Introduction:Systemic lupus erythematosus (SLE) is a multisystem disease with a heterogenous pathophysiological mechanisms that lead to a variety of clinical, immunological, and neuropsychiatric manifestations. Areas covered:In this review, we will summarize the current understanding of molecular pathways involved in SLE and neuropsychiatric manifestations, focusing on genetic and epigenetic mechanisms and the implications of these findings in differences observed in treatment response. Expert opinion:Great progress has been made in understanding the heterogeneity in SLE, which may help direct therapy. However, neuropsychiatric manifestations still are a challenge in clinical practice, and future studies are needed to identify relevant diagnostic and prognostic biomarkers.
Introduction:Colorectal cancer (CRC) is the fourth most common cancer and second leading cause of cancer-related death in the United States. The implementation of CRC screening has decreased CRC incidence in adults older than 65 years. However, among young adults who experience more aggressive disease progression, CRC incidence has been increasing for decades. Immunotherapy represents a collection of innovative and promising approaches with greater efficacy and safety. In this review, we discuss modalities and selected targets of immunotherapies for CRCs that are guided by precision medicine. Areas covered:The following review focuses on immunological approaches for CRCs, including therapeutic monoclonal antibodies, immune checkpoint blockade, cancer vaccines, and adoptive cell therapies. Expert opinion:Metastatic and refractory CRCs are significant causes of cancer-related mortality and remain difficult to treat with current standard therapies. Following multiple FDA approvals for hematologic malignancies, research into solid tumor immunotherapies has substantially increased. Several chimeric antigen receptor (CAR)-expressing T cell therapies are showing promise in CRC. Moreover, immune checkpoint blocking antibodies are transforming care for a subset of CRC patients. With advances in our understanding of oncogenic mechanisms and development of novel treatment approaches, personalized immunotherapies are poised to dramatically change the landscape of CRC treatment.
Introduction Precision medicine customizes prevention, diagnosis, and treatment based on individual characteristics. Despite advancements, significant challenges remain in the widespread implementation of precision medicine across low- to middle-income countries (LMICs) such as Colombia. This review aims to identify and propose possible solutions to help close this gap. Areas covered Implementing precision medicine in LMICs requires addressing key barriers such as limited technology, inadequate healthcare training, ethical considerations, insufficient insurance coverage, public attitudes, high costs, and lack of political support. Expert opinion Precision medicine has the potential to revolutionize patient care and healthcare practices. By addressing these challenges and prioritizing strategic development areas, LMICs can fully embrace it, leading to significant improvements in healthcare outcomes for their diverse populations.
Introduction The drug development process traditionally includes rigorous pre-clinical testing in laboratories and animal models to assess the safety, efficacy, pharmacokinetics, and toxicology of potential drug candidates before progressing to human clinical trials. Developing AI, machine ML algorithms, and PM approaches will facilitate identifying potential drug targets, predicting therapeutic outcomes, and optimizing the selection of lead compounds.
IntroductionThis review examines the impact of allergic rhinitis (AR) on health, emphasizing precision medicine as a transformative approach, with AR treatments to individual factors and explores allergen immunotherapy (AIT) as a disease-modifying strategy, stressing adherence to 2019 ARIA care pathways. The role of digital technologies and mobile health tools in supporting patient-centered care is emphasized. Challenges and future prospects, including improved AIT adherence and novel biomarkers, are addressed.Area coveredThis article provides a comprehensive overview of personalized medicine, encompassing its definition, key components, and transformative impact on healthcare. It explores the role of next-generation sequencing in advancing personalized medicine, highlighting potential benefits and challenges in healthcare system implementation. Additionally, the article explores the underlying mechanisms of allergic rhinitis, the efficacy of allergen immunotherapy, and the utilization of mobile apps to improve adherence and self-care.Expert opinionIt also delves into the pathophysiology of AR and the use of innovative technologies and advancements in the AR to improve patient care. The insights presented in this article are valuable for understanding the evolving landscape of precision medicine and its impact on AR.
Introduction Patient selection remains challenging as the clinical use of re-irradiation (re-RT) increases. Re-RT data are limited to retrospective studies and small prospective single-institution reports, resulting in small, heterogenous data sets. Validated prognostic and predictive biomarkers are derived from large-volume studies with long-term follow-up. This review aims to examine existing re-RT publications and available data sets and discuss strategies using artificial intelligence (AI) to approach small data sets to optimize the use of re-RT data.
IntroductionPatient selection remains challenging as the clinical use of re-irradiation (re-RT) increases. Re-RT data are limited to retrospective studies and small prospective single-institution reports, resulting in small, heterogenous data sets. Validated prognostic and predictive biomarkers are derived from large-volume studies with long-term follow-up. This review aims to examine existing re-RT publications and available data sets and discuss strategies using artificial intelligence (AI) to approach small data sets to optimize the use of re-RT data.MethodsRe-RT publications were identified where associated public data were present. The existing literature on small data sets to identify biomarkers was also explored.ResultsPublications with associated public data were identified, with glioma and nasopharyngeal cancers emerging as the most common tumor sites where the use of re-RT was the primary management approach. Existing and emerging AI strategies have been used to approach small data sets including data generation, augmentation, discovery, and transfer learning.ConclusionsFurther data is needed to generate adaptive frameworks, improve the collection of specimens for molecular analysis, and improve the interpretability of results in re-RT data.
BackgroundRadiological response assessment is becoming challenging with novel immune-based combinations for metastatic renal cell carcinoma (mRCC). RECIST criteria appear not exhaustively adequate to capture the kinetics of treatment response, which is better reflected by tumor growth rate (TGR). We explored TGR changes during first-line treatments and its association with clinical outcomes in mRCC.Research design and methodsWe retrospectively evaluated TGR in untreated patients undergoing pembrolizumab/axitinib (P/A) or tyrosine-kinase inhibitors (TKI). TGR was calculated at the first (TGR1, after 3 months) and the second (TGR2, after 6 months) evaluation, thus assessing the TGR2-TGR1 difference.ResultsThirty-three patients were included (P/A n = 15, TKIs n = 18). Volumes firstly decreased more rapidly with TKIs, and then more slowly. Volumes initially remained stable with P/A, quickly decreasing until the second evaluation. TGR1 was related to progression-free survival (PFS; p = 0.023) and overall survival (p = 0.046) with P/A. TGR2 was correlated with PFS in all patients (p = 0.025). Patients with higher velocity volume reduction appeared to have improved survival benefits than patients with lower velocity considering both treatments, but especially with P/A.ConclusionCombining immunotherapy with TKIs has an important role in enhancing the rapidity of tumor shrinkage. A rapid disease volume reduction correlates with better OS and PFS.
Introduction Radiation therapy (RT) is commonly used to treat cancer in conjunction with chemotherapy, immunotherapy, and targeted therapies. Despite the effectiveness of RT, tumor recurrence due to treatment resistance still lead to treatment failure. RT-specific biomarkers are currently lacking and remain challenging to investigate with existing data since, for many common malignancies, standard of care (SOC) paradigms involve the administration of RT in conjunction with other agents.Areas Covered Established clinically relevant biomarkers are used in surveillance, as prognostic indicators, and sometimes for treatment planning; however, the inability to intercept early recurrence or predict upfront resistance to treatment remains a significant challenge that limits the selection of patients for adjuvant therapy. We discuss attempts at intercepting early failure. We examine biomarkers that have made it into the clinic where they are used for treatment monitoring and management alteration, and novel biomarkers that lead the field with targeted adjuvant therapy seeking to harness these.Expert Opinion Given the growth of data correlating interventions with omic analysis toward identifying biomarkers of radiation resistance, more robust markers of recurrence that link to biology will increasingly be leveraged toward targeted adjuvant therapy to make a successful transition to the clinic in the coming years.
Introduction Peptide Receptor Radionuclide Therapy (PRRT) is a type of molecular-targeted endo-radionuclide therapy in which unsealed radiolabelled somatostatin analogues are specifically directed toward somatostatin receptors (SSTR) over-expressed in Neuroendocrine Neoplasms (NEN) and related malignancies. This modality has witnessed a benchmark growth over last decade and symbolizes remarkable development in precision oncology. The tumor selectivity and excellent tolerability with minimal side effects make this one of the preferred therapeutic options in metastatic progressive NENs. Areas covered This review deliberates upon fundamentals of PRRT, its indications and employment as a therapeutic modality for precision oncology. A few special scenarios based on our experiences and expertise have also been mentioned. A short discussion on current advancements worldwide and future directions has also been included. Expert opinion SSTR-based PET and PRRT are now an established theranostic approach in management of NENs. Its spectrum has expanded in the form of Neo-Adjuvant-PRRT, Sandwich Chemo-PRRT, Duo-PRRT, Salvage-PRRT, and Intra-arterial-PRRT. Its application to other SSTR-expressing tumors includes metastatic/inoperable medullary thyroid cancer, neural crest malignancies like pheochromocytomas-paragangliomas (PPGLs), Merkel cell carcinoma, radioiodine-refractory thyroid cancer, and meningiomas. Though substantial prospective evidence is still lacking, a multidisciplinary team should adopt PRRT in appropriate indications by using dual tracer PET imaging as a gatekeeper.
Objectives Currently, there is an active use of neural networks in various areas of human activity. Problems of recognition, diagnostics, optimization, forecasting, control, as well as obtaining new scientific knowledge are successfully solved. However, in medicine, due to the particular complexity of the human body, neural networks are mainly used only for solving the simplest problems of classification and diagnostics. The purpose of this article is to show that the possibilities of neural network modeling in medicine are much wider.Methods This goal is achieved by using special mathematical techniques developed by the authors that allow us to overcome these difficulties.Results The intellectual system created in this way made it possible to reveal a number of interesting scientific knowledge, which sometimes does not coincide with the generally accepted ideas of doctors. Virtual experiments conducted on computer models of patients using our intelligent system clearly demonstrate which lifestyle and medication variations can benefit a particular patient in the long term, and which can cause harm.Conclusion Our intellectual system allows us to identify new scientific knowledge, to carry out long-term forecasting of the development of the disease, to select the optimal courses of treatment and prevention of diseases.
Introduction: Many studies have reported brain region and age-dependent alterations in the expression of several subunits of the GABA(A) receptor in Fmr1 KO mice. GABA(A) receptors are located synaptic and extrasynaptic with differential subunit compositions and characteristics. Interestingly, the activity of many subunits of the GABA(A) receptor is amendable by differential pharmacological treatment. Areas Covered: The purpose of this review is to summarize the expression of GABA(A) receptor subunits in different brain regions of Fmr1 KO mice across different ages. The decreased expression of the synaptic alpha 2 subunit in juvenile, and the decreased expression of the extrasynaptic delta subunit in both juvenile and adult Fmr1 KO mice, are among the most consistent abnormalities reported. Both subunits are suitable for treatment and currently available compounds are discussed in this review along with their therapeutic potential. Expert Opinion: Pharmacological treatment targeting specific subunits of the GABA(A) receptor has shown selective improvements in fragile X syndrome. To our knowledge, combinatorial therapies targeting multiple subunits of the GABA(A) receptor have not been explored. We here argue that such a combination therapy could induce a synergistic effect to ameliorate the clinical symptoms of fragile X syndrome.
Introduction: Cardiovascular disease persists as the leading cause of death worldwide despite continued advances in diagnostics and therapeutics. Our current approach to patients with cardiovascular disease is rooted in reductionism, which presupposes that all patients share a similar phenotype and will respond the same to therapy; however, this is unlikely as cardiovascular diseases exhibit complex heterogeneous phenotypes. Areas covered: With the advent of high-throughput platforms for omics testing, phenotyping cardiovascular diseases has advanced to incorporate large-scale molecular data with classical history, physical examination, and laboratory results. Findings from genomics, proteomics, and metabolomics profiling have been used to define more precise cardiovascular phenotypes and predict adverse outcomes in population-based and disease-specific patient cohorts. These molecular data have also been utilized to inform drug efficacy based on a patient's unique phenotype. Expert opinion: Multiscale phenotyping of cardiovascular disease has revealed diversity among patients that can be used to personalize pharmacotherapies and predict outcomes. Nonetheless, precision phenotyping for cardiovascular disease remains a nascent field that has not yet translated into widespread clinical practice despite its many potential advantages for patient care. Future endeavors that demonstrate improved pharmacotherapeutic responses and associated reduction in adverse events will facilitate mainstream adoption of precision cardiovascular phenotyping.
Cholangiocarcinomas (CCAs) include a heterogeneous group of hepatobiliary tumors accounting for approximately the 10–15% of primary liver cancers [1]. Unfortunately, most of these tumors are diagnosed at an advanced stage, and more than ten years after the publication of the landmark phase III ABC-02 trial establishing gemcitabine-cisplatin as first-line standard for metastatic CCA, the prognosis of this patient population remains grim [2]. In fact, most of patients treated with front-line treatment fail to achieve a response or responses are short lived [3]. Recent years have witnessed the advent of molecular profiling in this setting, and new techniques and technologies have led to the identification of a variety of molecular alterations in CCA [4]. Over the last decade, several potentially actionable genetic aberrations have been highlighted, and precision oncology approaches have been evaluated and are under investigation in these hepatobiliary malignancies (Figure 1). A large number of anticancer agents are currently in development, including Fibroblast Growth Factor Receptor (FGFR) 2, Isocitrate Dehydrogenase 1 (IDH-1), and BRAF inhibitors [5]. FGFR2 aberrations have been reported in approximately the 20% of intrahepatic cholangiocarcinomas (iCCAs), with these alterations highlighted as most common in female patients and young adults [6]. Of note, FGFR2 aberrations are mainly represented by fusions, while mutations are detected only in a minority of patients. As regards IDH-1, missense mutations are the most frequent aberrations, involving a single residue in the active site of the enzyme [7]; typically, IDH-1 missense mutations have been reported to be more common in small duct type iCCAs and in poorly differentiated or undifferentiated forms [8]. Several other molecular aberrations have been observed in CCA patients, including BRCA mutations, NTRK fusions, and BRAF V600E mutations [9,10]. Nonetheless, several questions remain unanswered, and the adoption of precision oncology in CCA patients remains still far from everyday clinical practice, with some important exceptions. Among current obstacles, a crucial point to highlight is the limited access to anticancer treatments. For example, although the final overall survival (OS) analysis of the ClarIDHy phase III trial has been presented and on 25 August 2021 the FDA approved ivosidenib use in IDH-1 mutant iCCA, the IDH-1 inhibitor is not available in several countries, according to different choices by the regulatory agencies [11]. Second, biopsy samples are often inadequate for molecular profiling since tissue sampling has reported low sensitivity in the diagnosis of malignant biliary strictures; in fact, the highly desmoplastic nature of CCA severely limits the accuracy of pathological and cytological methodologies. On the basis of these premises, it is urgent to develop in this scenario novel strategies aimed at anticipating the diagnosis by detecting CCA at an early, resectable stage, as well as to obtain adequate material to perform genomic analysis. Among these strategies, liquid biopsy may represent a fundamental tool, although the use of this technique is still limited and has to be implemented in the near future [12]. A long-standing issue is also represented by the genomic diversity of CCAs that also mirrors anatomical, epidemiological, and therapeutical differences. In fact, it is currently well known that these malignancies should not be considered as a single entity but a group of tumors with heterogeneous features. However, several trials still group together different anatomical CCA subgroups, such as iCCA, perihilar CCA, and distal CCA, something that represents a ‘historical’ issue in clinical trial design in these hepatobiliary malignancies. Stratification of patients according to CCA subgroup should always be present in studies on these tumors, also considering that distinct subgroups are associated to different molecular features, clinical outcomes and prognosis. In our opinion, another landmark topic in this setting is represented by clinical trial enrollment, something that remains a priority in CCA due to the difficulties encountered in enrolling patients with these rare hepatobiliary tumors. For example, the ClarIDHy and the FIGHT-202 trials on ivosidenib and pemigatinib, respectively, enrolled more than a hundred CCA patients, requiring important efforts in terms of screening and enrollment [13–15]. Similarly, the investigators of the phase II, singlearm, ROAR trial evaluating dabrafenib plus trametinib in BRAF V600E-mutated CCAs, had to prescreen 626 subjects to enroll 43 CCA patients, a figure that highlights the difficulties in completing such a trial [16]. Conducting clinical studies in rare CCA subgroups with genetic aberrations remains a compelling challenge, and international collaborations are of pivotal importance in this setting. This is even more important in CCA patients whose disease has progressed following first-line or
Introduction Eating Disorders and Obesity are a primary global public health concern.Areas Covered This article aims to trace the neurochemical mechanisms of unwanted eating disorders and target specific loci, within the Brain Reward Cascade (BRC) for therapeutic interventions. Changes due to BRC polymorphisms in functional connectivity and neurotransmission can manifest as overeating, Bulimia Nervosa, and Anorexia Nervosa, and other related eating disorders.Expert opinion Variations in dopamine function within the Ventral Tegmental Area (VTA), Nucleus Accumbens (NAc), and Ventral Striatum of individuals result in different outcomes related to maladaptive eating behaviors. The goal is to reduce maladaptive eating behaviors by implementing novel strategies that induce Dopamine Homeostasis within the BRC. Clinicians determine genetic risk severity and identify polymorphic targets for either pharmaceutical or nutraceutical interventions. Precision neuro-nutrient formulations of KB220 (Research ID Code) matched precisely to deficient neurotransmitter systems may promote the long-term development of ‘dopamine homeostasis’ to treat and prevent overeating, Bulimia, and Anorexia Nervosa.
Introduction Immune-checkpoint inhibitors (ICI) works by blocking inhibitory signals of T cells. This produces an effective anti-tumor response but can also cause immune-related adverse events (irAEs). Most irAEs are transient, but ICI-induced inflammatory arthritis (ICI-IIA) might become chronic and affect the quality-of-life, or even necessitate treatment discontinuation. However, there exist no tools to identify patients that are susceptible to develop ICI-IIA.Areas covered This non-systematic review briefly presents a sparse number of studies, that have tried to identify circulating biomarkers for early prediction of ICI-IIA. Challenges, recommendations, and possibilities related to biomarker discovery in the context of ICI-IIA are then covered.Expert opinion Improved diagnosis adapted from rheumatological settings is needed for future studies to avoid a major pitfall of bad endpoints. Synovial tissue biopsies, omics technologies and particularly integration of multiple omics data is useful when searching for biomarkers of ICI-IIA and can also help unravel underlying biological mechanisms. Future biomarkers could ultimately aid clinical decision-making and facilitate early prophylaxis, pave the way for new treatment or even translational models to study autoimmune arthritis.
