The U.S. FDA currently recommends avoiding carbomer grades that contain benzene and recommends benzene-free alternatives (USFDA. Guidance for Industry: reformulating drug products that contain carbomers manufactured with benzene. Center for Drug Evaluation and Research (CDER), Pharmaceutical Quality/CMC. Published in December 2023. Available at: https://www.fda.gov/media/175083/download ). This means that if a finished product is authorized with a carbomer grade containing benzene, it needs to be replaced with a non-benzene carbomer grade. Such an update would also require detailed comparative studies-covering structure, performance, stability, and biological equivalence-to confirm consistent product quality and effectiveness. The current study attempted to replace Carbomer 940 (C940) with Carbomer 980 (C980) in 0.75% Metronidazole Gel. The two carbomer grades were characterized as powders using multiple spectroscopic techniques. A method for analyzing carboxylic acid content was developed and validated, using light-scattering resonance technology to improve accuracy. The formulation prepared with C940 and C980 was characterized for rheology, in vitro release and permeation, and stability, along with the reference formulation. Powder characterization shows slight differences in the absorption spectra across NMR and FTIR studies, while NIR spectra are the same. Additionally, C980 has a slightly higher molecular weight, degree of polymerization, apparent viscosity, and carboxylic acid content, but a lower water loss. The formulations prepared with C940 and C980 are rheologically equivalent to the reference formulation as assessed by flow curves, yield stress, linear viscoelasticity, and creep. The in vitro release and permeation study also demonstrates that the formulations prepared with C940 and C980 exhibit performance equivalence to the innovator formulation under the tested conditions. Hence, replacing the benzene-grade carbomer with the corresponding non-benzene-grade carbomer does not significantly affect product performance relative to the reference product.
Trochlear dysplasia is one of the most relevant anatomic factors predisposing patients to patellofemoral instability and its recurrence. This study introduces two novel radiographic measurements: the crossing-sign angle and the trochlear dysplasia length. A concordance study was conducted in patients aged 10-40 years with at least one episode of patellofemoral dislocation and radiographic evidence of trochlear dysplasia on a true lateral knee radiograph. Three observers independently measured the crossing-sign angle, the trochlear dysplasia length, and bump height, as well as classified the degree of trochlear dysplasia according to a modified Dejour classification. Inter- and intra-observer reliability for continuous variables were assessed using the intra-class correlation coefficient (ICC), while agreement for the modified Dejour classification was evaluated using Krippendorff's alpha (α) and weighted kappa (κ). Pearson correlation analysis was performed between the radiographic measurements, and analysis of variance (ANOVA) test between these and Dejour grades. Crossing sign angle demonstrated moderate inter-observer reliability (ICC = 0.71) and excellent intra-observer reliability (ICC = 0.96). Trochlear dysplasia length showed moderate inter-observer reliability (ICC = 0.73) and excellent intra-observer reliability (ICC = 0.95). Bump height exhibited good inter-observer reliability (ICC = 0.87) and excellent intra-observer reliability (ICC = 0.97). The modified Dejour classification demonstrated substantial inter-observer agreement (α = 0.62) and perfect intra-observer agreement (κ=1.00). Strong positive correlation was found between trochlear dysplasia length and bump height (r = 0.73; 95% CI 0.52 to 0.85; p < 0.001). Bump height and trochlear dysplasia length increased progressively from Dejour type A to higher grades (B and D, ANOVA p <0.001). Crossing sign angle and trochlear dysplasia length provide a novel quantification of trochlear dysplasia and demonstrate moderate inter- and excellent intra-observer reliability. Bump height and the modified Dejour classification, when using a standardized protocol, also showed high inter- and intra-observer reliability. Bump height and trochlear dysplasia length have strong positive correlation. The clinical and surgical implications of these new parameters need further investigation in future studies. II.
Clomiphene citrate (CC) is a longstanding human fertility drug that has yet to be investigated in horses. The objective was to evaluate effects of CC on mare reproduction. After follicle ablation on Day 0, treatment mares (n=5) received 2 grams of CC intravenously on Days 1-5 while control mares (n=4) received no treatment. Transrectal ultrasonography was performed on Days 1-5 and 8, and transvaginal oocyte aspiration occurred on Day 8. Hormones were analyzed on Days 0-5, 8, 11, and 15. Mares receiving CC exhibited higher uterine edema grades compared to control mares (P=0.009). Antral follicle count and size of largest follicle did not differ between groups (P>0.05). Treated mares had higher luteinizing hormone (LH, P=0.04) and anti-müllerian hormone (AMH, P=0.05) compared to control mares. While CC treated mares had higher uterine edema and serum LH and AMH, significant changes in follicle stimulating hormone, estradiol, and follicular development were not demonstrated.
Structural inequities, including historical redlining, have created compounding climate-related vulnerabilities in marginalized communities, with potential implications for pediatric cardiometabolic diseases (CMD). However, the joint effects of redlining, climate risk, and urban heat on pediatric CMD remain poorly understood. Using New York State hospital administrative data (2018-2022), we examined associations between neighborhood redlining, climate risk, urban heat, and CMD-related emergency department (ED) and outpatient visits among children aged < 18 years. Exposures included historical redlining (Home Owners' Loan Corporation grades C/D vs. A/B), climate risk (high vs. low, based on the Climate Vulnerability Index), and urban heat (high vs. low, based on satellite-derived land surface temperature). Associations were estimated using Poisson regression with interaction terms and subtype-specific analyses. Among 342,220 CMD-related visits in the climate-risk cohort and 9,195 in the urban-heat cohort (mean age, 7.4 years; 49% female), residence in historically redlined neighborhoods was associated with increased rates of CMD-related ED visits (rate ratios [RRs] = 1.15; 95% CI, 1.12-1.18) and outpatient visits (RR = 1.18; 95% CI, 1.17-1.20), with the strongest associations observed for comorbidity, hypertension, and type 1 diabetes (T1D). High-climate risk was associated with modestly lower overall rates of CMD-related ED visits (RR = 0.95; 95% CI, 0.94-0.96) and outpatient visits (RR = 0.96; 95% CI, 0.96-0.97), although elevated risks remained evident for selected CMD subtypes (e.g., hypertension, obesity, T1D). In the urban-heat cohort, most associations were not statistically significant (RRs = 1.00-1.03), except for outpatient visits for T1D, where higher urban heat exposure was associated with increased risk (RR = 1.28; 95% CI, 1.04-1.57). Co-exposure to historical redlining and high-climate-risk was associated with a modest increase in CMD-related ED visits (RR = 1.04; 95% CI, 1.01-1.07), whereas no significant associations were observed for co-exposure to redlining and urban heat (RR = 1.08; 95% CI, 0.78-1.49). Associations for outpatient visits were attenuated in both analyses. These findings suggest that redlining may be a stronger determinant of pediatric CMD healthcare utilization than climate-related hazards alone, highlighting the enduring health consequences of structural inequities and underscoring the need for targeted, climate-adaptive interventions, especially in historically redlined communities.
To investigate the convergent validity of Stamey's Incontinence Scoring System, a simple tool, in assessing post-prostatectomy incontinence at different time points after surgery. This was a retrospective study. 331 patients who underwent radical prostatectomy from January 2024 to May 2025 took part; 295 completed the study. Data of Stamey's Grade, ICI-Q-SF, and daily pad use at 1.5, 3, 6, and 12 months postoperatively were recorded. Spearman's rank correlation assessed the correlation between Stamey's grade and ICI-Q-SF. Quadratic weighted Kappa compared daily pad use and Stamey's grade for their agreement with ICI-Q-SF, with four severity levels defined according to guidelines. Bootstrap estimated differences in Kappa coefficients. Trends in severity and recovery time across grades were evaluated. Across 735 data records at different time points, this system showed strong positive correlations with ICI-Q-SF (correlation coefficients = 0.699, 0.752, 0.920, 0.947; all P<0.001). Bootstrap comparisons showed that the agreement of Stamey's Scoring System with ICI-Q-SF (Kappa = 0.445, 0.486, 0.747, 0.659) was significantly higher than that of daily pad use (Kappa = 0.054, 0.017, 0.188, 0.214) at all postoperative time points (P<0.001). This system corresponded to the patients' recovery trend; There was an association between early severity grade and subsequent recovery. Compared with existing assessment tools, the Stamey's grade has a simpler questionnaire structure and higher consistency. This can make follow-up for patients after radical prostatectomy more efficient and reduce clinical workload.
To characterise gene expression differences between oral cavity squamous cell carcinoma (OSCC) and non-neoplastic oral mucosa using targeted transcriptome profiling and to evaluate gene expression patterns associated with tumour differentiation. Formalin-fixed, paraffin-embedded tissue from 16 resected OSCCs (3 well differentiated, 9 moderately differentiated and 4 poorly differentiated) and 7 non-neoplastic oral mucosa samples was analysed. RNA was isolated from microdissected tissue and profiled using a targeted next-generation sequencing assay. Differential gene expression and pathway enrichment analyses were performed, including comparisons across histologic grades. OSCC demonstrated broad transcriptomic differences compared with non-neoplastic oral mucosa, with enrichment of pathways related to extracellular matrix remodelling, cell adhesion, immune regulation, oncogenic signalling and cellular metabolism. Grade-stratified analyses identified additional differences involving epithelial differentiation, immune response, lipid metabolism and oxidative phosphorylation pathways. OSCC exhibits broad transcriptomic dysregulation involving extracellular matrix remodelling, cell adhesion, immune signalling, oncogenic signalling and cellular metabolism. Grade-stratified findings demonstrate molecular differences associated with tumour differentiation but require validation in larger independent cohorts. These findings may inform future studies of biomarkers and biologically relevant pathways in OSCC.
Although immune checkpoint blockade has improved systemic therapy for hepatocellular carcinoma (HCC), durable benefit is limited by primary resistance, poor tumor penetration of antibodies, and an immunosuppressive tumor microenvironment (TME). We identified integrin β5 (ITGB5) as an oncogenic and immune-associated target in HCC and developed an ITGB5-directed nanobody. Integrative analyses of TCGA/ICGC/TIMER2.0/HPA datasets, tissue microarrays, and functional assays showed that ITGB5 is upregulated in HCC and correlates with poor prognosis, higher tumor grade, increased immunosuppressive macrophage infiltration, reduced CD8+ T-cell abundance, and predicted resistance to sorafenib, oxaliplatin, and axitinib. Gain- and loss-of-function studies demonstrated that ITGB5 promotes proliferation, clonogenicity, migration/invasion, cell-cycle progression, and tumor growth while suppressing apoptosis, with transcriptomic signatures implicating ECM-receptor interaction, cytokine signaling, TNF/NF-κB, MAPK, and TGF-β pathways. From a yeast-display library we isolated Anti-ITGB5-Nb#2, a high-affinity nanobody that recognizes human and murine ITGB5, validated by flow cytometry, immunofluorescence, molecular docking, and surface plasmon resonance. Anti-ITGB5-Nb#2 inhibited growth and motility of ITGB5-high HCC cells and suppressed tumor progression in subcutaneous and orthotopic models, including an immunocompetent murine HCC model, without overt toxicity. Single-cell RNA sequencing revealed TME remodeling characterized by enhanced cytotoxic immune infiltration and reduced immunosuppressive signaling. These results establish ITGB5 as a prognostic, therapeutically actionable target in HCC and support Anti-ITGB5-Nb#2 as a nanobody-based strategy to complement current therapies.
The extent of resection (EOR) in giant pituitary adenomas (PAs) is influenced by multiple anatomical and morphological factors. While conventional radiological assessment relies primarily on tumor size and invasion, the role of three-dimensional tumor geometry remains unclear. This study evaluated tumor shape irregularity and its association with surgical outcomes following endoscopic transsphenoidal surgery (ETSS). A retrospective analysis was conducted on 26 patients who underwent ETSS for giant PA between 2009 and 2016. Giant PA was defined as a tumor > 3 cm on preoperative MRI. Tumor volume was assessed using an ellipsoid model and segmentation-based volumetry. Tumor shape irregularity was quantified as the relative volume difference (VD%). Residual tumor volume (RV), its proportion relative to preoperative tumor volume (RV%), and EOR were assessed on postoperative MRI. Mean tumor volume was 17 ± 9 cm3 using the ellipsoid model and 18 ± 9 cm3 using segmentation-based volumetry (p = 0.316). Gross total resection was achieved in 19%. Higher Knosp grade was associated with increased RV (p = 0.006) and RV% (p = 0.027). After adjustment for anteroposterior (AP) dimension and Knosp grade, higher VD% was associated with greater RV (B = 0.124; 95% CI, 0.022-0.225; p = 0.019). Visual improvement occurred in 67% of patients with preoperative visual impairment, while the complication rate was 23%. Higher VD% was associated with greater RV after adjustment for AP dimension and Knosp grade. VD% may complement established radiological measures in the preoperative assessment of giant PAs, although validation is required.
Rare and ultra-rare genetic diseases (GDs) involve complex, multidimensional burdens not fully captured by clinical endpoints, highlighting uncertainties in the availability, scope, and quality of Health-Related Quality-of-life patient-reported outcome measures (HRQoL-PROMs). To identify PROMs developed or validated to assess HRQoL in rare and ultra-rare GDs, map their content using the International Classification of Functioning, Disability and Health (ICF), and evaluate their measurement properties according to COSMIN methodology. Original studies reporting PROM development or measurement properties in rare or ultra-rare GDs were included. PubMed, Embase, PsycINFO, Web of Science, registries, outcome-measure repositories, reference lists, and citation tracking were searched from inception to March 26, 2026, without language restrictions. Study selection, data extraction, and risk-of-bias (RoB) assessment were performed independently. Methodological quality was evaluated using the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) RoB checklist. Measurement properties were rated as sufficient, insufficient, indeterminate, or inconsistent, and certainty of evidence was assessed using a modified GRADE approach. PROM content was mapped to ICF components and synthesized narratively; no meta-analysis was conducted due to heterogeneity. Fifty-nine studies were included, covering 45 PROMs across 29 rare or ultra-rare GDs. Instruments were predominantly disease-specific, although generic and adapted measures were also identified. PROMs mainly addressed body functions and activities/participation, while environmental factors, social participation, stigma, and access-to-care domains were consistently underrepresented. Internal consistency and construct validity were most frequently assessed, whereas responsiveness, measurement error, and cross-cultural validity were rarely evaluated. Only three PROMs (HAE-QoL, NF1-AdQoL, EPP-QoL) were classified as COSMIN category A and recommended; most were category B, and five were category C. The evidence is limited and methodologically weak, and many QoL-PROMs fail to capture key multidimensional aspects of QoL; more rigorous, patient-centered, disease-specific development and validation are needed. This review examined questionnaires used to assess health related quality of life in people with rare and ultra-rare genetic diseases. Although 45 PROMs were identified, only three had enough evidence to be recommended. Many questionnaires focused mainly on symptoms and physical functioning, while important aspects such as social participation, stigma, care access, and environmental support were often missing. Future PROMs should be developed with strong patient involvement and validated across age groups, languages, and disease contexts.
Radiation-induced peripheral neuropathy (RIPN) is a well-known late adverse effect of radiotherapy (RT) in humans, but to date, is not reported in companion animals. An 11-year-old spayed female beagle was presented for evaluation regarding a progressive left sciatic neuropathy. The dog had received stereotactic RT (20 Gy) following excision of a grade 2 soft tissue sarcoma over the proximo-caudal aspect of the left thigh approximately 19 months prior to the onset of signs. Computed tomography and magnetic resonance imaging of the left sciatic nerve was consistent with RIPN, and histopathology of the sciatic nerve supported severe nerve fiber loss. No improvement was observed with an anti-inflammatory course of corticosteroids, and the affected limb was subsequently amputated.
To identify risk factors associated with inpatient mortality among under-five children admitted with complicated severe acute malnutrition (cSAM) at Woldia Comprehensive Specialized Hospital, Ethiopia. Hospital-based unmatched case-control study conducted from 1 January 2016 to 30 December 2022. Data were extracted from 588 medical records (147 cases and 441 controls). Bivariable and multivariable logistic regression analyses were performed to identify predictors of mortality. Adjusted ORs (AORs) with 95% CIs were used to measure associations and statistical significance was set at p<0.05. Stabilisation centre of Woldia Comprehensive Specialized Hospital, Northeastern Ethiopia. Under-five children admitted with cSAM. Inpatient mortality among under-five children with cSAM. A total of 588 records were included in the analysis. In multivariable logistic regression, grade I nutritional oedema (AOR 13.70; 95% CI 1.09 to 172.76), history of bottle feeding (AOR 5.43; 95% CI 1.09 to 26.98), vomiting (AOR 7.96; 95% CI 1.97 to 32.17), pale conjunctiva (AOR 8.68; 95% CI 2.47 to 30.53), shock (AOR 6.11; 95% CI 1.44 to 25.88), no vaccination history (AOR 11.83; 95% CI 3.09 to 45.29) and intravenous fluid administration (AOR 5.55; 95% CI 1.33 to 23.10) were independent predictors of mortality. Children in the first treatment phase had lower odds of death compared with those in later phases (AOR 0.017; 95% CI 0.003 to 0.098). Bottle feeding history, grade I nutritional oedema, shock, intravenous fluid administration, pale conjunctiva, lack of vaccination and treatment phase were independent predictors of mortality among under-five children with cSAM. Strengthening adherence to cSAM management protocols and improving routine immunisation coverage may reduce inpatient mortality.
Artificial intelligence scribes are increasingly common in clinical settings, but a blueprint for deploying them efficiently at scale is lacking. We share information about the Cleveland Clinic's vendor-health system deployment partnership consisting of four pillars: governance, training and onboarding, support, and real time learning. This partnership enabled deployment and onboarding of over 4000 ambulatory care clinicians in 4 months and can inform other health systems tasked with rapid enterprise-wide deployment.
The period of transfer from hospital to home is challenging for patients with coronary artery disease (CAD). Transitional care is an effective approach to bridge this gap, reduce readmission risk and improve secondary prevention. Components necessary for optimal models of transitional care in CAD are unknown. To synthesise evidence describing nurse-led transitional care model (TCM) for patients with CAD. The specific review objectives are: (1) To identify the components and characteristics of TCM for patients with CAD and (2) To evaluate the effectiveness of the TCM interventions compared with usual care. A systematic review (± meta-analysis) of randomised controlled trials. Multiple databases including the Cumulative Index to Nursing and Allied Health Literature, Medical Literature Analysis and Retrieval System Online, Cochrane Central Register of Controlled Trials, the Excerpta Medica Database, PyscINFO and Emcare will be searched. Independent screening in Covidence, data extraction and quality assessment will be undertaken by two reviewers with a third available for arbitration of disagreements. Two reviewers will use the Consolidated Standards of Reporting Trials (CONSORT) checklist to assess methodological quality, and the Cochrane Risk of Bias 2 (RoB 2) tool to assess risk of bias in included trials. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework will be used to determine certainty in the evidence. Narrative synthesis will be used to describe model components. Approaches to meta-analyses to assess effectiveness of transitional care models will be determined by type and frequency of reported outcome measures. Identifying key model components and characteristics in the context of CAD management should reveal gaps in evidence for best practice, providing opportunities to improve outcomes associated with care transitions.Registration: PROSPERO International Prospective Register of Systematic Reviews, registration number CRD420251182328.
To evaluate whether baseline T2-mapping MRI is associated with pathologic response to neoadjuvant therapy (nT), lymphovascular invasion (LVI) and perineural invasion (PNI) in locally advanced esophageal squamous cell carcinoma (ESCC). This single-center retrospective study enrolled 212 ESCC patients with pre-nT 3 T MRI including T2 mapping at a university-affiliated hospital. Patients were stratified by pathologic tumor regression grade (TRG) into pathologic complete response (pCR, TRG 0) vs non-pCR (npCR, TRG ≥ 1), good response (GR, TRG ≤ 1) vs poor response (PR, TRG ≥ 2), plus LVI/PNI status. Univariate/multivariable logistic regression identified predictors, with performance assessed via ROC analysis. Patients were grouped as pCR (n = 56), GR (n = 81), LVI (n = 67), PNI (n = 32). T2 values were markedly higher in pCR (98.0 ± 12.2 ms vs 82.6 ± 11.5 ms, P < .001; AUC = 0.822) and GR (94.8 ± 12.6 ms vs 81.7 ± 11.7 ms, P < .001; AUC = 0.734) vs npCR and PR. Conversely, T2 values were lower in LVI (79.0 ± 12.8 ms vs 90.5 ± 12.3 ms, P < .001; AUC = 0.840) and PNI (73.6 ± 9.7 ms vs 89.1 ± 12.8 ms, P < .001; AUC = 0.844). T2 value was independently associated with all endpoints in multivariate analysis. Pre-nT T2 values were associated with pathologic response, LVI, and PNI in locally advanced ESCC, which may inform personalized treatment planning in future studies.
Objective.Radiation pneumonitis (RP) is an important toxicity following breast radiotherapy. Although modern treatment techniques limit lung exposure, some patients still develop symptomatic RP, and predicting who is at risk remains difficult. This study aimed to develop and validate machine learning (ML) models based on ipsilateral-lung dosimetric parameters to predict clinically significant RP after breast radiotherapy.Approach.We retrospectively studied 184 women with breast cancer treated with three-dimensional conformal radiotherapy using either conventional or hypofractionated fractionation schemes, with or without regional nodal irradiation, including internal mammary node irradiation when indicated. Clinically significant RP was defined as Common Terminology Criteria for Adverse Events (CTCAE v5.0) grade ⩾2 within six months of treatment. Ipsilateral-lung dose-volume metrics (V5Gy-V45Gy), maximum lung dose (Dmax), mean lung dose (MLD), and effective dose (Deff) were extracted from treatment plans. Four ML models (LightGBM, random forest, support vector machine, and logistic regression) were trained and evaluated using cross-validation. Model performance and feature reduction were analyzed.Results.Fifty-two patients (28%) developed clinically significant RP. All four models showed good and consistent predictive performance, with cross-validated AUC values >0.8. Across all models, high-dose lung parameters were the most reliable predictors. Models with reduced features (using V45Gy,Dmax,Deff, and MLD) showed competitive performance metrics compared to the respective full models.Significance.ML models built from simple, routinely available lung dosimetric data can effectively predict clinically significant RP after breast radiotherapy. Our findings suggest that small regions of the lung receiving higher doses play a greater role in RP risk than low-dose exposure alone. With further validation, this approach could support more personalized treatment planning and earlier identification of patients who may benefit from closer monitoring or preventive strategies.
Fatty infiltration (FI) of the rotator cuff (RC) muscles reflects chronic deterioration in muscle quality associated with tendon injury, disuse, ageing and nerve injury. Accurate and reliable assessment of FI based on imaging interpretation is essential for evaluating muscle degeneration, guiding rehabilitation planning and enabling meaningful comparisons across clinical and research settings. Several semi-qualitative grading systems and quantitative measurement approaches across imaging modalities, including CT, MRI, ultrasound and advanced techniques such as Dixon MRI have been used to assess FI; however, the reproducibility of FI grading or quantification at the level of image interpretation varies widely. This protocol outlines a systematic review and meta-analysis designed to evaluate the inter-rater and intra-rater reliability of imaging-based FI assessment at the level of image interpretation in RC disorders. The review will follow the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P) guidelines and is preregistered in PROSPERO (CRD420251242564). Searches will be conducted in MEDLINE, Embase, CINAHL, Web of Science and the Cochrane Library from inception to the search date. Two reviewers will independently screen, extract data and assess study quality using the Quality Appraisal of Reliability Studies (QAREL) checklist. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) framework will be used to guide interpretation of reliability-related measurement properties. The primary outcomes will be inter-rater and intra-rater reliability reflecting the consistency of image-based FI grading or quantification. Where appropriate, pooled reliability estimates will be calculated separately by imaging modality (eg, MRI, CT and US) and by type of reliability (inter-rater and intra-rater). When quantitative pooling is not feasible because of limited studies or substantial heterogeneity, findings will be synthesised narratively and presented in summary tables. These will be synthesised using a restricted maximum likelihood random-effects model in R software, version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria) with the metafor package. Ethical approval is not required as the review will use only published data. The results will be disseminated through a peer-reviewed publication and conference presentations to inform research and clinical practice in musculoskeletal imaging. CRD420251242564.
Orally administered small-molecule programmed death ligand 1 (PD-L1) inhibitors may have the potential to improve patient outcomes in the treatment of a range of cancers compared with their antibody-based counterparts. A small molecule might achieve better tumor tissue penetration, and oral administration could significantly improve convenience and access for patients. Three phase 1 open-label, non-randomized, dose escalation, and expansion studies evaluated the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of three agents in patients with advanced solid tumors: INCB086550 (NCT03762447), INCB099280 (NCT04242199), and INCB099318 (NCT04272034). Overall, 138, 182, and 104 patients received INCB086550, INCB099280, and INCB099318, respectively. Most had previously received ≥2 lines of cancer therapy for advanced or metastatic disease; 9.6%-16.5% had received prior immunotherapy. All three agents were rapidly absorbed and showed stable dose-dependent PK. With INCB086550, 88 patients (63.8%) had ≥1 treatment-related treatment-emergent adverse event (TEAE), and 19 (13.8%) had ≥1 treatment-related grade ≥3 TEAE. In total, 14 patients (10.1%) had a nervous system-associated TEAE for which an immune-mediated etiology could not be ruled out; events were predominantly peripheral sensory and motor neuropathies. With INCB099280 and INCB099318, 144 (79.1%) and 69 (66.3%) of patients had ≥1 treatment-related TEAE, and 25 (13.7%) and 12 (11.5%) had ≥1 treatment-related grade ≥3 TEAE, respectively. The most frequent immune-related adverse events were skin reactions (INCB099280 and INCB099318) and hepatitis (INCB099280). No dose-limiting toxicities (DLTs) occurred during dose escalation with INCB086550 or INCB099318; two DLTs occurred in two patients with INCB099280 (grade 2 vomiting with 600 mg once daily and grade 2 maculopapular rash with 800 mg two times per day). Overall objective response rates for INCB086550, INCB099280, and INCB099318 were 10.9% (95% CI 6.2% to 17.3%; n=15), 8.8% (95% CI 5.1% to 13.9%; n=16), and 8.7% (95% CI 4.0% to 15.8%; n=9), respectively. Target engagement and PD activity were demonstrated, including PD-L1 binding, and increases in cytokine and chemokine production, as well as T-cell activation and proliferation. Both INCB099280 and INCB099318 had an acceptable safety profile, with preliminary evidence of antitumor activity. The risk of immune-mediated neuropathy led to discontinuation of the clinical program for INCB086550.
The 2021 WHO classification reclassified "IDH-mutant glioblastoma (GBM)" as "Astrocytoma, IDH-mutant, grade 4." This study aims to provide real-world validation of this reclassification using the specific ICD-O-3 code (9445/3) from the Surveillance, Epidemiology, and End Results (SEER) "Transition Era" (2018-2022) and develop a machine learning (ML)-based prognostic model. Patients diagnosed with IDH-mutant GBM (9445/3) and GBM NOS (9440/3) were identified. Propensity Score Matching (PSM) and Inverse Probability of Treatment Weighting (IPTW) were employed to minimize bias. A doubly robust Cox regression model was constructed to quantify survival benefits. Nine ML algorithms were integrated to develop a prognostic signature, which was interpreted using SHAP (Shapley Additive exPlanations) analysis. Of 13,443 patients, 312 were IDH-mutant. After matching, the IDH-mutant group exhibited significantly superior overall survival (OS) and cancer-specific survival (CSS) (p < 0.001). IDH mutation emerged as a potent independent favorable prognostic factor, associated with a 65.0% lower mortality risk (HR = 0.350, p < 0.001). Subgroup analysis confirmed robust benefits from chemotherapy. The Random Forest (RF) model achieved the best performance (Test AUC = 0.698). SHAP analysis identified IDH status, chemotherapy, and age as the top predictors. This study provides compelling evidence in support of the clinical rationale for the WHO 2021 reclassification. Despite a favorable prognosis, aggressive multimodal therapy was strongly associated with improved survival, though potential indication bias necessitates cautious interpretation and prospective validation. The developed ML model serves as a robust tool for personalized risk stratification.
Botulinum neurotoxin type A (BoNT-A) is an effective treatment for facial nerve palsy sequelae; however, its use in patients with myasthenia gravis (MG) is generally contraindicated due to the risk of exacerbating neuromuscular blockade. We report a female in her 40 s with a 10-year history of generalized, seronegative MG who presented with facial tightness and mild synkinesis due to facial nerve palsy sequelae. As BoNT-A is contraindicated for MG patients in Japan, we obtained approval for off-label use from the Division of Patient Safety Management in our hospital. Under a predefined risk management protocol established to meet the approval conditions, a reduced dose of BoNT-A (3 units) was administered to the affected side. Safety measures included pre- and post-injection vital sign monitoring, frequent follow-ups, and advance information sharing with the on-call otolaryngologists. The patient experienced no respiratory failure or systemic MG exacerbation. At 2 months post-injection, objective grading (Sunnybrook Facial Grading System) and patient-reported outcomes (Facial Clinimetric Evaluation scale) demonstrated sustained improvement, particularly in facial tightness and psychological well-being. This case supports the cautious use of BoNT-A for facial palsy sequelae in patients with underlying MG when a predefined risk management protocol and low-dose strategy are employed.
To describe the aetiologies of thrombocytopenia in patients with antiphospholipid syndrome (APS) and to assess the frequency and characteristics of immune thrombocytopenia (ITP), including its association with SLE. We retrospectively analysed patients with APS who experienced at least one episode of thrombocytopenia (platelet count <100 x 10ˆ9/L) in a tertiary referral cohort enriched in severe cases, particularly catastrophic antiphospholipid syndrome (CAPS). Individual medical records were systematically reviewed to determine the cause of thrombocytopenia. ITP was stringently defined by exclusion of alternative diagnoses and by a documented response to ITP-specific therapies. Clinical, biological and therapeutic characteristics were analysed. The risk of severe haemorrhagic events was evaluated. Among 351 patients with APS, 102 (29.1%) experienced thrombocytopenia and were included in the study. The median platelet nadir was 34.5 x 10ˆ9/L, and 33 (32.4%) had severe thrombocytopenia (<20 x 10ˆ9/L). The most frequent cause of thrombocytopenia was CAPS (n=75, 73.5%), followed by ITP (n=12, 11.8%), including two patients who had both CAPS and ITP. 11 (10.8%) patients had other identified causes, while thrombocytopenia remained unexplained in six patients (5.9%).Patients with ITP more frequently had associated SLE than those with CAPS (80.0% vs 35.6%, p=0.013). Overall, isolated ITP without SLE accounted for only 0.6% of the entire APS cohort. In survival analysis, a graded increase in the risk of severe haemorrhagic events was observed with increasing thrombocytopenia severity, although the association did not reach statistical significance (HR 2.55, 95% CI 0.94 to 6.94 for platelet nadir <20 x 10ˆ9/L vs >100 x 10ˆ9/L). In patients with APS, the underlying cause of thrombocytopenia can be identified in most cases through careful review of medical records. True ITP is uncommon and appears to be exceptionally rare in patients with APS without concomitant SLE. These findings highlight the importance of thoroughly investigating alternative causes of thrombocytopenia and of systematically screening for SLE before diagnosing ITP in patients with APS. NCT02782039.