Real-World Multicenter Study of PD-1 Blockade in HIV-Associated Classical Hodgkin Lymphoma Across the United States.

BACKGROUND: Despite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in HIV-associated cHL (HIV-cHL). PATIENTS/METHODS: We retrospectively identified patients with HIV-cHL from the "Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)" database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4+ T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification. RESULTS: We identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4+ T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4+ cells/µL (P = .95). CONCLUSION: Our findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL.

Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium.

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 <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was -0.06 months (95% CI, -5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, -4.02 to 8.48; P = .48) for OS. 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.

The Potential Revolution of Cancer Treatment with CRISPR Technology.

Immuno-oncology (IO) and targeted therapies, such as small molecule inhibitors, have changed the landscape of cancer treatment and prognosis; however, durable responses have been difficult to achieve due to tumor heterogeneity, development of drug resistance, and adverse effects that limit dosing and prolonged drug use. To improve upon the current medicinal armamentarium, there is an urgent need for new ways to understand, reverse, and treat carcinogenesis. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) 9 is a powerful and efficient tool for genome editing that has shown significant promise for developing new therapeutics. While CRISPR/Cas9 has been successfully used for pre-clinical cancer research, its use in the clinical setting is still in an early stage of development. The purpose of this review is to describe the CRISPR technology and to provide an overview of its current applications and future potential as cancer therapies.

Treatment Equity in the Immunotherapy Era: Options for Patients with Both Autoimmune Disease and GU Cancers.

Numerous immunotherapeutic agents, such as immune checkpoint inhibitors (ICIs), have been approved for the treatment of genitourinary (GU) malignancies. While ICIs have improved treatment outcomes and expanded treatment options, they can cause immune-related adverse events (irAEs). The scope of irAEs is broad, and this paper aims to review the rheumatologic side effects associated with immunotherapy drugs approved for bladder cancer and renal cell carcinoma. IrAEs are graded by the common terminology criteria for adverse events (CTCAE), which ranges from 1 to 5. The management of irAEs includes corticosteroids or other immunosuppressive therapies, and it may require discontinuation of immunotherapy. Several real world experience studies suggest that most patients with pre-existing autoimmune diseases treated with ICI did not have to discontinue treatment due to immune-mediated side effects. While data suggest autoimmune side effects are manageable, patients with pre-existing autoimmune diseases are often excluded from immunotherapy clinical trials. Better understanding of these irAEs will improve its safety and expand its use in those with underlying autoimmune disease.

Surrogate Perspectives on Patient Preference Predictors: Good Idea, but I Should Decide How They Are Used.

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.

Immunotherapy and Metastatic Renal Cell Carcinoma: A Review of New Treatment Approaches.

INTRODUCTION: Renal cell carcinomas (RCC) have been treated with immunotherapy for decades; the use of immune checkpoint inhibitors represents the most recent advance. In this review, we compare these new RCC immunotherapies, with a focus on achieving durable complete responses (CR). REVIEW: Sorafenib and sunitinib were the first Food and Drug Administration (FDA)-approved targeted agents for RCC, with sunitinib eventually becoming the standard-of-care agent against which novel therapies are compared. In the last five years, many combination therapies based on the use of immune checkpoint inhibitors (ICIs) and receptor tyrosine kinase inhibitors (TKIs), including ipilimumab/nivolumab, nivolumab/cabozantinib, avelumab/axitinib, pembrolizumab/axitinib, and pembrolizumab/lenvatinib, have demonstrated superior overall survival (OS) and progression-free survival (PFS) compared to sunitinib. Ongoing clinical trials of hypoxia-induced factor-2 alpha (HIF-2a) inhibitors, chimeric antigen receptor T cell (CAR-T) therapy targeting CD70, and other new combination therapies have also shown promise and are currently under investigation. CONCLUSIONS: Many new combination therapies are approved for RCC treatment, and CR rates suggest that, in the era of immunotherapy, it may be possible to achieve durable responses and survival benefit in patients with metastatic RCC.

Impact of the elimination of the donation service area on United States lung transplant practices and outcomes at high and low competition centers.

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 < .0001) but no difference in the need for pretransplant ECMO (incidence rate ratio = 1.16, P = .12). Median LOS increased from 17 to 19 days in the post-DSA era (P = .01). There was no difference in posttransplant outcomes, including prolonged ventilation, new dialysis, or early survival, in the general cohort or between competition groups. High competition centers saw an 18.5-minute increase in ischemic time compared to low competition centers (P = .04) but did not differentially increase single lung transplants or pretransplant ECMO utilization. Overall, DSA elimination was associated with increased posttransplant LOS but no significant differences in pretransplant ECMO or other posttransplant outcomes. Effects were largely similar at low and high competition centers.

pH-Driven Mechanistic Switching from Electron Transfer to Energy Transfer between [Ru(bpy)3]2+ and Ferrocene Derivatives.

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 (ferrocenyl-trimethylammonium, 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.

The Effect of Peer Review on the Quality of Data Graphs in Annals of Emergency Medicine.

STUDY OBJECTIVE: We determine how peer review affects the quality of published data graphs and how the appointment of a graphics editor affects the quality of graphs in an academic medical journal. METHODS: We conducted an observational time-series analysis to quantify the qualities of data graphs in original manuscripts and published research articles in Annals of Emergency Medicine from 2006 to 2012. We retrospectively analyzed 3 distinct periods: before the use of a graphics editor, graph review after a manuscript's acceptance, and graph review just before the first request for revision. Raters blinded to study year scored the quality of original and published graphs using an 85-item instrument. Editorial comments about graphs were classified into 4 major and 16 minor categories. RESULTS: We studied 60 published articles and their corresponding original submissions during each period (2006, 2009, and 2012). The number of graphs increased 31%, their median data density increased 50%, and quality (completeness [+42%], visual clarity [+64%], and special features [+66%]) increased from submission to publication in all 3 periods. Although geometric mean (0.69, 0.86, and 1.2 pieces of information/cm2) and median data density (0.44, 0.70, and 1.2 pieces of information/cm2) were higher in the graphics editor phases, mean data density, completeness, visual clarity, and other markers of quality did not improve or decreased with dedicated graphics editing. The majority of published graphs were bar or pie graphs (49%, 53%, and 60% in 2006, 2009, and 2012, respectively) with low data density in all 3 years. CONCLUSION: Peer review unquestionably improved graph quality. However, data densities of most graphs barely exceeded that of printed text, and many graphs failed to present the majority of available data and did not convey those data clearly; there remains much room for improvement. The timing of graphics editor involvement appears to affect the effect of the graph review process.

Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death.

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.