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Background: SAR442257 (SAR'257) is a trispecific antibody that targets CD38, CD3 and CD28. Simultaneous CD3 and CD28 binding triggers T cell co-signaling, and additional CD38 recognition directs the T cells to CD38+ cancer cells such as multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). This is a first-in-human phase 1 study investigating the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) profile of SAR'257 in patients (pts) with refractory and relapsed (rr) MM and rrNHL. Methods: This is a multicenter, international, open-label, dose-escalation study (NCT04401020) of SAR'257 in pts with rrMM refractory to standard-of-care (SOC) options, including anti-CD38 monoclonal antibodies, and in pts rrNHL without any SOC options. SAR'257 was administered intravenously with lead-in doses (Day 1−5) in the first week, followed by twice weekly (BIW) or once weekly (QW) dosing; 11 target dose levels (TDLs) in pts with rrMM (9 TDLs: 0.06-11 µg/kg BIW; 2 TDLs: 18-27 µg/kg QW), and 2 TDLs in pts with rrNHL (2 µg/kg BIW and 4 µg/kg QW). Results: As of February 19, 2024, 47 pts (rrMM, n=40; rrNHL, n=7) received SAR'257. The median ages (years) were 64 (rrMM; range: 40−84) and 70 (rrNHL; range: 18−75). The median number of prior lines was 5 (range: 3−12) for rrMM and 5 (range: 2−7) for rrNHL cohort. In rrMM cohort, all (100%) pts had prior exposure to an anti-CD38 monoclonal antibody (MAb) and were refractory to anti-CD38 and in rrNHL cohort all were anti-CD38 naïve. The median time from last anti-CD38 dose was 2.7 (range: 1−65) months for rrMM cohort. Safety analysis revealed that 68% (n=32) pts had treatment-emergent adverse events (TEAEs; 26 pts in rrMM and 6 pts in rrNHL); 21.3% pts (n=10) Grade (G) ≥3 TEAEs (7 in rrMM and 3 in rrNHL). Cytokine release syndrome (CRS) was the most common TEAE, occurring in 52.5% of rrMM pts across all TDLs (n=21; G≥3 in 1 pt from 11 µg/kg BIW TDL) and in 57.1% of rrNHL pts (n=4; no G≥3) at the two TDLs tested. Repetitive CRS episodes (>1 episode) were more frequent at higher TDLs. Infusion-related reactions (IRRs; any G) were observed in 22.5% pts with rrMM (n=9; no G≥3) and in 28.5% pts with rrNHL (n=2; G≥3 in 1 pt). Epstein-Barr virus (EBV) infection/reactivation was reported in 17.5% (n=7; G≥3 in 4 pts) and 28.6% (n=2; no G≥3) pts with rrMM and rrNHL respectively. Further, 15% (n=6, G≥3 in 2 pts) from rrMM and 14.3% (n=1; G2 CMV reactivation) pts from rrNHL cohort reported cytomegalovirus (CMV) infection/reactivation. One case of immune effector cell-associated neurotoxicity syndrome (ICANS) was reported (G4) in the rrNHL cohort. Four dose-limiting toxicities (DLTs) were observed in the rrMM cohort [1 at 4 µg/kg BIW (G3 hepatotoxicity); 1 at 11 µg/kg BIW (G5 CRS−EBV reactivation; and 2 at 27 µg/kg QW (G3 CMV infection reactivation and G3 febrile neutropenia in same pt)]. Three DLTs were observed in the rrNHL cohort (2 at 2 µg/kg BIW [G4 neutropenia and G4 thrombocytopenia; same pt] and 1 at 4 µg/kg QW [ICANS G4]). For pts with rrMM, the maximum plasma concentration of SAR'257 reached within or above the theoretical efficacious range (0.1−1nM; extrapolated from ex vivo models), starting at 8 µg/kg BIW and 18 µg/kg QW in the first treatment cycle. As of July 08, 2024, the overall response rate (ORR), defined as partial response (PR) or better, was 5% (n=2) in the rrMM cohort: 1 pt exhibited stringent complete response (duration of response [DOR]=8.1 months, on-going) and 1 showed a complete response (CR) at 27 µg/kg QW TDL. In rrNHL cohort, the ORR was 14.3%, 1 pt achieved PR (DOR=7.1 months) at 2 µg/kg BIW TDL. The disease control rate (stable disease or better for >8 weeks) was 60% (n=24) and 28.6% (n=2) in the rrMM and rrNHL cohorts respectively. For both cohorts exploratory biomarker analysis revealed that: (1) SAR'257 treatment activated peripheral blood T cells and reduced regulatory T cell numbers and CD4/CD8 ratio; (2) CD38 expression on plasma cells positively corelated with time since the last anti-CD38 MAb dose; (3) Among the pts experiencing CRS, the peak values of cytokines (Interleukin (IL)-6, IL-8, and C-reactive protein) were significantly higher during the first cycle in comparison to subsequent cycles. Conclusion: This Phase 1 study of SAR'257 showed an anti-tumor response in a small number of pts from the rrMM and rrNHL cohorts. Due to safety concerns, in particular high rates of EBV and CMV reactivation and recurrent episodes of CRS in the higher dose levels, the study was terminated during dose escalation.

Abstract Background Dermatological health-related quality of life (HRQoL) among solid organ transplant recipients (SOTRs) may be adversely affected by various factors, including skin cancer. However, there has been limited assessment of dermatological HRQoL in SOTRs. This study aimed to evaluate the impact of skin cancer on quality of life (QoL) in SOTRs and to compare HRQoL measures between SOTRs with and without skin cancer. Methods This cross-sectional study was conducted at the Mayo Clinic Florida from June 2023 to March 2024. Adult patients who underwent solid organ transplantation between June 1995 and December 2023 were assessed using the Dermatology Life Quality Index (DLQI) and Skindex-29 questionnaires. For SOTRs with keratinocyte carcinoma (KC), the Basal and Squamous Cell Carcinoma Quality of Life (BaSQoL) questionnaire was also administered. Results A total of 150 adult SOTRs were included, with 82 having developed post-transplant skin cancer, including melanoma and keratinocyte carcinomas (KC). SOTRs with skin cancer were older at first transplant (Median: 61.8 vs. 57.3 years, P = 0.0073) and had a higher proportion of males (76.8% vs. 55.9%, P = 0.0086). Fitzpatrick skin type III-VI was less prevalent (8.5% vs. 38.2%, P < 0.0001). The frequency of SCC and BCC was 92.7% and 41.5%, respectively. DLQI scores were higher in SOTRs with skin cancer, however, the difference was not statistically significant (P ≥ 0.065). SOTRs with skin cancer had higher total Skindex-29 scores (P = 0.012) and “emotion” subscale scores (P = 0.0049), indicating a negative impact on QoL. BaSQoL scores showed a moderate negative effect on QoL, with a higher number of KCs correlating with lower QoL (P < 0.05). Female gender had higher DLQI total score (P = 0.0042) and BaSQoL diagnosis and treatment (P = 0.031). Conclusions: SOTRs with skin cancer exhibited lower overall QoL, with a greater number of skin cancers linked to more pronounced negative impacts on QoL across all assessment instruments. Female gender was also associated with lower QoL scores. Recognizing the potential for reduced QoL in SOTRs is essential for developing tailored management strategies to support this population.

BACKGROUND While there has been improved gender representation in dermatology, there remains areas for improvement, especially in leadership positions. Studies have evaluated diversity in various dermatology subspecialties, but evaluation of gender diversity in cosmetic dermatology is lacking. OBJECTIVE To evaluate the temporal trends in gender diversity within the American Society for Dermatologic Surgery (ASDS) Cosmetic Dermatologic Surgery Fellowship Programs from 2013 to 2022. To discuss strategies for improvement. MATERIALS AND METHODS The ASDS Cosmetic Dermatologic Surgery Fellowship program directors and fellows were reviewed from 2013 to 2022. Gender was determined through online professional websites and biographies. The number and proportion of each gender was determined for each year, and the change over time was calculated. RESULTS The number of fellowship positions and program directors has increased from 2013 to 2022. Most of the fellows have been women. The average yearly rate of change for fellows is +1.67 and +0.67 for men and women. Most of the fellowship directors have been men. The average yearly rate of change is +1.56 and +0.44 for men and women. CONCLUSION Gender inequalities remain across leadership positions and further studies are necessary to better determine why these discrepancies exist and how to improve this inequality.

Abstract: Background: Allergic contact dermatitis is a common, pruritic, debilitating skin disease, affecting at least 20% of the population. Objective: To prospectively validate a computer vision algorithm across all Fitzpatrick skin types. Methods: Each participant was exposed to 10 allergens. The reference criterion was obtained 5 days after initial patch placement by a board-certified dermatologist. The algorithm processed photographs of the test site obtained on Day 5. Human performance in reading the photographs was also evaluated. Results: A total of 206 evaluable participants [mean age 39 years, 66% (136/206) female, and 47% with Fitzpatrick skin types IV–VI] completed testing. Forty-two percent (87/206) of participants experienced 1 or more allergic reaction resulting in a total of 132 allergic reactions. The model provided high discrimination (AUROC 0.86, 95% CI: 0.82–0.90) and specificity (93%, 95% CI: 92%–94%) but with lower sensitivity (58%, 95% CI: 49%–67%). Human performance interpreting the photographs ranged from providing similar performance to the algorithm to providing superior performance when combined across readers. There were no serious adverse events. Conclusions: The combination of a smartphone capture of patch testing sites with deep learning yielded high discrimination across a diverse sample.

Abstract Ageing‐related neuromuscular dysfunction is associated with reduced tropomyosin‐related kinase receptor subtype B (TrkB) signalling and accumulation of damaged cytoplasmic aggregates in motor neurons. Autophagy functions to remove these damaged aggregates, and we previously reported increased cervical motor neuron expression of LC3 and p62 in old age. We hypothesized that inhibition of TrkB kinase activity results in an increase in the relative expression of both LC3 and p62 in cervical motor neurons, consistent with impaired progression of autophagy. TrkB F616A mice, which possess a mutation that renders TrkB kinase activity susceptible to rapid inhibition by 1NMPP1, were treated at 6, 18 or 24 months of age with vehicle or 1NMPP1 for 7 days. Immunofluorescence intensity was measured to determine LC3 and p62 expression in choline acetyltransferase‐positive motor neurons in the cervical spinal cord. The effect of inhibiting TrkB kinase activity on progression of autophagy was age dependent. In 6‐month‐old mice, inhibiting TrkB kinase activity increased cervical motor neuron expression of LC3 by 11% ( P < 0.001) and p62 by 8% ( P = 0.019) compared with vehicle treatment. In 18‐ and 24‐month‐old mice, there was no effect of inhibiting TrkB kinase activity on motor neuron LC3 or p62 expression. We provide evidence that inhibition of TrkB signalling impairs progression of autophagy in motor neurons of young mice, similar to the response to ageing. Accordingly, a reduction of TrkB signalling in old age might contribute to neuromuscular dysfunction by impairing progression of autophagy in motor neurons.

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity through the nuclear retention and reactivation of tumor suppressor proteins, reduced translation of oncogenes, and decreased expression of anti-apoptotic proteins. As a single agent, SEL has demonstrated brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS Through an NCI Project Team, we developed a multi-institutional phase I/II clinical trial which opened across the NCI Experimental Therapeutics Clinical Trial Network. Eligibility included histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. We evaluated safety, tolerability, and dose finding with an IQ 3 + 3 design of TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. RESULTS From October 2022 to March 2024, we enrolled 12 patients (n=11 evaluable) into phase I of the study. Patient characteristics included 82% male, median age 62 (range 50-77), 64% white. The median number of cycles administered was 6 (range 1-12). Two dose levels (SEL 60mg and SEL 80mg) were evaluated. No dose-limiting toxicities (DLTs) were observed. The most common treatment related adverse events were nausea (58%), decreased platelet count (50%), fatigue (50%), constipation (42%), vomiting (25%), decreased lymphocyte count (25%), and decreased neutrophil count (25%). Grade 3+ treatment related adverse events included nausea, grade 3 (n=1); decreased lymphocyte count, grades 3-4 (n=2); and anorexia, grade 3 (n=1). Phase I has completed enrollment and the recommended phase II dose will be SEL 80mg. Additional results will be presented. CONCLUSION Results suggest that a sequential dosing regimen of SEL+TMZ is feasible, well-tolerated, and may minimize the cumulative toxicity of SEL. The phase II randomized portion of this trial is enrolling nationwide and will investigate efficacy and candidate molecular signatures of vulnerability (NCI #10505, NCT05432804).

Abstract Background MASLD is a leading reason for liver transplant waitlisting. The relationship between cardiorespiratory fitness (CRF) and liver fibrosis in patients with MASLD remains unclear. This study aims to provide further evidence supporting the relationship between liver fibrosis and CRF. Methods Subjects with MASLD across various fibrosis stages, including those with cirrhosis awaiting liver transplantation from three U.S. transplant centers, underwent cardiopulmonary exercise testing (CPX). We compared participants based on fibrosis stage (F0-F1, F2-F3, and F4) and CPX parameters such as VO2peak, respiratory exchange ratio (RER), ventilatory efficiency (VE/VCO2), double product (DP) and chronotropic incompetence (CI). Multivariable models were then built to evaluate factors associated with these parameters. Results Sixty-one subjects underwent CPX testing across three centers. Subjects with F4 had lower VO2peak (11.8 mL/kg/min) compared to F0-F1 (22.2 mL/kg/min) and F2-F3 (22.9 mL/kg/min), p < 0.001. Subjects with F4 had higher RER (median 1.25) compared to F0-F1 (1.08) and F2-F3 (1.05), p = 0.001. Similarly, F4 subjects exhibited higher VE/VCO2 (median 36.5) compared to F0-F1 (31) and F2-F3 (30), p < 0.001. Additionally, F4 subjects had lower DP values (median 17,696) compared to F0-F1 (25,460) and F2-F3 (25,372), and higher prevalence of CI (90%) compared to F0-F1 (39%) and F2-F3 (25%), both p = < 0.001. Multivariable modeling confirmed advanced fibrosis (F > 3) as an independent predictor of low CRF. Conclusions In MASLD patients, advanced liver fibrosis, particularly cirrhosis, is associated with reduced CRF and poorer hemodynamic performance during CPX. Prioritizing exercise training for those in earlier stages (F3) may prevent fitness decline, which could hinder physical training and liver transplantation candidacy.

Abstract Introduction There is limited real-world evidence comparing the effectiveness of ozanimod to vedolizumab as first-line advanced therapies in patients with ulcerative colitis (UC). Methods We conducted a retrospective cohort study using TriNetX, a multi-institutional US database in adults with UC who were initiated on ozanimod compared to vedolizumab between January 1, 2021 and 22 June, 2024. The primary outcome was to compare the risk of a composite outcome of corticosteroid use, colectomy, or change to another advanced therapy between the 2 cohorts within 12 months. 1:1 propensity score matching (PSM) was performed for demographics, comorbid conditions, disease extent, laboratory parameters, and previous corticosteroid use. The risk was expressed as an adjusted odds ratio (aOR) with 95% CIs. Results We identified 222 patients in the ozanimod cohort (mean age 41.2 ± 15.7, 46.3% male sex, 68% White, and 22.5% ulcerative proctitis), and 4145 patients in the vedolizumab cohort (mean age 47.4 ± 18.3, 45.2% male sex, 69.7% White, and 17.2% ulcerative proctitis). After PSM, there was no significant difference in the risk of the composite outcome (aOR 0.92, 95% CI, 0.63-1.36) and corticosteroid use (aOR 0.80, 95% CI, 0.53-1.18) between the 2 cohorts within 12 months. There was a higher risk of change in therapy in the ozanimod cohort (aOR 1.95, 95% CI, 1.09-3.49) compared to the vedolizumab cohort. Colectomy rates were low in both cohorts (&lt;0.04%). Conclusions Our real-world study showed that ozanimod use is associated with similar corticosteroid use but higher odds of a change in therapy compared to vedolizumab when used as first-line therapy in patients with UC. Further prospective studies are needed to understand long-term outcomes.