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Abstract Introduction Approximately 40% of patients with DLBCL will experience relapse after initial treatment with standard-of-care chemo-immunotherapy. Effective treatment options are limited for patients who experience first-line treatment failure, particularly for those with R/R disease following CAR T-cell therapy or those not able to receive CAR T-cell therapy (Sehn et al, N Engl J Med. 2021). GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin) and immunomodulatory activity. In the two-part, multicenter, first-in-human Phase 1/2 study (CC-99282-NHL-001; NCT03930953), GOLCA was well tolerated and effective in patients with R/R DLBCL (Bachy et al, ICML 2025, #148). Here, we provide longer follow-up in patients with R/R DLBCL from Part B of the study. Methods Patients with R/R DLBCL and disease progression after ≥ 2 lines of therapy or transplant-ineligible patients after ≥ 1 line of therapy were included in the study. Patients received GOLCA monotherapy orally, once daily at different dosing schedules in Part A. In Part B, GOLCA was dosed at 0.2 or 0.4 mg (14 days on/14 days off) ± R. Total GOLCA treatment duration was up to 2 years or until progressive disease (PD)/unacceptable toxicity. Primary objectives included safety and recommended Phase 2 dose determination. Results As of April 3, 2025, a total of 77 patients with R/R DLBCL were enrolled in Part B Cohort C (GOLCA 0.2 mg + R, n = 39; GOLCA 0.4 mg + R, n = 38). Median age was 66 years (range, 20–86). Patients were heavily pre-treated; median number of prior treatments was 4 (range, 1–11), 55% of pts had prior CAR T-cell therapy, 38% had prior bispecific antibody treatment, and 44% were refractory to last treatment. Ten patients (13%) were ongoing, 4 completed 2 y of treatment, and 63 (82%) had discontinued treatment, mostly due to PD (n = 48 [62%]). The most common any-grade (G) treatment-emergent adverse events (AEs) in the 0.2- and 0.4-mg cohorts, respectively, were neutropenia (54% and 84%), an on-target side effect of GOLCA, and anemia (44% and 45%). G3/4 neutropenia was reported in 49% of patients with 0.2 mg and 79% with 0.4 mg, and febrile neutropenia (FN) in 5% and 16%, respectively. Granulocyte colony-stimulating factor was used in 81% and 88% of patients with neutropenia and 50% and 100% of patients with FN in the 0.2-mg and 0.4-mg cohorts. Dose interruptions (mainly due to infections/neutropenia) occurred in 49% and 53% of patients and discontinuations due to AEs occurred in 10% and 3% with 0.2 and 0.4 mg. One G5 pneumonia was considered related to study treatment (0.2 mg). The median follow-up was 11.8 months (range, 3.1–35.1) with 0.2 mg and 16.2 months (range, 3.8–31.4) with 0.4 mg. The overall response rate (ORR) in efficacy evaluable patients was 34% (complete response rate [CRR], 20%) with 0.2 mg (n = 35) and 58% with 0.4 mg (n = 36), including a CRR of 44% with this dose. In patients with prior T-cell–redirecting treatment, the ORR was 33% (CRR, 22%) with 0.2 mg (n = 18) and 56% (CRR, 38%) with 0.4 mg (n = 16). Seven of 35 (0.2 mg) and 14 of 36 (0.4 mg) patients experienced durable response > 12 months. The median time to response with both 0.2 and 0.4 mg was 1.8 months. In patients with durable responses (remained in response [CR or partial response] for more than two consecutive efficacy assessments) to GOLCA, circulating tumor DNA reduction from baseline continues to deepen over time. Response was similar across clones/tumor variants. Conclusions With additional follow-up, GOLCA + R continued to demonstrate a predictable and manageable safety profile, with no new safety signals observed at longer follow-up. Durable responses were shown in heavily pretreated patients with R/R DLBCL, including those with prior T-cell–redirecting therapy. GOLCA + R induced a decrease in circulating tumor DNA across tumor variants. These data support the ongoing development of GOLCA + R in patients with R/R non-Hodgkin lymphoma.

Background: Piperacillin-Tazobactam (PTZ) is often used to treat community-acquired intra-abdominal infections (CA-IAIs) despite common causative pathogens being susceptible to more narrow-spectrum agents. However, susceptibility to PTZ among these predominant pathogens has been declining. Antibiotic de-escalation to non-antipseudomonal beta-lactams whenever possible is an important strategy to prevent the development of resistance to PTZ. Objective: The purpose of this study is to assess PTZ length of therapy in patients with CA-IAI, by comparing patients who received a pharmacist-led intervention involving the de-escalation of PTZ to narrow-spectrum regimens with those who did not receive the intervention. Methods: A retrospective analysis was conducted among patients >18 years old and admitted with CA-IAI empirically placed on PTZ between January 1, 2022, through June 30, 2022 (pre-intervention group), and January 1, 2024, through June 30, 2024 (post-intervention group). A total of 246 patients were included in the pre-intervention group and 129 patients in the post-intervention group. The utilization of PTZ, hospital length of stay (LOS), and treatment-associated complications were assessed using linear and logistic regression model, respectively. Results: Compared with patients in the pre-intervention group, those in the post-intervention group had a mean 1.2-day reduction in PTZ length of therapy (2.3 vs 1.2 days, P < 0.001). There was no difference in LOS, (β = 0.001, 98% confidence interval [CI] −1.29 to 1.29; P = 0.477), hospital readmission within 30 days due to IAI (odds ratio [OR] = 0.85, 98% CI = 0.51 to 1.44; P = 0.56), treatment-associated complications during current hospitalization (OR = 0.77, 98% CI = 0.45 to 1.32; P = 0.35), development of Clostridium difficile -associated diarrhea (OR = 3.29, 98% CI = 0.77 to 22.4; P = 0.14), or medication toxicity (OR = 2.07, 98% CI = 0.79 to 6.08; P = 0.15). Conclusion and relevance: The use of narrow-spectrum antibiotics for the empiric treatment of CA-IAI-reduced PTZ length of therapy and did not result in adverse clinical outcomes.

Abstract Description Glioblastoma (GBM), the most common and malignant primary brain tumor, exhibits profound immune suppression, hindering immunotherapy efficacy. GBM-derived extracellular vesicles (EVs) play a major role through the immunosuppressive polarization of myeloid cells. Inhibition of EV-myeloid cell interactions thus represents a novel target to mitigate GBM-mediated immune suppression. However, there are multiple mechanisms of EV-target interaction, and downstream pathways of GBM-EV signaling are poorly understood. We explored two pharmacological agents targeting different mechanisms of EV uptake: Methyl-B-cyclodextrin (MBCD), which disrupts lipid rafts, and cytochalasin D, which inhibits actin polymerization. Our results showed immunosuppressive myeloid cell (CD11b+/ CD15-/ HLA-DRlow/ CD14high) populations increased upon GBM-EV treatment. Following cytochalasin D treatment, fewer immunosuppressive myeloid cells were observed (7.40%±1.01 vs. untreated 9.66%±2.86), with rescuing T cell proliferation. Conversely, MBCD treatment increased immunosuppressive myeloid cell levels (10.42%±2.38 vs. untreated 8.87%±3.97) without impacting T cell proliferation. This study demonstrates the feasibility of pharmacologically targeting EV-myeloid cell interactions to rescue tumor mediated immune suppression by inhibiting actin-dependent endocytosis with cytochalasin D. The converse results using MBCD treatment indicate differential importance of different EV uptake pathways in monocyte regulation. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Description Glioblastoma (GBM), the most common and malignant primary brain tumor, exhibits profound immune suppression, hindering immunotherapy efficacy. GBM-derived extracellular vesicles (EVs) play a major role through the immunosuppressive polarization of myeloid cells. Inhibition of EV-myeloid cell interactions thus represents a novel target to mitigate GBM-mediated immune suppression. However, there are multiple mechanisms of EV-target interaction, and downstream pathways of GBM-EV signaling are poorly understood. We explored two pharmacological agents targeting different mechanisms of EV uptake: Methyl-B-cyclodextrin (MBCD), which disrupts lipid rafts, and cytochalasin D, which inhibits actin polymerization. Our results showed immunosuppressive myeloid cell (CD11b+/ CD15-/ HLA-DRlow/ CD14high) populations increased upon GBM-EV treatment. Following cytochalasin D treatment, fewer immunosuppressive myeloid cells were observed (7.40%±1.01 vs. untreated 9.66%±2.86), with rescuing T cell proliferation. Conversely, MBCD treatment increased immunosuppressive myeloid cell levels (10.42%±2.38 vs. untreated 8.87%±3.97) without impacting T cell proliferation. This study demonstrates the feasibility of pharmacologically targeting EV-myeloid cell interactions to rescue tumor-mediated immune suppression by inhibiting actin-dependent endocytosis with cytochalasin D. The converse results using MBCD treatment indicate differential importance of different EV uptake pathways in monocyte regulation. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Abstract Description Glioblastoma (GBM), the most common and deadly primary brain tumor in adults, is associated with profound local and systemic immune suppression. Increasing evidence points to tumor-derived extracellular vesicles (EVs) as key mediators of this immunosuppression. In surveying the tumor-immune microenvironment in samples of ultrasonic aspirate collected during surgical resection of GBM (n = 12), we identified several key immunomodulatory markers expressed across a range of immune cells in the tumor microenvironment. Particularly, we found TIGIT, classically understood as a T cell inhibitory protein, expressed across a range of myeloid cell populations, including in myeloid-derived suppressor cells (MDSCs, 46.84±16.78% of total monocytic MDSCs). Co-culture of healthy donor monocytes (n = 10) with patient-derived EVs replicated similar effects (control 11.69±1.87 vs EV treated 23.32±2.0). Furthermore, Induced MDSCs significantly inhibit T cell proliferation (30.65±5.97% proliferation, v/s control 86.47±2.94, p = 0.0001), concomitant with a surge in Th2 immune responses via TIGIT+ suppressive monocytes. Targeted TIGIT inhibition restored T cell proliferation (64.13±1.327% v/s non-inhibited, 30.65±5.97%; p = 0.02) and protective immune response, confirming a pivotal role of TIGIT in immune suppressive GBM microenvironment. Furthermore, TIGIT inhibition may unmask NLRP3 function, potentially contributing to immune rescue. Funding Sources Neurosurgery Research& Education Foundation, K12 grant Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Abstract Glioblastoma (GBM) progression and recurrence are often driven by therapy-resistant cellular states emerging within hypoxic tumor niches. While hypoxia is a hallmark of GBM, the spatial transcriptomic heterogeneity that underpins resistance in these regions remains poorly characterized. Here, we employ pimonidazole labeling in conjunction with high-resolution spatial and single cell transcriptomics across 29 primary, treatment-naive human GBM samples, syngeneic mouse models, and patient-derived glioma-initiating cells exposed to hypoxia to define the hypoxia-specific tumor microenvironment and its associated cellular programs. We reveal spatially organized sub-niches within hypoxic regions, each supporting diverse cellular programs yet coexisting tumor lineage states with minimal transitions between cell states. Phylogenetic reconstruction based on inferred copy number variations demonstrates consistent evolutionary trajectories from non-hypoxic to hypoxic tumor loci. Specific copy number alterations were enriched in hypoxic regions and associated with immune infiltration and poor prognosis in MGMT-methylated tumors. Cross-species analyses confirmed the conservation of hypoxia-associated gene programs and spatial architectures. Together, our study delineates the cellular, evolutionary, and spatial complexity of hypoxia in GBM, identifies hypoxia-induced genomic alterations that may promote tumor fitness, and offers insights into new therapeutic vulnerabilities within hypoxic niches.

Abstract Brain metastases (BMs) are a common and often fatal progression of systemic cancers, affecting up to 25% of patients. Despite advances in surgical resection and radiotherapy, the median survival remains limited to 10–16 months. While genomic profiling has enabled the development of targeted therapies, there remains a paucity of prognostic tools for clinical use. To address this, we explored the utility of DNA methylation profiling—an epigenetic marker increasingly recognized for its diagnostic and prognostic value. We profiled fresh-frozen tissue from 327 surgically resected BM samples of lung, breast, melanoma, and gastrointestinal (GI) origin using the Illumina Infinium MethylationEPIC BeadChip array. Unsupervised analysis via partitioning around medoids (PAM) clustering identified five robust groups. Four of these correlated closely with primary tumor origin. However, a distinct “Poly-Origin Cluster” emerged, comprising tumors from multiple primary sites with a shared epigenetic signature. Poly-Origin tumors showed improved survival outcomes compared to origin-aligned clusters (20.2 vs. 10.1 months, p=0.0018), independent of clinical covariates. Notably, these tumors were enriched for immune cell infiltration—including CD14+ macrophages, CD19+ B-cells, and CD56+ NK cells—based on deconvolution analysis, and exhibited reduced genomic instability as measured by copy number variation. These tumors were enriched for pathways related to cell signaling. We validated the prognostic significance of the Poly-Origin methylation signature in a publicly available independent cohort (n=96), and found that high signature concordance correlated with extended survival. Finally, we demonstrated the feasibility of detecting this signature in plasma-derived cell-free DNA using cfMeDIP-seq, with high classification accuracy (AUC = 0.98). These findings reveal a clinically meaningful subtypes of BM not captured by tissue origin or mutation status alone. Our work suggests that DNA methylation profiling may be a powerful tissue- and liquid biopsy–based tool that holds promise as a non-invasive prognostic biomarker in the management of brain metastasis.

Abstract Glioblastoma (GBM), the most aggressive primary brain tumor in adults, is marked by profound immune suppression. Tumor-derived extracellular vesicles (TEVs) are increasingly recognized as key mediators of this immunosuppressive environment. In this study, we examined the tumor-immune microenvironment using ultrasonic aspirate samples from GBM patients (n = 14). Several immune checkpoint molecules, including PDL1, B7-H3, and VISTA, were notably elevated. TIGIT, a receptor typically associated with T cells, was widely expressed across multiple myeloid subsets, including monocytic myeloid-derived suppressor cells (mMDSCs; 64.27 ± 7.99%) and non-classical monocytes (NCM; 39.8 ± 4.37%). Co-culture of healthy donor monocytes (n=10) with TEVs replicated similar effects (control 11.69±1.87 vs EV treated 23.32±2.0). We found CD155, the primary TIGIT ligand, to be heavily enriched in TEVs and co-expressed with TIGIT in co-culture, suggesting the TIGIT/CD155 axis may be involved in promoting immune suppression. Additionally, induced MDSCs significantly inhibit T cell proliferation (30.65±5.97% proliferation, v/s control 86.47±2.94, p=0.0001), concomitant with a surge in Th2 immune responses via TIGIT+ monocytes along with an increase in NLRP3 and IL-1β expressing cells. Interestingly, TIGIT knockdown did not affect NLRP3 expression but did restore T cell proliferation (64.13 ± 1.33%; p = 0.02) and pro-inflammatory cytokine production. However, the restoration of T cell proliferation was lost when NLRP3 was also silenced, indicating its essential role in mediating immune rescue. Overall, our findings highlight a crucial role of TIGIT in driving myeloid-mediated immune suppression in GBM. Furthermore, TIGIT inhibition may unmask NLRP3 function, potentially contributing to immune rescue.

Abstract Objective: The National Institutes of Health (NIH) Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) is a validated laptop-based battery of executive functioning tests. A modified tablet version of the EXAMINER was developed on the UCSF Tablet-based Cognitive Assessment Tool (TabCAT-EXAMINER). Here we describe the battery and investigate the reliability and validity of a composite score. Methods: A diagnostically heterogeneous sample of 2135 individuals (mean age = 65.58, SD = 16.07), including controls and participants with a variety of neurodegenerative syndromes, completed the TabCAT-EXAMINER. A composite score was developed using confirmatory factor analysis and item response theory. Validity was evaluated via linear regressions that tested associations with neuropsychological tests, demographics, clinical diagnosis, and disease severity. Replicability of cross-sectional results was tested in a separate sample of participants ( n = 342) recruited from a frontotemporal dementia study. As this separate sample also collected longitudinal TabCAT-EXAMINER measures, we additionally assessed test-retest reliability and associations between baseline disease severity and changes in TabCAT-EXAMINER scores. Results: The TabCAT-EXAMINER score was normally distributed, demonstrated high test-retest reliability, and was associated in the expected directions with independent tests of executive functioning, demographics, disease severity, and diagnosis. Greater baseline disease severity was associated with more rapid longitudinal TabCAT-EXAMINER decline. Conclusions: The TabCAT-EXAMINER is a tablet-based executive functioning battery developed for observational research and clinical trials. Performance can be summarized as a single composite score, and results of this study support its reliability and validity in cognitive aging and neurodegenerative disease cohorts.

BACKGROUND: Pelvic exenteration is the treatment of choice for selected patients with locally advanced primary and recurrent rectal cancer. Involvement of major pelvic neurovascular structures and bone was historically considered a contraindication due to unacceptably high rates of morbidity and low R0 resection rates. OBJECTIVE: To compare the outcomes of these “high-complexity” exenterative resections to those of “conventional” pelvic exenteration. DESIGN: International multicenter retrospective cohort study. SETTINGS: Sixteen specialized exenteration centers. PATIENTS: Those who underwent total pelvic exenteration for locally advanced primary and recurrent rectal cancer between 2018 and 2023 at participating centers. MAIN OUTCOME MEASURES: Perioperative resource utilization, morbidity, mortality, and R0 resection rates were reported. RESULTS: Seven hundred sixty-three patients underwent total pelvic exenteration, of whom 478 (63%) and 285 (37%) required conventional and high-complexity procedures, respectively. High-complexity pelvic exenteration was associated with longer operating time (600 vs 480 minutes, p < 0.001 for locally advanced primary rectal cancer, 623 vs 480 minutes, p < 0.001 for locally recurrent rectal cancer), intensive care stay (2 vs 1 day, p < 0.001 and 3 vs 1 day, p < 0.001), hospital stay (19 vs 15 days, p = 0.008 and 23 vs 15 days, p < 0.001), and higher blood loss (2000 vs 1236 mL, p < 0.001 and 3000 vs 1600 mL, p < 0.001). Morbidity and mortality outcomes and R0 resection rates were similar between the groups. LIMITATIONS: Generalizability of findings outside of expert units. CONCLUSIONS: High-complexity pelvic exenteration for the treatment of rectal cancer is associated with similar morbidity, mortality, and R0 resection rates, but it has a significantly higher operative time, blood loss, and hospital resource utilization compared to conventional pelvic exenteration. In high-volume, specialized centers, these techniques are considered the standard of care for appropriately selected patients with tumors that involve major pelvic bone or neurovascular structures. See Video Abstract . EXENTERACIÓN PÉLVICA TOTAL CONVENCIONAL FRENTE A EXENTERACIÓN PÉLVICA TOTAL DE ALTA COMPLEJIDAD PARA EL CÁNCER RECTAL LOCALMENTE AVANZADO Y LOCALMENTE RECURRENTE: UN ESTUDIO MULTICÉNTRICO INTERNACIONAL ANTECEDENTES: La exenteración pélvica es el tratamiento de elección para determinados pacientes con cáncer rectal primario y recurrente localmente avanzado. La afectación de las principales estructuras neurovasculares y óseas pélvicas se consideraba históricamente una contraindicación debido a las tasas inaceptablemente altas de morbilidad y a las bajas tasas de resección R0. OBJETIVO: Comparar los resultados de estas resecciones exenteración «de alta complejidad» con los de la exenteración pélvica «convencional». DISEÑO: Estudio de cohorte retrospectivo multicéntrico internacional. ENTORNOS: Dieciséis centros especializados en exenteración. PACIENTES: Aquellos que se sometieron a una exenteración pélvica total por cáncer rectal primario y recurrente localmente avanzado entre 2018 y 2023 en los centros participantes. PRINCIPALES MEDIDAS DE RESULTADOS: Se informaron la utilización de recursos perioperatorios, la morbilidad, la mortalidad y las tasas de resección R0. RESULTADOS: 763 pacientes se sometieron a una exenteración pélvica total, de los cuales 478 (63 %) y 285 pacientes (37 %) requirieron procedimientos convencionales y de alta complejidad, respectivamente. La exenteración pélvica de alta complejidad se asoció con un tiempo quirúrgico más prolongado (600 frente a 480 minutos, p < 0,001 para el cáncer rectal primario localmente avanzado, 623 frente a 480 minutos, p < 0,001 para el cáncer rectal localmente recurrente), estancia en cuidados intensivos (2 frente a 1 día, p < 0,001 y 3 frente a 1 día, p < 0,001), estancia hospitalaria (19 frente a 15 días, p = 0,008 y 23 frente a 15 días, p < 0,001) y mayor pérdida de sangre (2000 frente a 1236 ml, p < 0,001 y 3000 frente a 1600 ml, p < 0,001). Los resultados de morbilidad y mortalidad, así como las tasas de resección R0, fueron similares entre los grupos. LIMITACIONES: Generalización de los resultados fuera de las unidades especializadas CONCLUSIONES: La exenteración pélvica de alta complejidad para el tratamiento del cáncer de recto se asocia con tasas similares de morbilidad, mortalidad y resección R0, pero con un tiempo quirúrgico, una pérdida de sangre y una utilización de recursos hospitalarios significativamente mayores en comparación con la exenteración pélvica convencional. En centros especializados con un gran volumen de casos, estas técnicas se consideran el tratamiento estándar para pacientes adecuadamente seleccionados con tumores que afectan a los huesos pélvicos principales o a las estructuras neurovasculares. ( AI-generated translation )