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Tumour-infiltrating lymphocyte (TIL) therapy has emerged as a promising adoptive cell transfer strategy for solid tumours. The recent accelerated approval of lifileucel by the Food and Drug Administration marks a significant milestone in the clinical application of TIL therapy. This review comprehensively examines the historical development, biology, clinical efficacy, safety and limitations of TIL therapy. We explore advancements in TIL manufacturing, including novel culture techniques, genetic modifications and automation, to enhance scalability and effectiveness. Despite promising results, TIL therapy faces challenges such as high-dose interleukin-2 toxicity, complex manufacturing processes and immune evasion mechanisms. Emerging strategies, including checkpoint inhibitor combinations, engineered TIL constructs and metabolic reprogramming, aim to improve TIL therapeutic efficacy. This review provides insights into the evolving landscape of TIL therapy and its potential to enhance current cancer immunotherapy.

Abstract Background Despite advances in diagnosis and management, the interstitial lung disease (ILD) lexicon is plagued by ambiguous and inconsistent terminology that complicates communication and impedes knowledge generation. The objective of this Fleischner Society Consensus Statement was to produce standardized terminology for ILD multidisciplinary diagnoses and major phenotypes. Methods Interviews with 10 experts were used to identify ILD clinical diagnoses and major phenotypes. The preferred terms for each entity and potential alternatives were identified, alongside the rationale for the preferred term. Entities with more than one potential term were the subject of an online modified Delphi survey posed to the 29 committee members, aiming to achieve consensus. Committee members rated their agreement with the initially preferred term—5 (strongly agree), 4 (agree), 3 (neutral/unsure), 2 (disagree), and 1 (strongly disagree)—with the option to provide additional comments. Median score ≥4 and interquartile range ≤1 were considered consensus agreement. Terms not reaching agreement were discussed by video conference, followed by an additional survey that incorporated feedback. Results From the 60 initial terms, there were two root terms that required upfront consensus before survey initiation (ILD and interstitial pneumonia) and another eight terms that had no alternative suggested by the committee or in the literature. Agreement was met by 47/50 terms (94%) in Round 1 of the survey. The three terms (6%) that did not reach agreement met agreement in Round 2. Conclusions This document provides standardized recommended terms for ILD multidisciplinary diagnoses and major phenotypes that will facilitate communication among clinicians, researchers, patients, and other stakeholders.

Abstract Introduction Alice in Wonderland Syndrome (AIWS) is an uncommon condition manifesting visual and somatosensory disturbances in which patients may perceive objects, including their own bodies, as larger or smaller than they are. In adults, AIWS typically is associated with migraine and epilepsy but has been reported as an adverse effect of topiramate, which is used to treat both illnesses, making it difficult to ascertain whether illness or medication causes altered perceptions. Reported is a case of topiramate-associated AIWS, which adds to the limited reports published on this unique phenomenon. Case Report A 40-year-old woman admitted to a 3-week pain rehabilitation program to treat chronic migraine reported macrosomatognosia that she retrospectively recalled beginning during titration of topiramate. The symptoms of AIWS resolved after the topiramate was discontinued. An assessment with the Naranjo ADR Probability Scale indicated a possible association between topiramate and macrosomatognosia. Discussion In this patient with migraine, the onset of AIWS coincided with titration of topiramate, providing a clue that its emergence may have been an adverse drug reaction rather than the underlying illness. Consistent with previous reports, AIWS resolved shortly after topiramate was discontinued, lending credence to this conclusion. However, the mechanism of AIWS is unknown and may be multifactorial, leaving the possibility that migraine predisposed the patient to develop AIWS from topiramate. Conclusion The long association of AIWS with migraine and epilepsy makes it possible that cases caused by medications used to treat these illnesses, like topiramate, are underreported. Awareness of the temporal relationships between the course of illness and the timing of drug therapy can help guide the recognition of AIWS as a potential adverse event.

Abstract Background Patients with cancer treated with immune checkpoint inhibitors are at increased risk of myocardial infarction and ischemic stroke. The mechanism is incompletely understood but may involve accelerated atherosclerosis due to plaque inflammation. Pre-clinical studies may provide insight in these mechanisms. Aim To assess the effects of modulating co-inhibitory immune checkpoint proteins on atherosclerosis progression in animal models. Methods A systematic review was performed in MEDLINE, Embase, Web of Science, and Scopus up to September 2023. Animal studies were included if the effect of modulation of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and/or lymphocyte-activation gene 3 (LAG-3) on atherosclerotic plaque size was evaluated. Secondary outcomes were plaque composition and systemic inflammation. The ratios of means (RoM) across the studies were pooled in a random effects meta-analysis. Results 1,655 studies were identified of which twelve were included. All studies used an atherosclerotic mouse model (Apoe-/-, Ldlr-/-, or ApoE3*Leiden) and either evaluated pharmacological or genetic modulation of co-inhibitory immune checkpoint proteins. Upon inhibition, atherosclerotic plaque size in the aorta was 49% higher in exposed mice compared to control mice (RoM, 1.49; 95% CI, 1.12-1.82; I2=86%). Plaque composition was predominantly characterized by a greater abundance of CD4+ T cells, CD8+ T cells, and macrophages. Studies stimulating co-inhibitory immune checkpoint proteins corroborated these findings and demonstrated that atherosclerotic plaque size was reduced by 28% in treated mice compared to controls (RoM, 0.72; 95% CI, 0.65-0.80; I2=85%). This reduction was paralleled by a decrease in the number of macrophages and T cells in plaques. Conclusion Immune checkpoint inhibition leads to plaque inflammation and a significant increase in murine atherosclerotic plaque size. These changes may reflect the cause of the increased risk of myocardial infarction and ischemic stroke in patients treated with immune checkpoint inhibitors.

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ABSTRACTBackgroundThe Pediatric Oncology Group P9262 Phase 2 study of single‐agent paclitaxel demonstrated one complete response (CR), one partial response (PR), and four with stable disease (SD) among 15 patients with recurrent Wilms tumor (WT). Based on this activity, paclitaxel‐containing regimens have been used as salvage therapy for treatment‐refractory WT. We conducted a multi‐institutional retrospective study to further characterize the clinical activity of paclitaxel‐containing regimens in recurrent WT.MethodsTwelve institutions submitted anonymized data from patients with relapsed WT treated with paclitaxel. Response after one or two cycles of a paclitaxel‐containing regimen was reported according to Response Evaluation Criteria in Solid Tumors.ResultsTwenty‐eight patients with a median age at diagnosis of 5.5 years (range: 3 months to 31.9 years) were reported. Twenty had non‐anaplastic WT; eight had diffuse anaplasia (DA). Stage at diagnosis was I (n = 1), II (n = 1), III (n = 11), IV (n = 14), and V (n = 1). Patients received a mean of 8.5 anticancer drugs (range: 6–12) before paclitaxel, including eight who received high‐dose therapy/stem cell transplant. Paclitaxel (n = 13) or nab‐paclitaxel (n = 15) were predominantly administered in combination with other agents, most commonly doxorubicin and/or gemcitabine. Eleven of 26 patients with measurable disease had a partial response (7 = non‐anaplastic; 4 = DA), four had stable disease, and 11 had progressive disease. Two patients without measurable disease maintained a complete response for 12 and 16 months. The mean duration without progression was 7.6 months (range: 1–35 months).ConclusionsPaclitaxel‐containing regimens appear to be active against heavily pretreated WT with either non‐anaplastic or DA histology. Prospective studies are warranted to formally evaluate the efficacy of paclitaxel‐based therapies.

Abstract Endoscopic mucosal resection (EMR) techniques for large (≥20 mm) nonpedunculated colorectal polyps (LNPCPs) have expanded with the introduction of ablation and cold EMR. This study assessed adverse events (AEs) for the newer EMR techniques, including cold EMR, compared with hot EMR. We conducted a secondary analysis of four prospective multicenter studies of consecutive patients with LNPCPs undergoing EMR from 2019 to 2024. The primary outcome was serious AEs (SAEs) with cold and hot EMR. Secondary outcomes included SAEs in the hot EMR subgroups (no ablation [hEMR], margin ablation [hEMR-m], margin and base ablation [hEMR-mb]). 1762 patients (mean age 65.8; 1890 LNPCPs) were included: 522 cold and 1368 hot EMRs (368 hEMR, 770 hEMR-m, 230 hEMR-mb). SAEs were higher with hot EMR (4.7%, 95%CI 3.6%–5.9%) vs. cold EMR (1.9%, 95%CI 0.9%–3.5%), also for the subgroups of hEMR (6.0%, 95%CI 3.8%–8.9%), hEMR-m (3.9%, 95%CI 2.6%–5.5%), and hEMR-mb (5.2%, 95%CI 2.7%–8.9%). Serious postendoscopic bleeding (PEB) was numerically higher with hot EMR (2.3%, 95%CI 1.6%–3.3%) vs. cold EMR (1.3%, 95%CI 0.5%–2.7%), also for the subgroups of hEMR (3.0%, 95%CI 1.5%–5.3%), hEMR-m (1.9%, 95%CI 1.1%–3.2%), and hEMR-mb (2.6%, 95%CI 1.0%–5.6%). Perforation, intraprocedural and post-procedural, was numerically higher with hot EMR (1.2%, 95%CI 0.7%–2.0%) vs. cold EMR (0.2%, 95%CI 0.0%–1.1%). hEMR-m and hEMR-mb with clipping had lower rates of serious and overall PEB than no clipping. Cold EMR demonstrated lower rates of SAEs, serious PEB, and perforation compared with hot EMR. Perforation and mortality occurred almost exclusively after hot EMR. Hot EMR with margin +/− base ablation did not increase SAEs compared with hot EMR without ablation.

Background: Proximal pole scaphoid fracture nonunions are challenging conditions to treat. When significant comminution of the proximal pole and avascular necrosis is present, scaphoid proximal pole reconstructive options are considered. The proximal pole of the hamate is a local autograft option; however, little has been described on the outcomes of this procedure. Methods: Patients who underwent proximal pole scaphoid reconstruction using proximal hamate autograft at 3 tertiary care centers were retrospectively reviewed. Radiographic union was classified by greater than 50% bony trabeculae across the reconstruction site on computed tomography scan. Results: Ten patients were included. Average age at the time of surgery was 27.9 years, and 60% were men. Average length of proximal hamate autograft harvested was 10 mm. All patients healed at an average of 14.3 weeks following surgery. At final follow-up, 3 patients reported no pain, 3 reported mild occasional pain, 2 reported moderate tolerable pain (1 at the hamate graft site), and 2 had no reports on their pain level. Conclusions: In small proximal pole scaphoid nonunions with fragmentation and avascular necrosis, ipsilateral proximal hamate autograft reconstruction of the scaphoid proximal pole is a viable and reproducible option with high rates of union and patient satisfaction.

Abstract Front-line pharmaceutical interventions for treating acute graft-versus-host disease (GVHD) are not uniformly effective and have toxic side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with potent in vitro and in vivo immunosuppressive functions. Clinical translation of in vitro–generated MDSCs has been limited because of requirements for multiple, high infusion doses, the relatively low yield from peripheral blood–sourced MDSCs (PB-MDSCs), and inconsistent product quality. To circumvent these obstacles, we developed a methodology to generate MDSCs using human induced pluripotent stem cell (iPSC)–derived CD34+ cells. Compared with PB-MDSCs, iPSC-derived MDSCs (iMDSCs) shared similar morphology, phenotype, and suppressive function. We found that the CD14+ iMDSC subset possessed the highest suppressor function. In previous studies, we reported that MDSCs transferred into mice with GVHD lost suppressor function because of inflammasome activation and immature myeloid cell maturation. In striking contrast to human PB-MDSCs, we show herein that iMDSCs retained 95% of suppressor function in vitro despite exposure to lipopolysaccharide (LPS) plus adenosine triphosphate (ATP), which are stimuli that activate the inflammasome via danger-associated molecular patterns released during early posttransplant conditioning and GVHD-induced injury. In an in vivo xenogenic GVHD model with PB mononuclear cells, iMDSCs significantly increased recipient survival without loss of antileukemia effects. iMDSC RNA sequencing and gene knockdown studies revealed that the maintenance of the purine metabolizing enzyme, phosphoglycerate dehydrogenase, during LPS plus ATP treatment, was linked to iMDSC inflammasome resistance. Taken together, these findings provide a platform for translating in vitro–generated, off-the-shelf iMDSCs into the clinic for suppressing a spectrum of adverse immune responses, including GVHD.