Citations

Abstract Introduction:AFOP is a pattern of lung injury with intra-alveolar fibrin balls and organizing pneumonia. In 2013, the ATS/ERS revised their classification of idiopathic-interstitial-pneumonia to include acute-fibrinous-organizing-pneumonia(AFOP) in their rare histologic patterns. Methods: MEDLINE(PubMed), EMBASE, and Cochrane were searched for AFOP-related case reports/case series. Mesh terms used included (“acute fibrinous and organizing pneumonia” OR AFOP OR “acute fibrinous organizing pneumonia” OR (“acute fibrinous” AND “organizing pneumonia”) OR (“acute fibrinous” AND “organizing pneumonia”). A total of 177 patients were synthesized in these 169 articles, 9 of which were case series and the rest individual case reports. A quality review and data extraction was done on Covidence using a JBI checklist.Results:Mean age of 52.2 +/- 17.4 years with 55% of them were males. The associations were; malignancy (16%), smoking (14%), organ transplant (13%), Hypertension (10%), and use of immunosuppressive agents (6%) were frequent risk factors. Cough (73%), shortness of breath (71%), and fever (61%) were found highly frequent symptoms. Predominant radiological findings were multifocal infiltrates/consolidation (50%) and ground glass appearance (39%). Leukocytosis and inflammatory markers were elevated in most cases. Transbronchial/EBUS (32%), open surgical (29%), imaging-guided (22%), and VATS (14%) were common modes of lung biopsy. Treatment is usually steroids (88%) and antibiotics (69%). Death occurred in 23% of the cases, clinical or radiological improvement was achieved in 69%, while only three recurrences were reported. Most cases are either idiopathic or associated with myelodysplastic syndrome as causative factors reported by authors. DiscussionAFOP presents non-specific symptoms and a community-acquired pneumonia-like clinical picture. Treatment included antibiotics, corticosteroids, and other immunosuppressants with variable outcomes. Discontinuation of suspected drug was the sole treatment strategy reported in some cases. Partial lobectomy/lesion resection was a successful treatment in some instances with localized disease.The survival in AFOP was significantly worse than obliterative bronchiolitis (median time to death 101 vs. 294 days; P = 0.02). A statistically non-significant trend towards higher mortality associated with higher body mass index (BMI) and a long interval between symptom onset and diagnosis of AFOP was reported by Kim et al. in a cohort from South Korea. Conclusion:AFOP being a rare histological pattern of acute lung injury, is a relatively new entity that requires a better clinical and radiologic understanding for the clinical challenge it poses. This systematic review will be able to provide answers to clinicians to think in that direction and manage acute lung injury accordingly.

Abstract Background: Given the dramatic rise in incidence of colorectal cancer in young adults, there remain limited treatment options effective in metastatic disease. Although T cell-based therapies have been successful in treating highly antigenic cancers, like melanoma and lung, they have not yet been shown to induce consistent and durable tumor regression in common epithelial malignancies, including metastatic colorectal cancer (mCRC). CISH (Cytokine inducible SH2 containing protein) is a novel intracellular checkpoint target demonstrating PD-L1 ligand independent mechanisms of enhanced anti-cancer activity. Given that CISH is not currently tractable via antibody or small molecule drug modalities, we employed CRISPR for precise inhibition of CISH in tumor infiltrating lymphocytes (TILs). Here, we provide the first clinical report of safety and anti-tumor activity of CISH edited TILs in 12 patients with metastatic gastrointestinal cancers (NCT04426669), including a clinical complete response (CR) in a young-adult patient with immunotherapy-refractory mCRC. Methods: Tumors were surgically resected for TIL harvest, followed by a rapid expansion protocol and CRISPR/Cas9 knockout (KO) CISH. CISH KO, neoantigen-reactive TILs were expanded, then infused following non-myeloablative lymphocyte depleting (LD) chemotherapy (cyclophosphamide & fludarabine) followed by high-dose IL-2. To establish mechanistic attribution of the CR, we used iR-RepSeq+ for serial analysis of the TCR immune repertoire. Results: Our CRISPR engineering led to KO of CISH in T cells with high-efficiency (>90%) without detectable off-target editing. We safely dosed patients at all five dose levels (range: 1.91e8 to 9.93e10 cells). No dose-limiting toxicities attributable to the CISH-KO TIL product were observed. Adverse events were consistent with established risks of LD chemotherapy, IL-2, or disease progression. A durable ongoing complete response (>21 months) was achieved in a patient with microsatellite instability-high (MSI-H) mCRC refractory to anti-PD1/CTLA-4 combination therapy. Conclusions: We provide the first clinical report of CISH checkpoint targeting via genetically modified T cell therapy, with complete response in a patient with mCRC. Persistence and expansion of unique TCR clonotypes detected in neoantigen responsive TIL was temporally consistent with spikes in CISH edited alleles detected by NGS assay; in the patient with CR, four of the clonotypes exhibiting prolonged persistence greater than one-year post-infusion exhibited significantly reduced or undetectable expression of CISH compared to the total infused TIL population. Given these findings, further investigation of CISH checkpoint inhibition, via gene and cell therapy, and next-generation small molecule drugging modalities, is underway. Citation Format: Emil Lou, Modassir S. Choudhry, Timothy K. Starr, Timothy Folsom, Jason Bell, Blaine Rathmann, Anthony P. DeFeo, Ji Hyun Kim, Nicholas Slipek, Zhaohui Jin, Darin Sumstad, Christopher A. Klebanoff, Katherine Ladner, Akshat Sarkari, R Scott McIvor, Thomas A. Murray, Jeffrey Miller, Madhuri Rao, Eric Jensen, Jacob Ankeny, Mahmoud A. Khalifa, Anil Chauhan, Benjamin Spilseth, Ajay Dixit, Paolo P. Provenzano, Wenjing Pan, Daniel Weber, Miranda Byrne-Steele, Tom Henley, David H. McKenna, Matthew J. Johnson, Beau R. Webber, Branden S. Moriarity. First-in-human trial in patients with metastatic colorectal cancer using CRISPR-engineered tumor infiltrating lymphocytes in which the intracellular immune checkpoint CISH is inhibited [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT269.

AbstractBackgroundOvarian juvenile granulosa cell tumors (juvGCT) are rare sex cord‐stromal tumors that occur primarily in children and adolescents. This study summarizes the clinical presentation and outcomes of patients with juvGCT.MethodsPatients were enrolled in the International Ovarian and Testicular Stromal Tumor and/or International Pleuropulmonary Blastoma/DICER1 Registries. Available medical records were abstracted, and pathology was centrally reviewed. Surgical staging was classified using the 2014 International Federation of Gynecology and Obstetrics (FIGO) criteria.ResultsIn total, 70 patients with juvGCT enrolled and were diagnosed between 2001 and 2024; most patients (81%, 57 of 70) presented with FIGO stage I disease. Adjuvant chemotherapy was given in 30% (21 of 70); all regimens were platinum‐based. Three‐year event‐free survival among patients with stage IA tumors was 80.2% (95% confidence interval [CI], 62.4%–100.0%), IC1 was 87.4 (95% CI, 72.4%–100.0%), IC2‐IC3 was 63.6% (95% CI, 40.7%–99.5%), and II‐IV was 48% (95% CI, 24.6%–93.8%). Of the patients with recurrent juvGCT with known mitotic index (MI), all had MI greater than 19 mitoses per 10 high power fields (HPF) at diagnosis.ConclusionOutcomes were worse for patients with FIGO stage ≥IC2 disease and for tumors with >19 mitoses per 10 HPF. Given the prognostic significance of MI, the authors strongly recommend the assessment of MI for all juvGCTs. More information about tumor biology is critical to identify which patients may benefit from adjuvant chemotherapy and to facilitate the development of novel therapies.

Abstract Multiple myeloma (MM) is a complex hematological malignancy characterized by genomic changes and transcriptomic dysregulation. Initial exome sequencing approaches have failed to identify any single, frequent (>25%) mutation in the coding genome. However, using whole-genome sequencing, we found that one of the genomic regions most frequently mutated (62% of the patients with MM) was the 5′ untranslated region and/or intron 1 of the BCL7A gene. RNA-sequencing data from a large cohort suggest a loss of BCL7A expression in a large majority of patients with MM as compared with normal plasma cells. BCL7A loss of function in a panel of MM cell lines led to a highly proliferative phenotype in vitro and in vivo, whereas its ectopic expression significantly reduced cell viability, suggesting a tumor suppressor function for BCL7A in MM. We studied the cellular and molecular effects of BCL7A loss and observed that it endows myeloma cells with proliferative potential in cooperation with the plasma cell–defining transcription factor IRF4. BCL7A is involved in a direct protein-protein interaction with IRF4, limiting its DNA-binding activity. Loss of BCL7A thus enhances the expression of IRF4-associated cytokines and reduces mitochondrial metabolism and reactive oxygen species levels. Our study therefore suggests that BCL7A loss provides the necessary molecular change to allow IRF4-mediated transcriptional activity and MM cell growth and survival.

Background: Sarcoidosis is a multisystem disorder characterized by non-caseating granulomas in various organs. While cardiac sarcoidosis (CS) is clinically rare, it has significant implications, including heart failure, ventricular arrhythmias, and sudden cardiac death. Speckle-tracking echocardiography has emerged as a promising tool for detecting subclinical myocardial dysfunction, which is cost-efficient and readily available. This meta-analysis aims to evaluate differences in functional echocardiographic parameters between patients with CS and extracardiac sarcoidosis (ECS) to improve early recognition and management. Methods: A comprehensive search of major bibliographic databases was conducted to identify studies up to December 2024. Mean differences (MDs) with 95% CIs were pooled using the inverse-variance random-effect model. Results: Seven studies with 478 patients with sarcoidosis (CS: 159 and ECS: 319) were included. Patients with CS had a significant reduction in left ventricular global longitudinal strain (MD: −2.73; 95% CI: −4.09, −1.38; p < 0.0001) and tricuspid annular plane systolic excursion (MD: −0.59; 95% CI: −1.12, −0.05; p = 0.03) compared to patients with ECS. No significant differences in the LV global circumferential strain, interventricular septum thickness, left ventricular ejection fraction, E/A ratio, E/E’ ratio, LV end-diastolic diameter, and LV end-systolic diameter were noted. Conclusions: LV GLS and TAPSE are promising parameters for the early detection of cardiac involvement in sarcoidosis, with significant prognostic implications. Although STE provides a cost-effective and accessible alternative to CMR and FDG-PET, further research is needed to standardize its use and validate diagnostic cut-offs.

Increased infiltration of CD3 + and CD8 + T cells into ovarian cancer (OC) is linked to better prognosis, but the specific antigens involved are unclear. Recent reports suggest that HLA class I can present peptides from noncoding genomic regions, known as noncanonical or cryptic peptides, but their immunogenicity is underexplored. To address this, we used immunopeptidomic analysis and RNA sequencing on five metastatic OC samples, which identified 311 cryptic peptides (40 to 83 per patient). Despite comprising less than 1% of total peptides, cryptic peptides from noncoding transcripts emerged as the predominant antigen class when compared to the other major classes of known tumor-specific and tumor-associated antigens in OC samples. Notably, nearly 70% of the prioritized cryptic peptides elicited T cell activation, as evidenced by increased 4-1BB and IFN-γ expression in autologous CD8 + T cells. This study reveals noncoding cryptic peptides as an important class of immunogenic antigens in OC.