Sirolimus monotherapy for Kasabach-Merritt phenomenon in a neonate; Case report.

INTRODUCTION AND IMPORTANCE: The Kasabach-Merritt Phenomenon (KMP), characterized by thrombocytopenia and consumptive coagulopathy due to endothelial cell growth in the infantile vascular tumor kaposiform hemangioendothelioma, presents a therapeutic challenge. This case highlights the novel use of sirolimus in a neonate, an approach less explored in this age group. CASE PRESENTATION: A female neonate presented with a right anterior chest mass, progressing to respiratory distress and congestive heart failure. Diagnosed with KMP, she exhibited low platelet count and coagulation abnormalities. Treatment with sirolimus (0.06 mg/day) led to mass reduction, improved bleeding, and a stable tumor after 12 months, without side effects. This case contrasts with existing literature advocating for combination therapy or higher sirolimus concentrations for effective treatment. Yet, our patient achieved favorable outcomes with low-dose monotherapy, suggesting a potentially safer approach in neonates with immature hepatic and renal metabolism. CLINICAL DISCUSSION: This case demonstrates the efficacy of low-dose sirolimus monotherapy in treating KMP in a neonate, challenging current preferences for combination therapies or higher doses. It emphasizes the need for further research into age-specific treatment protocols in KMP, considering the unique metabolic profiles of neonates and infants. CONCLUSION: Sirolimus has demonstrated potential in treating KMP in pediatric patients. While initial results are promising, determining optimal dosages and trough concentrations, especially in neonates and infants, remains essential.

Imaging Biomarkers of Osteoarthritis.

Currently no disease-modifying osteoarthritis drug has been approved for the treatment of osteoarthritis (OA) that can reverse, hold, or slow the progression of structural damage of OA-affected joints. The reasons for failure are manifold and include the heterogeneity of structural disease of the OA joint at trial inclusion, and the sensitivity of biomarkers used to measure a potential treatment effect.This article discusses the role and potential of different imaging biomarkers in OA research. We review the current role of radiography, as well as advances in quantitative three-dimensional morphological cartilage assessment and semiquantitative whole-organ assessment of OA. Although magnetic resonance imaging has evolved as the leading imaging method in OA research, recent developments in computed tomography are also discussed briefly. Finally, we address the experience from the Foundation for the National Institutes of Health Biomarker Consortium biomarker qualification study and the future role of artificial intelligence.

A perspective on the evolution of semi-quantitative MRI assessment of osteoarthritis: Past, present and future.

OBJECTIVE: This perspective describes the evolution of semi-quantitative (SQ) magnetic resonance imaging (MRI) in characterizing structural tissue pathologies in osteoarthritis (OA) imaging research over the last 30 years. METHODS: Authors selected representative articles from a PubMed search to illustrate key steps in SQ MRI development, validation, and application. Topics include main scoring systems, reading techniques, responsiveness, reliability, technical considerations, and potential impact of artificial intelligence (AI). RESULTS: Based on original research published between 1993 and 2023, this article introduces available scoring systems, including but not limited to Whole-Organ Magnetic Resonance Imaging Score (WORMS) as the first system for whole-organ assessment of the knee and the now commonly used MRI Osteoarthritis Knee Score (MOAKS) instrument. Specific systems for distinct OA subtypes or applications have been developed as well as MRI scoring instruments for other joints such as the hip, the fingers or thumb base. SQ assessment has proven to be valid, reliable, and responsive, aiding OA investigators in understanding the natural history of the disease and helping to detect response to treatment. AI may aid phenotypic characterization in the future. SQ MRI assessment's role is increasing in eligibility and safety evaluation in knee OA clinical trials. CONCLUSIONS: Evidence supports the validity, reliability, and responsiveness of SQ MRI assessment in understanding structural aspects of disease onset and progression. SQ scoring has helped explain associations between structural tissue damage and clinical manifestations, as well as disease progression. While AI may support human readers to more efficiently perform SQ assessment in the future, its current application in clinical trials still requires validation and regulatory approval.

How AI May Transform Musculoskeletal Imaging.

While musculoskeletal imaging volumes are increasing, there is a relative shortage of subspecialized musculoskeletal radiologists to interpret the studies. Will artificial intelligence (AI) be the solution? For AI to be the solution, the wide implementation of AI-supported data acquisition methods in clinical practice requires establishing trusted and reliable results. This implementation will demand close collaboration between core AI researchers and clinical radiologists. Upon successful clinical implementation, a wide variety of AI-based tools can improve the musculoskeletal radiologist's workflow by triaging imaging examinations, helping with image interpretation, and decreasing the reporting time. Additional AI applications may also be helpful for business, education, and research purposes if successfully integrated into the daily practice of musculoskeletal radiology. The question is not whether AI will replace radiologists, but rather how musculoskeletal radiologists can take advantage of AI to enhance their expert capabilities.

Drug-induced Interstitial Nephritis in a Patient with Ulcerative Colitis Treated with 5-Aminosalicylic Acid.

This report describes the case of a 76-year-old man with ulcerative colitis who developed interstitial nephritis after starting 5-Aminosalicylic acid (5-ASA) therapy. The patient experienced an initial improvement in symptoms, but developed fatigue, anorexia, and severe renal dysfunction 2.5 months later. Renal biopsy confirmed drug-induced interstitial nephritis, and conservative treatment with fluid replacement and the discontinuation of 5-ASA improved the patient's condition. Clinicians should monitor patients receiving 5-ASA therapy for potential adverse effects, particularly renal injury, and promptly investigate symptoms of renal dysfunction. Early recognition and discontinuation of the offending agent may prevent further damage and improve patient outcomes.

A Natural Organic Compound "Decursin" Has Both Antitumor and Renal Protective Effects: Treatment for Osteosarcoma.

Osteosarcoma is a rare malignant tumor that commonly occurs in children. Anticancer drugs, for example, cisplatin, aid in postsurgery recovery but induce side effects such as renal damage, affecting the life prognosis of patients. Decursin which is one of the bioactive components has been reported for its anti-inflammatory, antioxidant, and antitumor effects, but the effect on osteosarcoma is unexplained. In this study, the research theme was to examine the sensitizing effect of decursin and its influence on cisplatin-induced nephrotoxicity. The cell viability and half maximal inhibitory concentration (IC50), apoptosis induction, and effect on cell cycle and Akt pathways were examined. In vivo, we examine the effects of decursin on tumors and mice bodies. Additionally, the effects of the cisplatin-decursin combination were evaluated in vitro and in vivo. Decursin suppressed cell viability and induced apoptosis via the cell cycle. Decursin also inhibited the Akt pathway by suppressing the phosphorylation of Akt. It enhanced apoptosis induction and lowered cell viability in combination with cisplatin. The increasing tumor volume was suppressed in the decursin-administrated group with further suppression in combination with cisplatin compared to sole cisplatin administration. The decrease in renal function and renal epithelial cell damage caused by cisplatin was improved by the combinatorial treatment with decursin. Therefore, decursin demonstrated an antitumor effect on the osteosarcoma cells and a renal protective effect in combination with cisplatin. Therefore, decursin is a prospective therapeutic agent against osteosarcoma.

Impact of Initial Body Weight Loss on Prognosis in Advanced Pancreatic Cancer: Insights From a Single-Center Retrospective Study.

BACKGROUND: Pancreatic cancer (PC) has a poor prognosis, with body weight loss commonly observed at diagnosis. However, the impact on PC prognosis of weight loss at the time of diagnosis on PC prognosis is unknown. METHODS: This retrospective, single-center study enrolled consecutively patients diagnosed with metastatic or locally advanced PC or resectable PC who were intolerant of or refused surgery. Patients who had lost more than 5% of their body weight or more than 2% and had a body mass index (BMI) of less than 20 kg/m2 at diagnosis were classified as experiencing body weight loss. Patients were subclassified into 2 groups: patients with and without weight loss. The study evaluated patient-related and PC-related factors affecting prognosis. Cox proportional hazards models were used to assess factors affecting prognosis. The primary endpoint was overall survival. Additionally, 1:1 propensity score matching was performed to reduce bias. RESULTS: In total, 220 patients were included in the study. The median age of the patients was 74 years, and 49.1% were male. Weight loss at diagnosis was observed in 43.2% of patients. There were no significant differences in clinical factors, except for anthropometric parameters, between the groups. The median survival time did not differ between the weight loss and no weight loss groups (149 and 173 days, respectively, P = .669). After matching, no significant differences in survival times were observed between the 2 groups. CONCLUSIONS: This study found no association between weight loss at diagnosis and prognosis in patients with advanced PC treated with best supportive care or chemotherapy.

Emerging Quantitative Imaging Techniques in Sports Medicine.

This article describes recent advances in quantitative imaging of musculoskeletal extremity sports injuries, citing the existing literature evidence and what additional evidence is needed to make such techniques applicable to clinical practice. Compositional and functional MRI techniques including T2 mapping, diffusion tensor imaging, and sodium imaging as well as contrast-enhanced US have been applied to quantify pathophysiologic processes and biochemical compositions of muscles, tendons, ligaments, and cartilage. Dual-energy and/or spectral CT has shown potential, particularly for the evaluation of osseous and ligamentous injury (eg, creation of quantitative bone marrow edema maps), which is not possible with standard single-energy CT. Recent advances in US technology such as shear-wave elastography or US tissue characterization as well as MR elastography enable the quantification of mechanical, elastic, and physical properties of tissues in muscle and tendon injuries. The future role of novel imaging techniques such as photon-counting CT remains to be established. Eventual prediction of return to play (ie, the time needed for the injury to heal sufficiently so that the athlete can get back to playing their sport) and estimation of risk of repeat injury is desirable to help guide sports physicians in the treatment of their patients. Additional values of quantitative analyses, as opposed to routine qualitative analyses, still must be established using prospective longitudinal studies with larger sample sizes.

Detection of transient abnormal myelopoiesis blasts in a liver biopsy specimen by double-immunostaining for full-length GATA1 and CD42b.

BACKGROUND: Transient abnormal myelopoiesis (TAM) is characterized by leukocytosis with increased circulating megakaryoblasts that harbor N-terminal truncating mutations in the GATA1 gene. Approximately 10% of affected patients experience early death. OBSERVATIONS: A 2-month-old boy with Down syndrome was diagnosed with TAM and followed without treatment. Although the blasts in the peripheral blood disappeared, liver failure progressed. A pathological examination revealed liver fibrosis, and double-immunostaining for full-length GATA1 and CD42b identified megakaryocytes with a GATA1 mutation. CONCLUSIONS: This simple and cost-effective method can be applied in routine practice to detect TAM blasts during assessment in a TAM crisis.

Role of imaging for eligibility and safety of a-NGF clinical trials.

Nerve growth factor (a-NGF) inhibitors have been developed for pain treatment including symptomatic osteoarthritis (OA) and have proven analgesic efficacy and improvement in functional outcomes in patients with OA. However, despite initial promising data, a-NGF clinical trials focusing on OA treatment had been suspended in 2010. Reasons were based on concerns regarding accelerated OA progression but were resumed in 2015 including detailed safety mitigation based on imaging. In 2021, an FDA advisory committee voted against approving tanezumab (one of the a-NGF compounds being evaluated) and declared that the risk evaluation and mitigation strategy was not sufficient to mitigate potential safety risks. Future clinical trials evaluating the efficacy of a-NGF or comparable molecules will need to define strict eligibility criteria and will have to include strategies to monitor safety closely. While disease-modifying effects are not the focus of a-NGF treatments, imaging plays an important role to evaluate eligibility of potential participants and to monitor safety during the course of these studies. Aim is to identify subjects with on-going safety findings at the time of inclusion, define those potential participants that are at increased risk for accelerated OA progression and to withdraw subjects from on-going studies in a timely fashion that exhibit imaging-confirmed structural safety events such as rapid progressive OA. OA efficacy- and a-NGF studies apply imaging for different purposes. In OA efficacy trials image acquisition and evaluation aims at maximizing sensitivity in order to capture structural effects between treated and non-treated participants in longitudinal fashion. In contrast, the aim of imaging in a-NGF trials is to enable detection of structural tissue alterations that either increase the risk of a negative outcome (eligibility) or may result in termination of treatment (safety).

A call for screening MRI as a tool for osteoarthritis clinical trials.

Conventional radiography is the most commonly used imaging modality for the evaluation of osteoarthritis (OA) in clinical trials of disease-modifying OA drugs (DMOADs). Unfortunately, radiography has many shortcomings as an imaging technique to meaningfully assess the pathological features of OA. In this perspective paper, we will describe the reasons why radiography is not an ideal tool for structural OA assessment and why magnetic resonance imaging (MRI) should be preferred for such purposes. These shortcomings include a lack of reproducibility of radiographic joint space measurements (if conducted without using a standardized positioning frame), a lack of sensitivity and specificity, an insufficient definition of disease severity, a weak association of radiographic structural damage and pain, a lack of ability to depict many faces of OA, and incapability to depict diagnoses of exclusion. MRI offers solutions to these limitations of radiography. Several different phenotypes of OA have been recognized and it is important to recruit appropriate patients for specific therapeutic approaches in DMOAD trials. Radiography does not allow such phenotypical stratification. We will explain known hurdles for widespread deployment of MRI at eligibility screening and how they can be overcome by technological advances and the use of simplified image assessment.

Strategic application of imaging in DMOAD clinical trials: focus on eligibility, drug delivery, and semiquantitative assessment of structural progression.

Despite decades of research efforts and multiple clinical trials aimed at discovering efficacious disease-modifying osteoarthritis (OA) drugs (DMOAD), we still do not have a drug that shows convincing scientific evidence to be approved as an effective DMOAD. It has been suggested these DMOAD clinical trials were in part unsuccessful since eligibility criteria and imaging-based outcome evaluation were solely based on conventional radiography. The OA research community has been aware of the limitations of conventional radiography being used as a primary imaging modality for eligibility and efficacy assessment in DMOAD trials. An imaging modality for DMOAD trials should be able to depict soft tissue and osseous pathologies that are relevant to OA disease progression and clinical manifestations of OA. Magnetic resonance imaging (MRI) fulfills these criteria and advances in technology and increasing knowledge regarding imaging outcomes likely should play a more prominent role in DMOAD clinical trials. In this perspective article, we will describe MRI-based tools and analytic methods that can be applied to DMOAD clinical trials with a particular emphasis on knee OA. MRI should be the modality of choice for eligibility screening and outcome assessment. Optimal MRI pulse sequences must be chosen to visualize specific features of OA.

Overuse-Related Injuries of the Knee.

Overuse-related injuries of the knee joint and periarticular soft tissues include a heterogenous group of sports and nonsports-related injuries. These conditions include friction and impingement syndromes, bone stress injuries, bursitis, and tendon-related pathology such as tendinopathy and snapping. Traction apophysitis are also discussed as commonly seen in the pediatric population. Although multiple imaging modalities can be used, this review focuses on MR imaging, which is the most common and, often, the only modality used.

Update on recent developments in imaging of inflammation in osteoarthritis: a narrative review.

Synovitis is an important component of the osteoarthritis (OA) disease process, particularly regarding the "inflammatory phenotype" of OA. Imaging plays an important role in the assessment of synovitis in OA with MRI and ultrasound being the most deployed imaging modalities. Contrast-enhanced (CE) MRI, particularly dynamic CEMRI (DCEMRI) is the ideal method for synovitis assessment, but for several reasons CEMRI is not commonly performed for OA imaging in general. Effusion-synovitis and Hoffa-synovitis are commonly used as surrogate markers of synovitis on non-contrast-enhanced (NCE) MRI and have been used in many epidemiological observational studies of knee OA. Several semiquantitative MRI scoring systems are available for the evaluation of synovitis in knee OA. Synovitis can be a target tissue for disease-modifying OA drug (DMOAD) clinical trials. Both MRI and ultrasound may be used to determine the eligibility and assess the therapeutic efficacy of DMOAD approaches. Ultrasound is mostly used for evaluation of synovitis in hand OA, while MRI is typically used for larger joints, namely knees and hips. The role of other modalities such as CT (including dual-energy CT) and nuclear medicine imaging (such as positron-emission tomography (PET) and its hybrid imaging) is limited in the context of synovitis assessment in OA. Despite research efforts to develop NCEMRI-based synovitis evaluation methods, these typically underestimate the severity of synovitis compared to CEMRI, and thus more research is needed before we can rely only on NCEMRI.

Structural phenotypes of knee osteoarthritis: potential clinical and research relevance.

A joint contains many different tissues that can exhibit pathological changes, providing many potential targets for treatment. Researchers are increasingly suggesting that osteoarthritis (OA) comprises several phenotypes or subpopulations. Consequently, a treatment for OA that targets only one pathophysiologic abnormality is unlikely to be similarly efficacious in preventing or delaying the progression of all the different phenotypes of structural OA. Five structural phenotypes have been proposed, namely the inflammatory, meniscus-cartilage, subchondral bone, and atrophic and hypertrophic phenotypes. The inflammatory phenotype is characterized by marked synovitis and/or joint effusion, while the meniscus-cartilage phenotype exhibits severe meniscal and cartilage damage. Large bone marrow lesions characterize the subchondral bone phenotype. The hypertrophic and atrophic OA phenotype are defined based on the presence large osteophytes or absence of any osteophytes, respectively, in the presence of concomitant cartilage damage. Limitations of the concept of structural phenotyping are that they are not mutually exclusive and that more than one phenotype may be present. It must be acknowledged that a wide range of views exist on how best to operationalize the concept of structural OA phenotypes and that the concept of structural phenotypic characterization is still in its infancy. Structural phenotypic stratification, however, may result in more targeted trial populations with successful outcomes and practitioners need to be aware of the heterogeneity of the disease to personalize their treatment recommendations for an individual patient. Radiologists should be able to define a joint at risk for progression based on the predominant phenotype present at different disease stages.

Assessment of an artificial intelligence aid for the detection of appendicular skeletal fractures in children and young adults by senior and junior radiologists.

BACKGROUND: As the number of conventional radiographic examinations in pediatric emergency departments increases, so, too, does the number of reading errors by radiologists. OBJECTIVE: The aim of this study is to investigate the ability of artificial intelligence (AI) to improve the detection of fractures by radiologists in children and young adults. MATERIALS AND METHODS: A cohort of 300 anonymized radiographs performed for the detection of appendicular fractures in patients ages 2 to 21 years was collected retrospectively. The ground truth for each examination was established after an independent review by two radiologists with expertise in musculoskeletal imaging. Discrepancies were resolved by consensus with a third radiologist. Half of the 300 examinations showed at least 1 fracture. Radiographs were read by three senior pediatric radiologists and five radiology residents in the usual manner and then read again immediately after with the help of AI. RESULTS: The mean sensitivity for all groups was 73.3% (110/150) without AI; it increased significantly by almost 10% (P<0.001) to 82.8% (125/150) with AI. For junior radiologists, it increased by 10.3% (P<0.001) and for senior radiologists by 8.2% (P=0.08). On average, there was no significant change in specificity (from 89.6% to 90.3% [+0.7%, P=0.28]); for junior radiologists, specificity increased from 86.2% to 87.6% (+1.4%, P=0.42) and for senior radiologists, it decreased from 95.1% to 94.9% (-0.2%, P=0.23). The stand-alone sensitivity and specificity of the AI were, respectively, 91% and 90%. CONCLUSION: With the help of AI, sensitivity increased by an average of 10% without significantly decreasing specificity in fracture detection in a predominantly pediatric population.