Progression Status Research Articles

Systemic Oxidative Stress Correlates with Sarcopenia and Pruritus Severity in Primary Biliary Cholangitis (PBC): Two Independent Relationships Simultaneously Impacting the Quality of Life—Is the Low Absorption of Cholestasis-Promoted Vitamin D a Puzzle Piece?

Background: Unlike other chronic liver disorders, in primary biliary cholangitis (PBC), systemic oxidative stress (SOS) worsens along with liver disease progression status (DPS), influencing muscle metabolism, muscle quantity (MQ), and itch pathways. Synergistically, cholestasis contributes to reduced vitamin D absorption, with a negative impact on MM and SOS. Despite this evidence, the prevalence of sarcopenia in PBC, and the SOS-MQ relationship comparing PBC with other CLDs, has never been investigated. Moreover, the relationship between vitamin D and MQ-SOS, and the correlation between SOS and pruritus severity, remains unexplored in PBC. Methods: A total of 40 MASLD, 52 chronic HBV infections, 50 chronic HCV infections, and 41 ursodeoxycholic acid/antioxidant-naïve PBC patients were enrolled. Biochemical, nutritional, and liver stiffness (LSM) data were collected, and sarcopenia was assessed after a normalizing 3-month dietetic–physical exercise regimen. The d-ROMs/BAP tests evaluated SOS. The validated “PBC-40 questionnaire” estimated pruritus and quality of life (QoL). Results: Unlike other CLDs, in PBC patients, sarcopenia was more prevalent in initial mild fibrosis (PBC: 57.10% vs. MASLD: 30.76%, HBV: 22.60%, HCV: 20.70%, all p < 0.0001), and SOS significantly correlated with MQ (dROMs-ASM/h2, p: 0.0002; BAP-ASM/h2: p: 0.0092). PBC patients presented lower vitamin D levels and a significant correlation of these with SOS and MQ (all p < 0.0001). SOS also correlated with pruritus severity (dROMs, R: 0.835; BAP, R: −0.775, p < 0.0001). QoL impairment was significantly more represented in PBC individuals with sarcopenia, SOS imbalance, and relevant pruritus (p: 0.0228). Conclusions: In PBC, SOS correlates with MQ impairment and pruritus severity, configuring two independent relationships simultaneously impacting QoL.

CTNI-21. PIVOTAL, PHASE 2B RENEU TRIAL OF MIRDAMETINIB IN CHILDREN AND ADULTS WITH NEUROFIBROMATOSIS TYPE 1-ASSOCIATED PLEXIFORM NEUROFIBROMA (NF1-PN): A SPOTLIGHT ON PATIENTS ACHIEVING DEEP RESPONSE

Abstract BACKGROUND Patients with NF1-PN in the phase 2b ReNeu trial (NCT03962543) of mirdametinib in adults (N=58, ≥18y) and children (N=56, 2-17y) had a deeper median (range) best reduction (adults: -41% [-90% to 13%]; children: -42%, [-91% to 48%]) from baseline in target PN volume than previously published in trials of other agents in NF1-PN. METHODS In the 24-cycle (1-cycle=28d) treatment phase, objective response rate (ORR) was the percentage with confirmed objective responses (OR) of ≥20% target PN volume reduction from baseline on consecutive MRIs (by blinded independent central review). This analysis includes patients achieving deep response (>50% best reduction from baseline in target PN volume) regardless of OR and inclusive of patients in the long-term follow-up. Exploratory analysis of baseline characteristics compared patients with deep response and patients with ≤50% volume reduction. RESULTS ORR was 41% (24/58) in adults and 52% (29/56) in children treated with mirdametinib. 62% (15/24) of adults and 52% (15/29) of children who achieved OR had deep response. To further characterize deep response, 2 adults and 3 children with deep response without confirmation or in long-term follow-up were included. Of those with a deep response, 35% (6/17) of adults and 72% (13/18) of children were investigator-defined as having progressing PN. Patients achieved deep response regardless of baseline age, sex, target PN volume, tumor location, or progression status. For adults and children, median time to best percent change from baseline in PN volume for patients achieving deep response was 25.4 and 21.8mo; for patients with reductions of ≥20% to ≤50% was 15.3 and 15.2mo; for patients with reductions of <20% was 7.8 and 4.2mo, respectively. CONCLUSIONS Patients had a similar likelihood of achieving deep response across assessed baseline characteristics. A trend between deep response and longer treatment duration suggests a benefit of prolonged therapy with mirdametinib.

CTNI-71. RELA FUSION-POSITIVE EPENDYMOMA, DIFFUSE MIDLINE GLIOMA AND GRADE 4 IDH MUTANT ASTROCYTOMA TREATED WITH VAL-083 UNDER EXPANDED ACCESS: CASE REPORTS

Abstract RELA fusion-positive ependymoma is associated with supratentorial location, higher WHO grade and poor prognosis. Diffuse Midline Glioma (DMG) is a relatively rare CNS tumor, originating in the midline location of the brain. Surgical intervention is restricted to biopsy and radiation. Grade-4 astrocytoma, is highly aggressive with rapid progression. Standard treatment includes surgery and radiation therapy, with limited systemic options other than clinical trials for recurrent disease. VAL-083 is a DNA-targeting agent which rapidly induces inter-strand DNA cross-links at O6- and N7-guanine inducing double-strand breaks causing cell death and acts independent of MGMT DNA repair in high-grade gliomas. We report on 4 patients who had recent disease progression and unmethylated MGMT promoter status treated with VAL-083 under an expanded access program: Case #1: a 47-yo male diagnosed with IDHwt, RELA fusion-positive ependymoma. Case #2: an 18-yo male diagnosed with IDHwt, MAP2K1 and RELA fusion-positive ependymoma. Case #3: a 25-yo male diagnosed with IDHmut Grade 4 astrocytoma, with ATRX, INPP4A, RET and TP53 mutations. Case #4: a 21 yo male diagnosed with IDHwt DMG of the brain stem. All patients had multiple recurrences, received radiation and multiple systemic treatment regimens. They received VAL-083 (30 mg/m2 for 3 days every 21 days) under an expanded access program. Patients with ependymoma received 6 and 5 cycles of VAL-083, (case 1 and 2, respectively), while the patients with IDHmut Gr 4. astrocytoma and DMG received 5 and 18 cycles of VAL-083, respectively. No adverse events were reported and no dose reductions were required. These cases highlight that VAL-83 may be a treatment option for recurrent RELA fusion-positive ependymoma, Gr4. IDHmut astrocytoma, and DMG refractory to other treatment regimens. Additional outcomes related to these cases will be presented at the meeting. Clinicaltrials.gov Identifier: NCT03138629. The treatment plans for the EA patients were approved by MD Anderson Cancer Center IRB

Effects of Denosumab Therapy on Renal Function in Multiple Myeloma Patients: A Single Center Retrospective Analysis

Background: Bone antiresorptive agents are standard of care for patients with multiple myeloma (MM) to reduce the risk of pathologic fractures, hypercalcemia and to prevent other sequelae of myeloma bone disease. However, chronic kidney disease (CKD) is common in this population, and is a limiting factor in the use of antiresorptive agents such as bisphosphonates. Denosumab is considered a safer option in patients with CKD. Here, we investigated denosumab efficacy and effects on renal function and bone-mineral metabolism in MM patients ineligible for bisphosphates and/or with pre-existing renal disease. Methods:We performed a single center, retrospective review of adults with MM who received denosumab at our institution from January 1, 2016 to January 1, 2023. Cockroft-Gault creatinine clearance (CrCl), albumin-adjusted serum calcium level (sCa), and serum alkaline phosphatase (sAP) were measured before the first administration of denosumab and after treatment. Incidence of hypocalcemia, fractures, or osteonecrosis of the jaw (ONJ) at any point during denosumab treatment was recorded. Changes in renal function were correlated with baseline CrCl prior to starting denosumab and with relapsed myeloma. Statistical significance was obtained by paired t-test and Chi-square test. Results: Data for 97 patients were collected. Median age was 67 years (range 42-96); 47% were men. Twenty-six were newly diagnosed and on first-line MM therapy, 21 patients were on salvage therapy, and 50 had stable disease, most of whom were on maintenance therapy. Sixty-two patients had received prior bisphosphonates (zoledronic acid). Baseline CrCl before starting denosumab was ≥ 60 ml/min in 51 patients, ≥ 30-60 ml/min in 27 patients, and < 30 ml/min in 19 patients including 9 on hemodialysis. Patients received denosumab at a dose of 120 mg monthly (n = 63), every 3 months (n=14), every 6 months (n = 3), and the remainder received treatment less frequently. There was a significant decrease in CrCl after denosumab treatment (5.59 ml/min; p = 0.0086), especially in patients with baseline CrCl ≥ 30 ml/min (7.56 ml/min; p = 0.0028) and in patients receiving denosumab monthly (4.79 ml/min; p = 0.036). When stratified by progression status, MM with stable disease had a mean decrease in CrCl of 9.15 ml/min (p = 0.0002), whereas those with relapsed MM did not have a statistically significant change (1.95 ml/min; p = 0.76). Overall, 53% of the patients experienced hypocalcemia, correlating with decreased CrCl (χ2 = 13.58, p = 0.019) and most frequently in patients on hemodialysis (89%). No statistically significant associations were seen with hypocalcemia and denosumab dosing frequency (χ2 = 2.96, p = 0.23). There was no significant change in sAP level with denosumab (mean = 3.72 IU/L, p = 0.62). Four patients developed ONJ, of which 3 patients had prior treatment with zoledronic acid. Fifteen patients had skeletal-related events: atypical femoral fractures (n = 3); compression fractures (n = 7), and traumatic fractures (n = 5) Conclusions: Our findings suggest that denosumab is safe in regard to renal function for MM patients with severe CKD (baseline CrCl < 30 ml/min). Hypocalcemia is a concern, especially for those with severe CKD or on hemodialysis, and needs careful monitoring and replacement therapy. Lower pretreatment sCa level was a reason to hold therapy so the impact of denosumab is not clear. The cause of decline in CrCl seen in patient with CrCl ≥ 30 ml/min is unclear, and of uncertain clinical consequences. Further prospective studies with larger cohorts and longer follow up are needed to confirm the safety of denosumab and possibly explore lower dosing and infrequent schedule in MM patients with various degrees of renal insufficiency to better define treatment guidelines.

[Artículo traducido] Adherencia al tratamiento con quimioterapia oral en pacientes con cáncer de pulmón no microcítico localmente avanzado o metastásico: protocolo para un estudio de vida real realizado en farmacia hospitalaria

ObjectiveThis article describes a study protocol for evaluating adherence to oral chemotherapy (OCT) in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) in Spain. MethodsThis multicenter, observational, prospective study will be conducted by six hospital pharmacists from six Spanish hospitals. The study will include men and women aged 18 years or older with a diagnosis of locally advanced or metastatic NSCLC who are being treated or have been prescribed OCT. Once included, the patient will be active and prospectively followed up for 3 months, including four study visits to record information on sociodemographic variables, antineoplastic treatment and adherence, pharmaceutical care, clinical variables, and patient-reported outcomes (PRO) (the 3-level version of EQ-5D, the EORTC Core Quality of Life Questionnaire, the Brief Illness Perception Questionnaire, the Treatment Satisfaction with Medicines Questionnaire, and the PRO version of Common Terminology Criteria for Adverse Events). Twelve months after patient inclusion, we will record information on the disease progression status and dispensed prescriptions. The primary outcome is the percentage of treatment adherence that will be calculated based on the pill count as follows: the difference between the number of pills dispensed minus the number of unused pills will be divided by the number of days of treatment multiplied by the number of pills/day prescribed by the oncologist; this quotient will be multiplied by 100 to obtain the percentage of adherence. Based on the that pill count reconciliation, those with a percentage adherence greater than80% will be primarily categorized as adherent. Secondarily, treatment adherence will be also calculated based on the proportion of days covered and the 4-items Morisky Green Levine Medication Adherence Scale. To analyze the impact of patients' and treatment characteristics on adherence, bivariate analyses will be performed using different adherence cut-off points. To evaluate the impact of adherence on treatment efficacy as evaluated by progression-free survival, we will be using the Kaplan–Meier method and compare it with the log-rank test and univariate Cox regression analysis. ConclusionsWe expect that our study will provide initial information on key aspects of adherence to OCT (measurement, facilitators, and barriers) and its relationship with patients' and clinically relevant outcomes in the setting of NSCLC, and that this information will help in designing pharmaceutical interventions to improve adherence.

Genetic variations in PEAR1 are associated with progression of coronary artery disease

Abstract Aim Platelet endothelial aggregation receptor 1 (PEAR1) is a newly discovered membrane protein mainly expressed in endothelial cells and platelets. Previous researches have indicated the effect PEAR1 had on inflammation. This study aims to investigate the association between PEAR1 genetic variations and coronary artery disease (CAD) progression, which was regarded as a chronic inflammatory procedure. Methods We genotyped twelve common single nucleotide polymorphisms (SNPs) (rs2768759, rs2768762, rs12566888, rs12041331, rs11264579, rs77235035, rs57731889, rs822441, rs822442, rs11264581, rs56260937, and rs4661012) and detected the DNA methylation level of fourteen CpG loci in the promoter of PEAR1 in 162 Chinese patients with CAD. We accessed the association between PEAR1 genetic variants and the progression status of CAD, separated into stable angina, unstable angina, non-ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). Results This CAD cohort included 40 (24.7%) with stable angina, 85 (52.5%) with unstable angina, 33 (20.4%) with NSTEMI, and 4 (2.5%) with STEMI. After adjusting for age, sex, hyperlipidemia, and diabetes mellitus as covariates in multiple logistic regression, rs12041331 was the only SNP that significantly associated with CAD type. Carriers of the A allele in rs12041331 were more likely to develop an unstable state (RR=1.996, 95%CI=1.075~3.710, p-value=0.029, Fig. 1). Carriers of A allele in rs11264579 is a potential risk factor of progression of atherosclerosis (RR=2.84, 95%CI=0.99~8.10, p-value=0.051, Fig. 1). Compared with other sites, SNPs of intron 1 were more likely to be associated with the risk of atherosclerosis progression (Fig.2). Conclusion Carriers of A allele in rs12041331 may lead to an increased risk of CAD progression. Region-specific genetic variant reinforces the association between PEAR1 and the risk of atherosclerosis progression.Effect of PEAR1 genetic variants.Correlation between PEAR1 SNPs and risk.

The benefit and risk of addition of chemotherapy to EGFR tyrosine kinase inhibitors for EGFR-positive non-small cell lung cancer patients with brain metastases: a meta-analysis based on randomized controlled trials.

Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with chemotherapy (ETC) offers more advantages for patients with EGFR-positive non-small cell lung cancer (NSCLC) than using EGFR TKIs alone (ET). However, whether this conclusion applies to patients with brain metastases (BM) remains controversial. This meta-analysis was performed to evaluate the benefits and risks of the two groups. Six databases were systematically searched for relevant literatures comparing ETC versus ET in treating EGFR-positive NSCLC patients with BM. The primary outcome assessed was overall survival (OS), while secondary outcomes included progression-free survival (PFS), and central nervous system (CNS)-PFS, responses, progression status and safety. Seven studies based on five randomized clinical trials with 550 patients were included. The ETC group exhibited better OS (hazard ratio [HR]: 0.64 [0.48, 0.87]), PFS (HR: 0.42 [0.34, 0.52]), and CNS-PFS (HR: 0.42 [0.31, 0.57]). The benefits in survival for OS, PFS, and CNS-PFS were validated in nearly all subgroups. Meanwhile, the overall objective response rate (ORR) (risk ratio [RR]: 1.25 [1.02, 1.52]) and CNS-ORR (RR: 1.19 [0.93, 1.51]) also tended to favor the ETC group. However, the addition of chemotherapy also brought about more grade 3-5/serious adverse events (AEs). The top five grade 3-5 AEs in the ETC group were alanine aminotransferase increase (11.25%), neutropenia (7.5%), nausea (7.5%), anorexia (5%), and diarrhea (5%). ETC appears to be better than ET in treating EGFR-positive NSCLC patients with BM, with better OS, PFS, CNS-PFS, and responses. However, its poorer safety profile also needs to be taken into consideration. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024551073.

Multimodal deep learning radiomics model for predicting postoperative progression in solid stage I non-small cell lung cancer

PurposeTo explore the application value of a multimodal deep learning radiomics (MDLR) model in predicting the risk status of postoperative progression in solid stage I non-small cell lung cancer (NSCLC).Materials and MethodsA total of 459 patients with histologically confirmed solid stage I NSCLC who underwent surgical resection in our institution from January 2014 to September 2019 were reviewed retrospectively. At another medical center, 104 patients were reviewed as an external validation cohort according to the same criteria. A univariate analysis was conducted on the clinicopathological characteristics and subjective CT findings of the progression and non-progression groups. The clinicopathological characteristics and subjective CT findings that exhibited significant differences were used as input variables for the extreme learning machine (ELM) classifier to construct the clinical model. We used the transfer learning strategy to train the ResNet18 model, used the model to extract deep learning features from all CT images, and then used the ELM classifier to classify the deep learning features to obtain the deep learning signature (DLS). A MDLR model incorporating clinicopathological characteristics, subjective CT findings and DLS was constructed. The diagnostic efficiencies of the clinical model, DLS model and MDLR model were evaluated by the area under the curve (AUC).ResultsUnivariate analysis indicated that size (p = 0.004), neuron-specific enolase (NSE) (p = 0.03), carbohydrate antigen 19 − 9 (CA199) (p = 0.003), and pathological stage (p = 0.027) were significantly associated with the progression of solid stage I NSCLC after surgery. Therefore, these clinical characteristics were incorporated into the clinical model to predict the risk of progression in postoperative solid-stage NSCLC patients. A total of 294 deep learning features with nonzero coefficients were selected. The DLS in the progressive group was (0.721 ± 0.371), which was higher than that in the nonprogressive group (0.113 ± 0.350) (p < 0.001). The combination of size、NSE、CA199、pathological stage and DLS demonstrated the superior performance in differentiating postoperative progression status. The AUC of the MDLR model was 0.885 (95% confidence interval [CI]: 0.842–0.927), higher than that of the clinical model (0.675 (95% CI: 0.599–0.752)) and DLS model (0.882 (95% CI: 0.835–0.929)). The DeLong test and decision in curve analysis revealed that the MDLR model was the most predictive and clinically useful model.ConclusionMDLR model is effective in predicting the risk of postoperative progression of solid stage I NSCLC, and it is helpful for the treatment and follow-up of solid stage I NSCLC patients.

Avelumab First-Line Maintenance for Locally Advanced or Metastatic Urothelial Carcinoma: Results From the Real-World US PATRIOT-II Study

IntroductionIn JAVELIN Bladder 100, avelumab first-line maintenance (1LM) improved overall survival (OS) and progression-free survival (PFS) in patients with locally advanced/metastatic urothelial carcinoma (la/mUC) without progression following 1L platinum-based chemotherapy (PBC) versus best supportive care. PATRIOT-II describes real-world outcomes with avelumab 1LM. Patients and MethodsThis observational, retrospective study of avelumab 1LM in US community/academic centers used medical record data collected from avelumab initiation for ≥12 months to assess survival, safety, and healthcare resource utilization; analyses are descriptive. ResultsThe study included 160 patients from 37 centers (median age, 70 years; 77% male). Avelumab 1LM was initiated at a median of 4 weeks (IQR 3-6) after PBC completion. Median follow-up from avelumab 1LM was 16 months (IQR 11-21). At study end, 19.4% of patients continued avelumab; 73.7% had discontinued due to progression, adverse events (AEs), or performance status deterioration. Median PFS and OS from avelumab initiation were 5.4 months (95% CI, 3.8-6.9) and 24.4 months (95% CI, 20.4-28.4), respectively. Grade ≥3 treatment-related AEs (TRAEs) occurred in 15 patients (9.4%); 35 (21.9%) had any-grade immune-related AEs, and 23 (14.3%) received high-dose systemic corticosteroids for AEs. Forty-four patients (27.5%) were hospitalized during the avelumab treatment period, of whom 13 (8.1%) were hospitalized due to TRAEs. Limitations of this study include a small sample size, potential selection bias, and missing/unknown data. ConclusionThese results align with the JAVELIN Bladder 100 clinical trial and other real-world studies, supporting avelumab 1LM use in patients with la/mUC without progression following 1L PBC.

CLAG±DAC regimen in the treatment of refractory/relapsed acute myeloid leukemia

Objective: To investigate the efficacy and prognosis of CLAG±DAC (Clofarabine, Cytarabine, G-CSF±Decitabine) chemotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML) . Methods: Continuous cases of R/R AML treated with the CLAG+DAC protocol or CLAG alone at the First Affiliated Hospital of Soochow University from January 2017 to December 2021 were retrospectively analyzed. The baseline characteristics, individual treatment regimen, treatment effect, disease progression, and survival status of patients were recorded. The factors influencing the efficacy of the CLAG±DAC chemotherapy regimens were analyzed, and the overall survival (OS) time after reinduction was calculated using the Kaplan-Meier method. Results: This study included a total of 53 patients, with 33 male patients and an average age of 40.6 years. Thirty-three patients achieved complete remission (CR+CRi) of the disease after the CLAG±DAC chemotherapy regimen and six patients achieved partial remission (PR), while 14 did not. Thirty-two patients eventually underwent hematopoietic stem cell transplantation, and the median OS of the patients was 55.9 months until follow-up. Patients with disease remission after the application of the CLAG±DAC chemotherapy had a significantly longer survival time than those without remission (P<0.001). The results of the multifactorial analysis have revealed that combined DAC (OR=4.60, 95% CI 1.14-23.5, P=0.04) and DNMT3A mutation (OR=0.14, 95% CI 0.01-0.89, P=0.05) were the factors influencing the efficacy of the CLAG±DAC chemotherapy regimen. The remission rate was relatively higher in patients with R/R AML combined with FLT3-ITD mutation by applying the DAC+CLAG regimen (OR=10.84, 95%CI 1.48-288.50, P=0.04) . Conclusion: The CLAG±DAC regimen is considered effective in patients with R/R AML, whereas decitabine combined with the CLAG regimen is more suitable for patients with R/R AML combined with FLT3-ITD mutation.

Different Associations between Lipid Levels and Risk for Heart Failure according to Diabetes Progression.

The relationship between circulating lipid levels and the risk for heart failure (HF) is controversial. We aimed to examine this association, and whether it is modified by the duration of diabetes or treatment regimens in people with type 2 diabetes mellitus. Individuals (n=2,439,978) who underwent health examinations in 2015 to 2016 were identified from the Korean National Health Information Database. Subjects were categorized according to the duration of diabetes (new-onset, <5, 5-10, or ≥10 years) and number of antidiabetic medications. Incident HF was defined according to the International Classification of Diseases, 10th Revision (ICD-10) code I50 as the primary diagnosis during hospitalization. The risk for HF was estimated using multivariate Cox proportional hazard analysis. During a median follow-up of 4.0 years, 151,624 cases of HF occurred. An inverse association between low-density lipoprotein cholesterol (LDL-C) levels and incident HF was observed in the new-onset diabetes group, with an approximately 25% lower risk in those with LDL-C levels of 100-129, 130-159, and ≥160 mg/dL, compared to those with levels <70 mg/dL. However, J-shaped associations were noted in the long-standing diabetes group, with a 16% higher risk in those with LDL-C level ≥160 mg/dL, compared to those with levels <70 mg/dL. Similar patterns were observed in the relationship between total cholesterol or non-high-density lipoprotein cholesterol and the risk for HF, and when subjects were grouped according to the number of antidiabetic medications instead of diabetes duration. Different associations between lipid levels and the risk for HF were noted according to disease progression status among individuals with diabetes.

Budget impact of resmetirom for the treatment of adults with non-cirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis)

Aims This study assessed the budget impact of resmetirom as a treatment for adults with non-cirrhotic non-alcoholic steatohepatitis (NASH) with moderate-to-advanced liver fibrosis and estimated total costs for a hypothetical private payer in the United States. Materials and methods A three-year budget impact analysis based on an open cohort state transition model was developed for a hypothetical one-million-member private health plan. The comparator was Standard of Care (SOC), defined as routine care for non-cirrhotic NASH patients with moderate-to-advanced liver fibrosis. Each year, the number of resmetirom treatment-eligible patients was estimated through prevalent, incident, and diagnostic rate estimates. Costs included resources incurred by the medical and pharmacy benefits of private payers, including resmetirom drug acquisition costs, diagnosis and monitoring, other medical and other prescription costs stratified by disease progression status (i.e. non-cirrhotic vs. cirrhotic/advanced liver diseases). Resmetirom adverse event management costs were included in sensitivity analysis. Drug costs were estimated based on the average wholesale acquisition cost as of March 2024. Other costs were based on published sources and inflated to 2023 US dollars. Budget impact outcomes were presented in aggregate, net, and on a per-member per-month (PMPM) basis. Results Compared with a scenario without resmetirom, the introduction of resmetirom yielded results ranging from 50 to 238 treated patients, net budget impact of $2.2 to $9.5 million, and PMPM from $0.19 to $0.80 over years one and three. Net costs excluding resmetirom declined over time. In sensitivity analyses, results were most sensitive to diagnostic and epidemiologic inputs. Limitations Market shares are based on internal forecasts, a short time horizon, average treatment effects, and other limitations common to BIMs. Conclusion The adoption of resmetirom on the formulary for the treatment of non-cirrhotic NASH with moderate-to-advanced liver fibrosis resulted in a moderate increase in budget impact with declining costs related to NASH progression.

Outcomes of EGFR, ALK, ROS1, BRAF, MET, and RET mutated non-small cell lung cancer with brain metastases (NSCLC BM).

201 Background: Non-small cell lung cancer (NSCLC) is a leading cause of brain metastases. Advances in gene-directed therapies have shifted the focus away from traditional platinum-based chemotherapies. Key targeted mutations in NSCLC include EGFR, ALK, BRAF, MET exon skipping, RET fusions, and ROS1 rearrangements. This retrospective study aims to explore overall survival (OS) and progression-free survival (PFS) in NSCLC BM patients with these gene mutations. Methods: In this retrospective study, conducted by the Department of Medical Oncology at Beijing Tiantan Hospital and the First Medical Center, PLA General Hospital, we reviewed 1526 patients with NSCLC brain metastasis from 2010 to 2022. Data collected included molecular marker status, systemic therapies, and dates of progression. The analysis focused on determining OS and PFS from the time of brain metastasis diagnosis to the last follow-up or death. Statistical analysis used the Cox proportional hazards model. Results: The study reviewed 1526 patients, identifying the following mutation distribution: EGFR mutations in 628 patients, ALK rearrangements in 207 patients, ROS1 rearrangements in 64 patients, BRAF mutations in 31 patients, MET exon skipping in 55 patients, and RET fusions in 42 patients. Significant variations in median OS (mOS) and median PFS (mPFS) were observed across these mutation groups. Patients with EGFR and ALK mutations demonstrated longer mOS and mPFS. Patients with RET and ROS1 mutations also showed better outcomes compared to those with BRAF and MET mutations. Conclusions: This study highlights the importance of molecular mutations in NSCLC BM as prognostic indicators and therapeutic targets. EGFR and ALK mutations were associated with more favorable outcomes, emphasizing the need for personalized medicine in managing NSCLC BM. The study suggests further research focused on specific mutation types is crucial to refine treatment strategies and improve patient care.

Factors associated with radiographic progression and neurologic decline in patients with isolated traumatic subarachnoid hemorrhage

BackgroundComplicated mild traumatic brain injury (cmTBI) is a common neurosurgical disorder that consumes a significant amount of healthcare resources without a clearly established benefit. Best practices for the management of cmTBI regarding triage, hospital admission, and the necessity for repeat imaging are controversial. Our objective is to describe the rate of radiographic progression and neurologic decline for isolated traumatic subarachnoid hemorrhage (itSAH) patients admitted to the hospital. We hypothesized that only a minority of itSAH patients suffer radiographic progression and that radiographic progression is not necessarily associated with neurologic decline.MethodsDatabase queries and direct patient chart reviews were used to gather patient data. T-tests and Fisher’s exact tests were performed.ResultsA total of 340 patients with cmTBI associated with itSAH were included for analysis. The radiographic progression rate was 5.6%. There was no statistically significant association between age, gender, GCS at presentation, anticoagulation status, and risk of radiographic progression. However, subgroup analysis on anticoagulated patients did show those on warfarin had a statistically significant risk of radiographic progression (p = 0.003). No patient developed neurologic decline, irrespective of whether they developed radiographic progression.ConclusionSecondary triaging, hospital admission, ICU stay, and repeat HCT might not be necessary for awake, GCS 13–15 patients with itSAH without any other significant injuries. In the case of anticoagulant use, but not necessarily antiplatelet use, the medication should be reversed, and admission should be considered.

Lifestyle Intervention Modulates the CD4+ T Cell Profile in the Blood of Crohn's Disease Patients.

Crohn's disease (CD) significantly affects patients' well-being and is influenced by stress and lifestyle factors, highlighting the importance of improving quality of life in CD management. An imbalance between pro- and anti-inflammatory CD4+ T cell responses is a key factor in CD, and stress has been shown to alter the function of CD4+ T cells. Therefore, this study aimed to evaluate the effect of a mind-body medicine stress management and lifestyle modification (MBM) program on the CD4+ T cell profile in CD patients. Circulating CD4+ T cells from CD patients were analyzed by flow cytometry following the MBM program. Patients were randomly assigned to either a guided intervention group (IG) or a self-guided waitlist control group (CG) over a 9-month trial and compared with healthy blood donors. Lifestyle intervention reduced regulatory T cell (Treg) frequencies in the blood of CD patients. Notably, we observed a significant correlation between the quality of life improvement and Treg frequencies in the IG but not in the CG. Furthermore, differential activation and expression of the gut-homing molecules G protein-coupled receptor 15 and CCR9 on circulating Tregs and CD4+ effector T cells were detected in both the IG and CG. The MBM program, whether guided or self-directed, has the potential to restore the CD4+ T cell profile of CD patients to levels comparable to healthy blood donors. Lifestyle interventions may benefit CD progression, symptoms, and immunological status, but further analysis is needed to substantiate these findings and to fully understand their clinical implications. (ClinicalTrials.gov: NCT05182645).

Low expression of Lnc-ENST00000535078 inhibits the migration, invasion, and enhances apoptosis of CTPE-induced malignantly transformed BEAS-2B cells.

Long non-coding RNA (LncRNA) plays an important role in malignant transformation of cells. This study aimed to explore the role of Lnc-ENST00000535078 in the malignant transformation of immortalized human bronchial epithelial cells (BEAS-2B) induced by coal tar pitch extract (CTPE). The malignant transformation model of BEAS-2B cells exposed to CTPE. Cell proliferation was examined by Cell counting kit-8 (CCK-8) assay. Colony formation assay was used to assess the colony of cells. Cell migration and invasion were detected by Transwell analysis. Cell cycle progression and apoptotic status were assessed by flow cytometry. Differentially expressed genes were screened by RNA sequencing. The results showed that Lnc-ENST00000535078 expression was highest in malignantly transformed BEAS-2B cells passaged to the 30th generation. Knockdown of Lnc-ENST00000535078 inhibited the migration, invasion and anti-apoptotic abilities of malignantly transformed BEAS-2B cells. Transcriptome analysis found 608 differential genes. CCND1 and FOS genes were screened out because of their levels were positive correlation with the expression of Lnc-ENST00000535078, which were consistent with the RNA sequencing results. In conclusion, Low expression of Lnc-ENST00000535078 inhibits the migration and invasion of malignant transformed BEAS-2B cells and promotes apoptosis in these cells. Lnc-ENST00000556926 might affect the malignant transformation of cells through the regulation of CCND1 and FOS. This study may provide a potential target for intervention in CTPE-induced lung cancer.

Effect of Statins on Patients With Osteoradionecrosis of the Jaw

BackgroundOsteoradionecrosis of the jaw (ORN) is a refractory late complication of radiation therapy. Radiation-induced fibrosis (RIF) is the most likely mechanism for developing ORN, and statins are effective against RIF. However, no reports have indicated the direct effectiveness of statins in treating ORN. PurposeThis study aimed to measure the association between statin exposure and ORN disease resolution. Study design, setting, sampleThis retrospective cohort study included patients with ORN diagnosed between January 2008 and December 2020 at the Hospital’s Department of Oral and Maxillofacial Surgery. Patients who were immunocompromised or followed up for < 6 months were excluded. Predictor variableThe predictor variable was statin exposure, which was defined as the use of statins for dyslipidemia by coincidence. Main outcome variableThe main outcome variable was ORN disease progression status (good prognosis). Patients who showed full recovery and improvement were included in the good prognosis group, and those who showed invariance and deterioration were included in the poor prognosis group. CovariatesWe analyzed the clinicodemographic including the age of onset, sex, history of smoking, alcohol consumption, history of chemotherapy, tumor site, association with dental treatment, location (maxilla or mandible), the time to ORN onset from radiation therapy, and stage of ORN, and treatment characteristics including hyperbaric oxygen therapy, long-term macrolide administration, and sequestrectomy. AnalysesWe analyzed the association between statin exposure/covariates and time to ORN improvement using bivariate and multivariate Cox regression. The significance level was set at p = 0.05. ResultsWe analyzed 102 patients, and the improvement rate was 32.4%. The favorable prognostic factors were statin exposure (adjusted hazard ratio [HR], 3.71; 95% confidence interval [CI], 1.62–8.50; p = 0.002), onset in the maxilla (HR, 2.15; 95% CI, 1.02–4.55; p = 0.045), and stage 1 of ORN (HR, 2.65; 95% CI, 1.20–5.83; p = 0.016). Conclusions and RelevanceIn this study, statin exposure, onset in the maxilla, and stage 1 of Lyons’s classification were favorable prognostic factors for ORN. Statins may be a novel and effective treatment for ORN.

Concordance and Prognostic Relevance of Different Definitions of Systemic Sclerosis Interstitial Lung Disease Progression.

Interstitial lung disease (ILD) in systemic sclerosis (SSc) is a common complication that has varied progression rate and prognosis. Different progression definitions are available: include minimal clinically important worsening of forced vital capacity (FVC MCIW), EUSTAR (EUropean Scleroderma Trials and Research group) progression, OMERACT (Outcome Measures in Rheumatology Clinical Trials) progression, and Erice ILD working group progression. Pulmonary function and symptoms changes may act as specific confounding factors applying these definitions in SSc. To assess the concordance and prognostic value of four different definitions in SSc-ILD patients overall and specific clinical groups. Progression status in consecutive SSc-ILD patients was assessed over 24 months, 60-month disease-related mortality risk was compared between progressors and non-progressors using the four definitions. Among 245 patients, 26 SSc-related deaths were reported. Mortality was linked to progression for FVC MCIW (HR 2.27, 95% CI 1.03-4.97), OMERACT (HR 2.90, 95% CI 1.28-6.57), and Erice definitions (HR 11.02, 95% CI 2.38-51.08). The association between progression and mortality was poor in patients with disease duration ≥3 years, mild functional impairment, and pulmonary artery systolic pressure (PASP)≥40 mmHg. Erice criteria appeared superior in patients with duration ≥3 years, limited cutaneous variant, and PASP<40 mmHg. OMERACT criteria performed better in diffuse cutaneous variant patients with severe functional impairment. The four evaluated definitions of progression in SSc-ILD are not interchangeable, resulting in up to a third of cases being classified differently based on the adopted criteria, and presenting different prognostic values, particularly within specific clinical groups.

Segmental deformity markers offer novel indicators of deformity progression risk in deformity-matched adolescent idiopathic scoliosis patients.

Identification of adolescent idiopathic scoliosis (AIS) patients with mild curvatures who pose significant risk of progressing to severe levels of curvatures is of paramount importance for clinical care. This study aimed to compare segmental deformity changes in AIS sub-cohorts that are dichotomised by progression status. Thirty-six female participants with Lenke 1 AIS curves were investigated with sequential MRIs during growth. Scans were reformatted to measure orthogonal segmental parameters, including sagittal/coronal wedging angles and axial rotation angles. Participants were dichotomised by progression. Two-tailed, independent sample t-tests were used to compare sub-cohort multi-segmental and segmental deformity parameters. Measurements were compared at each scan number and variable rates of change were determined using actual time between measures. AIS progression status sub-cohorts were comparable at scan 1 for multi-segmental deformity parameters (e.g. major thoracic curve angle, rib hump, kyphosis) (P > 0.05). However, apical measures of coronal IVD wedging, axial IVD rotation and axial vertebral rotation were segmental parameters at scan 1 which were larger for participants whose AIS would later go on to clinically progress (all P < 0.05). Measures of segmental hypokyphosis were comparable between groups. As development was tracked at each subsequent scan, coronal and axial plane differences between groups increased in both magnitude and number of differences. Initial disparity and then subsequent increasing magnitude of change of axial rotation may indicate a higher propensity to clinically progress in the future. This knowledge hopes to provide useful management information for AIS care providers and prognostic education for patients alike. II.

Gamification as a panacea to workplace cyberloafing: an application of self-determination and social bonding theories

PurposeGamification has been constantly demonstrated as an effective mechanism for employee engagement. However, little is known about how gamification reduces cyberloafing and the mechanism by which it affects cyberloafing in the workplace. This study draws inspiration from self-determination and social bonding theories to explain how game dynamics, namely, personalised challenges, social interactivity and progression status, enhance tacit knowledge sharing behaviour, which, in turn, reduces cyberloafing. In addition, the study also examines the negative moderating effect of fear of failure on the positive relationship between game dynamics and tacit knowledge sharing.Design/methodology/approachUsing a sample of 250 employees from information technology organisations, the study employed a 3-wave study to examine the conditional indirect effects.FindingsThe results ascertain that tacit knowledge sharing plays a central role in the relationship between gamification and cyberloafing. Further, game dynamics positively influenced tacit knowledge sharing, which in turn reduced cyberloafing. Especially, social interactivity and progression status greatly reduced cyberloafing behaviour when the fear of failure was low.Originality/valueThis study is one of the initial studies that suggest gamification as a progressive tool to reduce workplace cyberloafing behaviours. It utilises a problematisation approach to analyse and criticise the in-house assumptions regarding cyberloafing prevention measures. Further, the study proposes a conceptual model explaining the link between gamification and cyberloafing through alternate assumptions.