Prior Treatment Research Articles

Assessment of Intestinal Free Fatty Acid Binding Protein 4 in Alopecia Areata Patients

Introduction: Alopecia areata (AA) is an immune-mediated disease characterized by non-scaring hair loss. High levels of FABP4 have been implicated in different inflammatory diseases. We aim to assess and correlate the level of FABP4 in AA patients and compare with healthy controls. Methods: Eighty-Eight subjects enrolled subdivided equally into AA and healthy controls. AA patients were classified according to the severity and pattern of the disease. The concentration level of FABP4 in serum was assessed and compared to healthy controls using ELISA. Results: The level of FABP4 tends to increase in AA patients than controls with a significant difference (p = 0.0001).There were no statistically significant differences between FABP4 and gender, history, family history, related diseases, or prior treatments. There is a high significant difference between patients with relapse and progressive patients with p = 0.037. Also patients with positive effects in other body sites have higher FABP4 levels than patients without infection in other sites with p = 0.05. The level of FABP4 tends to increase with the severity of the patients. Findings show that there are positive correlations between FABP4 and (disease duration; number of attacks; SALT Score) with r = 0.45, p = 0.0021; r = 0.41, p = 0.007, and r = 0.88, p < 0.0001, respectively. Conclusion: Elevation of FABP4 in serum may correlate with disease severity and could play a vital role in the diagnosis of AA.

Short- and long-term effects of beta-blockers on symptoms of anxiety and depression in patients with myocardial infarction and preserved left ventricular function: a pre-specified quality of life sub-study from the REDUCE-AMI trial.

Among patients with myocardial infarction (MI) with preserved left ventricular ejection fraction (LVEF), the REDUCE-AMI trial did not demonstrate a benefit of beta-blocker vs. no beta-blocker treatment on all-cause mortality and recurrent myocardial infarction. The aim of this pre-specified sub-study was to investigate effects of beta-blockers on self-reported symptoms of anxiety and depression. In this parallel-group, open-label, registry-based randomized trial, assessments with the Hospital Anxiety and Depression Scale were obtained at hospitalization and two follow-up points (6-10 weeks and 12-14 months) after MI. Analyses were based on the intention-to-treat principle using linear mixed models, calculating both short- and long-term effects. From August 2018 through June 2022, 806 patients were enrolled. At baseline, 27% of patients were possible cases of anxiety (m, 5.6; SD, 3.9) and 14% were possible cases of depression (m, 3.9; SD, 3.2). Beta-blocker treatment had a negative effect on depressive symptoms at both follow-ups 1 (β = 0.48; 95% CI 09-0.86; P = 0.015) and 2 (β = 0.41; 95% CI = 0.01-0.81; P = 0.047), but no effect on anxiety. Beta-blocker treatment led to a modest increase in depressive symptoms among MI patients with preserved LVEF. This observed effect was most pronounced in individuals with prior beta-blocker treatment. In routine initiation and continuation of beta-blocker treatment, a risk of slightly increased depressive symptoms should be considered.

Reactivation of stable neovascular age-related macular degeneration following treat-and-extend regimen discontinuation.

To describe the incidence and pattern of reactivation of neovascular age-related macular degeneration (nAMD) following successful treatment with treat-and-extend intravitreal anti-vascular endothelial growth factor therapy. Consecutive patients with treated nAMD who did not require further treatment over a 6-month period and who attended their 3-monthly optical coherence tomography monitoring clinic in Moorfields Eye Hospital from 1 November 2019 to 31 January 2020 were included. Patients with diagnoses of macular neovascularization other than AMD, and patients with incomplete data were excluded. Baseline demographics recorded were age, sex, race, laterality, cause of macular neovascularization, drug, number of injections, and duration of treatment. Date, setting, symptoms, and time to retreatment were collected among patients with disease reactivation. The medical records of 286 patients were included. Most patients were female (64.3%), white (68.18%), and were receiving aflibercept monotherapy (55.2%). Mean number of injections at baseline was 17.79 ± 11.74 (range 3-62) with a mean treatment duration of 39.47 ± 30.68 months (range 2-139). Reactivation of AMD was identified in 32.2% of cases with 87% of recurrences identified via scheduled visit. The most common symptom was blurring of vision in 44.6%, while 39.1% were asymptomatic. Mean time from baseline to retreatment was 29.37 ± 22.40 months (range 5-104), with 20.7%, 73.9% and 88.04% of these patients requiring retreatment within 1, 3, and 5 years, respectively. Despite prior treatment with no reactivation in 6 months, 32.2% reactivate, 73.9% of which within 3 years. A significant proportion, 39.1%, reactivated without symptoms necessitating regular monitoring in the first 5 years.

Prediction of PD-L1 expression in unresectable hepatocellular carcinoma with gadoxetic acid-enhanced MRI

ObjectivesTo develop a model to predict programmed death-ligand 1 (PD-L1) expression in unresectable hepatocellular carcinoma (HCC) based on gadoxetic acid-enhanced magnetic resonance imaging (MRI) findings and clinical characteristics. Materials and methodsWe enrolled patients with unresectable HCC who underwent gadoxetic acid-enhanced MRI between January 2021 and May 2023. Immunohistochemical staining of PD-L1 was performed on a biopsy specimen. Patients with a history of any prior treatment for HCC or those lacking an MRI scan within 30 days of the biopsy date were excluded. Using the clinical and MRI findings, we developed a PD-L1 prediction score using logistic regression. ResultsThis study included 49 patients with HCC (median age, 64 years; interquartile range, 57–73 years; 44 men). Among these, 15 (31 %) were positive for PD-L1 expression. The PD-L1 prediction score was defined as the sum of arterial phase hypoenhancement (score 1), necrosis (score 1), and AFP >4000 ng/mL (score 2). The AUC value of the PD-L1 prediction score was 0.838 (95 % confidence interval [CI], 0.715–0.962). When the PD-L1 prediction score was ≥3, the sensitivity, specificity, and positive predictive value of PD-L1 positivity were 67 %, 91 %, and 77 %, respectively. ConclusionWe developed a PD-L1 prediction score for unresectable HCC with high specificity that could potentially contribute to the identification of effective candidates for immune checkpoint inhibitors.

Evaluating Biparametric Versus Multiparametric Magnetic Resonance Imaging for Diagnosing Clinically Significant Prostate Cancer: An International, Paired, Noninferiority, Confirmatory Observer Study

Background and objectiveBiparametric magnetic resonance imaging (bpMRI), excluding dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), is a potential replacement for multiparametric MRI (mpMRI) in diagnosing clinically significant prostate cancer (csPCa). An extensive international multireader multicase observer study was conducted to assess the noninferiority of bpMRI to mpMRI in csPCa diagnosis. MethodsAn observer study was conducted with 400 mpMRI examinations from four European centers, excluding examinations with prior prostate treatment or csPCa (Gleason grade [GG] ≥2) findings. Readers assessed bpMRI and mpMRI sequentially, assigning lesion-specific Prostate Imaging Reporting and Data System (PI-RADS) scores (3–5) and a patient-level suspicion score (0–100). The noninferiority of patient-level bpMRI versus mpMRI csPCa diagnosis was evaluated using the area under the receiver operating curve (AUROC) alongside the sensitivity and specificity at PI-RADS ≥3 with a 5% margin. The secondary outcomes included insignificant prostate cancer (GG1) diagnosis, diagnostic evaluations at alternative risk thresholds, decision curve analyses (DCAs), and subgroup analyses considering reader expertise. Histopathology and ≥3 yr of follow-up were used for the reference standard. Key findings and limitationsSixty-two readers (45 centers and 20 countries) participated. The prevalence of csPCa was 33% (133/400); bpMRI and mpMRI showed similar AUROC values of 0.853 (95% confidence interval [CI], 0.819–0.887) and 0.859 (95% CI, 0.826–0.893), respectively, with a noninferior difference of –0.6% (95% CI, –1.2% to 0.1%, p < 0.001). At PI-RADS ≥3, bpMRI and mpMRI had sensitivities of 88.6% (95% CI, 84.8–92.3%) and 89.4% (95% CI, 85.8–93.1%), respectively, with a noninferior difference of –0.9% (95% CI, –1.7% to 0.0%, p < 0.001), and specificities of 58.6% (95% CI, 52.3–63.1%) and 57.7% (95% CI, 52.3–63.1%), respectively, with a noninferior difference of 0.9% (95% CI, 0.0–1.8%, p < 0.001). At alternative risk thresholds, mpMRI increased sensitivity at the expense of reduced specificity. DCA demonstrated the highest net benefit for an mpMRI pathway in cancer-averse scenarios, whereas a bpMRI pathway showed greater benefit for biopsy-averse scenarios. A subgroup analysis indicated limited additional benefit of DCE MRI for nonexperts. Limitations included that biopsies were conducted based on mpMRI imaging, and reading was performed in a sequential order. Conclusions and clinical implicationsIt has been found that bpMRI is noninferior to mpMRI in csPCa diagnosis at AUROC, along with the sensitivity and specificity at PI-RADS ≥3, showing its value in individuals without prior csPCa findings and prostate treatment. Additional randomized prospective studies are required to investigate the generalizability of outcomes.

Efficacy and safety of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, plus chemotherapy in patients with stage IV NSCLC

IntroductionIn a phase 1 study, bintrafusp alfa demonstrated encouraging clinical activity in patients with previously treated advanced non-small cell lung cancer (NSCLC). The current study evaluated the safety and efficacy of bintrafusp alfa with chemotherapy in patients with stage IV NSCLC regardless of the programmed death-ligand 1 (PD-L1) expression status. MethodsIn this open-label, phase 1b/2 study (NCT03840915), eligible patients were assigned to one of four cohorts. Patients with previously untreated metastatic NSCLC (cohorts A, B, and C) received bintrafusp alfa with chemotherapy as first-line treatment, whereas patients whose disease progressed on prior treatment with PD-1/PD-L1 inhibitors (cohort D) received bintrafusp alfa with chemotherapy as second-line treatment. The primary objective of this study was to evaluate the safety and tolerability of bintrafusp alfa with chemotherapy. ResultsFour serious and one nonserious treatment-emergent adverse events (AEs) were considered dose-limiting toxicities, none of which were assessed as related to bintrafusp alfa by the investigator. Any-grade bintrafusp alfa-related AEs occurred in 20.7% of patients in cohorts A+B+C and in 16.7% of patients in cohort D. Keratoacanthoma was the most common transforming growth factor-β inhibition-mediated skin lesion (cohorts A+B+C: 12.1% and cohort D: 8.3%). In cohorts A+B+C the overall response rate was 48.3% and in patients with PD-L1 tumor proportion score of ≥50.0% it was 71.4%. Based on an interim analysis, the data were considered mature, and no further analysis has been planned. ConclusionBintrafusp alfa with chemotherapy demonstrated a manageable safety profile and encouraging clinical activity in patients with stage IV NSCLC.

Impact of real-world remote symptom monitoring program on hospitalizations and ICU admissions.

377 Background: Previous randomized controlled trials have demonstrated benefits to patients from remote symptom monitoring (RSM) with electronic patient-reported outcomes (ePROs) including healthcare utilization. However, less is known about the impact of RSM in diverse, real-world populations. Methods: This cross-sectional analysis from a hybrid, type 2 implementation-effectiveness trial evaluated the impact of RSM on healthcare utilization amongst patients with cancer receiving chemotherapy, immunotherapy, monoclonal antibody, or targeted therapy at two academiccancer centers in the Southeastern United States. Modified Poisson regression models with robust standard error and 95% confidence interval (CI) was used to calculate the relative risk (RR) of any hospital or ICU utilization between patients receiving RSM and controls for 3 and 6 months after index date. Models were controlled for age at index, race, sex, cancer type, cancer stage, insurance, prior treatment, comorbidities, RUCA, and follow-up during COVID-19 pandemic. Additional logistic regression models were used to estimate odds ratios (OR) for subset analysis stratified by race (Black or African American, Other, or White), rurality using Rural-Urban Commuting Area Codes, and neighborhood disadvantage using Area Deprivation Index (ADI). Results: From 5/2021-2/2024, 1215 patients were enrolled in RSM; 27% were Black, 16% lived in a rural area, and 25% lived in an area with high neighborhood disadvantage. The populations receiving RSM were similar to the control population (n = 4559); 26% were Black, 22% lived in a rural area, and 28% lived in area with high neighborhood disadvantage. The unadjusted relative risk of hospitalization for patients receiving RSM and control patients were 0.70 (95% CI, 0.63-0.70) and 0.77 (95% CI, 0.71-0.85), respectively. In adjusted analyses, hospitalizations were lower amongst patients receiving RSM compared to control patients with a RR of 0.82 (95% CI 0.73-0.92). Similar patterns were observed for ICU admissions (RR 0.59; 95% CI,0.40-0.88). Analysis by patient subgroup was similar to the overall analysis. A lower odd of hospitalizations and ICU admissions at 6 months was observed across all subset analyses: Black vs. White patients (OR 0.80; OR 0.48); rural vs. urban patients (OR 0.78; OR 0.68); and patients living in areas of high vs. lower neighborhood disadvantage (OR 0.59; OR 0.33). Conclusions: The use of RSM amongst patients receiving treatment for cancer is associated with reductions in hospitalizations and ICU admissions in real-world, diverse settings. Further work to expand this intervention nationally is needed. Clinical trial information: NCT04809740 .

Predictors of Durable Remission After Successful Surgery for Cushing Disease: Results From the Multicenter RAPID Registry.

Cushing disease (CD) affects mortality and quality of life along with limited long-term remission, underscoring the need to better identify recurrence risk. The identification of surgical or imaging predictors for CD remission after transsphenoidal surgery has yielded some inconsistent results and has been limited by single-center, single-surgeon, or meta-analyses studies. We sought to evaluate the multicenter Registry of Adenomas of the Pituitary and Related Disorders (RAPID) database of academic US pituitary centers to assess whether robust nonhormonal recurrence predictors could be elucidated. Patients with treated CD from 2011 to 2023 were included. The perioperative and long-term characteristics of CD patients with and without recurrence were assessed using univariable and multivariable analyses. Of 383 patients with CD from 26 surgeons achieving postoperative remission, 288 (75.2%) maintained remission at last follow-up while 95 (24.8%) showed recurrence (median time to recurrence 9.99 ± 1.34 years). Patients with recurrence required longer postoperative hospital stays (5 ± 3 vs 4 ± 2 days, P = .002), had larger average tumor volumes (1.76 ± 2.53 cm 3 vs 0.49 ± 1.17 cm 3 , P = .0001), and more often previously failed prior treatment (31.1% vs 14.9%, P = .001) mostly being prior surgery. Multivariable hazard prediction models for tumor recurrence found younger age (odds ratio [OR] = 0.95, P = .002) and Knosp grade of 0 (OR = 0.09, reference Knosp grade 4, P = .03) to be protective against recurrence. Comparison of Knosp grade 0 to 2 vs 3 to 4 showed that lower grades had reduced risk of recurrence (OR = 0.27, P = .04). Other factors such as length of stay, surgeon experience, prior tumor treatment, and Knosp grades 1, 2, or 3 failed to reach levels of statistical significance in multivariable analysis. This multicenter study centers suggests that the strongest predictors of recurrence include tumor size/invasion and age. This insight can help with patient counseling and prognostication. Long-term follow-up is necessary for patients, and early treatment of small tumors may improve outcomes.

Real-world outcomes among patients with advanced EGFRm NSCLC previously treated with osimertinib and platinum-based chemotherapy.

396 Background: For patients with advanced EGFR-mutant non-small cell lung cancer (EGFRm aNSCLC) progressing after osimertinib (OSI) and platinum-based chemotherapy (PBC) no uniformly accepted standard of care exists. The study was to provide updated results with a refreshed dataset for a previous study describing clinical outcomes of treatment regimens initiated after OSI and PBC in real-world patients with similar baseline characteristics to those in HERTHENA-Lung01 (HL-01), a multinational single-arm phase II trial evaluating the safety and efficacy of patritumab deruxtecan [1] . Methods: This study analyzed data from the US nationwide Flatiron Health electronic health record–derived aNSCLC de-identified database from approximately 280 US cancer clinics (~800 sites of care). Adult patients with an aNSCLC diagnosis (after 01 January 2011) and prior treatment with OSI and PBC, who initiated a subsequent line of therapy (index LOT) before 01 August 2022 were included in the study. Patients were chosen to closely match the HL-01 eligibility criteria (documented exon 19 deletion or L858R mutation; Eastern Cooperative Oncology Group Performance Status of 0 or 1; and absence of relevant comorbidities at index date). To further balance patient characteristics, the sample was propensity-score (PS) weighted based on nine covariates. Real-world overall survival (rwOS), progression-free survival (rwPFS) and overall response (rwORR, defined as partial or complete response with ≥2 assessments ≥28 days apart) were assessed from the start of the index LOT with corresponding 95% confidence intervals (CI). Results: 179 patients in the database fulfilled the eligibility criteria, increasing the sample size by 42% compared to the previous study 1 . Median age of the unweighted sample at index was 68 years, 65.9% of patients were female, 40.2% had a history of smoking and 26.3% received more than 3 LOTs prior to the index LOT. In the PS-weighted cohort (standard mean difference of all covariates was ≤0.127) the median rwOS was 9.1 months (95% CI: 7.3 – 11.3) and median rwPFS was 3.5 months (95% CI: 2.7 – 4.6). For a subsample of 75 patients with qualifying response assessments, rwORR was 12.7% (95% CI: 4.8 – 25.7). Conclusions: These observations in patients with EGFRm NSCLC after OSI and PBC demonstrate a limited clinical benefit with currently available therapies. The results are consistent with the previously published study and increase precision of the outcome estimates 1 . They highlight the high unmet need and provide further context on clinical outcomes of HL-01 trial results. [1] Patel et al. Clinical Outcomes of Real-World Treatment for Metastatic EGFRm NSCLC after Osimertinib and Platinum-Based Chemotherapy. 2023 Sep 9-12 Singapore. P2.31.

Early real-world experience with intravitreal Faricimab for neovascular AMD: FAN study

PurposeThis study presents real-world experiences and clinical outcomes of patients who switched to faricimab after prior treatment with other anti-vascular endothelial growth factor medication for patients with neovascular age-related macular degeneration (nAMD) in 2022. DesignWe evaluated all consecutive patients that received an intravitreal injection (IVI) with faricimab for nAMD and had complete follow-up visits after at least three IVI. MethodsFunctional and structural parameters including best-corrected visual acuity (BCVA, logMAR), foveal centre point (FCP, µm), central subfield retinal thickness (CSRT, µm) and macular volume (mm3) were evaluated after three (n=71) and five (n=57) faricimab injections with complete follow-up visits. ResultsWe included 71 eyes of 63 patients. Mean BCVA at baseline was 0.49 logMAR (0 – 1.6) and did not change significantly after five faricimab injections (p=0.33). Significant reductions were seen for FCP, CSRT and macular volume after the first five consecutive injections when compared to baseline (p<0.0001 respectively). FCP was 388.35 µm (173-924 µm) at baseline and decreased to 279.16 µm (97 – 667) at visit 5. CSRT was 370.68 µm (202 – 1074) and decreased to 307.75 µm (168 – 590) at visit 5. Macular volume was reduced from 2.59 mm3 (1.83 – 4.90) to 2.31 mm3 (1.80 – 3.19) at visit 5. Intraocular inflammation was observed in one eye showing anterior chamber cells that resolved with topical corticosteroid treatment. ConclusionsThe results of the FAN (FAricimab for Neovascular AMD) study indicate that faricimab improves structural outcomes in patients with recalcitrant fluid due to nAMD with no major complications observed.

In Silico Investigation of Molecular Properties and Molecular Docking of Darunavir: An Anti‐HIV Drug

AbstractA second‐generation HIV protease enzyme inhibitor, darunavir is used in combination therapy for patients with history of prior antiretroviral treatments. It inhibits the cleavage of HIV encoded gag‐pol polyprotein in cells contaminated by a virus and thereby hinders the development of mature and infectious new virions. In this paper, optimization of molecular geometry of darunavir has been obtained by Density Functional Theory based B3LYP and ωB97XD methods with 6–311+G(d,p) basis set. The electro‐optical, global reactivity descriptors, and UV–visible spectrum of the drug have been examined using both the functionals. Further, binding affinity of darunavir at different sites of protein receptor (PDB ID: 5b18) has been analyzed using molecular docking technique. Results have been used to discuss electro‐optical and electronic properties of the drug along with its binding affinities with protein receptors.

Successful generation of fully human, second generation, anti-CD19 CAR T cells for clinical use in patients with diverse autoimmune disorders

BackgroundB-cell targeting chimeric antigen receptor (CAR) T-cell therapies, which lead to profound B-cell depletion, have been well-established in hematology-oncology. This deep B-cell depletion mechanism has prompted the exploration of their use in B-cell driven autoimmune diseases. We herein report on the manufacturing of KYV-101, a fully human anti-CD19 CAR T-cell therapy, derived from patients who were treated across a spectrum of autoimmune diseases. MethodsKYV-101 was manufactured from peripheral blood-derived mononuclear cells of 20 patients across 7 autoimmune disease types (neurological autoimmune diseases, n=13; rheumatological diseases, n=7). Patients ranged from 18–75 years of age. Duration of disease ranged from <1–23 years since diagnosis. Patients were heavily pretreated, and most were refractory to prior immunosuppressive treatments. Apheresis was collected across 9 sites, cryopreserved, and shipped to the manufacturing facility. Healthy donor apheresis samples were collected for manufacturing comparison. Manufacturing was performed using the CliniMACS Prodigy system. Cells were enriched for CD4+/CD8+ T cells, transduced with a 3rd generation lentiviral vector encoding the CAR, expanded in vitro, and harvested. Percent cell viability, T-cell purity, cellular expansion, and transduction efficiency were assessed. Activity was assessed using cytokine release assays for KYV-101 CAR T cells co-cultured with different CD19+/– target cell lines. ResultsKYV-101 was successfully manufactured for 100% of patients. Transduced cell populations were highly viable, with expansion ranging from 11–66 fold at Day 8, and were comparable across disease types. Healthy donor-derived controls displayed similar expansion ranges. High CAR expression and transduction rates were observed, ranging between 37–84% with low variation in transgene copy number (2 to 4 per cell). Cell viability of the final KYV-101 drug product ranged from 87–97%. KYV-101 displayed robust CD19-dependent and effector dose-related release of the pro-inflammatory cytokine IFN-γ. ConclusionsKYV-101 manufacturing yielded a CAR T-cell product with high viability and consistent composition and functionality, regardless of disease indication, pre-treatment, and heterogeneity of the incoming material. Cryopreservation of the apheresis and final drug product enabled widespread distribution. These results support the robustness of the manufacturing process for the fully human KYV-101 anti-CD19 CAR T-cell therapy drug product for patients across diverse autoimmune disease types.

Clinical utility of upfront liquid biopsy in non-small cell lung cancer in the community setting.

316 Background: Molecular diagnosis of advanced non-small cell lung cancer (NSCLC) is critical to guide therapeutic decisions. Blood next generation sequencing (NGS) allows for non-invasive screening for targetable genetic abnormalities. Many studies have validated using the liquid biopsies to screen for resistant mutations at the emergence of treatment failure. However, the clinical utility of liquid biopsy for newly diagnosed NSCLC, as part of a comprehensive molecular profiling, is an area of active research. Methods: Retrospective analysis of the molecular landscape and clinical outcomes in NSCLC patients who had liquid biopsy done between December of 2017 to February of 2022. Patients had EGFR, ALK, ROS-1, and BRAF tested in the tissue, and underwent liquid biopsy for broad molecular profiling. The plasma genotyping was conducted using a 73-gene panel by Guardant 360 test. Actionable mutations were stratified accordingly to the OncoKB database based on the level of preclinical and clinical evidence of drug targetability. Survival analysis was conducted by August of 2023. Results: We enrolled 122 NSCLC patients who 84% were treatment-naïve and 78% had the liquid biopsy performed at the initial diagnosis. We found that 86 patients had oncogenic mutations and 43 (35%) had actionable mutations, with 37 (29%) falling under level 1 of evidence mutations. EGFR and KRAS G12C mutations were the two most common level 1 genetic abnormalities (23% and 11% of all actionable mutations, respectively). We identified two germline BRCA carriers who were referred for genetic counselling. 25 patients (20%) received treatment based on the liquid biopsy results, with 15 (12%) achieving partial response. Six patients had liquid biopsy done at progression of EGFR or MET therapies, which identified a resistance mechanism in three of them. Conclusions: Upfront liquid biopsy identified a significant proportion of patients with targetable mutations. Here, we reported actionable mutations in 35% of our patients who 84% had no prior systemic treatment. Our results complement prior literature and shows that blood next generation sequencing can be a useful tool to guide upfront therapeutical options at the community healthcare setting.

Robot-assisted T-plasty for recalcitrant bladder neck stenosis: description of technique and initial results.

The aim of this study was to describe the technique and initial outcomes of robot-assisted T-plasty for recalcitrant bladder neck stenosis. Patients who underwent robot-assisted T-plasty for recalcitrant bladder neck stenosis in a single center were included. Presence of bladder neck stenosis was preoperatively confirmed by the combination of retrograde urethrography with voiding cysto-urethrography and flexible urethroscopy. Follow-up visits were performed with history taking, uroflowmetry and echographic residual urine measurement. Complications were graded according to the Clavien-Dindo classification. Patients without urinary symptoms and with a maximum uroflow of no less than 15mL/s were considered as successfully treated. Otherwise, cystoscopy would be performed, and recurrence was defined as the inability to pass a 14 French cystoscope through the bladder neck. Since 2018, seven patients were treated. The etiologies were transurethral resection of the prostate and simple prostatectomy in respectively 6 patients and 1 patient. Cystoscopy was able to diagnose bladder neck stenosis in all cases whereas urethrography was equivocal in 3 out of 7 cases. Median (range) age at surgery was 60 (54-75) years, and median number of prior endoscopic treatment for bladder neck stenosis was 3 (1-16). The median operative time was 123 (110-159) minutes. No intraoperative complications were reported. Three patients suffered a grade 2 complication. After a median follow-up of 27 (4-74) months, the recurrence-free rate was 100% with no evidence of de-novo incontinence or erectile dysfunction. In our series, robot-assisted T-plasty suggests positive and safe outcomes in treating recalcitrant bladder neck stenosis with a good patency rate and low incontinence rate. Additionally, cystoscopy is reliable in the diagnosis of patients with inconclusive urethrography results.

Sparsentan (SPAR) in Patients with Prior or Concurrent Immunosuppressive Treatment (IST) for IgA Nephropathy (IgAN): A Case Series

Sparsentan (SPAR) in Patients with Prior or Concurrent Immunosuppressive Treatment (IST) for IgA Nephropathy (IgAN): A Case Series

A phase 2 trial of gemcitabine plus toripalimab for cisplatin-ineligible patients with recurrent or metastatic nasopharyngeal carcinoma

Cisplatin is a cornerstone chemotherapy for nasopharyngeal carcinoma (NPC); however, certain patients are ineligible for cisplatin-based regimens. This phase 2 trial (NCT04405622) evaluated the efficacy and safety of gemcitabine and toripalimab in previously untreated patients with recurrent or metastatic NPC who were either ineligible for cisplatin or had experienced severe adverse events from prior cisplatin-based treatments. Patients received gemcitabine (1,000mg/m2) and toripalimab (240mg) every three weeks for six cycles, followed by toripalimab monotherapy for up to two years. The primary endpoint was the incidence of grade ≥3 adverse events, while secondary endpoints included objective response rate (ORR) and overall survival (OS). Of 30 screened patients, 21 were enrolled. No treatment-related fatalities occurred, with the most frequent adverse events being headache and nausea. The ORR was 61.9%, coupled with a disease control rate of 100%. Overall, gemcitabine plus toripalimab demonstrated low toxicity and promising efficacy for this specific patient cohort.

Real world experience with cladribine tablets in the management of relapsing multiple sclerosis in Qatar

ObjectivesTo study the 30-month safety and effectiveness of Cladribine tablets (CladT) in relapsing multiple sclerosis (RMS) months in a real-world setting. MethodsRetrospective single-centre observational study in Qatar (January 2018–Feb 2023). Clinical and MRI data, lymphocyte counts and adverse events (AE) were recorded for patients with RMS who received at least one course of CladT. ResultsForty-six patients were included (mean follow-up 22 months); 34 (74%) were female, 22 (48%) were disease-modifying therapy (DMT) naïve, 16 (35%) had switched from platform DMT and 8 (17%) from high efficacy (HE) DMD. Mean age was 26.7±7.2y, mean disease duration was 7.2±6.0y. Common reasons for treatment with CladT were MS activity (91%), pregnancy planning (17%), AE (20%), compliance (9%). 44/46 ( 96%) received the year 2 course of CladT. Annualised relapse rate (ARR) fell from 1.02 (baseline) to 0.1, 0, 0.1, 0.1 and 0.1 for years 1–5 post-treatment, respectively; 87.5–100% were free of relapses at these times, vs. 21% at baseline. There were no relapses in year 2; 78%, 100%, 84%, 80% and 100%, respectively, were free of GD+ MRI lesions at years 1–5, vs. 31% at baseline. Most clinical AE were mild (1 moderate, no severe AE); 12 contracted Covid-19 (no hospitalisations). Grade 3 lymphopenia occurred in 5 patients. ConclusionsCladT appeared to be effective and safe in our retrospective study, irrespective of prior treatments, consistent with other real world data that support the early use of CladT in the management of RRMS.

Effects of Sulfur Thermal Water inhalations in long-COVID syndrome: spa-centred, double-blinded, randomised case-control pilot study

BackgroundThe long-COVID syndrome is characterised by a plethora of symptoms. Given its social and economic impact, many studies have stressed the urgency of proposing innovative strategies other than hospital settings. In this double-blind randomised case-control trial, we investigate the effects of sulfur thermal water inhalations, rich in H2S, compared to distilled water inhalations on symptoms, inflammatory markers, nasal microbiome in long-COVID patients. Methods30 outpatients aged 18-75, with positive diagnosis for long-COVID were randomised in two groups undergoing 12 consecutive days of inhalations. The active Group (STW) received sulfur thermal water inhalations whereas the placebo group received inhalations of sterile distilled non-pyrogenic water (SDW). Each participant was tested prior treatment at day 1 (T0), after the inhalations at day 14 (T1) and at 3 months follow-up (T2). At each time point, blood tests, nasal swabs for microbiome sampling, pulmonary functionality tests (PFTs) and pro-inflammatory marker measure were performed. ResultsThe scores obtained in the administered tests (6MWT, Borg score, and SGRQ) at T0, showed a significant variation in STW group, at T1 and T2. Serum cytokine levels and other inflammatory biomarkers reported a statistically significant decrease. Some specific parameters of PFT's showed ameliorations in STW group only. Changes in the STW nasopharyngeal microbiota composition were noticed, especially from T0 to T2. ConclusionsInhalations of sulfur thermal water exerted objective and subjective improvements on subjects affected by long-COVID. Significant reduction of inflammatory markers, dyspnea scores and quantitative and qualitative changes in the nasopharyngeal microbiome were also assessed.

Estudio palinológico de las Licofitas (Lycopodiopsida) de las Sierras Pampeanas centrales de Argentina

Background and aims: The Sierras Pampeanas Centrales of Argentina constitute the fourth centre of diversity of lycophytes and ferns in the Cono Sur, where representatives of four families of lycophytes live: Huperziaceae, Lycopodiaceae, Isoetaceae and Selaginellaceae. The aim of this work is to provide data of the morphology of their spores observed with optical and scanning electron microscopes, as a contribution to the taxonomy and conservation. M&amp;M: The materials were analysed without prior chemical treatment and photographic records were obtained with both observation equipments. Results: The morphological diagnostic features of the spores are presented. The Huperziaceae and Lycopodiaceae are isosporous with trilete spores. Huperziaceae presents foveolated or fossulated spores, while Lycopodiaceae spores are reticulate, scabrate and baculate. In Isoetes hieronymi (heterosporate), the microspores are monolete with echinate ornamentation, while the megaspores are trilete, with reticulate ornamentation. The Selaginellaceae, all heterosporate, produce trilete microspores and megaspores, both with varied ornamentation. Conclusions: Spore characteristics provide relevant information for regional floristic studies as well as for taxonomic assignments, both of extant flora and fossil records. Also, for studies of the composition of soil spore banks as a tool for the conservation of local floristic biodiversity.

TAS-102 (trifluridine/tipiracil) plus bevacizumab versus TAS-102 alone as salvage treatment options for metastatic colorectal cancer in routine clinical practice.

Both regimens of TAS-102 (trifluridine/tipiracil) with and without bevacizumab are considered standard options for salvage treatment in patients with refractory metastatic colorectal cancer. This analysis included patients with metastatic colorectal cancer who received either TAS-102 plus bevacizumab or TAS-102 alone between July 2022 and November 2023 at Samsung Medical Center. We evaluated the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety profile of both regimens. In total, 139 patients were included in this analysis. Median age was 60.8 years, and median number of previous lines of therapy was four (range: 2.45-6.55). More than half of the subjects (56.8%) had RAS mutations and 92.9% received previous anti-VEGF therapy. 83 (59.7%) patients received the combination of TAS-102 and bevacizumab and 56 (40.3%) received TAS-102 alone. The number of patients with prior regorafenib treatment was 14 in the TAS-102 with bevacizumab group and 5 in the TAS-102 alone group. The disease control rate was 51.8% in the combination group and 32.1% in the TAS-102 alone group. The median PFS was 3.3 months (95% CI, 2.7-6.6) in the combination group and 2.5 months (95% CI, 2.0-3.8) in the TAS-102 alone group (HR, 0.56; 95% CI, 0.38-0.82; p=0.003). The median OS in these two groups was 10.8 months (95% CI, 8.4-NA) and 6.0 months (95% CI, 4.8-9.8), respectively (HR, 0.62; 95% CI, 0.40-0.97, p=0.033). In the exploratory analysis of TAS-102 + Bev group, patients with the KRAS G12 mutation had inferior OS compared to those without the mutation (HR, 2.01, 95% CI, 1.04-3.90, p=0.035). Commonly observed adverse events were hematologic-related, including neutropenia, anemia, and thrombocytopenia, as well as nausea. While any grade neutropenia was observed at similar frequencies in the two groups (57.8% and 57.1%), grade 3 or higher neutropenia was more frequent in the combination group than the TAS-102 alone group (31.3% vs. 17.9%). Among patients who received subsequent anticancer therapy after treatment failure, 74.1% received regorafenib. The combination of TAS-102 and bevacizumab resulted in a better survival outcome than TAS-102 monotherapy, consistent with previous studies. This analysis supports the use of the combination of TAS-102 and bevacizumab as the best therapeutic option for patients with refractory metastatic colorectal cancer in clinical practice.