[Treatment of Graves' disease is moving towards precision medicine]. / Behandling av Graves sjukdom.

This is the first national guideline in hyperthyroidism to harmonise and update clinical practice according to what is evidence based and direct care from patients' needs. We present 4 articles in Läkartidningen of different views of the guideline, including family care perspectives, patient care perspectives and perspectives on ophthalmology. This article concerns treatment of Graves' disease and includes endocrinological, surgical and oncological perspectives on what is established practice, but also news in the national guideline that remain to be fully implemented in Sweden in the years to come. News are precision medicine using the GREAT score, preoperative calcium/D vitamin treatment, individualized levothyroxine treatment after thyroid surgery, uniformed levothyroxine replacement strategy, access to national patient information and national guidelines on radiation protection and treatment schemes for radioactive iodine. A national guideline is the creation of many persons' views, including patient representatives, and the recommendations have undergone a thorough national review process from stakeholders. It is a guideline with future perspectives for an improved care.

Individualized Traditional Chinese Medicine treatment antibiotics for recurrent urinary tract infections: a multicenter, randomized controlled study.

OBJECTIVE: To systematically assess the effects of individualized Chinese medicines on recurrent urinary tract infections (rUTIs). METHODS: This study recruited 230 adult female patients in the remission phase of rUTIs from five hospitals in China. The patients were randomly allocated to two groups: an individualized Chinese medicine group (n = 114) and a control group (n = 116). Patients in the Chinese medicine group received individualized Chinese herbs, which were evaluated for syndrome differentiation. Patients in the control group received antibiotic treatment combined with a Chinese medicine placebo. The duration of treatment was three courses of four weeks each, with a three-month subsequent follow-up. UTI recurrence rate, Traditional Chinese Medicine (TCM) syndrome scores, 36-item Short Form Survey (SF-36) score, and urine secretory immunoglobulin A (SIgA) were measured and analyzed before and after treatment in each group. RESULTS: Patients from the Chinese medicine group exhibited significant decreases in both short- and long-term UTI recurrence rates compared with the control group (P < 0.05). The changes in TCM syndrome scores between the Chinese medicine and control groups were significant (P < 0.05). The changes in the average SF-36 quality-of-life scores in the Chinese medicine group were also significantly higher than those in the control group after treatment (P < 0.05). The Chinese medicine group also demonstrated a significant increase in urine SIgA expression. CONCLUSION: Taken together, compared to the often-used long-term antimicrobial prophylaxis during the remission stage of rUTIs, treating patients with an individualized Chinese medicine decoction by syndrome differentiation could effectively reduce the recurrence rate, improve the patients' TCM syndrome scores and quality of life, and enhance immunity, which in turn helps to prevent antibiotic resistance.

Personalized mechanical ventilation guided by ultrasound in patients with acute respiratory distress syndrome (PEGASUS): study protocol for an international randomized clinical trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a frequent cause of hypoxemic respiratory failure with a mortality rate of approximately 30%. Identifying ARDS subphenotypes based on "focal" or "non-focal" lung morphology has the potential to better target mechanical ventilation strategies of individual patients. However, classifying morphology through chest radiography or computed tomography is either inaccurate or impractical. Lung ultrasound (LUS) is a non-invasive bedside tool that can accurately distinguish "focal" from "non-focal" lung morphology. We hypothesize that LUS-guided personalized mechanical ventilation in ARDS patients leads to a reduction in 90-day mortality compared to conventional mechanical ventilation. METHODS: The Personalized Mechanical Ventilation Guided by UltraSound in Patients with Acute Respiratory Distress Syndrome (PEGASUS) study is an investigator-initiated, international, randomized clinical trial (RCT) that plans to enroll 538 invasively ventilated adult intensive care unit (ICU) patients with moderate to severe ARDS. Eligible patients will receive a LUS exam to classify lung morphology as "focal" or "non-focal". Thereafter, patients will be randomized within 12 h after ARDS diagnosis to receive standard care or personalized ventilation where the ventilation strategy is adjusted to the morphology subphenotype, i.e., higher positive end-expiratory pressure (PEEP) and recruitment maneuvers for "non-focal" ARDS and lower PEEP and prone positioning for "focal" ARDS. The primary endpoint is all-cause mortality at day 90. Secondary outcomes are mortality at day 28, ventilator-free days at day 28, ICU length of stay, ICU mortality, hospital length of stay, hospital mortality, and number of complications (ventilator-associated pneumonia, pneumothorax, and need for rescue therapy). After a pilot phase of 80 patients, the correct interpretation of LUS images and correct application of the intervention within the safe limits of mechanical ventilation will be evaluated. DISCUSSION: PEGASUS is the first RCT that compares LUS-guided personalized mechanical ventilation with conventional ventilation in invasively ventilated patients with moderate and severe ARDS. If this study demonstrates that personalized ventilation guided by LUS can improve the outcomes of ARDS patients, it has the potential to shift the existing one-size-fits-all ventilation strategy towards a more individualized approach. TRIAL REGISTRATION: The PEGASUS trial was registered before the inclusion of the first patient, https://clinicaltrials.gov/ (ID: NCT05492344).

It provides families with other avenues for treatment when there are no other options Surgeons' perspectives of being part of a precision medicine trial for poor prognosis paediatric cancer patients: A short report.

OBJECTIVE: Precision medicine is transforming cancer treatment, yet the perspectives of surgeons who often play a critical role in the delivery of precision medicine remain understudied. METHODS: We conducted semi-structured interviews with 13 surgeons involved in a precision medicine trial for children with poor prognosis cancer. We explored knowledge of genetics, confidence with somatic and germline results, ratings of benefit to stakeholders and willingness to undertake surgical procedures. RESULTS: Surgeons generally had positive attitudes towards precision medicine but expressed concerns about families' unrealistic expectations, mixed opinions on the benefits and the use of research-only biopsies. Most surgeons rated their genetics knowledge as 'good' (69%) and felt 'very confident' in identifying genetic specialists (66%), but 'not confident' (66.6%) in making treatment recommendations. Surgeons' willingness to undertake a procedure was influenced by potential patient benefit. CONCLUSIONS: Our findings support the need for more workforce and training support for surgeons to fully engage with precision medicine.

Personalized Timing for Allogeneic Stem-Cell Transplantation in Hematologic Neoplasms: A Target Trial Emulation Approach Using Multistate Modeling and Microsimulation.

PURPOSE: Decision about the optimal timing of a treatment procedure in patients with hematologic neoplasms is critical, especially for cellular therapies (most including allogeneic hematopoietic stem-cell transplantation [HSCT]). In the absence of evidence from randomized trials, real-world observational data become beneficial to study the effect of the treatment timing. In this study, a framework to estimate the expected outcome after an intervention in a time-to-event scenario is developed, with the aim of optimizing the timing in a personalized manner. METHODS: Retrospective real-world data are leveraged to emulate a target trial for treatment timing using multistate modeling and microsimulation. This case study focuses on myelodysplastic syndromes, serving as a prototype for rare cancers characterized by a heterogeneous clinical course and complex genomic background. A cohort of 7,118 patients treated according to conventional available treatments/evidence across Europe and United States is analyzed. The primary clinical objective is to determine the ideal timing for HSCT, the only curative option for these patients. RESULTS: This analysis enabled us to identify the most appropriate time frames for HSCT on the basis of each patient's unique profile, defined by a combination relevant patients' characteristics. CONCLUSION: The developed methodology offers a structured framework to address a relevant clinical issue in the field of hematology. It makes several valuable contributions: (1) novel insights into how to develop decision models to identify the most favorable HSCT timing, (2) evidence to inform clinical decisions in a real-world context, and (3) the incorporation of complex information into decision making. This framework can be applied to provide medical insights for clinical issues that cannot be adequately addressed through randomized clinical trials.

Improved outcome with individualised antifibrinolytic therapy: what is the evidence?

Viscoelastic haemostatic testing (VHT) has been used to determine hyperfibrinolysis and hypofibrinolysis. When modified by addition of tissue plasminogen activator (tPA), VHT has been suggested to assess responses to antifibrinolytic therapy and to estimate the concentration of tranexamic acid in patients undergoing cardiac surgery. Despite some evidence that tPA-modified VHT might allow individualisation of antifibrinolytic therapy, further studies are warranted to prove its clinical benefit for postsurgical bleeding, transfusion of blood products, and thromboembolic events.

The combination of breast cancer PDO and mini-PDX platform for drug screening and individualized treatment.

The majority of advanced breast cancers exhibit strong aggressiveness, heterogeneity, and drug resistance, and currently, the lack of effective treatment strategies is one of the main challenges that cancer research must face. Therefore, developing a feasible preclinical model to explore tailored treatments for refractory breast cancer is urgently needed. We established organoid biobanks from 17 patients with breast cancer and characterized them by immunohistochemistry (IHC) and next generation sequencing (NGS). In addition, we in the first combination of patient-derived organoids (PDOs) with mini-patient-derived xenografts (Mini-PDXs) for the rapid and precise screening of drug sensitivity. We confirmed that breast cancer organoids are a high-fidelity three-dimension (3D) model in vitro that recapitulates the original tumour's histological and genetic features. In addition, for a heavily pretreated patient with advanced drug-resistant breast cancer, we combined PDO and Mini-PDX models to identify potentially effective combinations of therapeutic agents for this patient who were alpelisib + fulvestrant. In the drug sensitivity experiment of organoids, we observed changes in the PI3K/AKT/mTOR signalling axis and oestrogen receptor (ER) protein expression levels, which further verified the reliability of the screening results. Our study demonstrates that the PDO combined with mini-PDX model offers a rapid and precise drug screening platform that holds promise for personalized medicine, improving patient outcomes and addressing the urgent need for effective therapies in advanced breast cancer.

Landscape of Nuclear Medicine in China and Its Progress on Theranostics.

Nuclear medicine in China started in 1956 and, with the rapid development of the economy and continuous breakthroughs in precision medicine, has made significant progress in recent years. Almost 13,000 staff members in nearly 1,200 hospitals serve more than 3.9 million patients each year. Over the past decade, the radiopharmaceutical industry has developed rapidly, with the initial formation of a complete industrial chain of production of various radiopharmaceuticals for both clinical use and basic research. Advanced equipment such as PET/CT scanners is being manufactured domestically and even installed abroad. Recently, research into screening and synthesizing new target probes and their translation into the clinic has gained more attention, with various new tracers with potential clinical value being thoroughly studied. Simultaneously, 68Ga- and 177Lu-labeled tumor-targeted probes and others have been implemented for theranostics in an increasing number of hospitals and would be helped by approval from the National Medical Products Administration. Over the next 10-20 y, with the launch of the Mid- and Long-Term Development Plan for Medical Isotopes (2021-2035) by the Chinese government, there is great potential for nuclear medicine in China. With the rise in independent innovation in manufacturing, the shortage of radiopharmaceuticals will be effectively curtailed. We anticipate that the scale of nuclear medicine will at least double by 2035, covering all high-grade hospitals and leading to the aim of "one county, one department" in China.

Development of Personalized Strategies for Precisely Battling Malignant Melanoma.

Melanoma is the most severe and fatal form of skin cancer, resulting from multiple gene mutations with high intra-tumor and inter-tumor molecular heterogeneity. Treatment options for patients whose disease has progressed beyond the ability for surgical resection rely on currently accepted standard therapies, notably immune checkpoint inhibitors and targeted therapies. Acquired resistance to these therapies and treatment-associated toxicity necessitate exploring novel strategies, especially those that can be personalized for specific patients and/or populations. Here, we review the current landscape and progress of standard therapies and explore what personalized oncology techniques may entail in the scope of melanoma. Our purpose is to provide an up-to-date summary of the tools at our disposal that work to circumvent the common barriers faced when battling melanoma.

Integrated Analysis of Genomic and Genome-Wide Association Studies Identified Candidate Genes for Nutrigenetic Studies in Flavonoids and Vascular Health: Path to Precision Nutrition for (Poly)phenols.

Flavonoids exert vasculoprotective effects in humans, but interindividual variability in their action has also been reported. This study aims to identify genes that are associated with vascular health effects of flavonoids and whose polymorphisms could explain interindividual variability in response to their intake. Applying the predetermined literature search criteria, we identified five human intervention studies reporting positive effects of flavonoids on vascular function together with global genomic changes analyzed using microarray methods. Genes involved in vascular dysfunction were identified from genome-wide association studies (GWAS). By extracting data from the eligible human intervention studies, we obtained 5807 differentially expressed genes (DEGs). The number of identified upstream regulators (URs) varied across the studies, from 227 to 1407. The search of the GWAS Catalog revealed 493 genes associated with vascular dysfunction. An integrative analysis of transcriptomic data with GWAS genes identified 106 candidate DEGs and 42 candidate URs, while subsequent functional analyses and a search of the literature identified 20 top priority candidate genes: ALDH2, APOE, CAPZA1, CYP11B2, GNA13, IL6, IRF5, LDLR, LPL, LSP1, MKNK1, MMP3, MTHFR, MYO6, NCR3, PPARG, SARM1, TCF20, TCF7L2, and TNF. In conclusion, this integrated analysis identifies important genes to design future nutrigenetic studies for development of precision nutrition for polyphenols.

Optimizing Behçet Uveitis Management: A Review of Personalized Immunosuppressive Strategies.

Behçet uveitis poses significant management challenges, owing to its intricate pathogenesis and the severe prognosis it harbors, frequently culminating in irreversible visual impairment and an elevated risk of blindness. This review synthesizes contemporary insights into personalized immunosuppressive strategies for Behçet uveitis, emphasizing the necessity for a customized approach in recognition of the disease's heterogeneity and the variable responsiveness to treatment. This discourse elaborates on the application, efficacy, and safety profiles of traditional immunosuppressants, highlighting a paradigm shift toward integrative combination therapies aimed at diminishing reliance on glucocorticoids and mitigating their associated adverse effects. This thorough evaluation seeks to enlighten clinical practices and spearhead future investigations aimed at refining the management of Behçet uveitis, championing a personalized, multidisciplinary strategy to amplify therapeutic efficacy and enhance patient quality of life.

DLL3-guided therapies in small-cell lung cancer: from antibody-drug conjugate to precision immunotherapy and radioimmunotherapy.

DLL3 acts as an inhibitory ligand that downregulates Notch signaling and is upregulated by ASCL1, a transcription factor prevalent in the small-cell lung cancer (SCLC) subtype SCLC-A. Currently, the therapeutic strategies targeting DLL3 are varied, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies. Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development. Conversely, DLL3-targeted BiTEs have garnered significant clinical interest. Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review. Numerous ongoing phase III studies aim to further evaluate tarlatamab's clinical efficacy, alongside the development of novel DLL3-targeted T-cell engagers, both bispecific and trispecific. CAR-T cell therapies targeting DLL3 have recently emerged and are undergoing various preclinical and early-phase clinical studies. Additionally, preclinical studies have shown promising efficacy for DLL3-targeted radiotherapy, which employs ß-particle-emitting therapeutic radioisotopes conjugated to DLL3-targeting antibodies. DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes.

High-throughput molecular assays for inclusion in personalised oncology trials - State-of-the-art and beyond.

In the last decades, the development of high-throughput molecular assays has revolutionised cancer diagnostics, paving the way for the concept of personalised cancer medicine. This progress has been driven by the introduction of such technologies through biomarker-driven oncology trials. In this review, strengths and limitations of various state-of-the-art sequencing technologies, including gene panel sequencing (DNA and RNA), whole-exome/whole-genome sequencing and whole-transcriptome sequencing, are explored, focusing on their ability to identify clinically relevant biomarkers with diagnostic, prognostic and/or predictive impact. This includes the need to assess complex biomarkers, for example microsatellite instability, tumour mutation burden and homologous recombination deficiency, to identify patients suitable for specific therapies, including immunotherapy. Furthermore, the crucial role of biomarker analysis and multidisciplinary molecular tumour boards in selecting patients for trial inclusion is discussed in relation to various trial concepts, including drug repurposing. Recognising that today's exploratory techniques will evolve into tomorrow's routine diagnostics and clinical study inclusion assays, the importance of emerging technologies for multimodal diagnostics, such as proteomics and in vivo drug sensitivity testing, is also discussed. In addition, key regulatory aspects and the importance of patient engagement in all phases of a clinical trial are described. Finally, we propose a set of recommendations for consideration when planning a new precision cancer medicine trial.

Advances in personalized radiotherapy.

Radiotherapy is a mainstay of cancer treatment. The clinical response to radiotherapy is heterogeneous, from a complete response to early progression. Recent studies have explored the importance of patient characteristics in response to radiotherapy. In this editorial, we invite contributions for a BMC Cancer collection of articles titled 'Advances in personalized radiotherapy' towards the improvement of treatment response.

Tribulations and future opportunities for artificial intelligence in precision medicine.

Upon a diagnosis, the clinical team faces two main questions: what treatment, and at what dose? Clinical trials' results provide the basis for guidance and support for official protocols that clinicians use to base their decisions. However, individuals do not consistently demonstrate the reported response from relevant clinical trials. The decision complexity increases with combination treatments where drugs administered together can interact with each other, which is often the case. Additionally, the individual's response to the treatment varies with the changes in their condition. In practice, the drug and the dose selection depend significantly on the medical protocol and the medical team's experience. As such, the results are inherently varied and often suboptimal. Big data and Artificial Intelligence (AI) approaches have emerged as excellent decision-making tools, but multiple challenges limit their application. AI is a rapidly evolving and dynamic field with the potential to revolutionize various aspects of human life. AI has become increasingly crucial in drug discovery and development. AI enhances decision-making across different disciplines, such as medicinal chemistry, molecular and cell biology, pharmacology, pathology, and clinical practice. In addition to these, AI contributes to patient population selection and stratification. The need for AI in healthcare is evident as it aids in enhancing data accuracy and ensuring the quality care necessary for effective patient treatment. AI is pivotal in improving success rates in clinical practice. The increasing significance of AI in drug discovery, development, and clinical trials is underscored by many scientific publications. Despite the numerous advantages of AI, such as enhancing and advancing Precision Medicine (PM) and remote patient monitoring, unlocking its full potential in healthcare requires addressing fundamental concerns. These concerns include data quality, the lack of well-annotated large datasets, data privacy and safety issues, biases in AI algorithms, legal and ethical challenges, and obstacles related to cost and implementation. Nevertheless, integrating AI in clinical medicine will improve diagnostic accuracy and treatment outcomes, contribute to more efficient healthcare delivery, reduce costs, and facilitate better patient experiences, making healthcare more sustainable. This article reviews AI applications in drug development and clinical practice, making healthcare more sustainable, and highlights concerns and limitations in applying AI.

Precise execution of personalized surgical planning using three-dimensional printed guide template in severe and complex adult spinal deformity patients requiring three-column osteotomy: a retrospective, comparative matched-cohort study.

BACKGROUND: The surgical treatment of severe and complex adult spinal deformity (ASD) commonly required three-column osteotomy (3-CO), which was technically demanding with high risk of neurological deficit. Personalized three dimensional (3D)-printed guide template based on preoperative planning has been gradually applied in 3-CO procedure. The purpose of this study was to compare the efficacy, safety, and precision of 3D-printed osteotomy guide template and free-hand technique in the treatment of severe and complex ASD patients requiring 3-CO. METHODS: This was a single-centre retrospective comparative cohort study of patients with severe and complex ASD (Cobb angle of scoliosis > 80° with flexibility < 25% or focal kyphosis > 90°) who underwent posterior spinal fusion and 3-CO between January 2020 to January 2023, with a minimum 12 months follow-up. Personalized computer-assisted three-dimensional osteotomy simulation was performed for all recruited patients, who were further divided into template and non-template groups based on the application of 3D-printed osteotomy guide template according to the surgical planning. Patients in the two groups were age- and gender- propensity-matched. The radiographic parameters, postoperative neurological deficit, and precision of osteotomy execution were compared between groups. RESULTS: A total of 40 patients (age 36.53 ± 11.98 years) were retrospectively recruited, with 20 patients in each group. The preoperative focal kyphosis (FK) was 92.72° ± 36.77° in the template group and 93.47° ± 33.91° in the non-template group, with a main curve Cobb angle of 63.35° (15.00°, 92.25°) and 64.00° (20.25°, 99.20°), respectively. Following the correction surgery, there were no significant differences in postoperative FK, postoperative main curve Cobb angle, correction rate of FK (54.20% vs. 51.94%, P = 0.738), and correction rate of main curve Cobb angle (72.41% vs. 61.33%, P = 0.101) between the groups. However, the match ratio of execution to simulation osteotomy angle was significantly greater in the template group than the non-template group (coronal: 89.90% vs. 74.50%, P < 0.001; sagittal: 90.45% vs. 80.35%, P < 0.001). The operating time (ORT) was significantly shorter (359.25 ± 57.79 min vs. 398.90 ± 59.48 min, P = 0.039) and the incidence of postoperative neurological deficit (5.0% vs. 35.0%, P = 0.018) was significantly lower in the template group than the non-template group. CONCLUSION: Performing 3-CO with the assistance of personalized 3D-printed guide template could increase the precision of execution, decrease the risk of postoperative neurological deficit, and shorten the ORT in the correction surgery for severe and complex ASD. The personalized osteotomy guide had the advantages of 3D insight of the case-specific anatomy, identification of osteotomy location, and translation of the surgical planning or simulation to the real surgical site.

Are FGFR Fusions and Mutations the Next Tumor-Agnostic Targets in Oncology?

Gong et al present two NCI-MATCH tumor-agnostic trials evaluating erdafitinib for FGFR-altered cancers, marking steppingstones in precision oncology.