Prolactinomas are the most common neuroendocrine tumors of the pituitary and the leading cause of hyperprolactinemia. Dopamine Receptor Agonists (DAs), particularly cabergoline (CAB), effectively reduce prolactin levels and tumor volume, and are therefore the first-line therapy for prolactinomas. With long-term cabergoline use, adverse effects may become more consequential for some patients. Cabergoline-Associated Valvulopathy (CAV) primarily affects the mitral, tricuspid, and aortic valves, although its underlying mechanisms remain unclear. The potential link between CAB use and Valvular Heart Disease (VHD) in patients with prolactinomas remains controversial. This review summarizes current understanding of CAV and explores potential molecular mechanisms, including CAB's modulation of catecholaminergic, serotonergic, and Transforming Growth Factor-beta (TGF-β) related signaling pathways, along with inflammatory pathways. By integrating clinical patterns with mechanistic plausibility, we aim to support practical surveillance decisions and improve the long-term safety of CAB therapy in patients with prolactinomas.
Genome mutations in germ cells are fundamental to evolution and genetic diversity, while they also cause developmental abnormalities and genetic diseases, making their study essential in both biology and medicine. Research on germline mutations has advanced from classical genetic approaches, through transgenic model analyses, to next-generation sequencing, contributing to our understanding of germline mutations and their origins and inheritance. In particular, recent advances in sequencing technologies, including duplex sequencing and long-read sequencing, enable highly accurate detection of rare mutations and complex genomic alterations, including structural variants and repeat-associated changes, providing a more comprehensive view of mutational landscapes. Research progress has also been made in transposon regulation and spermatogonial stem cell dynamics, revealing additional layers of genome regulation in the germ line. These advances have greatly expanded our understanding of the germline genome and provide a foundation for future research in genetics, evolution, and reproductive biology.
Post operative patients often have break through nausea and vomiting (PONV) despite receiving ondansetron and/or dexamethasone intraoperatively. Studies show aromatherapy is effective in reducing PONV in the adult population and the use of aromatherapy in children is increasing. This evidence-based quality improvement initiative was implemented in a pediatric setting to measure aromatherapy usage for PONV to minimize antiemetic medication usage. The Pediatric Post Anesthesia Care Unit (PACU) employed aromatherapy as a first line treatment for PONV. The Nurse Scientist, EBP Coordinator, and the PACU project investigator developed an EBP initiative to look at the feasibility and effectiveness in utilizing aromatherapy prior to offering the patients rescue antiemetic medication. PACU Staff received education through multiple in-service opportunities. Monthly aromatherapy usage was tracked via a report of staff removal for peppermint aromatherapy sticks from the automated dispensing cabinet. A data report generated from electronic medical records was created to track patients who received antiemetic medications in the PACU. All data was audited by the project investigator to verify accuracy. Data was collected over 18 months and trends were reported to staff and management. Trends and associations between aromatherapy, antiemetic use, and costs were analyzed using Spearman correlation and linear regression. Data indicated a downward trend in antiemetic medication use as aromatherapy use increased. The number of patients who received aromatherapy significantly increased by 0.19 each month (p=0.017), while the number of patients who received antiemetic medication significantly decreased by 0.35 each month (p<0.001). The spearman correlation coefficient is -0.21 and did not reach statistical significance (p=0.406). However, this initiative led to monthly cost savings which significantly increased by $0.09 per month (p=0.002). Aromatherapy can be an effective, feasible and low-cost option for pediatric patients experiencing nausea and vomiting in the PACU. Aromatherapy should be offered as a first-line treatment for post-operative patients, prior to rescue antiemetic therapy.
This expert opinion review is intended to provide guidelines for diagnosis and management of intraocular inflammation (IOI) and vasculitis following pegcetacoplan. A case series of all post-marketing reports classified by experts as definite or suspected vasculitis over an 18-month period was assessed. A total of 306,000 pegcetacoplan intravitreal injections were given in the real world between March 1, 2023, and August 31, 2024. Twenty-four eyes from 22 patients (mean age 76 years, 59% female) with definite or suspected vasculitis were evaluated. Comorbidities included hypertension (55%), hypothyroidism (27%), and recent COVID-19 infection (14%). Twelve eyes were classified as vasculitis with occlusion, seven as vasculitis without occlusion, and five as suspected vasculitis. Median time from intravitreal injection to symptoms was 10 days and 88% (n = 21) occurred after the first injection. Symptoms included reduced vision (71%), eye pain (33%), and elevated intraocular pressure (50%). All patients received corticosteroids and 29% received antibiotics. At last follow-up, six eyes recovered visual acuity to within one line of baseline, seven lost between 2 to 5 lines, and 11 lost 6 lines or more. While IOI and vasculitis are rare, patients can be educated to call a retina specialist promptly if symptoms or any vision loss develop, especially within the 2 weeks following the first injection. In addition to excluding an infectious etiology, individualized management with multiroute corticosteroids can be considered.
By using the naphthalene group-containing β-diketone ligand and 5-nitro-1,10-phenanthroline, three novel heteroleptic eight-coordinate complexes of Eu(III), Tb(III), and Gd(III) have been synthesized. Methods such as elemental analysis, MALDI TOF-MS, UV-Vis, and FT-IR were used to determine the structural characterization of these compounds. The photoluminescent characteristics of the synthesized complexes of Eu(III), Tb(III), and Gd(III) were further investigated. The ligand (L1) and co-ligand 5-nitro-1,10-phenanthroline (L2) and its three lanthanide complexes [Eu(L1)3(L2)]·3H2O, [Tb(L1)3(L2)], and [Gd(L1)3(L2)] were tested in human breast (MCF-7), colon (DLD-1), and lung (A549) cancer cell lines for 72 h. Furthermore, these compounds were screened in a human embryonic kidney cell line (HEK-293T) for cytotoxicity. The results demonstrated that these compounds have antiproliferative activity in three cancer cell lines with low IC50 values. The probable mode of action for the cytotoxic effect was explored through molecular modeling. Previous studies reported epidermal growth factor receptor (EGFR)-inhibiting potential for compounds with similar scaffolds. The docking study demonstrated that the three chelates would have the potential to bind to the EGFR structure. The molecular dynamics (MD) simulation study consolidated this finding as the complex structures were found to be stable with some differences. MMPBSA (molecular mechanics with Poisson-Boltzmann and surface area solvation) energy calculation results also showed high binding affinities for the chelates.
Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment for metastatic renal cell carcinoma (mRCC). Nivolumab monotherapy remains an established option in previously treated patients; however, real-world data (RWD) from Central and Eastern Europe are limited. We conducted a retrospective multicenter cohort study using data from the RENIS II registry, including 501 patients with mRCC treated with nivolumab in the second or later line between 2013 and 2025 across the Czech Republic and Slovakia. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), safety, and exploratory analyses of baseline inflammatory indices (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], and systemic immune-inflammation index [SII]). Median OS was 24.2 months and median PFS was 8.6 months. The ORR was 28.8% and the DCR was 61.2% in the response-evaluable population. Grade 3/4 adverse events were recorded in 11.4% of patients. In exploratory analyses, higher baseline NLR, PLR, and SII were associated with inferior survival in univariable analyses. In multivariable models, NLR and PLR remained independently associated with OS and PFS, whereas SII did not retain independent prognostic significance. In this large multicenter real-world cohort, nivolumab monotherapy demonstrated consistent clinical activity and manageable toxicity in previously treated mRCC, with outcomes comparable to those reported in clinical trials and other European real-world studies. Baseline inflammatory indices, particularly NLR and PLR, showed potential prognostic value and warrant further investigation.
Vitamin K and D co-treatment may have additive effects on bone and cardiovascular health and is frequently used as an over-the-counter supplement. The primary aim of this study was to assess whether the effect of vitamin D supplementation on bone turnover markers and cardiovascular parameters is modified according to vitamin K status at baseline (i.e., serum levels of vitamin K1, MK4 and MK7). This is a post-hoc analysis of a randomized controlled vitamin D supplementation (2,800 international units daily for 8 weeks) trial in 200 participants. We measured vitamin K1, MK4 and MK7 by means of the currently available gold standard liquid chromatography tandem mass spectrometric and analysed cardiovascular and bone markers (including 24-h systolic and diastolic blood pressure, glucose and lipid parameters as well as osteocalcin, beta-crosslaps, and procollagen type 1 N-terminal propeptide). The main aim was to analyze whether pre-intervention vitamin K status (moderator) influenced the effects of vitamin D supplementation on outcome measures of bone and cardiovascular health after the intervention (moderation analyses). We also investigated whether vitamin D supplementation effects vitamin K status and whether vitamin K measures correlated with the outcome parameters. Moderation analyses showed no significant interaction between vitamin K status and the intervention (vitamin D supplementation/placebo) on cardiovascular or bone parameters. We observed no treatment effect of vitamin D on vitamin K status. In exploratory analyses, parameters of vitamin K status correlated only weakly and inconsistently with some bone and cardiovascular parameters. The data from this post-hoc analysis do not provide evidence for the assumption that vitamin K status modifies or enhances effects of vitamin D supplementation on cardiovascular or bone parameters. These findings are in line with current guidelines, which do not routinely recommend vitamin K and D co-treatment in patients with osteoporosis. However, further trials are needed to evaluate the potential benefits of vitamin K supplementation and its combination with vitamin D.
Lithium has a narrow therapeutic index and remains the first-line treatment for bipolar I and II disorders. Dosing this medication requires careful monitoring, and there is a risk of toxicity. This case follows a 43-year-old male with a medical history of alcohol use and bipolar I disorder, admitted to the hospital three days after an intentional lithium overdose. Initial management involved treating alcohol withdrawal with scheduled phenobarbital, lorazepam, and intravenous fluids. In the following days, he demonstrated a neurologic decline in the setting of subtherapeutic serum lithium levels. As the patient continued to worsen, hemodialysis was eventually initiated due to concern for lithium neurotoxicity. After completing three rounds of hemodialysis, the patient subsequently returned to a normal neurologic baseline. This case highlights the significance of clinical manifestations of lithium toxicity in the setting of subtherapeutic and down-trending serum lithium to manage lithium toxicity. Pre-existing tissue stores and rate of elimination contribute to the discrepancy between the severity of symptoms and serum levels in those with chronic lithium use.
A non-destructive diagnostic system based on the TM220 mode of a rectangular cavity has been developed for beam quadrupole moment measurements, and its application to indirect beam energy spread diagnostics is demonstrated for the first time. By installing the cavity downstream of a bending magnet, variations in beam energy spread lead to changes in the transverse beam distribution and the quadrupole moment, which can be measured via the TM220 mode. Motivated by the requirements of high-repetition-rate superconducting free-electron laser facilities and high-charge, high-current linear accelerators (linacs), where screen-based diagnostics become impractical, the cavity-based approach offers a narrowband response and a significantly improved signal-to-noise ratio compared with a conventional eight strip line monitor (ESM). The cavity design, fabrication, and radio frequency (RF) characterization are described, along with the electronics architecture and the implementation of online tests. Beam experiments demonstrated the capability of monitoring quadrupole moment and energy spread. For the cavity monitor, a quadrupole moment measurement uncertainty of 0.034 mm2 was achieved at 350 pC. Based on the measured quadrupole moment uncertainty and machine optics parameters of the present experiment, an energy spread resolution better than 10-5 is estimated, significantly outperforming the ESM under identical conditions. Furthermore, by correlating the cavity-based measurements with the RF accelerating phase, the feasibility of using the cavity for phase feedback was demonstrated. The observed phase dependence indicates the potential for high-resolution RF phase monitoring and feedback under practical operating conditions.
Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent among patients with type 2 diabetes mellitus (T2DM), a population at increased risk for advanced liver fibrosis. Current guidelines recommend the Fibrosis-4 (FIB-4) index as a first-line fibrosis risk stratification tool; however, its implementation in routine clinical practice remains uncertain. Aim To evaluate the real-world feasibility of FIB-4-based fibrosis risk stratification in patients with T2DM and MASLD. Methods We conducted a retrospective cross-sectional study including adult outpatients with T2DM and MASLD evaluated at a national referral center in Santo Domingo, Dominican Republic, between March 2022 and January 2025. Feasibility was defined as the proportion of patients with sufficient laboratory data to calculate FIB-4. Results A total of 397 patients were included. Only 143 patients (36.0%) had complete laboratory data required for FIB-4 calculation, while 254 (64.0%) lacked at least one required variable. AST and ALT were the most frequently missing laboratory parameters. Among patients with calculable FIB-4 values, 16 (11.2%) were classified as high risk for advanced fibrosis according to age-adjusted thresholds. Conclusions In this real-world cohort of patients with T2DM and MASLD, guideline-recommended FIB-4-based fibrosis risk stratification showed limited feasibility due to incomplete routine laboratory data. These findings highlight opportunities to improve the integration of standardized fibrosis risk assessment into routine diabetes care.
Adrenal malignancies include adrenocortical carcinoma (ACC) and pheochromocytoma/paraganglioma (PPGL), rare endocrine tumors that share an adrenal or extra-adrenal location but differ substantially in origin, hormonal activity, molecular alterations, metastatic potential, and systemic treatment. In ACC, management is guided by stage, resectability, Ki-67, hormone secretion, tumor volume, and pace of progression. Mitotane remains the central ACC-specific therapy, used according to recurrence risk after surgery and as monotherapy in selected patients with advanced, low-volume disease. When rapid tumor control is needed, etoposide, doxorubicin, cisplatin, and mitotane remains the standard first-line regimen. Immune checkpoint inhibitors and multikinase inhibitors have shown activity in some patients, but validated predictive biomarkers are lacking, and access across Europe is limited by reimbursement differences. In later lines, chemotherapy may still be appropriate, including platinum rechallenge in selected cases. PPGL care is increasingly driven by genetics, biochemistry, and functional imaging. Germline testing, biochemical phenotype, and imaging findings are essential for risk assessment and treatment choice. Cyclophosphamide, vincristine, and dacarbazine may be considered for aggressive disease, rapid growth, or high tumor burden. Targeted and radiopharmaceutical approaches have expanded options, including high-specific-activity 131I-iobenguane for MIBG-avid tumors, 177Lu-DOTATATE for somatostatin receptor-positive disease, antiangiogenic tyrosine kinase inhibitors, and HIF-2α inhibition with belzutifan in selected molecular contexts. For both ACC and PPGL, controlling steroid or catecholamine excess is crucial, because endocrine complications affect treatment tolerance and outcomes. Future progress requires robust biomarkers, rational treatment sequencing, and trials using disease-specific endpoints beyond radiographic response and integrating patient-centered endocrine, molecular, and overall clinical measures of benefit.
Canine mammary tumours (CMTs) and human breast cancer (HBC) share highly similar pathological characteristics. Cancer stem cells (CSCs) are critical to breast cancer invasion, metastasis, drug resistance, and recurrence. The experiment utilised CMT cell line CMT-U27 and HBC cell line MDA-MB-231. Cancer stem cell spheres were isolated from the two cell lines by serum-free culture respectively, named as CMT-U27 microspheres (CMT-U27S) and MDA-MB-231 microspheres (MDA-MB-231S), and the proportion of CSCs with the CD44+/CD24- phenotype was identified by flow cytometry. Monensin (MON), one of Polyether ionophore antibiotics, has been demonstrated to effectively suppress various types of CSCs, while erlotinib (ERL), as a tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR), effectively inhibits cancer cell growth. This study investigates the synergistic inhibitory effects of MON-ERL combination on CSCs derived from CMTs. Cell viability was analysed by CCK-8 assay, while cell invasion and mammosphere formation assays were conducted to evaluate changes. An orthotopic tumour model in nude mice using CMT-U27S was established for in vivo validation. The results suggested that MON and ERL combination synergistically inhibited CSCs viability and significantly suppress their invasion and mammosphere formation abilities. The expression of key proteins of the EGFR pathway-p-EGFR, PI3K, and p-AKT was significantly reduced. In animal experiments, tumour volumes in the combination treatment group were markedly reduced compared to those in all other groups (p < 0.05), and no lung metastases were observed only in the combination group. Immunofluorescence and immunohistochemistry results indicated a marked reduction of CD44+/CD24- cells in the combination group, along with suppressed expression of stem cell markers and proliferation/apoptosis proteins. In conclusion, MON combined with ERL effectively inhibits the proliferation, self-renewal, and metastatic capabilities of CSCs from CMTs by synergistically downregulating the EGFR/PI3K pathway, demonstrating promising antitumor potential and offering a new strategy for CMTs treatment.
Black tea processing generates large amounts of waste fiber that still retains considerable levels of bioactive compounds. In this study, black tea waste fiber was valorized for the production of instant tea powders, and the influence of extraction conditions on both bioactive composition and anticancer activity was investigated. Instant tea powders were produced using hot extraction (100 °C, 6 min) and cold extraction (25 °C, 2 h). Catechins, gallic acid, caffeine, theanine, theaflavin and thearubigins were quantified. Anticancer activity was evaluated by the MTT assay using prostate cancer cell lines (PC3, 22Rv1 and LNCaP), glioblastoma cell lines (U87MG and A172) and the breast cancer cell line MCF7. Hot extraction resulted in significantly higher levels of catechins, condensed phenolics and theanine (p < 0.05). In contrast, the extended extraction time applied in the cold method partially compensated for mass transfer limitations in the extraction of gallic acid and caffeine. The anticancer potential of the instant teas was evaluated in vitro using prostate cancer cell lines (PC3, 22Rv1, and LNCaP), glioblastoma cells (U87MG and A172), and breast cancer cells (MCF7). The hot-extracted instant tea infusion inhibited the proliferation of prostate cancer cells in a concentration-dependent manner (p < 0.05). Hot-extracted instant tea showed a particularly strong cytotoxic effect on U87MG glioblastoma cells, reducing cell viability to 2.7% at 1.25 mg/mL, whereas A172 cells exhibited greater resistance. In contrast, cold-extracted samples demonstrated stronger inhibitory effects on MCF7 breast cancer cells (p < 0.05). These findings demonstrate that black tea waste fiber can serve as a valuable raw material for functional instant tea production and highlight the importance of extraction conditions in shaping both the bioactive profile and biological activity of instant tea products derived from tea processing residues.
Septic shock remains a major cause of death in the ICU with high 28-day mortality, and concomitant left ventricular systolic dysfunction (LVSD) further worsens patient outcomes, while existing prediction models lack adequate specificity. This study aimed to establish and perform internal-external validation of a 28-day mortality prediction model specifically for septic shock patients with LVSD as a key risk factor. This retrospective multicenter cohort study enrolled 226 septic shock patients from September 2021 to October 2024 as the training cohort and 132 patients from November 2024 to December 2025 as the validation cohort, from ICUs of General Hospital and Cardiovascular Hospital of Ningxia Medical University. Baseline LVEF was measured at admission, with LVSD defined as LVEF < 50% or > 70%. Baseline data, clinical variables, myocardial biomarkers, and 28-day mortality were collected. Univariate and multivariate logistic regression identified independent predictors. A predictive nomogram was constructed and assessed using ROC, calibration curves, and DCA. Internal validation was performed via 1,000 bootstrap resamples, followed by external validation in the validation cohort. Independent predictors of 28-day mortality in patients with septic shock were: left ventricular systolic dysfunction, decreased pH, atrial arrhythmia, dopamine use, and reduced PaO2/FiO2. Based on these predictors, a predictive model for 28-day mortality in patients with septic shock was constructed, and a nomogram was developed. The area under the ROC curve (AUC) of the model in the training cohort was 0.767 (95% CI: 0.703-0.831). After internal validation via Bootstrap sampling, the mean AUC was 0.779 (95% CI: 0.713-0.841). The calibration curve approached the ideal line (Hosmer-Lemeshow test P = 0.476), and the DCA indicated clinically net benefit within the 0.05-0.85 probability threshold range. External validation confirmed the reliability of the predictive model. Further comparison revealed that the predictive performance of this model was significantly superior to that of the APACHE II score for predicting mortality (0.767 vs. 0.652, P = 0.006). This nomogram has been converted into a web-based dynamic nomogram calculator available for free public use (https://linjia.shinyapps.io/dynnomapp/). The 28-day mortality prediction model demonstrated excellent discriminative power, stability, and clinical applicability.
Hyponatremia is the most common electrolyte disorder found in hospitalized patients and is associated with an increased mortality. Urea has been proposed as an alternative to vasopressin receptor antagonists (VRA) in the treatment of SIAD though comparative data are scarce. The aim was to evaluate the effectiveness and safety of urea compared with tolvaptan for treating SIAD in hospitalized patients. Retrospective cohort study of adult inpatients with SIAD (serum sodium <130 mmol/L) treated with either urea or tolvaptan at a single institution between January 2015 and December 2023. Inverse probability of treatment weighting adjusted for confounders. Primary outcome was the proportion of patients achieving a serum sodium of >130 mmol/L. Secondary outcomes included time to treatment goal, serum sodium changes at 24, 48, and 72 hours, proportion of overcorrection (>10 mmol/L per 24 hours) and resource utilization. Of 537 patients, 463 received urea (median age 78 years; 57% female; baseline serum sodium 124.2 mmol/L, mean starting dose: 26 ± 6.1 g daily) and 74 received tolvaptan (68 years; 56% female; 123.6 mmol/L, mean starting dose 12.9 ± 6.5 mg daily). Similar proportions reached a serum sodium >130 mmol/L (79.7% vs 78.0%, P = 0.986). Time to target showed a trend favoring tolvaptan (2 (IQR 1-4) vs 3 (IQR 2-5) days, P = 0.077). Tolvaptan produced faster sodium increases at 48 hours (8.3 (IQR 4.4-12.0) vs. 5.6 (IQR 2.9-9.0) mmol/L), P = 0.001) but also more overcorrections (>10 mmol/L per 24 hours: 10.8% vs 3.2%, P = 0.011). Treatment duration was longer with tolvaptan (7 (IQR 4-11) vs 5 (IQR 3-8) days, P = 0.001), with substantially higher costs (€468 vs €12, P < 0.001). Urea may have a comparable effectiveness to tolvaptan with similar success rates but fewer overcorrections and substantially lower costs. These findings support urea as a safe and cost-effective first-line treatment option for appropriate patients with SIAD.
To evaluate whether pre-treatment coronary artery aneurysm (CAA) Z-score, inflammatory markers, and incomplete Kawasaki disease (KD) status are associated with intravenous immunoglobulin (IVIG) retreatment and early coronary outcomes in infants aged < 6 months. We retrospectively reviewed infants aged < 6 months who were treated with IVIG for KD between 2011 and 2024. Clinical, laboratory, treatment, and serial echocardiographic data were collected, and patient-level maximal coronary Z-scores were calculated. The primary outcome was additional IVIG; the secondary outcome was CAA Z-score (≥ 2.5) at approximately 1 month after illness onset. Among 76 infants (median age, 4.3 months), 17/76 (22.4%) required additional IVIG, 14/76 (18.4%) had CAA at approximately 1 month after illness onset, and 3/76 (3.9%) had residual CAA at or after 6 months. Additional IVIG was independently associated with pre-treatment CAA (Z ≥ 2.5), earlier illness day at initial IVIG, and higher neutrophil-to-lymphocyte ratio; the multivariable model showed good discrimination (area under the curve [AUC] 0.84). For CAA at 1 month, both a baseline-only model including pre-treatment CAA Z-score, albumin, and illness day at initial IVIG (AUC 0.91, 95% confidence interval [CI] 0.84-0.97) and a course-aware model including pre-treatment CAA Z-score and additional IVIG (AUC 0.90, 95% CI 0.84-0.97) showed high discrimination. CAA at 1 month with Z-max ≥ 5.0 was associated with residual CAA risk.  In infants aged < 6 months with KD, pre-treatment coronary involvement and higher inflammatory burden were strongly associated with additional IVIG, whereas pre-treatment coronary disease severity, lower albumin, and an early refractory course were strongly associated with CAA at 1 month. • Infants aged < 6 months with Kawasaki disease (KD) have higher non-response to intravenous immunoglobulin (IVIG) and more coronary artery abnormalities (CAA). • Guidelines recommend early transthoracic echocardiography and coronary Z-score assessment, but infant-specific prognostic data remain limited. • In this infant-only cohort, pre-treatment CAA Z-score ≥ 2.5 and neutrophil-to-lymphocyte ratio ≥ 2.15 were associated with additional IVIG. • Pre-treatment CAA Z-score, lower albumin, and an early refractory course were the factors most strongly associated with CAA at 1 month.
Macrophages undergo rapid transcriptional reprogramming upon LPS stimulation, but the early regulatory mechanisms (≤6 hours) remain poorly understood. This study investigates the immediate molecular responses in the RAW264.7 murine macrophage cell line, focusing on the interplay between immune activation, cell cycle modulation, and metabolic-epigenetic crosstalk. The metabolic and epigenetic crosstalk mentioned in this study is only inferred from transcriptomic data, and no direct experimental verification was performed. Transcriptomic profiling (RNA-seq) was performed on LPS-stimulated (6-hour) and control macrophages. Differentially expressed genes (DEGs) were analyzed via GO/KEGG enrichment and protein-protein interaction (PPI) networks. Key findings were validated by qPCR and Western blot. Identified 2,715 DEGs (716 upregulated, 1,999 downregulated), with Ikbke identified as a multi-pathway gene (14 pathways). LPS triggered activation of inflammatory pathways (NF-κB, TNF) and downregulation of cell cycle regulators. Ikbke and C5ar1 co-enriched in COVID-19 and viral infection pathways, reflecting their involvement in general innate immune signaling pathways. Transcriptomic findings were validated by qPCR and Western blot, confirming a 6.2-fold induction of Ikbke and significant downregulation of Ezh2. This study identifies Ikbke as a potential correlational candidate of early macrophage responses, linking TLR signaling, metabolic shifts, and viral defense mechanisms. All conclusions in this study are limited to the RAW264.7 immortalized murine macrophage cell line and require further verification in primary cells and in vivo models. These findings in the RAW264.7 cell model provide potential molecular targets for further investigating the modulation of early hyperinflammatory responses.
Surgical decision making in patients with brain metastasis is complex, particularly for patients with melanoma brain metastasis (MBM). Few studies specifically address neurosurgical outcomes based on histology. This study aims to identify clinical factors associated with early mortality and overall survival (OS) after tumor resection in patients with MBM. Patients diagnosed with MBM from 2009 to 2018 at our institution who underwent surgical resection as their first-line therapy were included in the study. The primary outcomes were postoperative OS, 90-day mortality, and leptomeningeal disease (LMD) incidence. Associations between OS and postoperative 90-day mortality with demographic/clinical factors were assessed using Cox proportional hazards regression models and logistic regression models, respectively. The cumulative incidence of LMD was determined using competing risks, and associations with demographic/clinical factors were assessed using proportional subdistribution hazards regression models. A total of 103 patients with MBM were included. Ninety-day mortality occurred in 18% (n = 19). Elevated lactate dehydrogenase at MBM diagnosis (odds ratio [OR] [95% CI]: OR = 7.17 [1.50-34.25]; P = .013) was associated increased odds of early mortality in multivariable analysis. Postoperative Karnofsky Performance Scale ≥80 (OR = 0.13 [0.03-0.62]; P = .010) and MBM at stage 4 diagnosis (OR = 0.11 [0.02-0.67]; P = .016) were associated with reduced odds of early mortality. Factors associated with better postoperative OS (hazard ratio [HR] [95% CI]) included synchronous diagnosis of MBM and stage 4 disease (HR = 0.59 [0.36-0.95]; P = .032), preoperative Karnofsky Performance Scale ≥80 (HR = 0.46 [0.27-0.80]; P = .006), adjuvant stereotactic radiosurgery (HR = 0.55 [0.32-0.93]; P = .026), and surgical reduction of volumetric intracranial tumor burden ≥95.6% (HR = 0.47 [0.28-0.80]; P = .005). No factors were significantly associated with cumulative incidence of LMD. This is the largest analysis of patients with MBM who underwent surgery as first-line therapy. We identified clinical factors associated with early postoperative mortality and survival including surgical reduction of intracranial tumor burden.
Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the first-line treatment of ALK-positive metastatic non-small cell lung cancer, frequently associated with psychiatric adverse events. This study presents the clinical case of a patient who was successfully treated with low-dose trazodone for lorlatinib-induced psychiatric symptoms. In addition, an overview of the existing literature on the management of psychiatric adverse events (AEs) associated with ALK inhibitors is provided. Based on the evidence presented and the preliminary outcomes observed in the reported case, this study aims to outline a management strategy for lorlatinib-related psychiatric complications.
At a Veterans Affairs medical center, an immunotherapy stewardship initiative was developed to optimize dosing of pembrolizumab, which accounted for Medicare Part B's largest single line item for total spending, at more than US$5.4 billion in 2023. Pembrolizumab received regulatory approval in 2014 at a personalized dose of 2 mg/kg every 3 weeks; however, in the United States, practice is now dominated by fixed 200 mg every-3-weeks dosing (approved in 2017) and 400 mg every-6-weeks dosing (approved in 2020), with all patients dosed on the assumption that they weigh 100 kg. This status quo very likely results in unnecessary drug use, excessive spending, and lost opportunities to improve patient experience. The authors developed a stewardship initiative around a 4 mg/kg every-6-weeks dosing option, now recommended in many contemporary oncology guidelines, which is more time-efficient for infusion centers and practices, more cost-effective for payers, more convenient for patients, and is supported by a strong pharmacologic rationale and international precedent. The stewardship initiative, which ran from July 1, 2024, through June 30, 2025, introduced dose banding, new electronic medical record (EMR) order sets, and pharmacist-led education to guide prescribers toward utilization of the more cost- and time-efficient dosing option. Quarterly audit feedback reinforced adoption. Evaluation included prescribing trends, drug utilization, and cost and patient time savings. Over the 12-month intervention, the every-6-weeks dosing option for pembrolizumab monotherapy increased from about 60% (among 25 unique patients in month 1) to 80% (among 34 unique patients per month in month 12), while the pembrolizumab administered as part of a combination regimen with intravenously administered chemotherapy (i.e., combination therapy) remained predominantly every 3 weeks owing to EMR and cultural barriers. Compared with counterfactual estimates, the program was associated with approximately US$296,000 in averted drug costs (about 6.5% of an expected US$4.55 million spend), capturing more than 90% of modeled potential savings. Time savings were notable: With a median infusion encounter lasting nearly 180 minutes, every-6-weeks dosing helped avert more than 450 hours of health care contact time, which is equivalent to approximately 6 hours saved per recipient over the course of 1 year. Limitations include some marginal uptake of every-6-weeks dosing, which most likely would have occurred even without the intervention, the financial analysis focusing solely on drug acquisition costs and not accounting for potential cost savings related to fewer infusions, and the lack of consideration of adjacent provider and health system efficiency gains. Nevertheless, the initiative demonstrates that pragmatic tools - dose banding, EMR redesign, pharmacist involvement, and feedback loops - can meaningfully improve the time- and cost-efficiency and patient experience without increasing drug-related spending. Stewardship offers a replicable framework for health systems to balance value, efficiency, and patient-centered care in oncology.