Such insights are essential for both clinicians and researchers navigating the complex landscape of bone metastasis diagnosis.

Diagnostic Performance of Positron Emission Tomography with Fibroblast-Activating Protein Inhibitors in Gastric Cancer: A Systematic Review and Meta-Analysis.

Various papers have introduced the use of positron emission tomography (PET) with [68Ga]Ga-radiolabeled fibroblast-activation protein inhibitor (FAPi) radiopharmaceuticals in different subtypes of gastric cancer (GC). Our aim was to assess the diagnostic performance of this novel molecular imaging technique in GC with a systematic review and meta-analysis. A straightforward literature search of papers concerning the diagnostic performance of FAP-targeted PET imaging was performed. Original articles evaluating this novel molecular imaging examination in both newly diagnosed GC patients and GC patients with disease relapse were included. The systematic review included nine original studies, and eight of them were also eligible for meta-analysis. The quantitative synthesis provided pooled detection rates of 95% and 97% for the assessment of primary tumor and distant metastases, respectively, and a pooled sensitivity and specificity of 74% and 89%, respectively, for regional lymph node metastases. Significant statistical heterogeneity among the included studies was found only in the analysis of the primary tumor detection rate (I2 = 64%). Conclusions: Beyond the limitations of this systematic review and meta-analysis (i.e., all the included studies were conducted in Asia, and using [18F]FDG PET/CT as a comparator of the index test), the quantitative data provided demonstrate the promising diagnostic performance of FAP-targeted PET imaging in GC. Nevertheless, more prospective multicentric studies are needed to confirm the excellent performances of FAP-targeted PET in this cluster of patients.

The Role of Low-Level Laser Therapy in Bone Healing: Systematic Review.

Low-level laser therapy (LLLT) is a treatment that is increasingly used in orthopedics practices. In vivo and in vitro studies have shown that low-level laser therapy (LLLT) promotes angiogenesis, fracture healing and osteogenic differentiation of stem cells. However, the underlying mechanisms during bone formation remain largely unknown. Factors such as wavelength, energy density, irradiation and frequency of LLLT can influence the cellular mechanisms. Moreover, the effects of LLLT are different according to cell types treated. This review aims to summarize the current knowledge of the molecular pathways activated by LLLT and its effects on the bone healing process. A better understanding of the cellular mechanisms activated by LLLT can improve its clinical application.

The role of [18F]FDG PET/CT in paraneoplastic autoimmune disorders: an umbrella review.

Paraneoplastic autoimmune disorders (PAD) are a group of autoimmune diseases associated with neoplasms. Several evidence-based articles (systematic reviews and meta-analyses) have reported data about the role of positron emission tomography (PET) and related hybrid modalities (e.g., PET/CT) using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in patients with PAD. We performed an umbrella review of published systematic reviews and meta-analyses in this setting to provide an evidence-based summary and suggestions for further studies. Several databases were searched to find systematic reviews and meta-analysis on [18F]FDG PET/CT in PAD. Evidence-based data support the use of [18F]FDG PET/CT in patients with suspected PAD for investigating an underlying malignancy even if it is still unclear whether [18F]FDG PET/CT should be performed after negative/inconclusive conventional imaging or as part of the initial workup of PAD.

The Role of PEMFs on Bone Healing: An In Vitro Study.

Bone responses to pulsed electromagnetic fields (PEMFs) have been extensively studied by using devices that expose bone cells to PEMFs to stimulate extracellular matrix (ECM) synthesis for bone and cartilage repair. The aim of this work was to highlight in which bone healing phase PEMFs exert their action. Specifically, we evaluated the effects of PEMFs both on human adipose mesenchymal stem cells (hASCs) and on primary human osteoblasts (hOBs) by testing gene and protein expression of early bone markers (on hASCs) and the synthesis of late bone-specific proteins (on hOBs) as markers of bone remodeling. Our results indicate that PEMFs seem to exert their action on bone formation, acting on osteogenic precursors (hASCs) and inducing the commitment towards the differentiation pathways, unlike mature and terminally differentiated cells (hOBs), which are known to resist homeostasis perturbation more and seem to be much less responsive than mesenchymal stem cells. Understanding the role of PEMFs on bone regenerative processes provides important details for their clinical application.

18F-Fluoroethylcholine PET/CT Radiomic Analysis for Newly Diagnosed Prostate Cancer Patients: A Monocentric Study.

AIM: The aim of this study is to assess whether there are some correlations between radiomics and baseline clinical-biological data of prostate cancer (PC) patients using Fluorine-18 Fluoroethylcholine (18F-FECh) PET/CT. METHODS: Digital rectal examination results (DRE), Prostate-Specific Antigen (PSA) serum levels, and bioptical-Gleason Score (GS) were retrospectively collected in newly diagnosed PC patients and considered as outcomes of PC. Thereafter, Volumes of interest (VOI) encompassing the prostate of each patient were drawn to extract conventional and radiomic PET features. Radiomic bivariate models were set up using the most statistically relevant features and then trained/tested with a cross-fold validation test. The best bivariate models were expressed by mean and standard deviation to the normal area under the receiver operating characteristic curves (mAUC, sdAUC). RESULTS: Semiquantitative and radiomic analyses were performed on 67 consecutive patients. tSUVmean and tSkewness were significant DRE predictors at univariate analysis (OR 1.52 [1.01; 2.29], p = 0.047; OR 0.21 [0.07; 0.65], p = 0.007, respectively); moreover, tKurtosis was an independent DRE predictor at multivariate analysis (OR 0.64 [0.42; 0.96], p = 0.03) Among the most relevant bivariate models, szm_2.5D.z.entr + cm.clust.tend was a predictor of PSA levels (mAUC 0.83 ± 0.19); stat.kurt + stat.entropy predicted DRE (mAUC 0.79 ± 0.10); cm.info.corr.1 + szm_2.5D.szhge predicted GS (mAUC 0.78 ± 0.16). CONCLUSIONS: tSUVmean, tSkewness, and tKurtosis were predictors of DRE results only, while none of the PET parameters predicted PSA or GS significantly; 18F-FECh PET/CT radiomic models should be tested in larger cohort studies of newly diagnosed PC patients.

Side effects of theragnostic agents currently employed in clinical practice.

Nuclear medicine plays an increasingly important role in several neoplasms management through a theragnostic approach by which targeted molecular imaging and radiotherapy are obtained with the use of radionuclide pairs with similar characteristics. In some cases, nuclear theragnostic use a pair of agents with identical chemical and biological characteristics while in others are employed theragnostic molecules which are not chemically or biologically identical but show similar biodistribution (so-called "twins in spirit" radiopharmaceuticals). This strategy was developed for the first time over 75 years ago, when iodine-131 was used for diagnostic imaging, confirmation of target expression and radionuclide therapy of thyroid cancer. Other theragnostic approaches were subsequently introduced with significant clinical results and some of them are currently considered standard treatment for different cancers. However, as any other therapy, also nuclear theragnostic treatment carries the potential risk of early deterministic and late stochastic off-target adverse effects, generally minimal and easily managed. This article reviews the reported side effects and risks of the main radiopharmaceuticals used for nuclear theragnostic in oncology for the treatment of thyroid cancer, neuroendocrine neoplasms, adrenergic tumors, metastatic prostate cancer, and liver tumors. Selecting appropriate patients using a multidisciplinary approach, meticulous pretreatment planning and knowledge of methods permit to decrease the incidence of these potential side effects.

Delta radiomics: a systematic review.

BACKGROUND: Radiomics can provide quantitative features from medical imaging that can be correlated with various biological features and clinical endpoints. Delta radiomics, on the other hand, consists in the analysis of feature variation at different acquisition time points, usually before and after therapy. The aim of this study was to provide a systematic review of the different delta radiomics approaches. METHODS: Eligible articles were searched in Embase, PubMed, and ScienceDirect using a search string that included free text and/or Medical Subject Headings (MeSH) with three key search terms: "radiomics", "texture", and "delta". Studies were analysed using QUADAS-2 and the RQS tool. RESULTS: Forty-eight studies were finally included. The studies were divided into preclinical/methodological (five studies, 10.4%); rectal cancer (six studies, 12.5%); lung cancer (twelve studies, 25%); sarcoma (five studies, 10.4%); prostate cancer (three studies, 6.3%), head and neck cancer (six studies, 12.5%); gastrointestinal malignancies excluding rectum (seven studies, 14.6%), and other disease sites (four studies, 8.3%). The median RQS of all studies was 25% (mean 21% ± 12%), with 13 studies (30.2%) achieving a quality score < 10% and 22 studies (51.2%) < 25%. CONCLUSIONS: Delta radiomics shows potential benefit for several clinical endpoints in oncology (differential diagnosis, prognosis and prediction of treatment response, and evaluation of side effects). Nevertheless, the studies included in this systematic review suffer from the bias of overall low quality, so that the conclusions are currently heterogeneous, not robust, and not replicable. Further research with prospective and multicentre studies is needed for the clinical validation of delta radiomics approaches.

Biomarkers for Ehlers-Danlos Syndromes: There Is a Role?

Ehlers-Danlos syndromes (EDS) are an inherited heterogeneous group of connective tissue disorders characterized by an abnormal collagen synthesis affecting skin, ligaments, joints, blood vessels, and other organs. It is one of the oldest known causes of bruising and bleeding, and it was described first by Hippocrates in 400 BC. In the last years, multiple gene variants involved in the pathogenesis of specific EDS subtypes have been identified; moreover, new clinical diagnostic criteria have been established. New classification models have also been studied in order to differentiate overlapping conditions. Moreover, EDS shares many characteristics with other similar disorders. Although distinguishing between these seemingly identical conditions is difficult, it is essential in ensuring proper patient care. Currently, there are many genetic and molecular studies underway to clarify the etiology of some variants of EDS. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. In this review, we focused on the study of two of the most common forms of EDS-classic and hypermobile-by trying to identify possible biomarkers that could be of great help to confirm patients' diagnosis and their follow up.

Pulsed Electromagnetic Fields in Bone Healing: Molecular Pathways and Clinical Applications.

In this article, we provide an extensive review of the recent literature of the signaling pathways modulated by Pulsed Electromagnetic Fields (PEMFs) and PEMFs clinical application. A review of the literature was performed on two medical electronic databases (PubMed and Embase) from 3 to 5 March 2021. Three authors performed the evaluation of the studies and the data extraction. All studies for this review were selected following these inclusion criteria: studies written in English, studies available in full text and studies published in peer-reviewed journal. Molecular biology, identifying cell membrane receptors and pathways involved in bone healing, and studying PEMFs target of action are giving a solid basis for clinical applications of PEMFs. However, further biology studies and clinical trials with clear and standardized parameters (intensity, frequency, dose, duration, type of coil) are required to clarify the precise dose-response relationship and to understand the real applications in clinical practice of PEMFs.

Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma.

The rarity of neoplastic cells in the biopsy imposes major technical hurdles that have so far limited genomic studies in classical Hodgkin lymphoma (cHL). By using a highly sensitive and robust deep next-generation sequencing approach for circulating tumor DNA (ctDNA), we aimed to identify the genetics of cHL in different clinical phases, as well as its modifications on treatment. The analysis was based on specimens collected from 80 newly diagnosed and 32 refractory patients with cHL, including longitudinal samples collected under ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy and longitudinal samples from relapsing patients treated with chemotherapy and immunotherapy. ctDNA mirrored Hodgkin and Reed-Sternberg cell genetics, thus establishing ctDNA as an easily accessible source of tumor DNA for cHL genotyping. By identifying STAT6 as the most frequently mutated gene in ∼40% of cases, we refined the current knowledge of cHL genetics. Longitudinal ctDNA profiling identified treatment-dependent patterns of clonal evolution in patients relapsing after chemotherapy and patients maintained in partial remission under immunotherapy. By measuring ctDNA changes during therapy, we propose ctDNA as a radiation-free tool to track residual disease that may integrate positron emission tomography imaging for the early identification of chemorefractory patients with cHL. Collectively, our results provide the proof of concept that ctDNA may serve as a novel precision medicine biomarker in cHL.

Impact of the COVID-19 pandemic in nuclear medicine departments: preliminary report of the first international survey.

PURPOSE: Coronavirus disease-19 (COVID-19) pandemic is challenging the availability of hospital resources worldwide. The Young Group of the Italian Association of Nuclear Medicine (AIMN) developed the first international survey to evaluate the impact of COVID-19 in nuclear medicine (NM). The aim of this study was to perform a preliminary report of the ongoing survey. METHODS: A questionnaire of thirty questions was prepared for all NM professionals addressing three main issues: (1) new scheduling praxes for NM diagnostic and therapeutic procedures, (2) assistance of patients with diagnosed or suspected COVID-19, and (3) prevention of COVID-19 spreading in the departments. An invitation to the survey was sent to the corresponding authors of NM scientific papers indexed in SCOPUS in 2019. Personal data were analysed per individual responder. Organisation data were evaluated per single department. RESULTS: Two-hundred and ninety-six individual responders from 220 departments were evaluated. Most of the responders were from Europe (199/296, 67%). Approximately, all departments already changed their scheduling praxes due to the pandemic (213/220, 97%). In most departments, scheduled diagnostic and therapeutic procedures were allowed but quantitatively reduced (112/220, 51%). A significant reduction of diagnostic and therapeutic procedures (more than 20%) affected 198/220 (90%) and 158/220 (72%) departments, respectively. Incidental COVID-19 signs in NM exams occurred in 106/220 departments (48%). Few departments were closed or shifted to assist patients with COVID-19 (36/220, 16%). Most of the responders thought that pandemic would not permanently change the work of NM departments in the future (189/296, 64%). CONCLUSIONS: According to this preliminary report of the first international survey, COVID-19 heavily impacted NM departments and professionals. New praxes for NM procedures, assistance, and prevention of COVID-19 have been applied during the pandemic.

The Progression of Hemophilic Arthropathy: The Role of Biomarkers.

BACKGROUND: Hemophilia A and B are X-linked congenital bleeding disorders characterized by recurrent hemarthroses leading to specific changes in the synovium and cartilage, which finally result in the destruction of the joint: this process is called hemophilic arthropathy (HA). This review highlights the most prominent molecular biomarkers found in the literature to discuss their potential use in the clinical practice to monitor bleeding, to assess the progression of the HA and the effectiveness of treatments. METHODS: A review of the literature was performed on PubMed and Embase, from 3 to 7 August 2020. Study selection and data extraction were achieved independently by two authors and the following inclusion criteria were determined a priori: English language, available full text and articles published in peer-reviewed journal. In addition, further articles were identified by checking the bibliography of relevant articles and searching for the studies cited in all the articles examined. RESULTS: Eligible studies obtained at the end of the search and screen process were seventy-three (73). CONCLUSIONS: Despite the surge of interest in the clinical use of biomarkers, current literature underlines the lack of their standardization and their potential use in the clinical practice preserving the role of physical examination and imaging in early diagnosis.

Lung uptake of fluorine-18 fluoroethyl-choline PET-CT in patients with prostate cancer.

BACKGROUND: Metastatic spreading to the lungs is a negative prognostic factor in patients with prostate cancer (PC). Aim of our study was to assess the prevalence of lung PC metastases in patients with fluorine-18 fluoroethyl-choline (F-18-FECh) PET-CT positive lung lesions and the role of Gleason Score (GS) and common biochemical markers in predicting metastatic spreading to the lungs. METHODS: We retrospectively evaluated the scans of 1283 patients ongoing (F-18-FECh) PET-CT for PC between May 2010 and July 2014. Patients with lung lesion with F-18-FECh uptake were included. Data concerning GS at diagnosis, "trigger" prostate-specific antigen (PSAtr), PSA doubling time (PSAdt), PSA velocity (PSAvel) and ongoing androgen deprivation therapy were collected. PET-CT findings were confirmed by histology or follow-up (FU) and classified as follows: inflammation, primary lung cancer or metastases from tumor other than PC, and lung metastases from PC. RESULTS: Twenty-two patients with F-18-FECh positive lung lesion and available histology or FU were identified. PSAdt was significantly (P=0.029) shorter in patients with lung metastases from PC (median PSAdt 1.7 months, interquartile range [IQR] 1.5-4.1 months) than in patients without lung PC relapse (median PSAdt 6.7 months, IQR 3.9-7.8); PSAvel was significantly (P=0.019) higher in patients with lung metastases from PC (median PSAvel 3.2 ng/mL/month, IQR 0.65-6.65 ng/mL/month) than in patients without lung PC relapse (median PSAvel 0.3 ng/mL/month, IQR 0.2-0.5 ng/mL/month). Patients with lung metastases from PC had significantly (P=0.006) higher GS at diagnosis (median GS 8) than the other ones (median GS 7). CONCLUSIONS: Our analysis shows that the prevalence of F-18-FECh positive lung metastases in patients with PC, especially with higher GS at diagnosis, is higher in presence of a steady increase in PSA values, confirmed by higher PSAvel and shorter PSAdt.

Performance of FDG-PET/CT in solitary pulmonary nodule based on pre-test likelihood of malignancy: results from the ITALIAN retrospective multicenter trial.

PURPOSE: The aim of this study was to determine the performance of 18F-FDG-PET/CT in patients with solitary pulmonary nodule (SPN), stratifying the risk according to the likelihood of pulmonary malignancy. METHODS: FDG-PET/CT of 502 patients, stratified for pre-test cancer risk, were retrospectively analyzed. FDG uptake in SPN was assessed by a 4-point scoring system and semiquantitative analysis using the ratio between SUVmax in SPN and SUVmean in mediastinal blood pool (BP) and between SUVmax in SPN and SUVmean in liver (L). Histopathology and/or follow-up data were used as standard of reference. RESULTS: SPN was malignant in 180 (36%) patients, benign in 175 (35%), and indeterminate in 147 (29%). The 355 patients with a definitive SPN nature (malignant or benign) were considered for the analysis. Considering FDG uptake ≥ 2, sensitivity, specificity, positive (PPV) and negative (NPV) predictive values, and accuracy were 85.6%, 85.7%, 86%, 85.2%, and 85.6% respectively. Sensitivity and PPV were higher (P < 0.05) in intermediate and high-risk patients, while specificity and NPV were higher (P < 0.05) in low-risk patients. On receiver operating characteristic curve analysis, the cut-offs for better discrimination between benign and malignant SPN were 1.56 (sensitivity 81% and specificity 87%) and 1.12 (sensitivity 81% and specificity 86%) for SUVmax/SUVmeanBP and SUVmax/SUVmeanL respectively. In intermediate and high-risk patients, including the SUVmax/SUVmeanBP, the specificity shifted from 85% and 50% to 100%. CONCLUSION: Visual FDG-PET/CT has an acceptable performance in patients with SPN, but accuracy improves when SUVratios are considered, particularly in patients with intermediate and high risk of malignancy.

The role of 18F-FDG-PET and PET/CT in patients with colorectal liver metastases undergoing selective internal radiation therapy with yttrium-90: a first evidence-based review.

PURPOSE: To provide a first evidence-based review of the literature on the role of fluorine-18-fluorodeoxyglucose positron emission tomography and positron emission tomography/computed tomography (FDG-PET and PET/CT) in patients with colorectal liver metastases (CRLM) undergoing selective internal radiation therapy (SIRT) with yttrium-90 ((90)Y) microspheres. METHODS: A comprehensive computer literature search was conducted to find relevant published articles on whole-body FDG-PET or PET/CT in patients with CRLM undergoing SIRT. RESULTS: We identified 19 studies including 833 patients with CRLM undergoing SIRT. The role of FDG-PET or PET/CT was analysed in treatment planning, treatment response evaluation, and as prognostic tool. CONCLUSION: FDG-PET and PET/CT provide additional information in treatment evaluation of CRLM patients treated with SIRT and may have a role in treatment planning and patient selection. FDG-PET/CT is emerging as good prognostic tool in these patients.