City of Hope

Platelets are crucial to the development of thrombosis and coagulation abnormalities in sepsis, but the mechanisms by which they contribute to these pathological processes are not fully understood. Here, we identify a key role for platelet-released heat shock protein 90α (HSP90α) in driving neutrophil extracellular trap (NET) formation and supporting thromboinflammation during sepsis. Proteomic analysis of platelets from patients with sepsis showed a significant increase in HSP90α, which we traced back to trafficking pathways originating from megakaryocytes. When activated, platelets translocate HSP90α to their plasma membrane and release it into the extracellular space in both free and exosome-associated forms. Extracellular HSP90α acts as a damage-associated molecular pattern that binds to toll-like receptor 4 (TLR4) on neutrophils. This binding activates a downstream MyD88-Beclin 1 signaling pathway, triggering autophagy and leading to NET formation. Blocking extracellular HSP90α with a neutralizing monoclonal antibody significantly reduced NET formation both in vitro and in vivo, resulting in decreased sepsis-related thrombosis and inflammation. This platelet-HSP90α-TLR4-autophagy-NET pathway not only deepens our understanding of platelet-induced immunothrombosis but also suggests potential targets for therapies aimed at reducing coagulation problems and organ failure in septic patients.

The detection rate of contralateral hilar involvement in NSCLC during EBUS-TBNA staging is not well established. We conducted a retrospective observational single-center study of all EBUS-TBNA staging examinations performed from 2016 through 2020 to determine the incidence of PET and CT negative N3 hilar metastasis by EBUS-TBNA in patients with radiographic T1-T4, N0-N3, M0 NSCLC. A total of 516 patients underwent EBUS-TBNA sampling of contralateral hilar lymph nodes. Metastatic non-small cell lung cancer was detected in one or more contralateral hilar lymph node stations in 5 patients (0.97%). Four of these patients had radiographic N2 or N3 disease on PET imaging. Patients with mediastinal N2/N3 disease by PET scan were at higher risk of having occult contralateral hilar disease as compared with mediastinal N0/N1 by PET (P=0.017). In individuals radiographically staged as mediastinal N3 by CT scan, 14 (95% CI: 3-78) patients would need to undergo EBUS-TBNA sampling of a CT negative contralateral hilar lymph node to identify malignant involvement of the latter. In cases radiographically staged as mediastinal N3 by PET scan, 25 (95% CI: 6-141) patients would need to undergo EBUS-TBNA sampling of a PET-negative contralateral hilar lymph node to identify malignancy involvement in this location. In patients with NSCLC undergoing EBUS staging for radiographic N0/N1 disease by PET, it is reasonable to not sample the contralateral hilar lymph node stations. In radiographic N2/N3 disease by PET or CT, sampling the contralateral hilar lymph node stations appears to be justified.

The average global life expectancy is predicted to increase to approximately 80years by 2040 [1]. Cancer is an ageing-related disease, and its prevalence will also increase with this ageing of the population [2]. This rise in older adults living with cancer will demand innovation in service delivery, multidisciplinary collaboration, and a renewed focus on compassionate, patient-centred care. We are therefore compelled to rethink how we approach cancer diagnosis, treatment, and survivorship. This white paper explores the potential realities and challenges through a multidimensional lens, addressing the intersection of demographic shifts, rapid technological advancements, and the evolving needs of older adults living with cancer. Key areas examined include the integration of precision medicine and digital health tools, the adaptation of healthcare delivery models, and the implications for workforce training and resource allocation. The discussion highlights disparities in care, the importance of personalised interventions, and strategies to enhance quality of life for older adults with cancer. By anticipating these developments, the paper offers critical insights for policymakers (who set the rules and goals and allocate funding), health system leaders (who manage the day-to-day operations), clinicians and allied health professionals (who are patient-facing), and patients and caregivers, aiming to promote equity, innovation, quality and resilience in the care of older adults with cancer as we approach the next decade. The paper seeks to consolidate and clarify the diverse issues and opportunities that will emerge as the global population ages and the burden of cancer among older adults rises. With average life expectancy predicted to approach 80years by 2040, and cancer recognised as a disease closely linked to ageing [3], the paper brings together expert perspectives to provide a sector-wide synthesis of the impending challenges. Its purpose is not to offer a conventional systematic review, but rather to serve as a strategic resource for policymakers, health system leaders, clinicians, allied health professionals, patients, and caregivers, informing the response to demographic shifts, technological advances and evolving patient needs. By consolidating insights on disparities in care, the necessity for personalised interventions, and strategies to enhance quality of life, the paper aims to inform and inspire innovation, equity and resilience in geriatric oncology as we approach the next decade.

Neutralizing antibodies are established correlates of protection against SARS-CoV-2, yet T-cell responses are also thought to contribute substantially to limiting disease severity and enhancing durability of protection. To examine whether cellular immunity alone can confer protection, we engineered DNA vaccines encoding modified Spike proteins, including C-terminal truncation (SARS-CoV-2-ΔC, ΔC) and cleavage-site–deleted, linker-inserted (SARS-CoV-2-Linker-ΔT, Linker-ΔT) variants, with or without genetic fusion to MIP3α, which has been shown to enhance targeting of antigen-presenting cells (APC) and preferentially induce T-cell responses. In BALB/c mice, ΔC constructs induced non-neutralizing Spike- and RBD-binding antibodies across variants, as well as robust CD4 + and CD8 + T cell responses, whereas Linker-ΔT elicited strong Th1-skewed cellular immunity in the absence of humoral responses. In K18-hACE2 mice antibody neutralizing activity was not detected by any of the vaccines, and none conferred protection following lethal virus challenge, despite robust specific T-cell cytokine responses. These findings support chemokine-fusion strategies to enhance T cell priming, while indicating that the cellular immunity elicited by this vaccine alone does not confer protection against SARS-CoV-2. Integrating such APC-targeting strategies with structural modifications that preserve pre-fusion neutralizing epitopes may be worthwhile.

N6-methyladenosine (m6A) is a chemical modification of adenosine in RNA that plays a crucial role in the regulation of gene expression. As the most abundant form of RNA chemical methylation, m6A is aberrantly expressed in hepatocellular carcinoma (HCC), where it affects multiple biological processes including targeted RNA splicing, transport, degradation, stabilization, and translation. RBM15B (RNA-binding motif protein 15B), is a gene that encodes a protein involved in RNA processing and regulation. RBM15B is a member of the RNA-binding motif (RBM) protein family, which plays diverse roles in post-transcriptional gene regulation. RBM15B is proven to be involved in mRNA processing, including pre-mRNA splicing, mRNA transport, and mRNA stability. It may also participate in other RNA-related processes such as mRNA translation and RNA decay. We investigated the phenotypes of RBM15B in HCC using the TCGA database, in-vitro, and in vivo assays. m6A dot blot was used to assess RNA methylation levels and Merip-seq/RNA-seq were employed to explore the biological effects and potential mechanisms of RBM15B in HCC. We hypothesized that RBM15B may regulate ITSN2 expression in HCC. To test this, RNA immunoprecipitation (RIP) followed by qRT-PCR was applied for the identification and characterization of target ITSN2 mRNA that interacted with RNA binding protein IGF2BP1, which may mediate the effects of RBM15B. To further elucidate the functional relationship between RBM15B and ITSN2, we performed rescue assays of cell proliferation and migration to determine whether RBM15B over-expression is able to restore the loss of function induced by ITSN2 knockdown to an extent. High levels of RBM15B were verified by both TCGA data and our cohort. High levels of RBM15B predicted a poor prognosis. RBM15B promotes HCC propagation and invasion in vitro and in vivo. RBM15B regulates the m6A of intersectin2 (ITSN2) mRNA via insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1)-facilitated stabilization of ITSN2 mRNA. ITSN2 depletion rescued the tumor-promoting phenotype induced by RBM15B overexpression. In summary, RBM15B-regulated m6A in ITSN2 mRNA facilitates HCC progression via IGF2BP1-guided stabilization of ITSN2 mRNA. Our study illustrates the importance of the RBM15B-IGF2BP1-ITSN2 regulatory axis based on m6A activity and provides new insights into epi-transcriptomic maladjustments of initiation and metastasis in HCC.

Fluorescence-guided surgery (FGS) has emerged as a powerful intraoperative tool to visualize tumors in real time, but its precision is often constrained by a fundamental limitation. Conventional FGS relies on fluorescence intensity, a relative measure that cannot distinguish specific probe binding in cancer from non-specific accumulation in other tissues, such as the liver or areas of inflammation. This ambiguity can compromise surgical decision-making. We investigate whether fluorescence lifetime analysis can provide a quantitative parameter that can more effectively distinguish tumor from normal tissues using an anti-CEA-IR800 fluorescent probe in a mouse model of colorectal cancer.

Background: Implant-based reconstruction (IBR) is the most common method of breast reconstruction after mastectomy. Prior studies have demonstrated that complications rates vary with incision type. We evaluated whether incision type affected culture positivity in IBR complications. Methods: A retrospective cohort study was performed of all patients undergoing mastectomy for cancer or cancer prophylaxis with IBR from 2012 to 2023. Abstracted data included patient characteristics, oncologic treatment history, mastectomy and reconstruction characteristics, culture positivity, infectious organism, and antibiotic treatment history. Results: A total of 6901 patients underwent post-mastectomy implant-based reconstruction, 183 (2.7%) patients had unplanned operative intervention for IBR complications, and 80/183 (43.7%) had culture-positive IBR infections. Culture-negative and culture-positive groups were similar in patient characteristics and oncologic treatment history. There was no difference in mastectomy incision types. The most common organisms were methicillin-sensitive Staphylococcus aureus, Pseudomonas aeruginosa, and coagulase-negative Staphylococcus. More patients in the culture-positive group were treated with antibiotics (81.2% vs. 51.5%, p = 0.0005). Antibiotic therapy duration was longer in the culture-negative group (8.52 vs. 5.78 days, p = 0.039). Among different incision types, there was no significant difference in duration of antibiotic therapy. Conclusions: No association between mastectomy incision type and culture-positive infections was observed among IBR complications in this study. Antibiotics may sterilize cultures, but operative intervention is still often required for IBR infections.

Purpose: Genetic classification may advance precision medicine in diffuse large B-cell lymphoma (DLBCL), but existing tools like LymphGen (LG) are limited by complexity, incomplete classification, and do not incorporate non-genetic features that impact disease biology and therapeutic outcomes. To address these limitations, we developed LymphGen-sig (LGsig), a gene expression-based platform that classifies all DLBCLs and harmonizes both genetic and non-genetic dimensions of the disease. Methods: LGsig was built on the distinct subtype-specific gene expression signature of each LG class using paired genomic and transcriptomic data (NCI/BCCA; n=764). Model development was restricted to DLBCLs classified into MCD, BN2, EZB, or ST2. Gene features were selected by differential gene expression, with 294 genes being optimal for classification using a nearest shrunken centroid classifier. LGsig classifications were designated MCDsig, BN2sig, ST2sig, and EZBsig. The final model was applied to RNAseq from archival samples from the POLARIX trial (n=678) to assess outcomes after polatuzumab vedotin-R-CHP (pola-R-CHP) or R-CHOP for each LGsig subtype. Results: LGsig accurately identified LG subtypes using transcriptional data alone, and extended assignments to all previously LG-unclassified cases. Importantly, LG-unclassified DLBCLs reassigned by LGsig, mirrored the transcriptional and clinical features of their corresponding LG counterparts, supporting their reclassification. Additionally, LGsig reassigned LG A53 DLBCLs, characterized by aneuploidy and TP53 alterations, into more biologically and therapeutically-relevant LGsig clusters. Lastly, LGsig improved the performance of LG as a biomarker in the POLARIX study, by identifying distinct DLBCL subtypes exhibiting a survival benefit with pola-R-CHP over R-CHOP in both LG-classified and LG-unclassified cases. Conclusion: LGsig expands molecular classification beyond current genetic classifiers in DLBCL by integrating both genetic and transcriptional dimensions of the disease to better inform subtype-specific therapeutic strategies.

Immunotherapy has been a pillar of the renal cell carcinoma (RCC) treatment landscape for over three decades. Some of the earliest cancer immunotherapies available, such as interleukin 2 and interferon-alpha, have resulted in complete responses, but only in a small number of patients. Immune checkpoint inhibitors (ICIs), however, have demonstrated improved response rates and prolonged survival for a greater number of patients, fully transforming the standard of care in first-line and subsequent-line settings. More recently, ICIs are also being used in the adjuvant setting for high-risk patients. However, treatment with ICIs requires a nuanced understanding of topics such as patient selection, histology and risk considerations, and integration with local therapies. As such, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline (CPG) on immunotherapy for the treatment of RCC. Drawing from published data and clinical experience, the Expert Panel developed evidence-based and consensus-based recommendations. Topics include therapy selection in the adjuvant and metastatic settings, considerations for special patient populations, response monitoring, and patient education and quality of life considerations, among others, with the goal of improving patient care by providing guidance to the oncology community.