Citations

Abstract Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of cancer. However, the durable response to this therapy remains low, and there is a risk of moderate-to-severe toxicities following treatment that requires close monitoring. Over the past decade, we have learned that cytokines play an important role in mediating CAR T cell–associated toxicities and efficacy. As such, cytokine modulation has become a popular area of investigation to improve therapeutic responses. Although the relationship of many cytokines with CAR T-cell therapy has been investigated, several recent studies suggest paradoxical roles for cytokines such as IFNγ, IL2, IL4, and IL10 in CAR T-cell response and toxicity. In this review, we summarize the history of these cytokines in immunotherapies, detail the contexts in which these cytokines have been beneficial or harmful in the context of CAR T-cell therapy, and discuss factors that may be dictating their pleiotropy.

Background: Posterior cortical atrophy (PCA) patients typically show progressive visual decline, although language impairment can be a prominent feature. Previous studies have explored language connectivity impairment in PCA; not much is known about the exact nature of language processing disruptions in PCA. Methods: Thirty-seven PCA patients were compared with 39 cognitively unimpaired (CU) individuals. Functional connectivity was evaluated for the language processing system, which consisted of language, perceptual, motor, and cognitive networks. Linear regression was performed to compare within- and between-network connectivity across networks and within the language network in PCA compared to CU individuals. Relationships between language network connectivity, clinical performance, and gray matter volumes were also evaluated. Results: PCA showed reduced connectivity within the language and perceptual networks, along with reduced between-network connectivity compared to CU individuals. Regional connectivity breakdown within the language network was also noted. Language processing system connectivity was not associated with clinical performance on language processing tests. However, a breakdown in Broca-Wernicke, Wernicke-middle frontal gyrus, and Wernicke-frontal orbital gyrus connectivity was related to worse performance on sentence repetition. Lastly, gray matter volume was not associated with language network connectivity. Discussion: Together, these results reiterate the breakdown of language network connectivity in PCA and highlight the disruption in connectivity at the regional level within the language network. Reduced connectivity within the perceptual network and associations between reduced language network connectivity and worse performance on sentence repetition imply a breakdown within the language processing systems in PCA.

Abstract Objective Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high seizure burden and mortality risk. Stiripentol, one of the first DS‐specific therapies, received FDA approval in 2018 but its real‐world use and impact post‐approval in the USA remain insufficiently characterized. The STIRUS study aimed to assess treatment patterns, clinical efficacy, and quality of life outcomes associated with stiripentol in a contemporary US cohort. Methods STIRUS was a retrospective, multicenter chart review of 98 DS patients who initiated stiripentol after FDA approval and were treated for at least 3 months. Data were collected from 10 USA epilepsy centers on seizure types and frequency, status epilepticus (SE), rescue medication use, emergency room visits, and quality of life, at baseline and during the first and final 3 months on stiripentol. Changes over time were assessed using generalized estimating equation models. Results Initiation of stiripentol was associated with a significant reduction in bilateral convulsive seizure frequency (OR = 2.16, p < 0.006) and a nearly 50% decrease in SE episodes (OR = 2.9, p < 0.003). Importantly, there was a marked decline in rescue medication use and seizure‐related hospital visits: the proportion of patients requiring no rescue medications increased from 23% to over 53%, and those needing frequent emergency interventions dropped from 39% at baseline to 14% during the final 3 months. Quality of life improved in more than half of patients and caregivers. Significance The STIRUS study supports the real‐world efficacy of stiripentol in reducing seizure burden and healthcare utilization in DS. Despite its demonstrated benefits and approval for use in infants, stiripentol remains underutilized and often introduced late in the treatment course. Early and broader adoption may help improve clinical outcomes and quality of life in this vulnerable population. Plain Language Summary The STIRUS study found that stiripentol, an anti‐seizure medication specifically approved for Dravet Syndrome, helped reduce seizures and hospital visits for children living with this severe form of epilepsy. Patients had fewer convulsive seizures, needed fewer rescue medicines, and reported better quality of life. Despite these benefits, stiripentol is still not widely used and often started too late in treatment, suggesting earlier use could further improve outcomes.

Abstract Purpose: Colorectal Cancer (CRC) is a leading cause of death from cancer globally. Surgery is the mainstay of treatment for localized CRC; however, little is known about survival outcomes following CRC surgery in low- and middle-income countries (LMICs). In this study, we examine the published literature for data on long-term outcomes following CRC resections in LMICs. Methods: We systematically reviewed PubMed, Web of Science, Embase, and Global Index Medicus for original research articles reporting survival data after CRC resection with curative intent in LMICs, published between January 2005 and May 2022. LMICs were defined according to the 2020 World Bank categories. We excluded studies without English full text or involving pediatric populations (&lt;18 years), non-primary colorectal, benign disease, and endoscopic/transanal resection only. Studies from China dominated the published literature and were excluded. Abstracts and full texts were reviewed by two independent reviewers, and a third reviewer resolved conflicts. Disease-free survival (DFS) and overall survival (OS) data were extracted, and random effects modelling was used to estimate the pooled survival rates. Results: Our search returned 32,261 articles. After deduplication, 20,729 abstracts were assessed for eligibility, with 154 articles meeting inclusion criteria, representing a total of 20,589 CRC patients. 98 (63.6%) studies were from upper-middle-income (UM) countries, 55 (35.7%) from lower-middle-income (LM) countries and only one was from a low-income (L) country. Notably, only 27 (20%) of the 137 LMICs were represented in the literature. Turkey accounted for the highest frequency (29%) of included articles. Most (60%) of the studies were retrospective cohort design, and only three (3) were randomized controlled trials. The pooled 5-year OS estimate was 88% (95% CI: 77–95) for Stage I disease, 76% (69–81) for Stage II, and 57% (49–64) for Stage III. 5-year DFS estimates were 82% (71–90), 76% (67–84), and 59% (51–65) for stages I, II and III respectively. Survival rates varied considerably between income groups, with the strongest disparity seen with Stage III OS data at 18 months: 89% in UM, 86% in LM, and 50% in L (p=0.0005). Conclusion: With the rising incidence of CRC in LMICs, our work highlights the dearth of data on long-term outcomes following CRC operations in LMICs and emphasizes the urgent need for research capacity building, especially in low-income countries. Citation Format: Oluwasegun Afolaranmi, Thomas M. Diehl, Sehar Salim Virani, Qiuyu Yang, Kenechukwu Okwunze, Adel H. Khan, Nabiha Akhlaq Mughal, Daniel Schroeder, Sheida Pourdashti, Leslie Christensen, Sadaf Khan, Syed Nabeel Zafar. Survival Following Colorectal Cancer Surgery in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis [abstract]. In: Proceedings of the 13th Annual Symposium on Global Cancer Research; 2025 Sep 16. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(12_Suppl):Abstract nr 84.

Aims Data on revision of unicompartmental knee arthroplasty (UKA) to total knee arthroplasty (TKA) are limited by low patient numbers and short-term follow-up. This study evaluated the mid-term outcomes of revision of UKA to TKA focusing on implant survival, radiological results, and clinical outcomes in a large series. Methods We identified 235 revisions of UKA to TKA performed between 1995 and 2022 utilizing our institutional total joint registry. The mean age was 65 years (SD 10), mean BMI was 32 kg/m 2 (SD 6), and 50% were female (n = 118). The most common indications for revision were aseptic loosening (37%; n = 83), progression of arthritis in adjacent compartments (35%; n = 81), and unexplained pain (20%; n = 47). The mean time from UKA to revision to a TKA was four years (26 days to 15 years). Posterior-stabilized constructs were used in 78% of the revisions (n = 184), varus-valgus constrained implants in 14% (n = 33), and cruciate-retaining implants in 7% (n = 16). Metaphyseal fixation devices were used in 8% of cases (n = 18) and augments in 31% (n = 73). Kaplan-Meier implant survival analyses were performed, radiographs reviewed, and clinical outcomes were measured with Knee Society Scores (KSSs). Mean follow-up was eight years (2 to 25). Results The five-year survival free of any re-revision was 93% (95% CI 89 to 97). There were 17 further re-revisions with femoral and/or tibial aseptic loosening (n = 7), periprosthetic joint infection (n = 4), and stiffness (n = 2) being the most common indications. The five-year survival free of any reoperation was 87% (95% CI 83 to 92). Stiffness (n = 7) and unresurfaced patellar clunk/crepitus (n = 4) were the most common indications for reoperations without implant exchange. There were 25 nonoperative postoperative complications, most commonly stiffness (n = 5), flexion instability (n = 4), and haematoma (n = 4). No unrevised TKAs showed signs of radiological loosening. KSS function score improved from 54 (SD 18) to 69 (SD 26; p = 0.003). Conclusion In this large series of 235 revisions of UKA to TKA, the five-year survival of the TKAs free of re-revision was good. Our data suggest that the implant survival and clinical outcomes were inferior to primary TKA. Tibial component aseptic loosening was the most common reason for re-revision. Cite this article: Bone Joint J 2025;107-B(12):1281–1287.

Aims The aim of this study was to achieve consensus for important topics related to periprosthetic infection (PJI) in orthopaedic oncology, and to identify areas for future research. Methods In January 2024, the Birmingham Orthopaedic Oncology Meeting (BOOM) held in Birmingham, UK, gathered 309 delegates from 53 countries to debate 20 consensus statements on PJI in orthopaedic oncology using a modified Delphi process. Results Of 20 questions and statements on PJI in orthopaedic oncology, none achieved unanimous consensus, 18 achieved strong consensus, one achieved moderate consensus, and one achieved weak consensus. The statements that reached consensus with notable agreement were on the prophylaxis of infection, management of leaking wounds, and surgical strategies for the treatment of PJI. Short-duration antibiotic prophylaxis was deemed as effective as longer courses for lower-risk reconstructions, and aggressive management was recommended for wounds draining beyond five to seven days to prevent deep infection. Furthermore, single-stage, two-stage, and 1.5-stage revision were recognized as valid strategies, with two-stage revision remaining the most reliable. The statements that did not achieve consensus were on the role of debridement, antibiotics, and implant retention and prolonged antibiotic use post-revision. Conclusion The BOOM meeting achieved consensus for important topics on periprosthetic infection in orthopaedic oncology, but highlighted the low quality of the underlying evidence. This study has provided recommendations for the treatment of leaky wounds, duration of postoperative antibiotic prophylaxis, and choice of revision strategy. Cite this article: Bone Joint J 2025;107-B(12):1352–1359.