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PURPOSE Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS This retrospective study included PWH treated with anti–PD-1- or anti–PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti–PD-1/anti–PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load CONCLUSION Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

Current practice frequently fails to provide care consistent with the preferences of decisionally-incapacitated patients. It also imposes significant emotional burden on their surrogates. Algorithmic-based patient preference predictors (PPPs) have been proposed as a possible way to address these two concerns. While previous research found that patients strongly support the use of PPPs, the views of surrogates are unknown. The present study thus assessed the views of experienced surrogates regarding the possible use of PPPs as a means to help make treatment decisions for decisionally-incapacitated patients.This qualitative study used semi-structured interviews to determine the views of experienced surrogates [n = 26] who were identified from two academic medical centers and two community hospitals. The primary outcomes were respondents' overall level of support for the idea of using PPPs and the themes related to their views on how a PPP should be used, if at all, in practice.Overall, 21 participants supported the idea of using PPPs. The remaining five indicated that they would not use a PPP because they made decisions based on the patient's best interests, not based on substituted judgment. Major themes which emerged were that surrogates, not the patient's preferences, should determine how treatment decisions are made, and concern that PPPs might be used to deny expensive care or be biased against minority groups.Surrogates, like patients, strongly support the idea of using PPPs to help make treatment decisions for decisionally-incapacitated patients. These findings provide support for developing a PPP and assessing it in practice. At the same time, patients and surrogates disagree over whose preferences should determine how treatment decisions are made, including whether to use a PPP. These findings reveal a fundamental disagreement regarding the guiding principles for surrogate decision-making. Future research is needed to assess this disagreement and consider ways to address it.

In November 2017, the donation service area (DSA) was removed as the primary unit of US donor lung allocation. Our primary objective was to evaluate the effect of this change on recipient characteristics, the use of pretransplant extracorporeal membrane oxygenation (ECMO), and on index hospitalization length of stay (LOS) and early posttransplant complications. We also assessed whether these outcomes differed in high and low competition centers, as defined by the Herfindahl-Hirschman Index. Following DSA removal, there was a 9-day decrease in median waitlist time (P = .001) and an increase in median lung allocation score (40 vs 42, P

Objective: Current practice frequently fails to provide care consistent with the preferences and values of decisionally-incapacitated, critically ill patients. It also imposes significant emotional burden on their surrogates. Algorithmic-based patient preference predictors (PPPs) have been proposed as a way to address these two concerns. While previous research found that patients strongly support the use of PPPs, the views of surrogates are unknown. This study assesses the views of experienced surrogates regarding the use of PPPs as a means to improve treatment decision making for incapacitated patients.Setting: Two academic medical centers and two community hospitals.Subjects: Experienced Surrogates [n=26].Interventions: An initial quantitative survey followed by an in-depth interview and a final quantitative survey.Measurements: Overall level of support for PPPs and views on how a PPP should be used, if at all, in practice.Main Results: Overall, 21 participants supported the use of PPPs. The remaining five indicated that they would not use a PPP because they made decisions based on the patient’s best interests, not based on which treatments the patient would choose for themselves. Some respondents expressed concern that PPPs might be used to deny expensive care or be biased against minority groups. Finally, 24 respondents indicated that surrogates, not patients, should decide how treatment decisions are made, including whether and how to use PPPs.Conclusions: Surrogates, like patients, strongly support the use of PPPs as a means to improving decision-making for incapacitated patients. These findings provide support for developing a PPP and assessing its use in practice. At the same time, patients and surrogates disagree over whose preferences should determine how treatment decisions, including whether to use a PPP, are made. These findings reveal a fundamental disagreement regarding the guiding principles for surrogate decision-making that need to be addressed by attempts to improve current critical care practice.

2649 Background: PLWH and ca are inadequately represented in clinical trials evaluating ICI especially in the setting of low CD4 counts (ct) and elevated HIV viral loads (VL). We assembled an international cohort of PLWH and ca treated with ICI to evaluate toxicity profiles and clinical outcomes. Methods: We retrospectively collected data on 204 PLWH and ca receiving ≥ 1 cycle of ICI between 2015-2021 at 14 academic medical centers in the US and Europe. Immune-related adverse events (irAEs) were graded per the Common Terminology Criteria for Adverse Events (CTCAE) V5.0. Baseline CD4 ct, CD8 ct and HIV VL were collected within 3 months (mo) of ICI initiation when available. Fisher’s exact test was performed to compare categorical variables. Median (med) Overall Survival (OS) and Objective Response Rate (ORR) were calculated for 186 pts treated in the metastatic (met) setting. Results: Among 204 PLWH treated with ICI, 174 (85%) were cis-gender males. 61 (31%) were Black and 34 (18%) were Hispanic/Latinx. Pts were treated with pembrolizumab (n=93), nivolumab (n=71), atezolizumab (n= 20), nivolumab and ipilimumab (n=13), durvalumab (n=6), or avelumab (n=1). Med number of prior lines of systemic therapy was 1 (range: 0-5). Among pts with available baseline data, 36/133 (27%) had CD4 ct

The metal-to-ligand charge transfer excited states of [Ru(bpy)(3)](2+) (bpy = 2,2′-bipyridine) may be deactivated via energy transfer or electron transfer with ferrocene derivatives in aqueous conditions. Stern–Volmer quenching analysis revealed that the rate constant for [Ru(bpy)(3)](2+) excited-state quenching depends on solution pH when a ferrocenyl-amidinium derivative (Fc–am) containing a proton-responsive functionality tethered to the ferrocene center was present. By contrast, the rate constant with which the [Ru(bpy)(3)](2+) excited state is quenched by an analogous ferrocene derivative (ferrocenyltrimethylammonium, Fc–mam) that lacks a protonic group does not depend on pH. These results show that the presence (or absence) of a readily transferrable proton modulates quenching rate constants in bimolecular events involving [Ru(bpy)(3)](2+) and ferrocene. More surprisingly, transient absorption spectroscopy reveals that the mechanism by which the [Ru(bpy)(3)](2+) excited state is quenched by Fc–am appears to be modulated by solution proton availability, switching from energy transfer at low pH when Fc–am is protonated, to electron transfer at high pH when Fc–am is deprotonated. The mechanistic switching that is observed for this system cannot be aptly explained using a simple driving force dependence argument, suggesting that more subtle factors dictate the pathway by which the [Ru(bpy)(3)](2+) excited state is deactivated by ferrocene in aqueous solutions. [Image: see text]

The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 and blocks its function. Treatment of cancer cells with selinexor results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leading to growth arrest and apoptosis. Recently, we described the selection of SINE compound resistant cells and reported elevated expression of inflammation-related genes in these cells. Here, we demonstrated that NF-κB transcriptional activity is up-regulated in cells that are naturally resistant or have acquired resistance to SINE compounds. Resistance to SINE compounds was created by knockdown of the cellular NF-κB inhibitor, IκB-α. Combination treatment of selinexor with proteasome inhibitors decreased NF-κB activity, sensitized SINE compound resistant cells and showed synergistic cytotoxicity in vitro and in vivo. Furthermore, we showed that selinexor inhibited NF-κB activity by blocking phosphorylation of the IκB-α and the NF-κB p65 subunits, protecting IκB-α from proteasome degradation and trapping IκB-α in the nucleus to suppress NF-κB activity. Therefore, combination treatment of selinexor with a proteasome inhibitor may be beneficial to patients with resistance to either single-agent.