Profiling lecanemab as a treatment option for Alzheimer's disease.

INTRODUCTION: In July 2023, the U.S. Food and Drug Administration (FDA) granted full approval to lecanemab for the treatment of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and mild AD dementia. Considering the limited treatment options for AD, the approval of lecanemab offers hope and opens the door for other disease-modifying therapies in the pipeline. AREAS COVERED: In this review, the authors summarize the FDA treatment guidelines, other anti-amyloid agents, and drug information relevant to prescribers, such as pharmacology and pharmacokinetics. Relevant clinical trial outcomes are discussed along with their significance and controversies. EXPERT OPINION: While questions remain about the magnitude of lecanemab's clinical impact, its approval signifies major progress in addressing the underlying pathology of AD. The authors have confidence in lecanemab as a promising treatment option and foresee exciting advancements on the 5-year horizon. Yet, further research is needed regarding trials beyond 18 months, post-marketing surveillance, and lecanameb in combination with existing treatments and lifestyle interventions.

Conjunctival melanoma: Insights into classification, outcomes, and biomarkers.

Conjunctival melanoma is quite rare, estimated at approximately 0.5 incidence per 1 million persons per year. This malignancy arises from a pre-existing nevus (7%), primary acquired melanosis (74%), or de novo without pre-existing condition (19%) and develops most often in patients with Fitzpatrick skin types I (23%) and II (62%). At initial presentation, the tumor size is approximately 13 mm in cross-sectional diameter and has 3-mm thickness, involving the bulbar (97%), forniceal (30%), tarsal (28%), or caruncular (11%) regions, often with corneal (54%) and rarely with orbital (4%) involvement. According to the eighth edition of the American Joint Committee on Cancer (AJCC), the tumor is classified as T1 (63%), T2 (18%), T3 (20%), and T4 (0%). Outcomes depend on several factors including patient age, AJCC classification, orbital invasion, and type of initial surgery, whereas tumor origin and Fitzpatrick skin type do not appear to impact outcomes. Older patients (≥70 years of age) demonstrate larger tumors, greater recurrence, and greater vision loss. Analysis of 425 patients by AJCC classification (T1 versus T2 versus T3) revealed increasing T category with greater lymph node metastasis (3% versus 13% versus 25%; P < .001), tumor-related systemic metastasis (13% versus 45% versus 40%; P < .001), and tumor-related death (8% versus 22% versus 37%; P < .001). Data of patients with orbital invasion revealed significantly greater 10-year rates of exenteration (P < .001), distant metastasis (P = .0005), and death (P = .001). Studies have demonstrated biomarkers related to conjunctival melanoma include mutations in BRAF, NRAS, ATRX, and NF1. Future therapies might be directed against these mutations or with small-molecule inhibitors and/or immunotherapy. In summary, conjunctival melanoma is a rare but ominous malignancy, imparting moderate risk for lymph node and systemic metastasis as well as death, depending on tumor features and classification. The first surgery is highly important in prevention of tumor seeding, recurrence, and metastasis.

Obstetric-Focused POCUS Training for Medical Students.

Point of care ultrasound (POCUS) is rapidly expanding throughout the United States. Due to its ability to quickly and accurately diagnose and guide therapy for critical conditions, POCUS is becoming routine in many specialties, with established guidelines in fields such as emergency medicine and critical care 1, 2, 3. For example, a study entitled "Ultrasound Integration in Undergraduate Medical Education: Comparison of Ultrasound Proficiency Between Trained and Untrained Medical Students" initiated an Emergency Medicine POCUS curriculum for first-year medical students that showed an increase in ultrasound capability 4. In short, as POCUS becomes more common practice, medical schools are beginning to implement POCUS training into their undergraduate medical education; studies from these institutions demonstrate that implementing a formal ultrasound curriculum into preclinical medical education significantly increases medical students' POCUS capabilities4, 5 and assisted in their understanding and learning of anatomy 6, 7.

Temporal trends in mortality location in patients with anal cancer in the USA: an analysis of the National Center for Health Statistics mortality data.

OBJECTIVES: Investigate trends in where patients died of anal cancer in the USA. METHODS: Retrospective cohort study using the US National Center for Health Statistics Wide-Ranging ONline Data for Epidemiologic Research platform from 2003 to 2020; all patients with death certificates listing anal cancer as the underlying cause of death in the USA. Main outcome measure of location of patient death: inpatient facility, home, hospice, nursing home/long-term care facility and other. RESULTS: There were a total of 16 296 deaths with anal cancer as the underlying diagnosis during the study period. The crude rate increased from 0.191 per 100 000 deaths in 2003 to 0.453 per 100 000 deaths in 2020. Over the study period, 22.4% of patient deaths occurred in inpatient facilities, 44.9% at home, 12.2% at hospice facilities and 13.1% at nursing homes/long-term care facilities. The percentage of deaths occurring in hospice facilities increased from 1.0% to 13.3% during the study period. Deaths at home also increased from 42.7% in 2003 to 55.8% in 2020. Meanwhile, inpatient deaths decreased from 33.5% in 2003 to 14.4% in 2020. CONCLUSIONS: There has been a significant increase in the proportion of patients with anal cancer dying at home or hospice from 2003 to 2020.

In-utero Diagnosis of Prostatic Embryonal Rhabdomyosarcoma.

Though rhabdomyosarcoma is the most common soft-tissue tumor diagnosed in children there are no reported cases of prenatally detected prostatic embryonal rhabdomyosarcoma. This report demonstrates the first reported case of this phenomenon and its subsequent workup, diagnosis, and treatment.

Performance of AAP Clinical Practice Guideline for Febrile Infants at One Pediatric Hospital.

BACKGROUND: In the absence of procalcitonin, the American Academy of Pediatrics' clinical practice guideline (CPG) for evaluating and managing febrile infants recommends using previously untested combinations of inflammatory marker thresholds. Thus, CPG performance in detecting invasive bacterial infections (IBIs; bacteremia, bacterial meningitis) is poorly understood. OBJECTIVE: To evaluate CPG performance without procalcitonin in detecting IBIs in well-appearing febrile infants 8 to 60 days old. METHODS: For this cross-sectional, single-site study, we manually abstracted data for febrile infants using electronic health records from 2011 to 2018. We used CPG inclusion/exclusion criteria to identify eligible infants and stratified IBI risk with CPG inflammatory marker thresholds for temperature, absolute neutrophil count, and C-reactive protein. Because the CPG permits a wide array of interpretations, we performed 3 sensitivity analyses, modifying age and inflammatory marker thresholds. For each approach, we calculated area-under-the-receiver operating characteristic curve, sensitivity, and specificity in detecting IBIs. RESULTS: For this study, 507 infants met the inclusion criteria. For the main analysis, we observed an area-under-the-receiver operating characteristic curve of 0.673 (95% confidence interval 0.652-0.694), sensitivity of 100% (66.4%-100%), and specificity of 34.5% (30.4%-38.9%). For the sensitivity analyses, sensitivities were all 100% and specificities ranged from 9% to 38%. CONCLUSION: Findings suggest that the CPG is highly sensitive, minimizing missed IBIs, but specificity may be lower than previously reported. Future studies should prospectively investigate CPG performance in larger, multisite samples.

Extracellular Vesicle-microRNAs as Diagnostic Biomarkers in Preterm Neonates.

Neonates born prematurely (<37 weeks of gestation) are at a significantly increased risk of developing inflammatory conditions associated with high mortality rates, including necrotizing enterocolitis, bronchopulmonary dysplasia, and hypoxic-ischemic brain damage. Recently, research has focused on characterizing the content of extracellular vesicles (EVs), particularly microRNAs (miRNAs), for diagnostic use. Here, we describe the most recent work on EVs-miRNAs biomarkers discovery for conditions that commonly affect premature neonates.

Retinal cavernous hemangioma in a newborn: an unusual presentation of a rare tumor.

Retinal cavernous hemangioma (RCavH) is an uncommon, benign, vascular tumor of venous aneurysms. It can be sporadic or inherited in an autosomal-dominant pattern as part of an oculoneurocutaneous syndrome. Some affected patients are asymptomatic, and others have symptoms related to retinal dragging and vitreous hemorrhage. In the case presented here, the tumor was located in the anterior retina overhanging the ciliary body with lens involvement and heterochromia. The differential diagnosis included traumatic hemorrhage, persistent fetal vasculature, juvenile xanthogranuloma, retinoblastoma, medulloepithelioma, and others. Fluorescein angiography documented the slow-filling cavernous aneurysms of RCavH.

Interaction between Discs large and Pins/LGN/GPSM2: a comparison across species.

The orientation of the mitotic spindle determines the direction of cell division, and therefore contributes to tissue shape and cell fate. Interaction between the multifunctional scaffolding protein Discs large (Dlg) and the canonical spindle orienting factor GPSM2 (called Pins in Drosophila and LGN in vertebrates) has been established in bilaterian models, but its function remains unclear. We used a phylogenetic approach to test whether the interaction is obligate in animals, and in particular whether Pins/LGN/GPSM2 evolved in multicellular organisms as a Dlg-binding protein. We show that Dlg diverged in C. elegans and the syncytial sponge Opsacas minuta and propose that this divergence may correspond with differences in spindle orientation requirements between these organisms and the canonical pathways described in bilaterians. We also demonstrate that Pins/LGN/GPSM2 is present in basal animals, but the established Dlg-interaction site cannot be found in either Placozoa or Porifera. Our results suggest that the interaction between Pins/LGN/GPSM2 and Dlg appeared in Cnidaria, and we therefore speculate that it may have evolved to promote accurate division orientation in the nervous system. This work reveals the evolutionary history of the Pins/LGN/GPSM2-Dlg interaction and suggests new possibilities for its importance in spindle orientation during epithelial and neural tissue development.

Methodological considerations for detection of terrestrial small-body salamander eDNA and implications for biodiversity conservation.

Environmental DNA (eDNA) can be used as an assessment tool to detect populations of threatened species and provide fine-scale data required to make management decisions. The objectives of this project were to use quantitative PCR (qPCR) to: (i) detect spiked salamander DNA in soil, (ii) quantify eDNA degradation over time, (iii) determine detectability of salamander eDNA in a terrestrial environment using soil, faeces, and skin swabs, (iv) detect salamander eDNA in a mesocosm experiment. Salamander eDNA was positively detected in 100% of skin swabs and 66% of faecal samples and concentrations did not differ between the two sources. However, eDNA was not detected in soil samples collected from directly underneath wild-caught living salamanders. Salamander genomic DNA (gDNA) was detected in all qPCR reactions when spiked into soil at 10.0, 5.0, and 1.0 ng/g soil and spike concentration had a significant effect on detected concentrations. Only 33% of samples showed recoverable eDNA when spiked with 0.25 ng/g soil, which was the low end of eDNA detection. To determine the rate of eDNA degradation, gDNA (1 ng/g soil) was spiked into soil and quantified over seven days. Salamander eDNA concentrations decreased across days, but eDNA was still amplifiable at day 7. Salamander eDNA was detected in two of 182 mesocosm soil samples over 12 weeks (n = 52 control samples; n = 65 presence samples; n = 65 eviction samples). The discrepancy in detection success between experiments indicates the potential challenges for this method to be used as a monitoring technique for small-bodied wild terrestrial salamander populations.

Discovery of candidate tumor biomarkers for treatment with intraperitoneal chemotherapy for ovarian cancer.

Tumor mRNA expression was used to discover genes associated with worse survival or no survival benefit after intraperitoneal (IP) chemotherapy. Data for high grade serous ovarian cancer patients treated with IP (n = 90) or IV-only (n = 398) chemotherapy was obtained from The Cancer Genome Atlas. Progression free survival (PFS) and overall survival (OS) were compared between IP and IV groups using Kaplan-Meier analysis and Cox regression. Validations were performed by analyses of microarray and RNA-Seq mRNA expression data. PFS and OS were compared between IP and IV groups by permutation testing stratified by gene expression. P-values are two-tailed. IP chemotherapy increased PFS (26.7 vs 16.0 months, HR 0.43 (0.28-0.66), p = 0.0001) and OS (49.6 vs 38.2 months, HR 0.46 (0.25-0.83), p = 0.01). Increased expression of NCAM2 and TSHR and decreased expression of GCNT1 was associated with decreased PFS and OS after IV chemotherapy (p < 0.05). High tumor expression of LMAN2, FZD4, FZD5, or STT3A was associated with no significant PFS increase after IP compared to IV chemotherapy. Low expression of APC2 and high expression of FUT9 was associated with 5.5 and 7.2 months, respectively, decreased OS after IP compared to IV chemotherapy (p ≤ 0.007).

On representing the prognostic value of continuous gene expression biomarkers with the restricted mean survival curve.

MOTIVATION: Researchers developing biomarkers for cancer prognosis from quantitative gene expression data are often faced with an odd methodological discrepancy: while Cox's proportional hazards model, the appropriate and popular technique, produces a continuous and relative risk score, it is hard to cast the estimate in clear clinical terms like median months of survival and percent of patients affected. To produce a familiar Kaplan-Meier plot, researchers commonly make the decision to dichotomize a continuous (often unimodal and symmetric) score. It is well known in the statistical literature that this procedure induces significant bias. RESULTS: We illustrate the liabilities of common techniques for categorizing a risk score and discuss alternative approaches. We promote the use of the restricted mean survival (RMS) and the corresponding RMS curve that may be thought of as an analog to the best fit line from simple linear regression. CONCLUSIONS: Continuous biomarker workflows should be modified to include the more rigorous statistical techniques and descriptive plots described in this article. All statistics discussed can be computed via standard functions in the Survival package of the R statistical programming language. Example R language code for the RMS curve is presented in the appendix.