Citations

Abstract Recent single-cell transcriptomic studies of follicular lymphoma (FL) have revealed heterogeneity among malignant B (MB) cells and selected components of the tumor microenvironment (TME), but have been constrained by relatively small sample sizes and a lack of spatial context. We performed comprehensive cellular profiling and spatial dissection of over five million cells by integrating single-nucleus RNA sequencing (snRNA-seq) from 182 samples (FL, n = 167; control, n = 15) with single-cell spatial transcriptomics (ST) from 386 samples (FL, n = 365; control, n = 21). After stringent quality control, 1,289,073 and 3,968,427 cells from snRNA-seq and ST data, respectively, were analyzed. Unsupervised clustering of snRNA-seq data identified 58 TME cell subtypes. To extend this classification to the ST dataset, we integrated snRNA-seq and ST data by co-embedding them into a shared principal component space, enabling robust batch correction and cell-type label transfer across modalities. Using this supervised annotation framework, ST data recapitulated 54 TME cell subtypes. MB, proliferating MB (MBprolif), and healthy B (HB) cells were classified using sample-level unsupervised clustering in ST. Macrophages exhibited previously uncharacterized heterogeneity in transcriptomic profiles and spatial distribution. We identified CXCL13-expressing macrophage subtypes with high intra- and peri-follicular abundance, termed follicular macrophages (FMs). Non-negative matrix factorization of intrafollicular cell fractions identified five TME archetypes: FM, follicular stroma, two follicular T, and HB archetypes. The FM archetype was enriched for intrafollicular macrophages, including FMs, and showed a significantly higher proportion of grade 3A/3B cases (53.4%) compared to other archetypes (≤16.5%). It was also associated with a higher frequency of high tumor burden requiring treatment initiation rather than a watch-and-wait (WW) approach. Among patients managed by WW, those with the FM archetype showed significantly shorter event-free survival (EFS) compared to those with non-FM archetypes, whereas this association was not observed among treated patients. The percentage of intrafollicular macrophages (IFMP) showed excellent predictive performance for the FM archetype (area under the curve: 0.90). IFMP calculated in a published multiplex spatial protein imaging dataset from an independent cohort of 242 FL patients validated the associations between high IFMP and both pathology grade 3A/3B and shorter EFS in WW patients. Consistently, spatial neighborhood and cell–cell communication analyses revealed co-localization of FMs and MBprolif cells, forming a distinct niche with activated signaling mediated by FM-derived CXCL13, APRIL, and BAFF. Our integrative multi-modal analysis defines previously unrecognized cellular heterogeneity and spatial architecture in FL and highlights macrophage-enriched follicular ecosystems associated with aggressive clinicopathological features, providing a framework for improved biological understanding and patient management. Citation Format: Yoshiaki Abe, Bijal Thakkar, Atish Kizhakeyil, Ashley Wilson, Andrew L. Feldman, Jared Henderson, Amy Ayers, Sara Borgschatz, R. Andrew Harkins, Priya Lakra, Daisuke Kaji, Jonathon B. Cohen, David Russler-Germain, Eric Mou, Francisco Vega, Jennifer Chapman, Giorgio Inghirami, Carla Casulo, Izidore S. Lossos, Jean L. Koff, Chijioke Nze, Peter Martin, Sergei Syrbu, Kiran Vij, David L. Jaye, James R. Cerhan, Christopher R. Flowers, Anne J. Novak, Richard Burack, Dai Chihara, Mamiko Sakata-Yanagimoto, Joshua Tobin, Xubin Li, Michael R. Green. Spatially resolved microenvironment profiling reveals distinct follicular lymphoma archetypes [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A049.

Abstract Autoinflammatory syndromes are increasingly recognized as heterogeneous disorders of innate immune dysregulation, often overlapping in clinical and genetic features. Although pulmonary manifestations are uncommon, several autoinflammatory conditions such as VEXAS syndrome, juvenile rheumatoid arthritis, adult-onset Still’s disease, and Familial Mediterranean Fever can produce inflammatory pulmonary nodules that mimic metastatic malignancy. Recognition of these presentations is critical, as they can respond dramatically to immunosuppressive therapy once the correct diagnosis is established. We describe a diagnostically challenging case of a young adult male initially suspected to have metastatic lung cancer, whose evaluation ultimately suggested a previously uncharacterized autoinflammatory process. We present a 26-year-old previously healthy male with progressive dry cough, exertional dyspnea, diffuse myalgias, small joint arthritis involving the fingers, wrists, and ankles, tendonitis, a Gottron-like rash on the hands and lower extremities, low-grade fevers, and occasional bloody stools. Initial external workup revealed a right infrahilar mass, right lower lobe pleural thickening, small pleural effusion, and mediastinal and hilar lymphadenopathy on CT chest, with corresponding PET activity. Initially suspected to have metastatic lung cancer, he was informed his prognosis was poor. However, transbronchial, EBUS, and mediastinal lymph node biopsies showed only active inflammation without malignancy. On presentation to our facility, a broad differential was pursued, with suspicion for an autoinflammatory or autoimmune etiology. Pulmonary function testing was normal. Laboratory evaluation revealed ESR >100, elevated CRP, positive ANA (1:160), negative HLA-B27, normal ferritin, and negative S100 staining. Cytokine analysis showed elevated TNF, IL-6, MCP-1, IL-2, and IL-18. Targeted variant testing identified a UBA1 gene variant, c.123G>T p.(M41L), with low-level mosaicism (0.004%), and a heterozygous MEFV mutation. Although his ethnicity made Familial Mediterranean Fever unlikely, these findings raised the possibility of overlapping somatic and germline contributions to innate immune activation. He was treated empirically with immunosuppression for a presumed multisystem inflammatory disorder, resulting in resolution of symptoms and marked radiologic improvement. This case highlights the expanding spectrum of adult-onset autoinflammatory diseases that may present with pulmonary findings mimicking malignancy. The coexistence of low-level UBA1 mosaicism and MEFV mutation suggests a potential interaction between somatic and inherited variants in triggering inflammation. Similar to the recent discovery of VEXAS syndrome, this case may represent a novel subtype of autoinflammatory disease. Continued genomic and immunologic investigation is warranted, as timely recognition and immunosuppressive therapy can lead to dramatic recovery. This abstract is funded by: None

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of postthymic T cell neoplasms, with ~40% classified as PTCL–not otherwise specified (PTCL-NOS). PTCL-GATA3, a molecularly defined subtype, associated with T helper 2 (T H 2)–like differentiation and poor prognosis, has frequent co-occurrence of TP53 loss/mutation and heterozygous PTEN loss. CD4+ T cell conditional mouse models with Trp53 mutation/deletion and Pten loss demonstrated mature T cell lymphomas (mTCLs) with T H 2-like transcriptomic and immunophenotypic profiles. Molecular studies revealed that codeletion of Trp53/Pten induced T cell receptor and Janus kinase–signal transducer and activator of transcription signaling, promoting T H 2 differentiation while inhibiting T H 1 differentiation. These findings were validated by CRISPR editing of TP53/PTEN loss in human CD4+ T cells and mechanistically evaluated the p53 binding region in intron-3 of GATA3, resulting in transcriptional repression. Transcriptomic profiles of m-TCLs recapitulated human-PTCL-GATA3 transcriptome and distinguished PTCL-NOS subtypes. Preclinical assessment of m-TCLs with PI3Kγ/δ inhibitors significantly improved survival, supporting a therapeutic approach for the p53-aberrant PTCL-GATA3.

BACKGROUND: “Days at home up to 30 days” is a novel patient-centered outcome metric that measures the number of days patients spend at home 30 days after surgery. It encompasses inpatient stay from index admission, interhospital transfers and step-downs, and readmissions across different hospitals. OBJECTIVE: Comparison of days at home up to 30 days and established outcome metrics after robotic versus 3-dimensional laparoscopic colorectal surgery. DESIGN: Prospective cohort study of consecutive patients. SETTING: Townsville University Hospital and Mater Private Hospital, Townsville, Queensland, Australia. PATIENTS: Adult patients undergoing robotic and 3-dimensional laparoscopic colorectal surgery. MAIN OUTCOME MEASURES: Days at home up to 30 days, 30-day readmission rate, index admission length, and 30-day postoperative complication rates. RESULTS: Of 82 patients, 32 (39%) underwent robotic and 50 (61%) underwent 3-dimensional laparoscopic colorectal surgery. Robotic ultralow and low anterior resection, as well as abdominoperineal resection, resulted in significantly more days at home (23 vs 15 days at home, p = 0.05) and a shorter length of index admission (7 vs 15 days in hospital, p = 0.0003). However, there was no significant difference in major postoperative complications and 30-day readmission rate. No significant differences were found between robotic and 3-dimensional laparoscopic right hemicolectomy or high anterior resection. LIMITATIONS: Unrandomized study. Patient selection for robotic and 3-dimensional laparoscopic surgery was at the surgeons’ discretion. CONCLUSIONS: Patients undergoing robotic ultralow and low anterior resection, as well as abdominoperineal resection, spent more days at home 30 days after index surgery due to a reduction in the length of the index hospital admission. Days at home up to 30 days may enhance the informed consent and complement traditional end points in future clinical trials. See Abstract Video. DÍAS EN CASA HASTA 30 DÍAS DESPUÉS DE LA CIRUGÍA COLORRECTAL ROBÓTICA FRENTE A LA LAPAROSCÓPICA ANTECEDENTES: «Días en el hogar hasta 30 días» es una nueva métrica de resultados centrada en el paciente que mide el número de días que los pacientes pasan en su hogar 30 días después de la cirugía. Abarca la estancia hospitalaria desde el ingreso inicial, los traslados entre hospitales y los traslados a unidades de cuidados intermedios, así como los reingresos en diferentes hospitales. OBJETIVO: Comparación de los días en casa hasta 30 días y las métricas de resultados establecidas tras la cirugía robótica frente a la cirugía laparoscópica tridimensional. DISEÑO: Estudio prospectivo de cohortes de pacientes consecutivos. ENTORNO: Hospital Universitario de Townsville y Hospital Privado Mater, Townsville, Queensland, Australia. PACIENTES: Pacientes adultos sometidos a cirugía colorrectal robótica y laparoscópica tridimensional. PRINCIPALES MEDIDAS DE RESULTADO: Días en el domicilio hasta 30 días, tasa de reingresos a los 30 días, duración de la admisión inicial y tasas de complicaciones postoperatorias a los 30 días. RESULTADOS: De los 82 pacientes, 32 (39 %) se sometieron a cirugía robótica y 50 (61 %) a cirugía colorrectal laparoscópica tridimensional. La resección anterior robótica ultrabaja y baja, así como la resección abdominoperineal, dieron lugar a un número significativamente mayor de días en el domicilio (23 frente a 15 días en el domicilio, p = 0,05) y a una menor duración de la hospitalización inicial (7 frente a 15 días en el hospital, p = 0,0003). Sin embargo, no se observaron diferencias significativas en las complicaciones postoperatorias graves ni en la tasa de reingresos a los 30 días. No se encontraron diferencias significativas entre la hemicolectomía derecha robótica y laparoscópica tridimensional, así como la resección anterior alta. LIMITACIONES: Estudio no aleatorizado. La selección de los pacientes para la cirugía robótica y laparoscópica tridimensional se realizó a criterio de los cirujanos. CONCLUSIÓN: Los pacientes sometidos a resección anterior robótica ultrabaja y baja, así como a resección abdominoperineal, pasaron más días en casa 30 días después de la cirugía índice debido a la reducción de la duración de la hospitalización índice. Los días en casa hasta 30 días pueden mejorar el consentimiento informado y complementar los criterios de valoración tradicionales en futuros ensayos clínicos. (AI-generated translation)

Transbronchial cryobiopsies (CB) are increasingly replacing surgical biopsies (video-assisted thoracoscopic/VATS biopsies) for diagnosing diffuse parenchymal lung disease (interstitial lung disease, ILD), but there is very little guidance for pathologists on CB interpretation. Here we propose a fairly simple approach. First, if the diagnosis can be made on a traditional forceps biopsy, it can be made on a cryobiopsy. Many diseases with specific features will fall into this category (eg, sarcoidosis or Langerhans cell histiocytosis). More problematic are patterns such as usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP), in which low-power architecture is the key to diagnosis. In this circumstance, an adequate sample is crucial to look for features such as fibroblast foci, because a combination of fibroblast foci plus any patchy old fibrosis, fibrotic architectural remodeling, or honeycombing, allows a diagnosis of a UIP pattern. However, in most instances, CB will not separate the UIP patterns seen in idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis, or connective tissue disease-interstitial lung disease (CTD-ILD), although giant cells/granulomas (uncommon findings) in this setting favor fibrotic hypersensitivity pneumonitis. Fibroblast foci can be difficult to differentiate from organizing pneumonia (OP), but granulation tissue plugs clearly in airspaces favor OP. Absent fibroblast foci, patchy old fibrosis, architectural distortion, and honeycombing by themselves do not allow a specific diagnosis. NSIP in CB microscopically looks like NSIP in VATS biopsies, and the presence of an NSIP or an NSIP+OP pattern is typical of CTD-ILD. All the above diagnoses require correlation with clinical and radiologic findings.

Abstract Introduction Rheumatoid arthritis (RA) is a systemic autoimmune rheumatic disease (SARD) primarily associated with articular involvement, but is often associated with lung involvement, sometimes preceding articular symptoms. Common pulmonary manifestations include interstitial lung disease (ILD), airway, and serosal involvement. RA-related pleural disease can mimic empyema due to the pleural fluid's green, pus-like appearance, exudative nature, low pH, markedly low glucose, and elevated lactate dehydrogenase (LDH) levels. Empyema sometimes yields negative cultures which can accentuate the diagnostic challenge in such cases. This report presents a patient with RA-related pleural lung disease who was referred to our hospital with trapped lung presumed to be secondary to empyema in the setting of pleural-based pulmonary abscess. Case Report A 66-year-old female with a 22-year history of RA presented with recurrent right-sided pleural effusions and progressive dyspnea over three years. Her initial presentation in 2022 involved a large right-sided pleural effusion, suspected to result from a ruptured pleural-based pulmonary abscess that led to empyema and subsequently a trapped lung. Pleural fluid analysis showed elevated LDH (1364 U/L), low glucose (45 mg/dL), high cholesterol (121 mg/dL), and low triglycerides (79 mg/dL). Due to refractory exudative effusion and a comprehensive negative infectious evaluation (bacterial, mycobacterial, and fungal cultures), RA-related pleural disease was suspected. The patient underwent video-assisted thoracoscopic surgery (VATS), which revealed pleural-based rheumatoid nodules and pleural thickening. (figure1) Lung and pleural biopsies confirmed RA-associated fibrinous pleuritis, RA-associated follicular bronchiolitis, and usual interstitial pneumonitis. Given the complexity of the infection, a thoracotomy with decortication and pleurectomy was planned and conducted in stages. Immunosuppressive regimen was switched from leflunomide to rituximab. Discussion This case underscores the diagnostic complexity in distinguishing RA-associated pleural effusion from empyema. Features such as pleural nodularity resembling a pulmonary abscess, unilateral exudative effusion, grossly purulent pleural fluid, low pH and glucose, and elevated LDH levels led to an initial misdiagnosis of empyema. Characteristic pleural fluid, along with persistent negative cultures and absence of sepsis pointed towards RA-related pleural disease. VATS and biopsy were instrumental in establishing the final diagnosis through characteristic histopathological findings of RA-associated pleural, parenchymal and airway involvement. Conclusion For RA patients with pleural effusion suggestive of empyema, especially in the context of negative cultures and no signs of sepsis, RA-related pleural disease should be a consideration. Early recognition and timely immunosuppressive therapy escalation can prevent complications such as trapped lungs and reduce the necessity for extensive surgical interventions. Figure1:

BACKGROUND: Using standard anterior approaches, consistent R0 resection of locally advanced primary and recurrent rectal and anal cancer involving the deep pelvic sidewall may be unattainable. Therefore, to improve R0 resection rates, we have used a posterior-first, then anterior 2-stage approach to resection of tumors in this location. OBJECTIVE: To assess the R0 resection rate and surgical outcomes of the first 10 patients operated on using this approach. DESIGN: We conducted a retrospective case series review of our prospectively maintained surgical pathology and tumor registries. SETTING: This study was conducted at the Mayo Clinic in Rochester, Minnesota. PATIENTS: Ten patients (6 female individuals, median age 53.5 years) with primary or recurrent anal or rectal cancer treated with a posterior-first, then anterior 2-stage approach were identified. MAIN OUTCOME MEASURES: The primary outcome measures were the R0 resection rate and surgical outcomes. RESULTS: An R0 resection was achieved in all 10 patients. Nine patients developed 1 or more 30-day Clavien-Dindo grade III complications. Nine patients developed gluteal wound complications ranging from superficial wound dehiscence to flap necrosis. During the follow-up period, 4 patients were found to have metastatic disease and 1 patient had local re-recurrence. LIMITATIONS: Small cohort with heterogeneous tumors and a short follow-up duration. CONCLUSION: A posterior-first, then anterior 2-stage approach has allowed us to achieve consistent R0 resection margins in locally advanced primary and recurrent rectal and anal cancers involving the deep pelvic sidewall. Poor wound healing of the posterior gluteal incision is a common complication. See Video Abstract. MEJORANDO LAS TASAS DE RESECCIÓN R0 CON UN ABORDAJE DE DOS ETAPAS PRIMERO POSTERIOR PARA LA RESECCIÓN EN BLOQUE DE CÁNCERES ANORRECTALES PRIMARIOS Y RECURRENTES LOCALMENTE AVANZADOS QUE AFECTAN LA PARED LATERAL PÉLVICA PROFUNDA ANTECEDENTES: Utilizando abordajes anteriores estándares, la resección R0 consistente del cáncer de recto y ano primario y recurrente localmente avanzado involucrando la pared lateral pélvica profunda puede ser inalcanzable. Por lo tanto, para mejorar las tasas de resección R0, hemos empleado un abordaje de 2 etapas primero posterior y luego anterior para la resección de tumores en esta ubicación. OBJETIVO: Este estudio tuvo como objetivo evaluar la tasa de resección R0 y los resultados quirúrgicos de los primeros 10 pacientes operados con este abordaje. DISEÑO: Realizamos una revisión retrospectiva de series de casos de nuestros registros de patología quirúrgica y tumores mantenidos prospectivamente. AJUSTE: Este estudio se realizó en la Clínica Mayo en Rochester, Minnesota, EE. UU. PACIENTES: Se identificaron diez pacientes (6 mujeres, mediana de edad 53.5 años) con cáncer anal o rectal primario o recurrente tratados con un abordaje de dos etapas, primero posterior y luego anterior. PRINCIPALES MEDIDAS DE RESULTADO: Las medidas de resultado primarias fueron la tasa de resección R0 y los resultados quirúrgicos. RESULTADOS: Se logró una resección R0 en los 10 pacientes. Nueve pacientes desarrollaron una o más complicaciones de grado III de Clavien-Dindo a los 30 días. Nueve pacientes desarrollaron complicaciones de la herida del glúteo que variaron desde dehiscencia superficial de la herida hasta necrosis del colgajo. Durante el período de seguimiento, se encontró que 4 pacientes tenían enfermedad metastásica y un paciente tuvo recurrencia local. LIMITACIONES: Cohorte pequeño con tumores heterogéneos y corta duración de seguimiento. CONCLUSIÓN: Un abordaje en 2 etapas, primero posterior y luego anterior, nos ha permitido lograr márgenes de resección R0 consistentes en cánceres de recto y anal primarios y recurrentes localmente avanzados que afectan la pared lateral pélvica profunda. La mala cicatrización de la incisión glútea posterior es una complicación común. (Traducción—Dr. Aurian Garcia Gonzalez)