Search

Background: For patients with psoriasis, discontinuation of biologics following remission has become more common in daily practice. Objective: We aimed to identify predictors and construct a predictive model for time to relapse following withdrawal from biologics. Methods: This 12-year, multicenter, observational cohort study was performed in six dermatology centers between February 2011 and February 2024. We identified biological treatment episodes in patients with moderate-to-severe psoriasis and included only treatment episodes in which a clinical response (≥ 50% reduction in Psoriasis Area and Severity Index score [PASI 50] from baseline) was achieved and the patient withdrew from biological therapy with a well-controlled status (PASI < 10 and ≥ 50% improvement in PASI from baseline). The primary outcome was time to relapse, which was defined as the period from the last biologic administration to relapse. An extended multivariate Cox proportional hazards analysis (Prentice–Williams–Peterson Gap time model) was used to predict relapse and generate a predictive model. Results: This study screened 1613 biological treatment episodes, and 991 treatment episodes were enrolled. The time to relapse decreased significantly as the number of previous withdrawals from biological treatment increased (p < 0.001). Similarly, the time to relapse decreased significantly as the number of previous biologics used increased (p < 0.001). The maximum PASI improvement during biological treatment decreased and the PASI score at withdrawal of biological treatment increased in parallel as the number of prior withdrawals from biologics increased. The time to relapse following withdrawal was longest for interleukin (IL)-23 inhibitors (IL-23i), followed by the IL-12/23i, IL-17 inhibitors (IL-17i), and tumor necrosis factor-α inhibitors. After adjustment, multivariate Cox regression identified the following significant predictors of relapse following withdrawal: the mechanisms of action of biologics (hazard ratio [HR] for IL-17i vs IL-12/23i, 1.59; HR for IL-23i vs IL-12/23i, 0.60), number of previous withdrawals from biological treatment (HR 1.23; 95% confidence interval [CI] 1.13‒1.33), time to achieve PASI 50 (HR 1.01; 95% CI 1.00‒1.02), maximum PASI improvement on biologics (HR 0.98; 95% CI 0.98‒0.99), and PASI at the end of therapy (HR 1.03; 95% CI 1.01‒1.05). The model had good predictive and discriminative ability. Conclusions: These results have the potential to help physicians and patients make individualized treatment decisions; information on the risk of relapse of psoriasis at specific timepoints following the withdrawal of biologics is particularly valuable for patients considering discontinuation of biologics or as-needed biologic therapy. However, the benefit and risk of repeated withdrawals of biologics should be carefully weighed, as the treatment efficacy and duration of remission decline as the number of withdrawals increases. [ABSTRACT FROM AUTHOR]

In classic galactosemia (CG) patients, aldose reductase (AR) converts galactose to galactitol. In a phase 1/2, placebo‐controlled study (NCT04117711), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of govorestat were evaluated after single and multiple ascending doses (0.5‐40 mg/kg) in healthy adults (n = 81) and CG patients (n = 14). Levels of govorestat in plasma and cerebrospinal fluid (CSF) and blood levels of galactitol, galactose, and galactose‐1‐phosphate (Gal‐1p) were measured for population PK and PK/PD analyses. Govorestat was well tolerated. Adverse event frequency was comparable between placebo and govorestat. Govorestat PK displayed a 2‐compartment model with sequential zero‐ and first‐order absorption, and no effect of demographic factors. Multiple‐dose PK of govorestat was linear in the 0.5‐40 mg/kg range, and CSF levels increased dose dependently. Elimination half‐life was ∼10 h. PK/PD modeling supported once‐daily dosing. Change from baseline in galactitol was −15% ± 9% with placebo and −19% ± 10%, −46% ± 4%, and −51% ± 5% with govorestat 5, 20, and 40 mg/kg, respectively, thus was similar for 20 and 40 mg/kg. Govorestat did not affect galactose or Gal‐1p levels. In conclusion, govorestat displayed a favorable safety, PK, and PD profile in humans, and reduced galactitol levels in the same magnitude (∼50%) as in a rat model of CG that demonstrated an efficacy benefit on neurological, behavioral, and ocular outcomes. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to comprehensively assess the safety of rimegepant administration in real-world clinical settings. Methods: Data from the Food and Drug Administration Adverse Event Reporting System (FAERS) spanning the second quarter of 2020 through the first quarter of 2023 were retrospectively analyzed in this pharmacovigilance investigation. This study focuses on employing subgroup analysis to monitor rimegepant drug safety. Descriptive analysis was employed to examine clinical characteristics and concomitant medication of adverse event reports associated with rimegepant, including report season, reporter country, sex, age, weight, dose, and frequency, onset time, et al. Correlation analysis, including techniques such as violin plots, was utilized to explore relationships between clinical characteristics in greater detail. Additionally, four disproportionality analysis methods were applied to assess adverse event signals associated with rimegepant. Results: A total of 5,416,969 adverse event reports extracted from the FAERS database, 10, 194 adverse events were identified as the "primary suspect" (PS) drug attributed to rimegepant. Rimegepant-associated adverse events involved 27 System Organ Classes (SOCs), and the significant SOC meeting all four detection criteria was "general disorders and administration site conditions" (SOC: 10018065). Additionally, new significant adverse events were discovered, including "vomiting projectile" (PT: 10047708), "eructation" (PT: 10015137), "motion sickness" (PT: 10027990), "feeling drunk" (PT: 10016330), "reaction to food additive" (PT: 10037977), etc. Descriptive analysis indicated that the majority of reporters were consumers (88.1%), with most reports involving female patients. Significant differences were observed between female and male patients across age categories, and the concomitant use of rimegepant with other medications was complex. Conclusion: This study has preliminarily identified potential new adverse events associated with rimegepant, such as those involving the gastrointestinal system, nervous system, and immune system, which warrant further research to determine their exact mechanisms and risk factors. Additionally, significant differences in rimegepant-related adverse events were observed across different age groups and sexes, and the complexity of concomitant medication use should be given special attention in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: The 48‐week, phase 2 SLEek study (NCT03978520) evaluated the efficacy and safety of upadacitinib (JAK inhibitor) and elsubrutinib (BTK inhibitor) alone or in combination (ABBV‐599) in adults with moderately to severely active systemic lupus erythematosus (SLE). Methods: Patients were randomized 1:1:1:1:1 to elsubrutinib 60 mg and upadacitinib 30 mg once daily (ABBV‐599 high dose), elsubrutinib 60 mg and upadacitinib 15 mg once daily (ABBV‐599 low dose), elsubrutinib 60 mg once daily (QD), upadacitinib 30 mg QD, or placebo QD. The primary endpoint was the proportion of patients achieving both Systemic Lupus Erythematosus Responder Index 4 (SRI‐4) and glucocorticoid dose ≤10 mg QD at week 24. Additional assessments through week 48 included British Isles Lupus Assessment Group‐Based Composite Lupus Assessment (BICLA) and Lupus Low Disease Activity State (LLDAS) responses, number of flares, time to first flare, and adverse events. Results: The study enrolled 341 patients. The ABBV‐599 low dose and elsubrutinib arms were discontinued after a planned interim analysis showed lack of efficacy (no safety concerns). More patients achieved the primary endpoint with upadacitinib (54.8%; P = 0.028) and ABBV‐599 high dose (48.5%; P = 0.081) versus placebo (37.3%). SRI‐4, BICLA, and LLDAS response rates were higher for both upadacitinib and ABBV‐599 high dose versus placebo at weeks 24 and 48. Flares were reduced, and time to first flare through week 48 was substantially delayed with both upadacitinib and ABBV‐599 high dose versus placebo. No new safety signals were observed beyond those previously reported for upadacitinib or elsubrutinib. Conclusion: Upadacitinib 30 mg alone or in combination with elsubrutinib (ABBV‐599 high dose) demonstrated significant improvements in SLE disease activity and reduced flares and were well tolerated through 48 weeks. [ABSTRACT FROM AUTHOR]

Background: Chronic migraine is closely related to the dysregulation of neurochemical substances in the brain, with metabolic imbalance being one of the proposed causes of chronic migraine. This study aims to evaluate the metabolic changes between energy metabolism and excitatory and inhibitory neurotransmitters in key brain regions of mice with chronic migraine-like state and to uncover the dysfunctional pathways of migraine. Methods: A chronic migraine-like state mouse model was established by repeated administration of nitroglycerin (NTG). We used von Frey filaments to assess the mechanical thresholds of the hind paw and periorbital in wild-type and familial hemiplegic migraine type 2 mice. After the experiments, tissue was collected from five brain regions: the somatosensory cortex (SSP), hippocampus, thalamus (TH), hypothalamus, and the spinal trigeminal nucleus caudalis (TNC). Proton magnetic resonance spectroscopy (1H-MRS) was employed to study the changes in brain metabolites associated with migraine, aiming to explore the mechanisms underlying metabolic imbalance in chronic migraine-like state. Results: In NTG-induced chronic migraine-like state model, we observed a significant reduction in energy metabolism during central sensitization, an increase in excitatory neurotransmitters such as glutamate, and a tendency for inhibitory neurotransmitters like GABA to decrease. The TNC and thalamus were the most affected regions. Furthermore, the consistency of N-acetylaspartate levels highlighted the importance of the TNC-TH-SSP pathway in the ascending nociceptive transmission of migraine. Conclusion: Abnormal energy metabolism and neurotransmitter imbalance in the brain region of NTG-induced chronic migraine-like state model are crucial mechanisms contributing to the chronicity of migraine. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study is to investigate the effect of anti-interleukin (IL)-1/-6 biologics on systemic juvenile idiopathic arthritis (sJIA)-associated macrophage activation syndrome (MAS). Methods Demographic, clinical and laboratory data of patients followed up with a diagnosis of sJIA-associated MAS assessed from sixteen paediatric rheumatology centres across the country. The clinical and laboratory features of MAS developing while on biological drugs were compared with those without this treatment. Results One hundred and sixty-two patients were included in the study. Forty-five of the MAS events were detected under the effect of anti-IL-1/-6 biologics, while the patients experiencing the remaining 155 events have not received biological treatment in the last three months. Platelet count [128 (72–232) vs 199 (130–371) 109/l], ferritin level on admission [1107 (676–2050) vs 2863 (1193–9562) ng/ml], C-reactive protein level [15.4 (2.9–56) vs 90 (32–160) mg/l], erythrocyte sedimentation rate [13 (3–36) vs 43.5 (13–77) mm/h] and fever duration [5 (4–7.5) vs 10 (7–14.3) days] were found lower in the group under the impact of anti-IL-1/-6 biologics. Among patients treated with biologics, 26.6% did not meet the published 2016 MAS classification criteria at presentation. The rates of hepatomegaly and splenomegaly were relatively lower in the canakinumab-treated group when compared with those receiving other biologicals or to patients, not on biologicals. Conclusion Anti-IL-1/-6 therapies can mask the clinical and laboratory features of MAS, and proposed guidelines for MAS classification criteria may not be met. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to examine whether creatine kinase (CK) elevation occurs with interleukin (IL)-6 inhibitors, as in Janus kinase (JAK) inhibitors, which are reported to increase CK levels in rheumatoid arthritis. Patients and methods: A multicenter database of JAK inhibitor and IL-6 inhibitor treatment was retrospectively searched between January 2016 to December 2022; 142 cases (117 females, 25 males, mean age: 63.8±13.0 years; range, 20 to 85 years), with 71 cases in each group, were extracted by propensity score matching using age, sex, body mass index, and CK at 0 weeks. The outlier rate was compared. Patients’ background characteristics related to elevated CK levels at 24 weeks were investigated by univariate and multivariate analyses. Results: Creatine kinase levels at 4 and 12 weeks were significantly higher with JAK inhibitors than with IL-6 inhibitors (four weeks, 72 vs. 87.5 IU/mL, p=0.016; 12 weeks, 71 vs. 95.5 IU/mL, p=0.028). The outlier rate (Grade 1) with JAK inhibitors increased significantly over time (0 weeks, 4.2%; four weeks, 18.1%; 12 weeks, 21.7%; 24 weeks, 18.3%; p=0.015), whereas that with IL-6 inhibitors increased slightly (0 weeks, 5.6%; four weeks, 9.2%; 12 weeks, 8.6%; 24 weeks, 8.5%; p=0.745), with a significant difference between the groups (p=0.035). No patients discontinued treatment due to myalgia or renal dysfunction. The factors significantly positively related to elevated CK levels at 24 weeks were male sex and creatinine. Those significantly negatively related were Steinbrocker stage and class, modified health assessment questionnaire scores, estimated glomerular filtration rate, and glucocorticoid dose. Conclusion: Mild CK elevations with JAK inhibitors are not a particular clinical problem. CK elevation might be specific to JAK inhibitors. [ABSTRACT FROM AUTHOR]

Objectives Fibrodysplasia ossificans progressiva (FOP) is one of the most catastrophic forms of genetic heterotopic ossification (HO). FOP is characterized by severe, progressive inflammatory flare-ups, that often lead to HO. The flare-ups are associated with increased inflammatory cytokine production, suggesting auto-inflammatory features driven by IL-1β. This study describes the short- and long-term responses of FOP patients to anti-IL-1 therapy. Methods Previously, we reported that a patient with FOP treated with anti-IL-1 agents showed dramatically lower rates of flare-ups, improved flare-up symptoms, decreased use of glucocorticoids and apparently decreased size of residual lesions. Plasma analyses also showed marked elevation in IL-1β levels during a FOP flare, further supporting a role of IL-1β in the pathogenesis of FOP flares. Here, we report results from long-term therapy with IL-1 inhibitors in that patient and describe 3 additional patients, from two medical centres. Results All 4 patients showed persistent improvement in flare activity during treatment with IL-1 inhibitors, with minimal formation of new HO sites. Two patients who stopped therapy experienced a resurgence of flare activity that was re-suppressed upon re-initiation. These patients had IL-1β levels comparable to those in IL-1β-driven diseases. Child Health Assessment Questionnaires confirmed extensive subjective improvements in the pain and general health visual analogue scales. Conclusion This case series demonstrates significant benefits from IL-1 inhibitors for reducing flare activity and improving the general health of patients with FOP. These data provide strong support for additional studies to better understand the function of IL-1 inhibition, primarily in reducing the formation of new HO. Funding RH received support from the International FOP Association ACT grant; ECH received support from NIH/NIAMS R01AR073015 and the UCSF Robert Kroc Chair in Connective Tissue and Rheumatic Diseases III. [ABSTRACT FROM AUTHOR]

Background: The optimal management of euvolemic and hypervolemic hyponatremia remains controversial. The effectiveness of the vasopressin receptor antagonist tolvaptan on serum sodium normalization has been well described in the literature, although the associated risk of serum sodium overcorrection limits its use. Urea has been proposed as an alternative treatment option due to its milder serum sodium raising effects and adverse event profile. Objective: This study aimed to compare urea and tolvaptan for their serum sodium raising effects and potential for overcorrection. Methods: In a multicenter retrospective review, 46 hospitalized patients who received either urea or tolvaptan for the management of hyponatremia were evaluated for the rate of serum sodium normalization and overcorrection. Results: Mean serum sodium concentrations at baseline were 125.91 mEq/L and 123.83 mEq/L for patients treated with urea and tolvaptan, respectively. After 12 hours, tolvaptan was associated with a significantly higher rate of serum sodium increase compared with urea (5.05 mEq/L vs 1.10 mEq/L; P =.001). However, no statistically significant differences were observed in the mean change in serum sodium concentrations at 24 hours, 48 hours, or with the proportion of patients who reached a serum sodium concentration of 135 mEq/L. Overcorrection rates were significantly higher with tolvaptan compared with urea at 43% and 9%, respectively. Conclusion: The results of this study suggest that urea has a comparable effectiveness profile to tolvaptan for the management of hyponatremia with a significantly reduced risk of overcorrection. [ABSTRACT FROM AUTHOR]

Simple Summary: Regorafenib offers longer survival for patients with refractory metastatic colorectal cancer (mCRC). We aimed to identify biomarkers for regorafenib through preclinical and translational studies. In silico analysis identified matrix metalloproteinase (MMP)-14 and MMP-9 as key biomarkers. Validation in patients receiving regorafenib or FTD/TPI showed that high MMP-14 levels were correlated with a better response to regorafenib. Additionally, lower MMP-9 levels before the second cycle were linked to improved disease control and survival. These findings suggest that MMP-14 and MMP-9 could serve as prognostic markers for regorafenib efficacy. In identifying biomarkers for anticancer drugs, the lack of objectivity in selecting candidate factors makes interpretation difficult. We performed preclinical analysis and a translational validation study to identify candidate biomarkers for regorafenib efficacy in metastatic colorectal cancer (mCRC). Using in silico COMPARE analysis with a human cancer cell line panel, JFCR39, we selected candidate biomarkers whose expression correlates with regorafenib sensitivity. We validated predictive values in mCRC patients receiving regorafenib (discovery, n = 53) and FTD/TPI (control, n = 16). Blood samples were obtained at baseline (BL), before the second cycle (2nd), and at progressive disease (PD), and biomarker levels were measured using ELISA. Our analysis showed that high matrix metalloproteinase (MMP)-14 expression was associated with a high sensitivity to regorafenib. In the discovery cohort, high MMP-14 levels at BL and PD were correlated with tumor shrinkage and longer progression-free survival (PFS). A subsequent analysis of other related factors further indicated that the patients with decreased MMP-9 levels at the 2nd had higher disease control rates, tumor shrinkage, longer PFS, and overall survival than those with increased changes. These findings were not observed in the control cohort. Our study suggests MMP-14 and MMP-9 may serve as prognostic markers for regorafenib and provide insights into novel combination therapies with anti-MMP-9 agents or FTD/TPI. [ABSTRACT FROM AUTHOR]

BI 187004, a selective small‐molecule inhibitor of 11β‐hydroxysteroid dehydrogenase‐1 (11β‐HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β‐HSD1 inhibition (50%) was detected in a very low‐dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose‐dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target‐mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high‐affinity and low‐capacity target 11β‐HSD1. The non‐intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small‐molecule compound. Among the various models explored, the best model was a two‐compartment TMDD model with three transit absorption components. The final model provides insights into 11β‐HSD1 binding‐related parameters for BI 187004, including the total amount of 11β‐HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM−1h−1), and the first‐order dissociation rate constant (estimated to be 0.11 h−1). Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004's future clinical trials. [ABSTRACT FROM AUTHOR]

The article focuses on evaluating real-world outcomes in psoriasis treatment when switching to interleukin-23 inhibitors (IL-23i) after ineffectiveness of ustekinumab. It explores drug survival (DS) and effectiveness of IL-23i in patients who previously discontinued ustekinumab due to ineffectiveness compared to those who had not used ustekinumab before. It uses data from the BioCAPTURE registry to analyze outcomes such as Psoriasis Area and Severity Index (PASI) scores and DS rates.

Phytochemical study on 90% ethanol extract from the green walnut husks of Juglans mandshurica Maxim. resulted into the isolation of three undescribed triterpenoids, juglansmanoids A–C (1–3). Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated components were evaluated in vitro for anti-hyaluronidase activities. As a result, triterpenoid 1 exhibited potent anti-hyaluronidase activity (IC50 = 9.78 μg/ml) three times more than the positive control drug oleanolic acid (IC50 = 40.12 μg/ml). [ABSTRACT FROM AUTHOR]

Objective: We assessed and compared immunologic differences and associations with clinical response to guselkumab, a fully human interleukin (IL)–23p19 subunit inhibitor, in participants with active psoriatic arthritis (PsA) who were biologic‐naive or had inadequate response to tumor necrosis factor inhibitors (TNFi‐IR). Methods: Serum biomarker levels at baseline and after treatment with guselkumab 100 mg every 8 weeks were compared between biologic‐naive (n = 251) and TNFi‐IR (n = 93) subgroups identified in the pooled DISCOVER‐1/DISCOVER‐2/COSMOS data set. Baseline biomarker levels determined by achievement of week 24 clinical responses (≥75%/90% improvement in Psoriasis Area and Severity Index [PASI 75/90], Investigator's Global Assessment [IGA] of psoriasis score 0/1 and ≥2‐point improvement], ≥20% improvement in American College of Rheumatology criteria [ACR20]) were compared between prior treatment subgroups. Results: Baseline IL‐22, TNFα, and beta defensin‐2 (BD‐2) levels were significantly lower in biologic‐naive than in TNFi‐IR participants. With guselkumab, week 24 IL‐17A, IL‐17F, IL‐22, serum amyloid A, C‐reactive protein, IL‐6, and BD‐2 levels were significantly reduced from baseline in biologic‐naive and TNFi‐IR participants (≥1.4‐fold difference, nominal P < 0.05). Clinical responders to guselkumab exhibited significantly higher baseline levels of several biomarkers than nonresponders (IL‐17A, IL‐17F, BD‐2 in biologic‐naive PASI 90 responders; IL‐17A, BD‐2 in TNFi‐IR IGA 0/1 responders; IL‐22, BD‐2 in TNFi‐IR PASI 90 responders [nominal P < 0.05]) and trended higher in TNFi‐IR ACR20 responders. Conclusion: Guselkumab modulates IL‐23 signaling and provides consistent pharmacodynamic effects in both biologic‐naive and TNFi‐IR PsA patients. Significantly elevated baseline IL‐22, TNFα, and BD‐2 levels and associations between baseline IL‐22, IL‐17A, and BD‐2 levels and skin responses to guselkumab suggest greater dysregulation of IL‐23/Th17 signaling in patients with TNFi‐IR. [ABSTRACT FROM AUTHOR]

Simple Summary: BET proteins (BRD2, BRD3, BRD4 and BRDT) serve as the readers of DNA acetylation and regulate the expression of key genes in cancer. BET inhibitors were recently developed and have shown efficacy in Phase I/II clinical trials in ovarian cancer. The most thoroughly studied BET protein is BRD4, which is amplified in ~18–19% of ovarian cancer cases according to The Cancer Genome Atlas (TCGA). We explored the prognostic role of the BRD4 gene and protein expression in advanced high-grade serous ovarian carcinoma (HGSC). Low BRD4 gene expression was associated with shorter overall survival compared to intermediate/high BRD4 gene expression at 12 months (95% CI; 1.75–30.49; p = 0.008). Low BRD4 gene expression was also associated with worse progression-free survival (PFS) both at 12 months (95% CI; 1.2–16.5; p = 0.03) and at 24 months (95% CI; 1.1–8.6; p = 0.048). There was no significant association between BRD4 protein expression and overall survival. Background: Bromodomain and extra-terminal (BET) domain proteins that bind to acetylated lysine residues of histones serve as the "readers" of DNA acetylation. BRD4 is the most thoroughly studied member of the BET family and regulates the expression of key oncogenes. BRD4 gene amplification has been identified in ovarian cancer (~18–19%) according to The Cancer Genome Atlas (TCGA) analysis. BET inhibitors are novel small molecules that displace BET proteins from acetylated histones and are currently tested in Phase I/II trials. We here aim to explore the prognostic role of the BRD4 gene and protein expression in the ascitic fluid of patients with advanced FIGO III/IV high-grade serous ovarian carcinoma (HGSC). Methods: Ascitic fluid was obtained from 28 patients with advanced stage (FIGO III/IV) HGSC through diagnostic/therapeutic paracentesis or laparoscopy before the initiation of chemotherapy. An amount of ~200 mL of ascitic fluid was collected from each patient and peripheral blood mononuclear cells (PBMCs) were isolated. Each sample was evaluated for BRD4 and GAPDH gene expression through RT-qPCR and BRD4 protein levels through enzyme-linked immunosorbent assay (ELISA). The study protocol was approved by the Institutional Review Board of Alexandra University Hospital and the Committee on Ethics and Good Practice (CEGP) of the National and Kapodistrian University of Athens (NKUA). Results: Low BRD4 gene expression was associated with worse prognosis at 12 months compared to intermediate/high expression (95% CI; 1.75–30.49; p = 0.008). The same association was observed at 24 months although this association was not statistically significant (95% CI; 0.96–9.2; p = 0.065). Progression-free survival was shorter in patients with low BRD4 gene expression at 12 months (5.6 months; 95% CI; 2.6–8.6) compared to intermediate/high expression (9.8 months; 95% CI; 8.3–11.3) (95% CI; 1.2–16.5; p = 0.03). The same association was confirmed at 24 months (6.9 months vs. 13.1 months) (95% CI; 1.1–8.6; p = 0.048). There was a trend for worse prognosis in patients with high BRD4 protein levels versus intermediate/low BRD4 protein expression both at 12 months (9.8 months vs. 7.6 months; p = 0.3) and at 24 months (14.2 months vs. 16.6 months; p = 0.56) although not statistically significant. Again, there was a trend for shorter PFS in patients with high BRD4 protein expression although not statistically significant both at 12 months (p = 0.29) and at 24 months (p = 0.47). Conclusions: There are contradictory data in the literature over the prognostic role of BRD4 gene expression in solid tumors. In our study, intermediate/high BRD4 gene expression was associated with a favorable prognosis in terms of overall survival and progression-free survival compared to low BRD4 gene expression. [ABSTRACT FROM AUTHOR]

Objective: We aimed to identify the crucial genes involved in dental pulp stem cell (DPSC) senescence and evaluate the impact of melatonin on DPSC senescence. Methods: Western blotting, SA‐β‐Gal staining and ALP staining were used to evaluate the senescence and differentiation potential of DPSCs. The optimal concentration of melatonin was determined using the CCK‐8 assay. Differentially expressed genes (DEGs) involved in DPSC senescence were obtained via bioinformatics analysis, followed by RT–qPCR. Gain‐ and loss‐of‐function studies were conducted to explore the role of MMP3 in DPSC in vitro expansion and in response to melatonin. GSEA was employed to analyse MMP3‐related pathways in cellular senescence. Results: Treatment with 0.1 μM melatonin attenuated cellular senescence and differentiation potential suppression in DPSCs due to long‐term in vitro expansion. MMP3 was a crucial gene in senescence, as confirmed by bioinformatics analysis, RT–qPCR and Western blotting. Furthermore, gain‐ and loss‐of‐function studies revealed that MMP3 played a regulatory role in cellular senescence. Rescue assays showed that overexpression of MMP3 reversed the effect of melatonin on senescence. GSEA revealed that the MMP3‐dependent anti‐senescence effect of melatonin was associated with the IL6‐JAK‐STAT3, TNF‐α‐Signalling‐VIA‐NF‐κB, COMPLEMENT, NOTCH Signalling and PI3K‐AKT‐mTOR pathways. Conclusion: Melatonin attenuated DPSC senescence caused by long‐term expansion by inhibiting MMP3. [ABSTRACT FROM AUTHOR]

Introduction In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need. Materials and Methods We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P  < .05) and Bayesian statistics (BF10). Results Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N  = 43, 63%), without Gorlin syndrome (N  = 56, 82%) and with head and neck area as primary site (N  = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N  = 50/61) due to toxicity (R1), and 18% (N  = 11/61) due to recurrence (R2). Conversely, 10% (N  = 7/68) continued vismodegib until last follow-up. In the whole population (N  = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P  < .01, BF10 = 39.2) and TTD (P  < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N  = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N  = 38, r  = 0.44, P  < .01) and in the recurrent patients who stopped vismodegib for toxicity (N  = 26, r  = 0.665, P  < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N  = 54 vs. ≤ 2 months, N  = 14: 470 vs. 175 d, P  < .01). Conclusions Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC. [ABSTRACT FROM AUTHOR]

* Context.--Unlike B-cell acute lymphoblastic leukemia/lymphoma (ALL/LBL), there have been few therapeutic advances in T-cell ALL (T-ALL)/LBL, an aggressive ALL/LBL subtype. Objective.--To perform a focused tissue array study to elucidate tumor markers of therapeutic potential in T-ALL/LBL. Design.--Using immunohistochemistry, we evaluated expression of leukemic antigens of interest, specifically CCchemokine receptor 4 (CCR4), among others, on available remnant diagnostic material, including tumor tissue slides obtained from formalin-fixed, paraffin-embedded preserved tissues. Results.--Our analysis identified, for the first time, expression of CCR4 in T-ALL/LBL in 11 of 27 cases (40.7%) and confirmed common expression of BCL2, CD38, and CD47, as reported previously. We also identified the expression of CD123 in 4 of 26 cases (15.4%), whereas BCL6 and PDL1 were expressed in a small number of T-ALL/LBL cases. The potential novel target CCR4 was significantly more common in the Pre/Pro-T immunophenotypic subtype, 6 of 9 (66.7%, P = .01). No additional differences in clinical and epidemiologic variables were noted among positive or negative CCR4 cases. Conclusions.--These findings support preclinical and clinical testing of therapies targeting CCR4, CD47, BCL2, CD38, and CD123 in T-ALL/LBL, and may help guide the development of targeted clinical trials in T-ALL/LBL, a rare disease in urgent need of novel therapies. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Tuberculosis has a major global impact. Immunocompetent hosts usually control this disease, resulting in an asymptomatic latent tuberculosis infection (LTBI). Because TNF inhibitors increase the risk of tuberculosis reactivation, current guidelines recommend tuberculosis screening before starting any biologic drug, and chemoprophylaxis if LTBI is diagnosed. Available evidence from clinical trials and real-world studies suggests that IL-17 and IL-23 inhibitors do not increase the risk of tuberculosis reactivation. Objective: To evaluate psoriasis patients with treated or untreated newly diagnosed LTBI who received IL-17 and IL-23 inhibitors and the tolerability/safety of tuberculosis chemoprophylaxis. Methods: This is a retrospective, observational, multinational study from a series of 14 dermatology centres based in Portugal, Spain, Italy, Greece and Brazil, which included adult patients with moderate-to-severe chronic plaque psoriasis and newly diagnosed LTBI who were treated with IL-23 or IL-17 inhibitors between January 2015 and March 2022. LTBI was diagnosed in the case of tuberculin skin test and/or interferon gamma release assay positivity, according to local guideline, prior to initiating IL-23 or IL-17 inhibitor. Patients with prior diagnosis of LTBI (treated or untreated) or treated active infection were excluded. Results: A total of 405 patients were included; complete/incomplete/no chemoprophylaxis was administered in 62.2, 10.1 and 27.7% of patients, respectively. The main reason for not receiving or interrupting chemoprophylaxis was perceived heightened risk of liver toxicity and hepatotoxicity, respectively. The mean duration of biological treatment was 32.87 ± 20.95 months, and only one case of active tuberculosis infection (ATBI) was observed, after 14 months of treatment with ixekizumab. The proportion of ATBI associated with ixekizumab was 1.64% [95% confidence interval (CI): 0–5.43%] and 0% for all other agents and 0.46% (95% CI 0–1.06%) and 0% for IL-17 and IL-23 inhibitors, respectively (not statistically significant). Conclusions: The risk of tuberculosis reactivation in patients with psoriasis and LTBI does not seem to increase with IL-17 or IL-23 inhibitors. IL-17 or IL-23 inhibitors should be preferred over TNF antagonists when concerns regarding tuberculosis reactivation exists. In patients with LTBI considered at high risk for developing complications related to chemoprophylaxis, this preventive strategy may be waived before initiating treatment with IL-17 inhibitors and especially IL-23 inhibitors. [ABSTRACT FROM AUTHOR]

Objective To evaluate clinical characteristics, effectiveness, and tolerability of preventive anti- calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) in the elderly. Anti-CGRP mAbs have demonstrated efficacy and safety in patients with migraine although there is limited information regarding the elderly. Design We performed a multicenter case-control study of cases (patients over 65 years old) and controls (sex-matched patients under 55 years old) with migraine receiving anti-CGRP mAbs. Methods We included the demographic characteristics, effectiveness—reduction in the number of monthly headache days (MHD) and monthly migraine days (MMD), 30%, 50%, and 75% responder rates—and treatment emergent adverse events (TEAEs). The primary endpoint was the 50% response rate regarding MHD at weeks 20–24; exploratory 50% response predictors in the elderly were evaluated. Results In total, 228 patients were included: 114 cases , 114 controls-. Among cases 84.2% (96/114) were women, 79.8% (91/114) CM; mean age of cases 70.1 years old (range: 66–86); mean age of controls was 42.9 years old(range: 38–49). Cases had a higher percentage of vascular risk factors (P  < .05),older age of onset (P  < .001) and more reported prior preventive treatments (P  < .001). Regarding effectiveness in cases, 50% response rate was achieved by 57.5% (42/73) at 20–24 weeks, with lower reduction in the MHD at 8–12 weeks (5 [7.2], 8 [9.1]; P  = .001) and a higher reduction in MMD at 20–24 weeks (10.7 [9.1], 9.2 [7.7]; P  = .04) compared to the control group. The percentage of TEAEs was similar in the 2 groups. Diagnosis of episodic migraine (EM) (P  = .03) and lower number of MHD at baseline (P  =.001) were associated with a 50% response in the elderly in univariate analysis. Conclusions Our study provides real world evidence of effectiveness and safety of anti-CGRP mAbs for migraine in patients without upper age-limit and possible predictors of anti-CGRP response in the elderly. [ABSTRACT FROM AUTHOR]

Polypharmacy is becoming increasingly troublesome in the treatment of cancer. The aim of this study was to explore the effects of concomitant polypharmacy comprising drugs that inhibit CYP3A4 and/or CYP2D6 on the oxycodone tolerability in patients with cancer. We conducted a multicenter retrospective study encompassing 20 hospitals. The data used for the study were obtained during the first 2 wk of oxycodone administration. The incidence of oxycodone discontinuation or dose reductions due to side effects and oxycodone-induced nausea and vomiting (OINV) were compared between patients not treated with either inhibitor and those treated with concomitant CYP3A4 or CYP2D6 inhibitors. The incidence of oxycodone discontinuation or dose reductions in patients treated with ≥3 concomitant CYP2D6 inhibitors (18.2%) tended to be higher than that in patients without this treatment (8.2%; p = 0.09). Moreover, the incidence of OINV in patients treated with 2 concomitant CYP3A4 inhibitors (29.8%) was significantly higher than that in patients without this treatment (15.5%; p = 0.049). Multivariate analysis showed that more than two concomitant CYP3A4 inhibitors and no concomitant use of naldemedine were independent risk factors for OINV. Concomitant polypharmacy involving CYP3A4 inhibitors increases the risk of OINV. Therefore, medications concomitantly used with oxycodone should be optimized. [ABSTRACT FROM AUTHOR]

Background and Aim: Acinetobacter baumannii (A. baumannii) is an important bacterium that can cause multidrug-resistant nosocomial infections in the patients who are admitted to different hospital wards. Various factors play role in the resistance of this bacterium to antibiotics, one of the most important of which is the presence of drug efflux pumps. This study aimed to investigate the presence of the AdeABC efflux system and its role in drug resistance by inactivating them. Materials and Methods: Clinical samples were collected from three hospitals in Tehran, Iran for one year. The initial diagnosis and identification of A. baumannii was done by culture and biochemical methods. Finally, the identified prototypes were confirmed by molecular method. To investigate the role of antibiotic efflux pump in the drug resistance, minimum inhibitory concentration (MIC) for ciprofloxacin in the presence and absence of an efflux pump inhibitor, carbonyl cyanide 3- chlorophenylhydrazone (CCCP), was determined by microdilution method. Additionally, the presence of adeB, adeR, and adeS genes related to the AdeABC depletion system was investigated by PCR. Results: The results showed that more than 98% of the isolated bacteria had adeB, adeR, and adeS genes in the AdeABC depletion system. Approximately, 47.18% of these bacteria displayed a fourfold reduction in ciprofloxacin MIC levels in the presence of CCCP. Conclusion: Administration of a suitable antibiotic along with a safe efflux pump inhibitor for the treatment of A. baumannii infections can help to reduce the material and spiritual damages caused by the resistant bacteria. [ABSTRACT FROM AUTHOR]

Objective The main aim of this study was to define the best treatment option for multisystem inflammatory syndrome in children (MIS-C) and to analyse the role of anakinra. Methods This is a multicentre retrospective cohort study. Patients were treated according to the attending physician's decision. The patients were divided into four groups on the basis of the first treatment at time of admittance: (i) IVIG, (ii) IVIG and methylprednisolone (≤2 mg/kg/day), (iii) IVIG with high-dose methylprednisolone (>2 mg/kg/day) and (iv) anakinra with or without IVIG and/or methylprednisolone. Primary outcomes were defined as the presence of at least one of the following features: death, the failure of initial treatment, meaning the need for additional treatment for clinical worsening and cardiac involvement at the end of follow-up. Results Two hundred thirty-nine patients were recruited. At univariate analysis, persistent heart involvement at discharge was more frequent in those not receiving anakinra as initial treatment (3/21 vs 66/189; P  = 0.047). After comparisons between the four treatment regimens, adjusting for the propensity score, we observed that early treatment with anakinra was associated with a lower probability of developing persistent heart disease at the end of follow-up (odds ratio: 0.6; 95% CI: 0.4–1.0). Conclusion We report that early treatment with anakinra is safe and very effective in patients with severe MIS-C. In addition, our study suggests that early treatment with anakinra is the most favourable option for patients with a higher risk of developing a severe disease outcome. [ABSTRACT FROM AUTHOR]

Objectives Anaemia, a common comorbidity of RA, is related to high disease activity and poor prognosis. It is unknown which biologic/targeted synthetic (b/ts)-DMARDs are optimal for patients with anaemia and RA in regulating anaemia and controlling disease activity. Methods We investigated the change in haemoglobin (Hb) levels, drug retention rates and disease activities after the administration of b/ts-DMARDs with different modes of action [TNF inhibitors (TNFis), immunoglobulin fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), IL-6 receptor inhibitors (IL-6Ris) and Janus kinase inhibitors (JAKis)] in patients with RA stratified by baseline Hb levels using the multicentre observational registry for patients with RA in Japan (ANSWER cohort). Results A total of 2093 patients with RA were classified into three groups based on tertiles of the baseline Hb levels (Hblow, anaemic; Hbint, intermediate; Hbhigh, non-anaemic). IL-6Ri increased Hb levels in all groups (the mean change at 12 months in Hblow was +1.5 g/dl, Hbint +0.7 g/dl and Hbhigh +0.1 g/dl). JAKis increased the Hb level in patients with anaemia and RA and retained or decreased the Hb level in non-anaemic patients (the mean change at 12 months in Hblow was +0.6 g/dl, Hbint 0 g/dl and Hbhigh −0.3 g/dl). In patients with anaemia and RA, overall adjusted 3-year drug retention rates were higher in JAKi followed by IL-6Ri, CTLA4-Ig and TNFi (78.6%, 67.9%, 61.8% and 50.8%, respectively). Change of disease activity at 12 months was not different among different b/ts-DMARDs treatments. Conclusion IL-6Ri and JAKi can effectively treat patients with anaemia and RA in a real-world setting. [ABSTRACT FROM AUTHOR]

Summary: C-X-C motif chemokine receptor 2 (CXCR2) has a role in tumor progression, lineage plasticity, and reduction of immune checkpoint inhibitor efficacy. Preclinical evidence suggests potential benefit of CXCR2 inhibition in multiple solid tumors. In this phase 2 study (NCT03473925), adults with previously treated advanced or metastatic castration-resistant prostate cancer (CRPC), microsatellite-stable colorectal cancer (MSS CRC), or non–small-cell lung cancer (NSCLC) were randomized 1:1 to the CXCR2 antagonist navarixin 30 or 100 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks up to 35 cycles. Primary endpoints were investigator-assessed objective response rate (RECIST v1.1) and safety. Of 105 patients (CRPC, n=40; MSS CRC, n=40; NSCLC, n=25), 3 had a partial response (2 CRPC, 1 MSS CRC) for ORRs of 5%, 2.5%, and 0%, respectively. Median progression-free survival was 1.8–2.4 months without evidence of a dose-response relationship, and the study was closed at a prespecified interim analysis for lack of efficacy. Dose-limiting toxicities occurred in 2/48 patients (4%) receiving navarixin 30 mg and 3/48 (6%) receiving navarixin 100 mg; events included grade 4 neutropenia and grade 3 transaminase elevation, hepatitis, and pneumonitis. Treatment-related adverse events occurred in 70/105 patients (67%) and led to treatment discontinuation in 7/105 (7%). Maximal reductions from baseline in absolute neutrophil count were 44.5%−48.2% (cycle 1) and 37.5%−44.2% (cycle 2) and occurred within 6−12 hours postdose in both groups. Navarixin plus pembrolizumab did not demonstrate sufficient efficacy in this study. Safety and tolerability of the combination were manageable. (Trial registration: ClinicalTrials.gov, NCT03473925). [ABSTRACT FROM AUTHOR]

Objective: Carbapenem-resistant Enterobacteriaceae (CRE) pose a significant threat to human health and have emerged as a major public health concern. We aimed to compare the efficacy and the safety of ceftazidime–avibactam (CAZ–AVI) and polymyxin in the treatment of CRE infections. Methods: A systematic review and meta-analysis was performed by searching the databases of EMBASE, PubMed, and the Cochrane Library. Published studies on the use of CAZ–AVI and polymyxin in the treatment of CRE infections were collected from the inception of the database until March 2023. Two investigators independently screened the literature according to the inclusion and exclusion criteria, evaluated the methodological quality of the included studies and extracted the data. The meta-analysis was performed using RevMan 5.4 software. Results: Ten articles with 833 patients were included (CAZ–AVI 325 patients vs Polymyxin 508 patients). Compared with the patients who received polymyxin-based therapy, the patients who received CAZ–AVI therapy had significantly lower 30-days mortality (RR = 0.49; 95% CI 0.01–2.34; I2 = 22%; P < 0.00001), higher clinical cure rate (RR = 2.70; 95% CI 1.67–4.38; I2 = 40%; P < 0.00001), and higher microbial clearance rate (RR = 2.70; 95% CI 2.09–3.49; I2 = 0%; P < 0.00001). However, there was no statistically difference in the incidence of acute kidney injury between patients who received CAZ–AVI and polymyxin therapy (RR = 1.38; 95% CI 0.69–2.77; I2 = 22%; P = 0.36). In addition, among patients with CRE bloodstream infection, those who received CAZ–AVI therapy had significantly lower mortality than those who received polymyxin therapy (RR = 0.44; 95% CI 0.27–0.69, I2 = 26%, P < 0.00004). Conclusions: Compared to polymyxin, CAZ–AVI demonstrated superior clinical efficacy in the treatment of CRE infections, suggesting that CAZ–AVI may be a superior option for CRE infections. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a disease specific to pregnancy that causes 9–10 % of maternal deaths. Early-onset PE (<34 weeks' gestation) is the most dangerous category of PE. Wnt7a and GPR124 (G protein-coupled receptor 124) are widely expressed in the human reproductive process. Especially during embryogenesis and tumorigenesis, Wnt7a plays a crucial role. However, few studies have examined the association between Wnt7a-GPR124 and early-onset PE. The aim of this study was to examine the significance of Wnt7a and GPR124 in early-onset PE as well as Wnt7a's role in trophoblast cells. Immunohistochemistry (IHC), real-time PCR, and western blotting (WB) were used to investigate Wnt7a and GPR124 expression in normal and early-onset PE placentas. Additionally, FACS, Transwell, and CCK-8 assays were used to diagnose Wnt7a involvement in migration, invasion, and proliferation. In the early-onset PE group, Wnt7a and GPR124 expression was significantly lower than in the normal group, especially in the area of syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). A negative correlation was found between Wnt7a RNA and GPR124 expression (r=−0.42, p<0.01). However, the Wnt7a RNA expression level was positive correlated with PE severity. In further cellular functional experiments, knockdown of Wnt7a inhibits HTR8/SVeno cells invasion and migration but has little effect on proliferation and apoptosis. Through the Wnt pathway, Wnt7a regulates trophoblast cell invasion and migration, and may contribute to early-onset preeclampsia pathogenesis. A molecular level study of Wnt7a will be needed to find downstream proteins and mechanisms of interaction. [ABSTRACT FROM AUTHOR]

Background: Recent studies have established cefepime as an effective treatment option for AmpC beta-lactamase (AmpC) Enterobacterales; however, the efficacy of beta-lactam/beta-lactamase inhibitors is unclear. Objective: The objective of this study was to determine if piperacillintazobactamis an appropriate alternative to cefepime for the treatment of intra-abdominal infections (IAIs) secondary to AmpC-producing organisms. Methods: This multicenter, retrospective cohort study was conducted in hospitalized adults with an IAI caused by an AmpC-producing organism and received either cefepime or piperacillin-tazobactam for definitive treatment after a source control procedure. The primary outcome was a composite of surgical site infections, recurrent IAIs, or in-hospital mortality. Secondary outcomes included the individual components of the composite outcome, hospital length of stay (LOS), microbiologic failure, study antibiotic duration, time to clinical resolution, and incidence of Clostridioides difficile infection (CDI). Results: This study included 119 patients. There was no difference in the primary outcome between the cefepime and piperacillin-tazobactam groups (35% vs 27%, P = 0.14). Microbiological failure was the only secondary outcome with an observed difference between groups (17% vs 0%, P = 0.01): hospital LOS (15 vs 13 days, P = 0.09), days of therapy (7 vs 7 days, P = 0.87), time to clinical resolution (7 vs 4 days, P = 0.30), and CDI (1% vs 2%, P = 0.58) were all similar. [ABSTRACT FROM AUTHOR]

Aims Literature regarding anticoagulants in older people affected by atrial fibrillation (AF) is limited to retrospective studies, poorly considering the importance of multidimensional frailty. The main objective of this study is to evaluate in hospitalised older persons with AF the benefit/risk ratio of the anticoagulant treatments, considering the severity of frailty, determined by the multidimensional prognostic index (MPI). Methods In this European, multicentre, prospective study, older hospitalised patients (≥65 years) with non-valvular AF were followed-up for 12 months. Anticoagulants' use at discharge ascertained using medical records. MPI was calculated using tools derived from comprehensive geriatric assessment, classifying participants in robust, pre-frail or frail. Mortality (primary outcome); vascular events, including ischemic heart disease or ischemic stroke, hemorrhagic stroke or gastrointestinal bleedings (secondary outcomes). Results 2,022 participants (mean age 82.9 years; females 56.6%) were included. Compared with people not taking anticoagulants (n  = 823), people using vitamin K antagonists (n  = 450) showed a decreased risk of mortality (hazard ratio, HR = 0.74; 95% CI: 0.59–0.93), more pronounced in patients using direct oral anticoagulants (DOACs) (n  = 749) (HR = 0.46; 95% CI: 0.37–0.57). Only people taking DOACs reported a significantly lower risk of vascular events (HR = 0.55; 95% CI: 0.31–0.97). The efficacy of DOACs was present independently from frailty status. The risk of gastrointestinal bleedings and hemorrhagic stroke did not differ based on the anticoagulant treatments and by MPI values. Conclusions Anticoagulant treatment, particularly with DOACs, was associated with reduced mortality in older people, without increasing the risk of hemorrhagic events, overall suggesting the importance of treating with anticoagulants older people with AF. [ABSTRACT FROM AUTHOR]

Introduction: Patients who should benefit from anti-amyloid therapies (AAT) are found across all geriatric settings. Yet, it remains unclear how the use of AAT in patients with geriatric syndromes, such as frailty and polypharmacy, has so far been discussed in the literature. Methods: Articles on aducanumab, gantenerumab, lecanemab, donanemab, crenezumab, solanezumab were retrieved in MEDLINE from inception to July 2023. For each article, identified geriatric relevant terms were assigned to five discussion contexts (eligibility of AAT study population, safety, prescription, patient clinical profile, alternative outcomes measurement). Article type and the involvement of geriatric healthcare professionals as an author were further extracted. Results: Out of 538 articles, 23 (4.27%) were published in journals from the geriatric category, 44 (8.18%) included an author affiliated with a geriatric institution. One hundred and sixteen (21.56%) articles included at least one geriatric relevant term, which were mostly discussed in the context of safety and eligibility. Articles mentioning geriatric syndromes were more frequently authored by a geriatric healthcare professional (p = 0.044). Discussion: The use of AAT in patients with geriatric syndromes has so far received poor attention in the literature raising concerns on their use in this patient group. The involvement of geriatric healthcare professionals in future studies may increase the relevance of AAT research in patients with geriatric syndromes. [ABSTRACT FROM AUTHOR]

Background: Patients with critical COVID-19 have a high risk of thromboembolism, but intensified thromboprophylaxis has not been proven beneficial. The activity of low-molecular-weight heparins can be monitored by measuring anti-Factor Xa. We aimed to study the association between anti-Factor Xa values and death, thromboembolism, and bleeding in patients with critical COVID-19. Method: This retrospective cohort study included adult patients with critical COVID-19 admitted to an intensive care unit at three Swedish hospitals between March 2020 and May 2021 with at least one valid peak and/or trough anti-Factor Xa value. Within the peak and trough categories, patients' minimum, median, and maximum values were determined. Logistic regressions with splines were used to assess associations. Results: In total, 408 patients had at least one valid peak and/or trough anti-Factor Xa measurement, resulting in 153 patients with peak values and 300 patients with trough values. Lower peak values were associated with thromboembolism for patients' minimum (p = 0.01), median (p = 0.005) and maximum (p = 0.001) values. No association was seen between peak values and death or bleeding. Higher trough values were associated with death for median (p = 0.03) and maximum (p = 0.002) values and with both bleeding (p = 0.01) and major bleeding (p = 0.02) for maximum values, but there were no associations with thromboembolism. Conclusions: Measuring anti-Factor Xa activity may be relevant for administrating low-molecular-weight heparin to patients with critical COVID-19. Lower peak values were associated with an increased risk of thromboembolism, and higher trough values were associated with an increased risk of death and bleeding. Prospective studies are needed to confirm the results. Trial registration: The study was retrospectively registered at Clinicaltrials.gov, NCT05256524, February 24, 2022. [ABSTRACT FROM AUTHOR]

Background: There are no randomized trials comparing andexanet alfa and 4 factor prothrombin complex concentrate (4F-PCC) for the treatment of factor Xa inhibitor (FXa-I)-associated bleeds, and observational studies lack important patient characteristics. We pursued this study to demonstrate the feasibility of acquiring relevant patient characteristics from electronic health records. Secondarily, we explored outcomes in patients with life-threatening FXa-I associated bleeds after adjusting for these variables. Methods: We conducted a multicenter, chart review of 100 consecutive adult patients with FXa-I associated intracerebral hemorrhage (50) or gastrointestinal bleeding (50) treated with andexanet alfa or 4F-PCC. We collected demographic, clinical, laboratory, and imaging data including time from last factor FXa-I dose and bleed onset. Results: Mean (SD) age was 75 (12) years; 34% were female. Estimated time from last FXa-I dose to bleed onset was present in most cases (76%), and patients treated with andexanet alfa and 4F-PCC were similar in baseline characteristics. Hemostatic efficacy was excellent/good in 88% and 76% of patients treated with andexanet alfa and 4F-PCC, respectively (P = 0.29). Rates of thrombotic events within 90 days were 14% and 16% in andexanet alfa and 4F-PCC patients, respectively (P = 0.80). Survival to hospital discharge was 92% and 76% in andexanet alfa and 4F-PCC patients, respectively (P = 0.25). Inclusion of an exploratory propensity score and treatment in a logistic regression model resulted in an odds ratio in favor of andexanet alfa of 2.01 (95% confidence interval 0.67-6.06) for excellent/good hemostatic efficacy, although the difference was not statistically significant. Conclusion: Important patient characteristics are often documented supporting the feasibility of a large observational study comparing real-life outcomes in patients with FXa-I-associated bleeds treated with andexanet alfa or 4F-PCC. The small sample size in the current study precluded definitive conclusions regarding the safety and efficacy of andexanet alfa or 4F-PCC in FXa-I-associated bleeds. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), has demonstrated significantly improved progression-free survival in patients with hormone receptor-positive, HER2-negative, advanced breast cancer, when used in combination with endocrine therapies. However, limited data exists on its cutaneous adverse events (AE). The aim of our retrospective study was to investigate the prevalence, types and management of cutaneous AE during CDK4/6i. 79 adult advanced breast cancer patients affected by 125 skin adverse events during treatment with CDK4/6i were recruited at eleven centers. The most frequent cutaneous reactions were pruritus (49/79 patients), alopecia (25/79), and ec-zematous lesions (24/79). We showed that skin reactions are usually mild in severity, and prompt management may limit the negative impact on patients, facilitating beneficial continuation of oncologic treatment. Background: The introduction of cyclin-dependent kinase inhibitors (CDK4/6i) was a great advance in therapeutics for patients with estrogen receptor+/human epidermal growth factor receptor (HER2) locally advanced and metastatic breast cancer. Despite the increasing use of these agents, their adverse drug-related events have not yet been fully characterized. We describe the spectrum of cutaneous adverse reactions occurring in advanced breast cancer patients treated with cyclin-dependent kinase inhibitors, analyzing types, severity, time to onset, and possible treatment outcomes. Methods: We performed a multicentric retrospective study including patients with advanced breast cancer who developed cutaneous lesions during treatment with CDK4/6i in the period from June 2020 to June 2021. Patients > 18 years were recruited at eleven onco-dermatology units located in Albania (1), Argentina (1), France (1), Greece (3), Italy (3), and Spain (2). We evaluated patients' epidemiological and clinical characteristics, types of cutaneous adverse events, their time to onset, and treatment outcomes. The severity of the skin reactions was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 score. Results: Seventy-nine patients (median age: 62.3 years; range 39–83 years) were included in the study, and, collectively, we recorded a total of 165 cutaneous adverse events during follow-up visits. The most frequent cutaneous reactions were pruritus (49/79 patients), alopecia (25/79), and eczematous lesions (24/79). Cutaneous toxicities were usually mild in severity (>65%) and occurred after a median of 6.5 months. Only four patients (5%) required treatment discontinuation due to the severity of the skin lesions. The majority of the skin reactions were managed with topical treatments. Conclusions: To the best of our knowledge, we present the largest case series of cutaneous adverse events developing in advanced breast cancer patients treated with CDK4/6i. We showed that cutaneous toxicities are usually mild in severity, and manageable with standard supportive care; however, in selected cases, they can lead to treatment discontinuation with possible implications for patients' clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: The balance of stroke risk reduction and potential bleeding risk associated with antithrombotic treatment (ATT) remains unclear in atrial fibrillation (AF) at non‐gender CHA2DS2‐VASc scores 0–1. A net clinical benefit (NCB) analysis of ATT may guide stroke prevention strategies in AF with non‐gender CHA2DS2‐VASc scores 0–1. Methods: This multi‐center cohort study evaluated the clinical outcomes of treatment with a single antiplatelet (SAPT), vitamin K antagonist (VKA), and non‐VKA oral anticoagulant (NOAC) in non‐gender CHA2DS2‐VASc score 0–1 and further stratified by biomarker‐based ABCD score (Age [≥60 years], B‐type natriuretic peptide [BNP] or N‐terminal pro‐BNP [≥300 pg/mL], creatinine clearance [<50 mL/min], and dimension of the left atrium [≥45 mm]). The primary outcome was the NCB of ATT, including composite thrombotic events (ischemic stroke, systemic embolism, and myocardial infarction) and major bleeding events. Results: We included 2465 patients (age 56.2 ± 9.5 years; female 27.0%) followed‐up for 4.0 ± 2.8 years, of whom 661 (26.8%) were treated with SAPT; 423 (17.2%) with VKA; and 1040 (42.2%) with NOAC. With detailed risk stratification using the ABCD score, NOAC showed a significant positive NCB compared with the other ATTs (SAPT vs. NOAC, NCB 2.01, 95% confidence interval [CI] 0.37–4.66; VKA vs. NOAC, NCB 2.38, 95% CI 0.56–5.40) in ABCD score ≥1. ATT failed to show a positive NCB in patients with truly low stroke risk (ABCD score = 0). Conclusions: In the Korean AF cohort at non‐gender CHA2DS2‐VASc scores 0–1, NOAC showed significant NCB advantages over VKA or SAPT with ABCD score ≥1. [ABSTRACT FROM AUTHOR]

Objectives: Our research aimed to evaluate the effectiveness of first‐line immune checkpoint inhibitors (ICIs) with etoposide and platinum (EP) for extensive‐stage small cell lung cancer (ES‐SCLC) and identify prognostic factors, as real‐world outcomes and the inconsistency of PD‐1 and PD‐L1 inhibitors are uncertain. Methods: We selected ES‐SCLC patients in three centers and conducted a propensity score‐matched analysis. The Kaplan–Meier method and Cox proportional hazards regression were conducted to compare the survival outcomes. We also performed univariate and multivariate Cox regression analyses to investigate predictors. Results: Among 236 patients included, 83 pairs of cases were matched. The EP plus ICIs cohort had a longer median overall survival (OS) (17.3 months) than the EP cohort (13.4 months) (hazard ratio [HR], 0.61 [0.45, 0.83]; p = 0.001). The median progression‐free survival (PFS) was also longer in the EP plus ICIs cohort (8.3 months) than in the EP cohort (5.9 months) (HR, 0.44 [0.32, 0.60]; p < 0.001). The EP plus ICIs group had a higher objective response rate (ORR) (EP: 62.3%, EP + ICIs: 84.3%, p < 0.001). Multivariate analysis presented that liver metastases (HR, 2.08; p = 0.018) and lymphocyte–monocyte ratio (LMR) (HR, 0.54; p = 0.049) were independent prognostic factors for OS, and performance status (PS) (HR, 2.11; p = 0.015), liver metastases (HR, 2.64; p = 0.002), and neutrophil‐lymphocyte ratio (NLR) (HR, 0.45; p = 0.028) were for PFS in patients with chemo‐immunotherapy. Conclusion: Our real‐world data demonstrated that ICIs with chemotherapy as the first‐line setting for ES‐SCLC are effective and safe. PS, liver metastases, and inflammatory markers could serve as valuable risk factors. [ABSTRACT FROM AUTHOR]

Copyright of Enfermería Investiga: Investigaciin, Vinculación, Docencia y Gestiin is the property of Revista Enfermeria Investiga and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: Previous analyses of pooled DISCOVER‐1 and DISCOVER‐2 data through Week 24 showed significantly higher rates of dactylitis resolution in patients treated with guselkumab compared with placebo. Here, we investigate associations between dactylitis resolution and other outcomes through 1 year. Methods: Patients were randomized 1:1:1 to receive subcutaneous injections of guselkumab 100 mg at Week 0, Week 4, and then every 4 or 8 weeks, or placebo with crossover to guselkumab at Week 24. Independent assessors determined dactylitis severity score (DSS; 0‐3/digit; total = 0‐60). Dactylitis resolution (DSS = 0) (prespecified) and at least 20%, at least 50%, and at least 70% DSS improvement from baseline (post hoc) were determined through Week 52 (nonresponder imputation for treatment failure through Week 24 and for missing data through Week 52). ACR50, tender/swollen joints, low disease activity (LDA) as assessed by composite indices, and radiographic progression (DISCOVER‐2 only) were assessed in patients with dactylitis versus without dactylitis resolution at Week 24 and Week 52. Results: Patients with dactylitis at baseline (473 of 1118) had more severe joint and skin disease than those without dactylitis (645 of 1118). At Week 52, approximately 75% of guselkumab‐randomized patients with dactylitis at baseline had complete resolution; approximately 80% had at least 70% DSS improvement. Through Week 52, new‐onset dactylitis (DSS ≥1) was uncommon among patients with a DSS of 0 at baseline. Guselkumab‐randomized patients with dactylitis resolution were more likely to achieve ACR50, at least 50% reduction in tender and swollen joints, and LDA at Week 24 and Week 52 than those without resolution. At Week 52, patients with dactylitis resolution had numerically less radiographic progression from baseline (DISCOVER‐2). Conclusion: Through 1 year, approximately 75% of guselkumab‐randomized patients had complete resolution of dactylitis; patients exhibiting resolution were more likely to achieve other important clinical outcomes. Given the high burden of dactylitis, resolution may be associated with better long‐term patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Preclinical data suggest that central renin-angiotensin system blockade by the brain aminopeptidase-A inhibitor firibastat can improve left ventricular ejection fraction (LVEF) after myocardial infarction (MI). Objectives: This study aimed to compare the effect of firibastat versus ramipril on post-MI LVEF. Methods: In this phase 2, randomized, double-blind trial, patients selected within 24 h of first acute anterior MI treated by primary percutaneous coronary intervention were randomly assigned (1:1:1) to firibastat 100 mg, firibastat 500 mg or ramipril 5 mg, each twice daily for 12 weeks. The primary endpoint was change in LVEF on cardiac magnetic resonance imaging (cMRI) from baseline to day 84 in the modified intent-to-treat (mITT) population (at least one dose received and one follow-up cMRI available) for each treatment group. Results: From June 4, 2019 to April 12, 2021, 294 patients were randomized and 229 were evaluable for the mITT analysis. After 12 weeks, mean ± standard deviation (SD) percent change in LVEF was 5.6 ± 1.2 with firibastat 100 mg, 5.3 ± 1.1 with firibastat 500 mg and 5.7 ± 1.1 with ramipril. The absolute ± SE adjusted difference in LVEF change from baseline between firibastat 500 mg and ramipril was − 0.36 ± 1.32% (p = 0.79). Occurrence of treatment-related adverse events was similar in the three groups. Conclusions: Firibastat was not superior to ramipril for prevention of left ventricular dysfunction after first acute anterior MI, and their safety profiles were similar. Registration: ClinicalTrials.gov identifier NCT03715998. [ABSTRACT FROM AUTHOR]

Objective: To evaluate potential drug–drug interactions of ubrogepant and atogepant. Background: Ubrogepant and atogepant, calcitonin gene‐related peptide (CGRP) receptor antagonists, are recently approved drugs for acute and preventive treatment of migraine, respectively. For patients with migraine who are prescribed atogepant for the preventive treatment of migraine, health care providers could prescribe ubrogepant for the acute treatment of breakthrough migraine attacks. Methods: A phase Ib, multi‐center, open‐label, fixed‐sequence study was conducted in participants diagnosed with migraine for at least 1 year. To assess the primary objective of pharmacokinetic interactions in this phase I trial, the highest United States Food and Drug Administration‐approved individual dose strengths of atogepant (60 mg once daily) and ubrogepant (100 mg) were utilized, with ubrogepant being administered on a fixed‐dose schedule every 3 days, regardless of whether a participant was experiencing a migraine attack. Secondary endpoints included safety and tolerability. Clinical safety measurements were monitored throughout the study. Results: Of the 31 participants enrolled, 26 completed the study. A single dose of ubrogepant had no statistically significant effect on atogepant pharmacokinetics. Co‐administration of ubrogepant with atogepant resulted in a 19% increase (geometric mean ratio 118.80, 90% confidence interval [CI] 108.69–129.84) in the ubrogepant area under the plasma concentration‐time curve and a 26% increase (geometric mean ratio 125.63, 90% CI 105.58–149.48) in the ubrogepant maximum plasma concentration. These statistically significant changes in ubrogepant exposure were not clinically meaningful, and no new safety concerns were identified for the combination. Conclusion: The combination use of atogepant and ubrogepant was safe and well tolerated in adult participants with a history of migraine enrolled in the study. Pharmacokinetic changes during co‐administration were not clinically meaningful. [ABSTRACT FROM AUTHOR]

Objective: To assess long‐term safety, tolerability, and efficacy of once‐daily oral atogepant 60 mg in adults with migraine. Background: Atogepant is an oral, small‐molecule, calcitonin gene–related peptide receptor antagonist approved for the preventive treatment of episodic migraine. Methods: A 52‐week, multicenter, randomized, open‐label trial of adults (18–80 years) with migraine. Lead‐in trial completers or newly enrolled participants with 4–14 migraine days/month were enrolled and randomized (5:2) to atogepant 60 mg once daily or oral standard care (SC) migraine preventive medication. The primary objective was to evaluate the safety and tolerability of atogepant; safety assessments included treatment‐emergent adverse events (TEAEs), clinical laboratory evaluations, vital signs, and Columbia‐Suicide Severity Rating Scale scores. Efficacy assessments (atogepant only) included change from baseline in mean monthly migraine days (MMDs) and the proportion of participants with reductions from baseline of ≥50%, ≥75%, and 100% in MMDs. Results: The trial included 744 participants randomized to atogepant 60 mg (n = 546) or SC (n = 198). The atogepant safety population was 88.2% female (n = 479/543) with a mean (standard deviation) age of 42.5 (12.0) years. TEAEs occurred in 67.0% (n = 364/543) of participants treated with atogepant 60 mg. The most commonly reported TEAEs (≥5%) were upper respiratory tract infection (10.3%; 56/543), constipation (7.2%; 39/543), nausea (6.3%; 34/543), and urinary tract infection (5.2%; 28/543). Serious TEAEs were reported in 4.4% (24/543) for atogepant. Mean (standard error) change in MMDs for atogepant was −3.8 (0.1) for weeks 1–4 and −5.2 (0.2) at weeks 49–52. Similarly, the proportion of participants with ≥50%, ≥75%, and 100% reductions in MMDs increased from 60.4% (310/513), 37.2% (191/513), and 20.7% (106/513) at weeks 1–4 to 84.2% (282/335), 69.9% (234/335), and 48.4% (162/335), at weeks 49–52. Conclusion: Daily use of oral atogepant 60 mg for preventive treatment of migraine during this 1‐year, open‐label trial was safe, well tolerated, and efficacious. [ABSTRACT FROM AUTHOR]

The assessment of p16INK4a (p16) in oropharyngeal squamous cell carcinoma (OPSCC) has been incorporated into tumor classification, as p16 has been shown to impact survival probability. However, a recent study demonstrated that human papillomavirus (HPV) status in addition to p16 may have a better discriminatory effect on survival probability. This study aims to determine the impact of combined evaluation of p16 and HPV on prognosis. This was a multicenter, multinational analysis including retrospective and prospective cohorts of patients treated for primary OPSCC with curative intent, based on the data of the HNCIG-EPIC study. The primary outcome was to determine how the combined assessment of HPV and p16 status predicts prognosis of patients with OPSCC compared to p16 assessment alone. We employed multivariable analyses models to compute hazard ratios regarding survival. Analyses were stratified by stage, smoking status, and sub-anatomical region. The study included 7654 patients, with approximately half of the tumors being p16-negative (50.3 %, n = 3849). A total of 9.2 % of patients had discordant p16 and HPV status (n = 704). HPV status significantly impacted overall survival and disease-free survival regardless of p16 status and across both UICC 8th stage I-II and III-IVb cancers. p16-positive/HPV-positive OPSCC patients exhibited the best survival probability. The detection of HPV had a significant impact on survival probability for OPSCC patients with both p16-positive and p16-negative tumors. HPV testing should be integrated in cancer staging, especially in regions of low attributable fraction, alongside p16 evaluation to ensure a comprehensive assessment of prognosis. • The study includes 7654 oropharyngeal cancer patients. • HPV impacts overall and disease-free survival, regardless of p16 status. • HPV exerts substantial influence on survival, regardless of stage. • Incorporating HPV in cancer staging, with p16, is crucial for precise prognosis.. [ABSTRACT FROM AUTHOR]

Purpose: Our purpose was to investigate radiation therapy (RT) toxicity when given with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) compared with RT alone.Methods and Materials: We conducted a retrospective cohort study of patients with hormonal receptor-positive and human epidermal growth factor-2 negative metastatic breast cancer treated with RT at 4 cancer centers in Alberta, Canada, between 2016 and 2020. Toxicity in patients treated with RT within 30 days of initiating to discontinuing CDK4/6i (RT + CDK4/6i) was compared with toxicity of RT in CDK4/6i-naïve patients (RT alone). The primary outcome was acute grade (G) 2 or higher, nonhematological toxicity within 30 days of RT. We also explored toxicity based on the timing of RT (prior, concurrent, post) in relation to CDK4/6i. Propensity score matching was applied to create comparable cohorts. A generalized linear mixed model was used to evaluate factors associated with acute toxicity.Results: One hundred thirty-two patients (220 RT sites) in the RT + CDK4/6i and 53 patients (93 RT sites) in RT alone were eligible. The rate of acute G2 or higher nonhematological toxicity was 11.5% versus 7%, respectively (P = .439), and acute G3 or higher nonhematological toxicity was 3.7% versus 0%, respectively (P = .151). Acute toxicity in RT + CDK4/6i group was mainly observed when RT was given concurrently (67%), with most of the G3 toxicity recorded. After propensity score matching, the association of acute toxicity with RT + CDK4/6i versus RT alone was not significant on multivariable analysis (odds ratio, 3.13; 95% confidence interval, 0.74-13.2; P = .121).Conclusions: We did not observe a significant association between CDK4/6i use and acute G2 or higher nonhematological toxicity in women with metastatic breast cancer receiving palliative RT. Given the findings of G3 toxicity, caution is advised whenever CDK4/6i is given concurrently with RT. [ABSTRACT FROM AUTHOR]

Background and objectives: The identification of predictors of response to antiCGRP mAbs could favor tailored therapies and personalized treatment plans. This study is aimed at investigating predictors of ≥ 50%, ≥ 75% and 100% response at 24 weeks in patients with high-frequency episodic (HFEM: 8–14 days/month) or chronic migraine (CM). Methods: This is a large, multicenter, cohort, real-life study. We considered all consecutive adult patients affected by HFEM or CM who were prescribed antiCGRP mAbs for ≥ 24 weeks in 20 headache centers. Patients were interviewed face-to-face using a shared semi-structured questionnaire carefully exploring socio-demographic and clinical characteristics. Patients received subcutaneous erenumab (70 mg or140 mg, monthly), galcanezumab (120 mg monthly, following a 240 mg loading dose), or fremanezumab (225 mg, monthly or 675 mg, quarterly) according to drug market availability, physician's choice, or patient's preference. The primary endpoint of the study was the assessment of ≥ 50% response predictors at 24 weeks. Secondary endpoints included ≥ 75% and 100% response predictors at 24 weeks. Results: Eight hundred sixty-four migraine patients had been treated with antiCGRP mAbs for ≥ 24 weeks (erenumab: 639 pts; galcanezumab: 173 pts; fremanezumab: 55 pts). The ≥50% response (primary endpoint) in HFEM was positively associated with unilateral pain (UP) + unilateral cranial autonomic symptoms (UAs) (OR:4.23, 95%CI:1.57–11.4; p = 0.004), while in CM was positively associated with UAs (OR:1.49, 95%CI:1.05–2.11; p = 0.026), UP + UAs (OR:1.90, 95%CI:1.15–3.16; p = 0.012), UP + allodynia (OR:1.71, 95%CI:1.04–2.83; p = 0.034), and negatively associated with obesity (OR:0.21, 95%CI:0.07–0.64; p = 0.006). The 75% response (secondary endpoint) was positively associated with UP + UAs in HFEM (OR:3.44, 95%CI:1.42–8.31; p = 0.006) and with UP + UAs (OR:1.78, 95%CI:1.14–2.80; p = 0.012) and UP + allodynia (OR:1.92, 95%CI:1.22–3.06; p = 0.005) in CM. No predictor of 100% response emerged in patients with HFEM or CM. Conclusions: A critical evaluation of headache characteristics indicating peripheral or central sensitization may help in predicting responsiveness to antiCGRP mAbs in HFEM and CM. A more precise pain profiling may represent a steppingstone for a mechanism-based approach and personalized treatment of migraine with compounds targeting specific molecular mechanisms. [ABSTRACT FROM AUTHOR]

Aim: The combination of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors plus endocrine therapy (ET) improved the survival outcomes and became the standard of care in the treatment of metastatic hormone-positive breast cancer. However, these combinations increased the risk of neutropenia compared with ET alone. While the infection-related mortalities did not seem to be increased, the exact risk of infections with CDK 4/6 inhibitor and ET combinations is relatively understudied. Therefore, we performed a meta-analysis of CDK 4/6 inhibitor clinical trials to assess the infection risk of adding CDK4/6 inhibitors to ET.Material and Method: We systemically searched the PubMed database for relevant clinical trials. For each study, all grade and grade 3 or higher infections, upper respiratory tract infections (URTI), urinary tract infections (UTI), pneumonia, and febrile neutropenia rates were recorded whenever available. The hazard ratios (HR) with a 95% confidence interval (CI) of infection risk were calculated via the generic inverse-variance method with a random-effects model.Results: Nine eligible studies were included in the analyses (MONALEESA-2,3,7, MONARCH-2,3, MONARCH plus, PALOMA-1,2,3). In the meta-analysis of these studies, CDK 4/6 inhibitors plus ET arms were associated with increased all grade infections (HR 1.77, 95% CI 1.56-2.01, p < 0.00001), grade 3 or higher infections, (HR 1.77, 95% CI 1.28-2.43, p = 0.0005), UTIs (HR 1.59, 95% CI 1.19-2.12, p = 0.002), and febrile neutropenia (HR 4.28, 95% CI 1.73-10.62, p = 0.002).Conclusion: In this meta-analysis, we observed that adding CDK4/6 inhibitors to ET significantly increased the risk of all grade, grade 3 or higher infections, and urinary tract infections. We propose that closer follow-up for infections should be considered for metastatic breast cancer patients using CDK 4/6 inhibitors. This may help clinicians to recognize infections earlier which prevents early death from infection. [ABSTRACT FROM AUTHOR]

Maintaining therapeutic levels of anticoagulation is essential to avoid health complications in people who take vitamin K antagonists. This study aimed to analyze the influence of people's characteristics and the presence of changes in their lives in the control of therapeutic levels of anticoagulation. A longitudinal multicenter study with a 1-year follow-up of a cohort of 199 people receiving anticoagulant therapy was performed. The effect of biological, clinical, social, lifestyle, and changes in life on the international normalized ratio (INR) was analyzed. During the follow-up, 46.7% of participants presented good INR control. At baseline, a diagnosis of atrial fibrillation (P =.00), the lack of comorbidities (P =.03), absence of depression (P =.04), and not following a pharmacological treatment with hypoglycemia drugs (P =.01) were associated with good INR control. During the follow-up, the variable of making changes to the usual diet was associated with poor INR control (P =.05). In the binary multiple regression model, factors associated with poor control were taking hypoglycemia drugs (P =.02) and the presence of depression (P =.04), and only the diagnosis of atrial fibrillation was associated with good control (P =.03). People with a diagnosis of atrial fibrillation had good INR control. Having comorbidities, suffering depression, taking hypoglycemia drugs, and making changes to the diet have a negative effect on INR control. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) fusions identify a limited subset of non–small cell lung cancer (NSCLC) patients, whose therapeutic approach have been radically changed in recent years. However, diagnostic procedures and clinical-radiological responses to specific targeted therapies remain heterogeneous and intrinsically resistant or poor responder patients exist. A total of 290 patients with advanced NSCLC defined as ALK+ by immunohistochemistry (IHC) and/or fluorescent in situ hybridisation (FISH) test and treated with single or sequential multiple ALK inhibitors (ALKi) from 2011 to 2017 have been retrospectively retrieved from a multicentre Italian cancer network database. In 55 patients with enough leftover tumour tissue, specimens were analysed with both targeted and customised next generation sequencing panels. Identified fusion variants have been correlated with clinical outcomes. Of the 55 patients, 24 received crizotinib as first-line therapy, 1 received ceritinib, while 30 received chemotherapy. Most of the patients (64%) received ALKi in sequence. An ALK fusion variant was identified in 73% of the cases, being V3 variant (E6A20) the most frequent, followed by V1 (E13A20) and more rare ones (e.g. E6A19). In three specimens, four new EML4-ALK fusion breakpoints have been reported. Neither fusion variants nor brain metastases were significantly associated with overall survival (OS), while it was predictably longer in patients receiving a sequence of ALKi. The presence of V1 variant was associated with progression-free survival (PFS) improvement when crizotinib was used (p = 0.0073), while it did not affect cumulative PFS to multiple ALKi. Outcomes to sequential ALKi administration were not influenced by fusion variants. Nevertheless, in V1+ patients a prolonged clinical benefit was observed. Fusion variant identification by NGS technology may add relevant information about rare chromosomal events that could be potentially correlated to worse outcomes. • NGS platforms add relevant information to refine diagnosis of ALK+ NSCLC patients. • RNA-based technologies allow the identification of rare/unknown EML4-ALK fusions. • Fusion variants correlate with clinical outcomes to single/sequential ALKi. • Molecular stratification of ALK+ patients may inform clinical strategies. [ABSTRACT FROM AUTHOR]

Objective: To compare effects of an initial dose of calcitonin gene‐related peptide (CGRP) monoclonal antibody (mAb) antagonists on gastrointestinal (GI) motility in patients with migraine and to explore if the mechanistic difference contributes to GI adverse events (AEs). Background: Different frequencies of constipation have been observed between CGRP mAbs that target the ligand (galcanezumab [GMB]) or receptor (erenumab [ERE]). Methods: Patients (n = 65) with migraine without significant GI symptoms were enrolled in a multi‐center, single‐blind phase IV clinical trial (NCT04294147) and randomized 1:1 to receive GMB (240 mg; n = 33) or ERE (140 mg; n = 32). GI whole and regional transit times were assessed using a wireless motility capsule 1 week before and 2 weeks after mAb administration. The primary endpoint was change from baseline in colonic transit time (CTT) within each treatment group. Other measures included GI Symptom Rating Scale (GSRS), Bristol Stool Form Scale (BSFS), and spontaneous bowel movement (SBM) evaluation. AEs were monitored throughout the study. Results: Baseline characteristics indicated significant GI transit time variability with minimal GI reported symptoms. While not statistically significant, a numerical mean increase in CTT was observed in ERE patients (n = 28, mean [SD] at baseline: 33.8 [29.4] h; least square [LS] mean [SE] change: 5.8 [5.7] h, 95% confidence interval [CI] −5.7 to 17.2, p = 0.320), while GMB decreased CTT (n = 31, mean [SD] at baseline: 29.3 [24.5] h; LS mean [SE] change: −5.4 [5.4] h, 95% CI −16.2 to 5.5, p = 0.328) compared to baseline. No meaningful changes were observed in other regional transit times. ERE significantly reduced BSFS (LS mean [SE] score −0.5 [0.2], p = 0.004) and SBM (LS mean [SE] −1.2 [0.5], p = 0.0120), and increased GSRS‐constipation compared to baseline (LS mean [SE] score 0.3 [0.1], p = 0.016). GMB increased GSRS‐constipation (LS mean [SE] score 0.4 [0.1], p = 0.002). There were no discontinuations due to or serious AEs. A higher percentage of treatment‐emergent AEs were reported with ERE than GMB (ERE: nine of 32 [28.1%] versus GMB: three of 33 [9.1%]), with constipation the most frequently reported (ERE: five of 32 [15.6%] versus GMB one of 33 [3.0%]). Conclusion: While the primary endpoint of this study was not met, secondary and tertiary endpoints support a within‐ and between‐treatment change in GI effects suggesting possible mechanistic differences between ligand (GMB) and receptor (ERE) antagonism. [ABSTRACT FROM AUTHOR]

Background: Targeting the MDM2-p53 interaction using AMG 232 is synergistic with MAPK inhibitors (MAPKi) in preclinical melanoma models. We postulated that AMG 232 plus MAPKi is safe and more effective than MAPKi alone in TP53-wild type, MAPKi-naïve metastatic melanoma. Methods: Patients were treated with increasing (120 mg, 180 mg, 240 mg) oral doses of AMG 232 (seven-days-on, 15-days-off, 21-day cycle) plus dabrafenib (D) and trametinib (T) (Arm 1, BRAFV600-mutant) or T alone (Arm 2, BRAFV600-wild type). Patients were treated for seven days with AMG 232 alone before adding T±D. Safety and efficacy were assessed using CTCAE v4.0 and RECIST v1.1 criteria, respectively. Pharmacokinetic (PK) analysis was performed at baseline and steady-state levels for AMG 232. Results: 31 patients were enrolled. Ten and 21 patients were enrolled in Arm 1 and Arm 2, respectively. The most common AMG 232-related adverse events (AEs) were nausea (87%), diarrhea (77%), and fatigue (74%). Seven patients (23%) were withdrawn from the study due to AMG 232-related AEs. Three dose-limiting AEs occurred (Arm 1, 180 mg, nausea; Arm 2, 240 mg, grade 3 pulmonary embolism; Arm 2, 180 mg, grade 4 thrombocytopenia). AMG 232 PK exposures were not altered when AMG 232 was combined with T±D. Objective responses were seen in 8/10 (Arm 1) and 3/20 (Arm 2) evaluable patients. The median progression-free survival for Arm 1 and Arm 2 was 19.0 months-not reached and 2.8 months, respectively. Conclusion: The maximum tolerated dose of AMG 232 for both arms was 120 mg. AMG 232 plus T±D exhibited a favorable PK profile. Although objective responses occurred in both arms, adding AMG 232 to T±D did not confer additional clinical benefit. [ABSTRACT FROM AUTHOR]

Abstract: Preclinical data support investigation of selective CDK4/6 inhibition as a therapeutic strategy for human papillomavirus (HPV)-unrelated head and neck squamous cell carcinoma (HNSCC). Phase 1 clinical trials established the feasibility of combining palbociclib with cetuximab in patients with recurrent or metastatic HNSCC. Nonrandomized phase II trials showed that palbociclib plus cetuximab resulted in efficacy outcomes better than cetuximab in biomarker-unselected, platinum-resistant or cetuximab-resistant, HPV-unrelated HNSCC. A double-blind, randomized phase II trial (PALATINUS) evaluated the efficacy of palbociclib or placebo and cetuximab in patients with biomarker-unselected, platinum-resistant, cetuximab-naive, HPV-unrelated HNSCC. Palbociclib and cetuximab did not significantly prolong overall survival compared with placebo and cetuximab. However, correlative biomarker analyses identified that trends for better overall survival with palbociclib and cetuximab were observed in certain prespecified subsets; the largest reduction in risk of death with palbociclib versus placebo and cetuximab occurred in the subset with CDKN2A mutations. Several phase II-III trials are underway investigating palbociclib in biomarker-selected patients with HPV-unrelated locally advanced or recurrent or metastatic HNSCC. [ABSTRACT FROM AUTHOR]