Non-oncological Applications Research Articles

Identification of a Selective FLT3 Inhibitor with Low Activity against VEGFR, FGFR, PDGFR, c-KIT, and RET Anti-Targets.

FLT3 is mainly expressed in immune and various cancer cells and is a drug target for acute myeloid leukemia (AML). Recently, FLT3 has also been identified as a potential target for treating chronic pain. Most FLT3 inhibitors (FLT3i) identified to date, including approved drugs such as gilteritinib, midostaurin, ponatinib, quizartinib, and FLT3i in clinical trials, such as quizartinib and crenolanib, also inhibit closely-related kinases that are important for immune (c-KIT), cardiovascular (KDR/VEGFR2, FGFR, PDGFR) or kidney (RET) functions. While the aforementioned FLT3i may increase survival rates in AML, they are neither ideal for AML maintenance therapy nor for non-oncology applications, such as for the treatment of chronic pain, due to their promiscuous inhibition of many kinase anti-targets. Here, we report the identification of new FLT3i compounds that have low activities against kinases that have traditionally been difficult to differentiate from FLT3 inhibition, such as KDR/VEGFR, FGFR, PGFR, c-KIT, and RET. These selective compounds could be valuable chemical probes for studying FLT3 biology in the context of chronic pain and/or may represent good starting points to develop well-tolerated FLT3 therapeutics for non-oncology indications or for maintenance therapy for AML.

An Overview of the Development and Preclinical Evaluation of Antibody-Drug Conjugates for Non-Oncological Applications.

Typically, antibody-drug conjugates (ADCs) are made up of a humanized antibody and a small-molecule medication connected by a chemical linker. ADCs' ability to deliver cytotoxic agents to the specific site with reduced side effects showed promising results in oncology. To date, fourteen ADCs have been approved by the US Food and Drug Administration, and approximately 297 ADCs are in pre-clinical/clinical stages in the oncology area. Inspired by these outcomes, a few scientists explored the potential of antibody-drug conjugates in non-oncological conditions such as arthritis, myasthenia gravis, immunological disorders, and kidney failure. However, there are limited data available on the non-oncological applications of antibody-drug conjugates. This current review focuses on the non-oncological applications of antibody-drug conjugates, their developmental studies, testing procedures, in vitro evaluations, and pre-clinical testing. Additionally, a summary of the restrictions, difficulties, and prospects for ADCs in non-oncological applications is provided.

3D Whole-Body MRI of the Musculoskeletal System.

With its outstanding soft tissue contrast, spatial resolution, and multiplanar capacities, magnetic resonance imaging (MRI) has become a widely used technique. Whole-body MRI (WB-MRI) has been introduced among diagnostic methods for the staging and follow-up assessment in oncologic patients, and international guidelines recommend its use. In nononcologic applications, WB-MRI is as a promising imaging tool in inflammatory diseases, such as seronegative arthritis and inflammatory myopathies. Technological advances have facilitated the introduction of three-dimensional (3D) almost isotropic sequences in MRI examinations covering the whole body. The possibility to reformat 3D images in any plane with equal or almost equal resolution offers comprehensive understanding of the anatomy, easier disease detection and characterization, and finally contributes to correct treatment planning. This article illustrates the basic principles, advantages, and limitations of the 3D approach in WB-MRI examinations and provides a short review of the literature.

Basic principles and new advances in kidney imaging

Over the past few years, clinical renal imaging has seen great advances, allowing assessments of kidney structure and morphology, perfusion, function and metabolism, and oxygenation, as well as microstructure and the interstitium. Medical imaging is becoming increasingly important in the evaluation of kidney physiology and pathophysiology, showing promise in management of patients with renal disease, in particular with regard to diagnosis, classification, and prediction of disease development and progression, monitoring response to therapy, detection of drug toxicity, and patient selection for clinical trials. A variety of imaging modalities, ranging from routine to advanced tools, are currently available to probe the kidney both spatially and temporally, particularly ultrasonography, computed tomography, positron emission tomography, renal scintigraphy, and multiparametric magnetic resonance imaging. Given that the range is broad and varied, kidney imaging techniques should be chosen based on the clinical question and the specific underlying pathologic mechanism, taking into account contraindications and possible adverse effects. Integration of various modalities providing complementary information will likely provide the greatest insight into renal pathophysiology. This review aims to highlight major recent advances in key tools that are currently available or potentially relevant for clinical kidney imaging, with a focus on non-oncological applications. The review also outlines the context of use, limitations, and advantages of various techniques, and highlights gaps to be filled with future development and clinical adoption.

Evaluation of a Low-Toxicity PARP Inhibitor as a Neuroprotective Agent for Parkinson's Disease.

Repurposing PARP-1 inhibitors (PARPi) for non-oncological applications offers an attractive therapeutic strategy for pathological conditions characterized by PARP-1 hyperactivity. In the context of Parkinson's disease (PD), PARP-1 hyperactivity has been linked to neuronal death and disease progression. From a therapy perspective, the evaluation of PARPi as neuroprotective agents may offer a new therapeutic alternative for neurodegenerative disorders. An ideal PARPi needs to inhibit PARP-1 hyperactivity while also limiting downstream DNA damage and cellular toxicity-an effect that is attractive in cancer but far from ideal in neurological disease applications. Consequently, in this study, we set out to evaluate the neuroprotective properties of a previously reported low-toxicity PARPi (10e) using in vitro neuronal models of PD. 10e is a structural analogue of FDA-approved PARPi olaparib, with high PARP-1 affinity and selectivity. Our studies revealed that 10e protects neuronal cells from oxidative stress and DNA damage. In addition, 10e exhibits neuroprotective properties against α-synuclein pre-formed fibrils (αSyn PFF) mediated effects, including reduction in the levels of phosphorylated αSyn and protection against abnormal changes in NAD+ levels. Our in vitro studies with 10e provide support for repurposing high-affinity and low-toxicity PARPi for neurological applications and lay the groundwork for long-term therapeutic studies in animal models of PD.

Design and synthesis of C-aryl angular luotonins via a one-pot aza-Nazarov–Friedlander sequence and their Topo-I inhibition studies along with C-aryl vasicinones and luotonins

A facile one-pot synthesis of C-ring substituted angular luotonins has been realized via a methanesulfonic acid mediated aza-Nazarov–Friedlander condensation sequence on quinazolinonyl enones. Topoisomerase I (topo-I) inhibition studies revealed that the angular luotonin library (7a-7l) and their regioisomeric analogs (linear luotonins, 8a-8l) are weak negative modulators, compared to camptothecin. These results would fare well for the design of topo-I-inert luotonins for non-oncological applications such as anti-fungal and insecticide lead developments. Surprisingly, the tricyclic vasicinones (9h, 9i, and 9j) showed better topo-I inhibition compared to pentacyclic C-aryl luotonins providing a novel pharmacophore for further explorations.

Non-Oncologic Applications of Nanomedicine-Based Phototherapy.

Phototherapy is widely applied to various human diseases. Nanomedicine-based phototherapy can be classified into photodynamic therapy (PDT) and photothermal therapy (PTT). Activated photosensitizer kills the target cells by generating radicals or reactive oxygen species in PDT while generating heat in PTT. Both PDT and PTT have been employed for treating various diseases, from preclinical to randomized controlled clinical trials. However, there are still hurdles to overcome before entering clinical practice. This review provides an overview of nanomedicine-based phototherapy, especially in non-oncologic diseases. Multiple clinical trials were undertaken to prove the therapeutic efficacy of PDT in dermatologic, ophthalmologic, cardiovascular, and dental diseases. Preclinical studies showed the feasibility of PDT in neurologic, gastrointestinal, respiratory, and musculoskeletal diseases. A few clinical studies of PTT were tried in atherosclerosis and dry eye syndrome. Although most studies have shown promising results, there have been limitations in specificity, targeting efficiency, and tissue penetration using phototherapy. Recently, nanomaterials have shown promising results to overcome these limitations. With advanced technology, nanomedicine-based phototherapy holds great potential for broader clinical practice.

RETRACTED: Medical wireless sensor network coverage and clinical application of MRI liver disease diagnosis

Abstract Diffusion-enhanced imaging (DWI) is a useful imaging method utilizing earthy colored movement of water atoms, has indicated the estimation of progressively different and non-oncological applications in oncology. Without intravenous difference operators, particularly in patients with unusual renal capacity, such access and get data on the usefulness of the level of trouble factors urge individuals to investigate the clinical utilization of DWI increasingly intrigued. DWI has indicated a scope of clinical application, from the neighborhood consistent subsequent observing to distinguish central liver sores in patients with fundamental treatment reaction. DWI has likewise been utilized to evaluate diffuse liver infections, for example, non-alcoholic greasy liver, liver fibrosis and cirrhosis. In this survey, we will inspect the essential standards of DW-MRI of the liver, innovation, clinical use of current and future patterns.

FAPI PET/CT: Will It End the Hegemony of 18F-FDG in Oncology?

For over 40 years, 18F-FDG has been the dominant PET tracer in neurology, cardiology, inflammatory diseases, and, most particularly, oncology. Combined with the ability to perform whole-body scanning, 18F-FDG has revolutionized the evaluation of cancer and has stifled the adoption of other tracers, except in situations where low avidity or high background activity limits diagnostic performance. The strength of 18F-FDG has generally been its ability to detect disease in the absence of structural abnormality, thereby enhancing diagnostic sensitivity, but its simultaneous weakness has been a lack of specificity due to diverse pathologies with enhanced glycolysis. Radiotracers that leverage other hallmarks of cancer or specific cell-surface targets are gradually finding a niche in the diagnostic armamentarium. However, none have had sufficient sensitivity to realistically compete with 18F-FDG for evaluation of the broad spectrum of malignancies. Perhaps, this situation is about to change with development of a class of tracers targeting fibroblast activation protein that have low uptake in almost all normal tissues but high uptake in most cancer types. In this review, the development and exciting preliminary clinical data relating to various fibroblast activation protein-specific small-molecule inhibitor tracers in oncology will be discussed along with potential nononcologic applications.

Non-oncological applications of RGD-based single-photon emission tomography and positron emission tomography agents.

Non-invasive imaging techniques (especially single-photon emission tomography and positron emission tomography) apply several RGD-based imaging ligands developed during a vast number of preclinical and clinical investigations. The RGD (Arg-Gly-Asp) sequence is a binding moiety for a large selection of adhesive extracellular matrix and cell surface proteins. Since the first identification of this sequence as the shortest sequence required for recognition in fibronectin during the 1980s, fundamental research regarding the molecular mechanisms of integrin action have paved the way for development of several pharmaceuticals and radiopharmaceuticals with clinical applications. Ligands recognizing RGD may be developed for use in the monitoring of these interactions (benign or pathological). Although RGD-based molecular imaging has been actively investigated for oncological purposes, their utilization towards non-oncology applications remains relatively under-exploited. This review highlights the new non-oncologic applications of RGD-based tracers (with the focus on single-photon emission tomography and positron emission tomography). The focus is on the last 10years of scientific literature (2009-2020). It is proposed that these imaging agents will be used for off-label indications that may provide options for disease monitoring where there are no approved tracers available, for instance Crohn's disease or osteoporosis. Fundamental science investigations have made progress in elucidating the involvement of integrin in various diseases not pertaining to oncology. Furthermore, RGD-based radiopharmaceuticals have been evaluated extensively for safety during clinical evaluations of various natures. Clinical translation of non-oncological applications for RGD-based radiopharmaceuticals and other imaging tracers without going through time-consuming extensive development is therefore highly plausible. Graphical abstract.

Pushing the Envelope: Advancement of ADCs Outside of Oncology.

The majority of ADCs in preclinical and clinical development are for oncology indications where cytotoxic payloads are targeted to antigen-expressing cancer cells. However, the modulation of pathogenic cellular activity via ADC-mediated delivery of bioactive small molecules is also an attractive concept for non-oncology indications leading to an expanded application of the technology. Here we summarize those ADCs that have been described so far for non-oncology applications and which cover a variety of payload mechanisms beyond cell killing, from early in vitro proof-of-concept experiments to clinical trials. As our understanding of ADC technology continues to grow, it is anticipated that the development of ADCs as therapeutics for disease areas outside of oncology will also increase.

Towards clinical application of image mining: a systematic review on artificial intelligence and radiomics

PurposeThe aim of this systematic review was to analyse literature on artificial intelligence (AI) and radiomics, including all medical imaging modalities, for oncological and non-oncological applications, in order to assess how far the image mining research stands from routine medical application. To do this, we applied a trial phases classification inspired from the drug development process.MethodsAmong the articles we considered for inclusion from PubMed were multimodality AI and radiomics investigations, with a validation analysis aimed at relevant clinical objectives. Quality assessment of selected papers was performed according to the QUADAS-2 criteria. We developed the phases classification criteria for image mining studies.ResultsOverall 34,626 articles were retrieved, 300 were selected applying the inclusion/exclusion criteria, and 171 high-quality papers (QUADAS-2 ≥ 7) were identified and analysed. In 27/171 (16%), 141/171 (82%), and 3/171 (2%) studies the development of an AI-based algorithm, radiomics model, and a combined radiomics/AI approach, respectively, was described. A total of 26/27(96%) and 1/27 (4%) AI studies were classified as phase II and III, respectively. Consequently, 13/141 (9%), 10/141 (7%), 111/141 (79%), and 7/141 (5%) radiomics studies were classified as phase 0, I, II, and III, respectively. All three radiomics/AI studies were categorised as phase II trials.ConclusionsThe results of the studies are promising but still not mature enough for image mining tools to be implemented in the clinical setting and be widely used. The transfer learning from the well-known drug development process, with some specific adaptations to the image mining discipline could represent the most effective way for radiomics and AI algorithms to become the standard of care tools.

Intraoperative ICG-fluorescence imaging for robotic-assisted urologic surgery: current status and review of literature.

With the availability of near-infrared fluorescence (NIRF) imaging using indocyanine green dye (ICG) to the robotic platform, utility of this imaging technology has evolved significantly across the board for ablative and reconstructive procedures. Herein, we describe the potential indications of indocyanine green for both oncologic and non-oncologic applications in robot-assisted laparoscopic urologic surgery. A narrative mini-review was performed in November 2018 using PubMed, Scopus, EMBASE, and Web of Science databases utilizing the following search phrase: "indocyanine green fluorescence robotic surgery" resulting in 104 articles of which 30 articles had urologic-pertinent applications. All 30 articles, and the references within, were reviewed and judged for scientific integrity and merit. Articles with non-novel findings or similar conclusions to original papers were omitted. ICG does not have a urologic FDA indication, though it has been used off-label for urologic surgery since 2006. Fluorescence-augmented surgery with ICG can facilitate oncologic surgery in the adrenal gland, kidney, bladder, prostate, and retroperitoneum, in addition to lymph node dissection for various malignant pathologies. ICG-NIRF can enhance non-oncologic surgery including ureterolysis, ureteroureterostomy, ureteral re-implantation, pyeloplasty, and urinary diversion in both the adult and pediatric populations. Although it is not necessary to utilize fluorescence-enhanced surgery in all cases, the authors find the utilization of ICG-NIRF in complex and highly technical surgeries useful.

Volumetric analysis at abdominal CT: oncologic and non-oncologic applications.

Volumetric analysis is an objective three-dimensional assessment of a lesion or organ that may more accurately depict the burden of complex objects compared to traditional linear size measurement. Small changes in linear size are amplified by corresponding changes in volume, which could have significant clinical implications. Though early methods of calculating volumes were time-consuming and laborious, multiple software platforms are now available with varying degrees of user-software interaction ranging from manual to fully automated. For the assessment of primary malignancy and metastatic disease, volumetric measurements have shown utility in the evaluation of disease burden prior to and following therapy in a variety of cancers. Additionally, volume can be useful in treatment planning prior to resection or locoregional therapies, particularly for hepatic tumours. The utility of CT volumetry in a wide spectrum of non-oncologic pathology has also been described. While clear advantages exist in certain applications, some data have shown that volume is not always the superior method of size assessment and the associated labor intensity may not be worthwhile. Further, lack of uniformity among software platforms is a challenge to widespread implementation. This review will discuss CT volumetry and its potential oncologic and non-oncologic applications in abdominal imaging, as well as advantages and limitations to this quantitative technique.

Clinical Nononcologic Applications of PET/CT and PET/MRI in Musculoskeletal, Orthopedic, and Rheumatologic Imaging.

With improvements in PET/CT and PET/MRI over the last decade, as well as increased understanding of the pathophysiology of musculoskeletal diseases, there is an emerging potential for PET as a primary or complementary modality in the management of rheumatologic and orthopedic conditions. We discuss the role of PET/CT and PET/MRI in nononcologic musculoskeletal disorders, including inflammatory and infectious conditions and postoperative complications. There is great potential for an increased role for PET to serve as a primary or complementary modality in the management of orthopedic and rheumatologic disorders.

Non-oncological applications of PET/CT

Non-oncological applications of PET/CT

Non-oncologic Applications of PET/CT and PET/MR in Musculoskeletal, Orthopedic, and Rheumatologic Imaging: General Considerations, Techniques, and Radiopharmaceuticals.

Positron Emission Tomography (PET) is often underutilized in the field of musculoskeletal imaging, with key reasons including the excellent performance of conventional musculoskeletal MRI, the limited spatial resolution of PET, and the lack of reimbursement for PET for non-oncologic musculoskeletal indications. However, with improvements in PET/CT and PET/MR imaging over the last decade as well as an increased understanding of the pathophysiology of musculoskeletal diseases, there is an emerging potential for PET as a primary or complementary modality in the management of rheumatologic and orthopedic patients. Specific advantages of PET include the convenience of whole body imaging in a single session, the relative resilience of the modality in the imaging of metallic implants compared to CT and MRI, the ability to evaluate deep joints not amenable to palpation, and the potential for improved specificity of diagnosis with novel radiopharmaceuticals. In this review, we discuss multiple radiopharmaceuticals and technical consideration of PET/CT and PET/MRI that can be employed in imaging of non-tumoral bone and soft tissue disorders. Both PET/CT and PET/MR hold significant promise in the field of musculoskeletal imaging, and with further radiopharmaceutical development and clinical research, these hybrid modalities can potentially transform the current management of patients with orthopedic and rheumatologic disease.

New horizons in multimodality molecular imaging and novel radiotracers

Positron emission tomography (PET)/computerised tomography is now established in clinical practice for oncologic and non-oncological applications. Improvement and development of scanner hardware has allowed faster acquisitions and wider application. PET/magnetic resonance imaging offers potential improvements in diagnostic accuracy and patient acceptability but clinical applications are still being developed. A range of new radiotracers and non-radioactive contrast agents is likely to lead to a growth in hybrid molecular imaging applications that will allow better characterisation of disease processes.

CT Texture Analysis: Definitions, Applications, Biologic Correlates, and Challenges.

This review discusses potential oncologic and nononcologic applications of CT texture analysis ( CTTA CT texture analysis ), an emerging area of "radiomics" that extracts, analyzes, and interprets quantitative imaging features. CTTA CT texture analysis allows objective assessment of lesion and organ heterogeneity beyond what is possible with subjective visual interpretation and may reflect information about the tissue microenvironment. CTTA CT texture analysis has shown promise in lesion characterization, such as differentiating benign from malignant or more biologically aggressive lesions. Pretreatment CT texture features are associated with histopathologic correlates such as tumor grade, tumor cellular processes such as hypoxia or angiogenesis, and genetic features such as KRAS or epidermal growth factor receptor (EGFR) mutation status. In addition, and likely as a result, these CT texture features have been linked to prognosis and clinical outcomes in some tumor types. CTTA CT texture analysis has also been used to assess response to therapy, with decreases in tumor heterogeneity generally associated with pathologic response and improved outcomes. A variety of nononcologic applications of CTTA CT texture analysis are emerging, particularly quantifying fibrosis in the liver and lung. Although CTTA CT texture analysis seems to be a promising imaging biomarker, there is marked variability in methods, parameters reported, and strength of associations with biologic correlates. Before CTTA CT texture analysis can be considered for widespread clinical implementation, standardization of tumor segmentation and measurement techniques, image filtration and postprocessing techniques, and methods for mathematically handling multiple tumors and time points is needed, in addition to identification of key texture parameters among hundreds of potential candidates, continued investigation and external validation of histopathologic correlates, and structured reporting of findings. ©RSNA, 2017.

Use of acellular dermal matrices in laryngotracheal and pharyngeal reconstruction: systematic review.

Acellular dermal matrices are increasingly used in laryngotracheal and pharyngeal reconstruction, but specific indications and the type of acellular dermal matrix used vary. The authors systematically reviewed outcomes relating to acellular dermal matrix use in head and neck reconstruction. Electronic databases were searched through 1 May 2016 for literature on acellular dermal matrix use in laryngotracheal and pharyngeal reconstruction. Studies were appraised for surgical indications, outcomes and study design. Eleven publications with 170 cases were included. Eight articles reported on acellular dermal matrix use in oncological reconstruction. Most studies were case series; no high-level evidence studies were identified. Graft extrusion was more common in non-oncological applications. In general, post-oncological reconstruction with an acellular dermal matrix demonstrated complication rates similar to those reported without an acellular dermal matrix. Evidence in support of acellular dermal matrix use in head and neck reconstruction is generally poor. Prospective comparative studies are required to define the indications, safety and effectiveness of acellular dermal matrices in laryngotracheal and pharyngeal reconstruction.