Search

Copyright of Diotima: Revue de Recherche Philosophique is the property of Evanghelos A. Moutsopoulos 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.)

Purpose: Effective treatment of locally advanced or metastatic urothelial carcinoma (mUC) remains an unmet need. Antibody-drug conjugates (ADC) providing targeted drug delivery have shown antitumor activity in this setting. AGS15E is an investigational ADC that delivers the cytotoxic drug monomethyl auristatin E to cells expressing SLITRK6, a UC-associated antigen., Patients and Methods: This was a multicenter, single-arm, phase I dose-escalation and expansion trial of AGS15E in patients with mUC (NCT01963052). During dose escalation, AGS15E was administered intravenously at six levels (0.10, 0.25, 0.50, 0.75, 1.00, 1.25 mg/kg), employing a continual reassessment method to determine dose-limiting toxicities (DLT) and the recommended phase II dose (RP2D) for the dose-expansion cohort. The primary objective was to evaluate the safety and pharmacokinetics of AGS15E in patients with and without prior chemotherapy and with prior checkpoint inhibitor (CPI) therapy. Best overall response was also examined., Results: Ninety-three patients were recruited, including 33 patients previously treated with CPI. The most common treatment-emergent adverse events were fatigue (54.8%), nausea (37.6%), and decreased appetite (35.5%). Peripheral neuropathy and ocular toxicities occurred at doses of ≥0.75 mg/kg. AGS15E increased in a dose-proportional manner after single- and multiple-dose administration; accumulation was low. Five DLT occurred from 0.50 to 1.25 mg/kg. The RP2D was assessed at 1.00 mg/kg; the objective response rate (ORR) was 35.7% at this dose level. The ORR in the total population and CPI-exposed subgroup were 18.3% and 27.3%, respectively., Conclusions: DLT with AGS15E were observed at 0.75, 1.00, and 1.25 mg/kg, with an RP2D of 1.00 mg/kg being determined., (©2023 The Authors; Published by the American Association for Cancer Research.)

Lessons Learned: The primary endpoint of this phase II study that evaluated the efficacy and safety of the investigational compound, AGS-16C3F, versus axitinib in previously treated patients with metastatic renal cell carcinoma (mRCC) was not met. Median progression-free survival, the primary endpoint, was 2.9 months with AGS-16C3F and 5.7 months with axitinib (HR, 1.676; 95% CI, 1.107-2.537; p = .015), per investigator assessment The safety profile for each study drug was as expected, with the most commonly reported adverse events being fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. These results provide a benchmark for axitinib use in heavily pretreated patients with mRCC., Background: AGS-16C3F is a novel antibody-drug conjugate that targets cell-surface ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) and is conjugated to a microtubule disruptive agent. Here we present findings from a phase II study of AGS-16C3F versus axitinib in metastatic renal cell carcinoma (mRCC)., Methods: Patients with mRCC of any histology and disease progression during or after their last treatment regimen were randomized 1:1 to intravenous AGS-16C3F 1.8 mg/kg every 3 weeks or oral axitinib 5 mg twice daily (starting dose). The primary objective was investigator-assessed progression-free survival (PFS) of AGS-16C3F versus axitinib (RECIST version 1.1)., Results: In the total population (N = 133), 63% (n = 84) of patients had completed the study at data cutoff (August 21, 2019). Median PFS was 2.9 months with AGS-16C3F and 5.7 months with axitinib (hazard ratio [HR], 1.676; 95% confidence interval [CI], 1.107-2.537; p = .015). There were no significant differences between arms in secondary efficacy endpoints, including overall survival (13.1 months, AGS-16C3F and 15.4 months, axitinib; HR, 1.079; 95% CI, 0.681-1.707; p = .747). In the safety population (n = 131), the most commonly reported adverse events were fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. The incidence of diarrhea was lower in the AGS-16C3F arm than in the axitinib arm (17% vs. 48%), and ocular toxicities were more frequent in the AGS-16C3F arm than in the axitinib arm (44% vs. 26%)., Conclusion: The investigational compound, AGS-16C3F, did not meet the primary endpoint of this trial. These study results provide a benchmark for axitinib use in heavily pretreated patients with mRCC., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Aims: The objective of the study was to compare the efficiency of 20 MHz skin ultrasonography and 40 MHz conventional ultrasonography in the assessment of plaque psoriasis and to assess the efficiency of 40 MHz real-time sonoelastography in the early detection of steroid-induced skin atrophy in psoriatic plaques., Patients and Methods: Ultrasonographic blinded evaluation was performed on 16 plaques in three consecutive patients, at baseline and after hydrocortisone acetate 1% ointment six-week application. The parameters were epidermal and dermal thicknesses for gray-scale ultrasonography and strain ratio for sonoelastography. Strain ratio was computed between the dermis and the adjacent hypodermis. Student's t-test for paired samples was performed. A confidence level of p<.05 was considered significant., Results: At follow-up, epidermal thickness was significantly reduced with 20 MHz (p = .002) and 40 MHz sonography (p = .032), while dermal thickness varied insignifcantly with 20 MHz (p = .35) and 40 MHz sonography (p = .33). Measurements at 40 MHz were significantly higher than their 20 MHz counterparts at baseline (epidermis: p < .001; dermis: p = .003) and at follow-up (epidermis: p < .001; dermis: p = .001). Strain ratio revealed no significant change of dermal elasticity (p = .96)., Conclusions: Although epidermal and dermal measurements varied significantly with 20 MHz and 40 MHz ultrasonography, both techniques efficiently quantified treatment response by measuring the reduction of epidermal thickness. Sonoelastographic findings were consistent with the expected outcome of short-term use of low-potency corticosteroid. Further studies are recommended.

Introduction: Asthma is a chronic inflammatory disease of the airways mainly related to allergen exposure, in which various cytokine-specific pathways interact among themselves to promote IgE hyperproduction, bronchial hyperresponsiveness, eosinophil local recruitment and airways remodeling. IL-13 is known for its prominent pathogenic role in this disease and therapeutic blocking approaches are underway., Areas Covered: Anti-IL-13 antibodies are currently investigated in clinical studies in uncontrolled asthma. Tralokinumab is a human IgG4 anti IL-13 antibody which was recently evaluated in a Phase II study demonstrating the maximal efficacy in a subset of asthma patients characterized by the highest sputum IL-13 levels. The results of this study are discussed in this paper., Expert Opinion: The IL-13 blockade with various therapeutic approaches such as tralokinumab has the potential to improve the asthma control in patients subsets in whom the blocked cytokine is demonstrated to be overexpressed.

Objective: We aimed to determine if gender differences exist in the selection and training of female and male gastroenterology fellows., Methods: One hundred seventy-six of 218 training program directors returned an 18-question survey about their programs, including leave policies, training, and prevalence of female faculty. Two cohorts of graduating trainees from 1993 and 1995 (N = 393) returned anonymous surveys regarding their training program experiences, demographics, and business training., Results: Female gastroenterology trainees are more likely to choose programs according to parental leave policies (p < 0.05), female faculty (0.2990 correlation coefficient), and "family reasons" (p < 0.04) than the male trainees. Female trainees were more likely to remain childless (p < 0.001) or have fewer children at the end of training despite marital status not unlike their male colleagues. Female trainees altered their family planning because of training program restrictions (20% vs 7%, p < 0.001). They perceived gender discrimination (39%) and sexual harassment (19%) during gastroenterology training. Trainees of both sexes had mentorship during training (65% vs 71%, ns); female trainees were more likely to have an opposite sex mentor (71% vs 3.4%) despite an almost 50% prevalence of female full-time and clinical faculty. Female trainees were apt to be less trained in advanced endoscopy (p < 0.005). Trainees of both sexes were influenced by the changing health care environment in career choice (49% vs 42%, ns); neither gender felt adequately prepared for the business aspects of gastroenterology., Conclusion: Alterations in gastroenterology training are needed to attract qualified female applicants. New graduates of both sexes lack practice management education.