In adults with classic Hodgkin lymphoma (cHL), metabolic tumour volume (MTV) is valuable for risk stratification. This systematic review explored the role of volumetric parameters in children, adolescents and young adults (CAYA) with cHL. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. Five databases were searched on 16 October 2024. Eligible studies were peer-reviewed manuscripts, written in English, published since database inception that included patients ≤21 years of age with a diagnosis of cHL treated with chemotherapy ± radiotherapy with a baseline 18F-Fluorodeoxyglucose (F-FDG) PET/CT scan for MTV quantification. The search strategy identified 3669 studies, of which 35 were eligible for inclusion. Fifteen studies (43%) evaluated a cohort exclusively ≤21 years of age. All eight studies that explored the association of baseline PET parameters with known risk factors identified a significant correlation. Nine of 12 papers (75%) demonstrated a statistically significant correlation with disease response to therapy on PET/CT. Fifteen of 20 papers (75%) demonstrated an independent statistically significant correlation with clinical outcomes. In the CAYAHL population, volumetric PET parameters are valuable for risk stratification despite heterogeneity in results. Future harmonization of the segmentation approach will facilitate incorporation of MTV into clinical practice.

Chimeric antigen receptor (CAR)-T cell therapy has shown limited success in the treatment of solid tumors, reinforcing the need to elucidate the in vivo biodistribution of these engineered T cells. Here, we integrate the anti-DOTA huC825 reporter ("Thor") platform into newly developed human anti-interleukin-13 receptor α-2 (IL13Rα2)-single-cell fragment variable (scFv)-derived CAR-T cells and investigate its utility for mapping CAR-T cell distribution in a xenograft mouse model of melanoma. Methods: We engineered anti-IL13Rα2-scFv-derived CAR-T cells expressing huC825 (KLG3BBz-huC825), evaluated detection sensitivity, and monitored CAR-T cell biodistribution via weekly [86Y]Y-aminobenzyl-DOTA PET/CT and therapeutic efficacy. Results: KLG3BBz-huC825 T cells demonstrated potent antigen-specific cytotoxicity and cytokine release in vitro. The Thor radiohapten capture platform offered exquisite detection sensitivity of only 3,000 engineered T cells and enabled prolonged spatiotemporal assessment of CAR-T cell kinetics up to 7 wk after infusion, corroborated by histopathology. Treatment with KLG3BBz-huC825 resulted in an overall survival benefit. Conclusion: The Thor platform offers a versatile and highly sensitive approach to study the real-time kinetics of CAR-T cells in vivo.

We report the case of a 72-y-old man with recurrent extranodal marginal-zone B-cell lymphoma who underwent dynamic long-axial-field-of-view 18F-FDG PET/CT. In addition to detecting extensive recurrent disease, a review of a maximum-intensity-projection cine derived from the dynamic acquisition demonstrated delayed uptake and excretion from the left kidney, consistent with impaired function. This incidental functional renal assessment supplemented standard anatomic imaging and influenced treatment management. This case highlights the emerging capability of dynamic long-axial-field-of-view 18F-FDG PET/CT to provide renal functional information in oncologic imaging.

Abstract Purpose: Circulating tumor DNA (ctDNA) has emerged as a sensitive biomarker for minimal residual disease detection, but its potential for real-time adaptation during curative therapy remains unexplored. Integrating ctDNA dynamics with imaging could enable more precise, risk-adapted treatment modifications beyond current radiological monitoring alone. HPV-associated oropharyngeal cancer (OPC) presents an ideal context given high cure rates, active treatment de-escalation efforts, and protracted chemoradiation courses allowing mid-treatment adaptation. We sought to determine whether longitudinal ctDNA profiling integrated with multimodal MRI could inform response-adapted treatment strategies. Methods: A total of 158 patients with HPV OPC were enrolled on a personalized de-escalation trial (NCT03323463). Blood samples for ctDNA analysis were collected pre-treatment and weekly during therapy, with 980 longitudinal samples obtained from 119 patients over up to 126 weeks (mean 8.2 samples/patient). We developed a dual Personalized Cancer Monitoring (PCM)-HPV ctDNA assay combining patient-specific tumor-informed variant detection (average 47 variants/patient) with probes targeting high-risk HPV subtypes, especially E6 and E7 genes of HPV-16 and HPV-18, both using anchored multiplex PCR (AMP) followed by high-throughput sequencing with Invitae (now Labcorp, San Francisco, CA). Weekly MRIs (T2-weighted) were performed concurrently to determine tumor volume. Results: Integrating somatic mutations with viral ctDNA detection increased baseline ctDNA detection from 80.3% (HPV ctDNA only) and 89.4% (PCM ctDNA only) to 93.9%. Baseline circulating HPV levels correlated with tumor volume, apoptotic signaling, necrosis, and primary tumor viral load (combined R2=0.54). During treatment, ctDNA showed broader dynamic range and faster kinetics than volumetric imaging. Critically, absolute ctDNA fraction at week 2 of treatment predicted patients requiring treatment intensification (p=0.0003). A multimodal model integrating on-treatment ctDNA assessment and imaging improved identification of patients with high-risk disease, surpassing either modality alone. Conclusions: Early on-treatment ctDNA dynamics capture aggressive disease biology during a critical window for adaptation. Multimodal integration of molecular and imaging assessments provides superior risk stratification, demonstrating that they capture complementary biology early in therapy and establishing a framework for real-time treatment personalization. Citation Format: Bill H. Diplas, David N. Brown, Xin Pei, Yingjie Zhu, Achraf Shamseddine, Chiharu Graybill, W. Michael Korn, Emily Westheimer, Luc GT Morris, Richard J. Wong, Sean M. McBride, Alan L. Ho, Heiko Schoder, Eric Sherman, Robert Daber, Nora Katabi, Jorge Reis-Filho, Britta Weigelt, Nancy Lee, Nadeem Riaz. Real time multimodal ctDNA and imaging assessment enables adaptive treatment in HPV related oropharyngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 96.

Introduction Persistent inflammation is associated with impaired CAR-T function. Bridging therapy (BT) is often used during CAR-T manufacturing, yet its systemic inflammatory impact is poorly understood. Although radiotherapy (RT) is classically viewed as pro-inflammatory in the short term, its influence on systemic cytokine milieu during the CAR-T preparative window is unknown. Objectives Using INFLAMIX (Raj et al, Nature Med 2025), a validated serum-based inflammatory signature associated with outcomes after CAR-T, we clustered patients as either “inflammatory” or “non-inflammatory”. We sought to evaluate how different BT modalities affect inflammation and metabolic tumor volume (MTV) between apheresis and lymphodepletion (LD) in large B-cell lymphomas. Methods We analyzed 264 patients treated with CD19-directed CAR-T (59% axi-cel, 25% tisa-cel or 16% liso-cel) with paired INFLAMIX clusters calculated pre-apheresis and pre-LD. Fisher's exact test was used to test for an association between INFLAMIX cluster with BT modality and with change in MTV pre-apheresis to pre-LD. Overall survival (OS) was described from CAR-T infusion using the Kaplan-Meier method. Results Of 264 patients, 60% (n=158) received systemic bridging alone (ST), 17% (n=45) received RT monotherapy, and 5% (n=13) received systemic bridging with RT. Patients receiving RT compared to ST had lower rates of advanced stage disease pre-apheresis (III/IV, 55% vs 76%, p<0.001), although 4% of patients receiving ST had no disease (0% in RT group); there was no difference in pre-apheresis MTV (p=1.0) or presence of bulky disease (≥7.5cm, 16% vs 12%, p=0.6). At apheresis, 43% were classified as inflammatory, decreasing to 31% after bridging. Those whose BT included RT (n=58) were more likely to transition from an inflammatory to noninflammatory phenotype by LD (p<0.001). The prevalence of inflammatory phenotype declined from 48% pre-apheresis to 12% pre-LD in RT-bridged patients versus 46%→44% for ST alone. Conversion to an inflammatory phenotype during RT bridging was rare (3%, Table 1). Noninflammatory status at LD correlated with improved OS, with similar survival outcomes whether a patient was baseline low prior to or normalized by BT (p<0.001, Fig 1A). Persistent inflammation was associated with poor OS for RT-bridged patients (p<0.001, Fig 1B). A change in inflammatory phenotype correlated with reductions in MTV (p=0.01). Conclusion Contrary to longstanding assumptions that RT amplifies inflammation, bridging RT reduces systemic inflammatory activity compared with other modalities. This may be mediated through rapid, effective cytoreduction pre-CAR-T as demonstrated through correlation with MTV reduction. These data support an expanded role for bridging RT beyond local tumor control, highlighting its potential as a systemic inflammatory recalibrator to optimize the CAR-T microenvironment.

We present the case of a patient with an elevated prostate-specific antigen level who underwent a prostate MRI that revealed a mass between the prostate and rectum, prompting further evaluation. Biopsy suggested low-grade B-cell lymphoma. A staging 18F-FDG PET/CT demonstrated a mildly avid pelvic mass and abdominal splenosis. Heat-damaged red blood cell scintigraphy showed uptake consistent with splenosis in the pelvis. A review of outside pathology confirmed no evidence of lymphoma, establishing splenosis as the diagnosis.

Abstract Purpose: Tumor hypoxia drives treatment resistance in head and neck cancer, yet its molecular determinants remain unclear. We previously demonstrated that HPV-related oropharyngeal cancer (OPC) exhibiting hypoxia is more aggressive necessitating escalated treatment. Here, we investigated the genetic drivers of tumor hypoxia and their impact on tumor evolution. Methods: We analyzed 152 patients with early-stage HPV-related OPC from a prospective hypoxia-directed dose de-escalation trial (NCT03323463). Comprehensive genomic profiling included WES (n=122) and RNA-seq (n=91). Tumor hypoxia was assessed using 18F-FMISO PET with a standardized hybrid method incorporating qualitative assessment of four image characteristics and quantitative tumor-to-background ratios (TBR >1.3 considered hypoxic). Clonal architecture was reconstructed using PhylogicNDT. We validated molecular correlates of hypoxia in two independent cohorts of HPV-related oropharyngeal cancer from the TCGA and JAVELIN-HN. Hypoxia in validation cohorts was determined using three established mRNA-based hypoxia signatures (Buffa, Winter, Toustrup). Results: Hypoxia as determined by FMISO PET was present in 72% of tumors at baseline, and correlated with well-established RNA-based signatures of hypoxia. Mutational profiling showed that hypoxic tumors were enriched for PI3K pathway alterations, most notably PIK3CA mutations (OR=5.45, adjusted p=0.05). Critically, this association was restricted to clonal PIK3CA mutations—subclonal mutations showed no hypoxia association, suggesting early selection under hypoxic conditions. This hypoxia-PI3K relationship was validated in independent cohorts of HPV-OPC (TCGA, JAVELIN-HN) using expression-based signatures of hypoxia (adjusted p<0.05 for Winter, Buffa and Toustrup hypoxia signatures). Lastly, clonal mapping further revealed that hypoxic tumors exhibited significantly greater clonal complexity (p < 0.05; Shannon diversity). Multi-region sequencing in a subset of 41 tumors confirmed extensive spatial heterogeneity, strongly linked to hypoxic tumors. Conclusions: Our findings show that hypoxia drives early selection for PI3K pathway alterations and promotes clonal complexity, demonstrating how the microenvironment directs tumor evolution in HPV-related OPC. Citation Format: Bill Diplas, Xin Pei, Yingjie Zhu, Shu Yazaki, Luc G.T. Morris, Richard J. Wong, Sean M. McBride, Heiko Schoder, Yao Yu, Alan L. Ho, Eric Sherman, Nora Katabi, Nancy Lee, Nadeem Riaz. Hypoxia selects for early PI3K pathway alterations and drives clonal complexity in HPV-positive oropharyngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7291.

Androgen receptor (AR) signaling is the key driver of prostate cancer. Thus, standard-of-care treatments focus on androgen-deprivation therapy followed by AR signaling inhibitors. Even when initially responsive, patients eventually develop resistance to therapies targeting AR signaling, leading to disease progression. To study lesion-to-lesion AR occupancy, the radiofluorinated analog of the endogenous androgen [18F]16β-fluoro-5α-dihydrotestosterone ([18F]FDHT) has been investigated as a potential AR imaging agent. In the literature, [18F]FDHT demonstrates slow clearance from healthy tissue, poor plasma stability in vivo, and nonapplicability in mouse studies. To overcome these limitations, we explored nonsteroidal selective androgen receptor modulator (SARM)-based pharmacophores as potential PET tracers. Here, we describe the performance of a 18F-radiolabeled AR tracer, [18F]F-SARM3. Methods: [18F]F-SARM3 was synthesized via 1-step copper-catalyzed radiofluorination, and its AR affinity (half-maximal inhibitory concentration [IC50]) and biological activity (half-maximal effective concentration [EC50]) were studied in various prostate cancer cell lines. The tracer's stability in vitro was also evaluated. [18F]F-SARM3 was evaluated in LNCaP and 22Rv1 (AR-positive) tumor-bearing male mice to assess its AR specificity and clearance profile, and its performance was compared with that of [18F]FDHT. Results: [18F]F-SARM3 was synthesized with a radiochemical yield and purity of 2.7 ± 1.4% and 97.9 ± 2.3%, respectively. In in vitro cell-binding assays, [18F]F-SARM3 demonstrated high affinity for ARs, similar to that of dihydrotestosterone (IC50, 20.2 ± 14.6 nM vs. 9.6 ± 4.0 nM, respectively, in 22Rv1 cells). [18F]F-SARM3 functions as a partial AR agonist, with an EC50 of 15.0 ± 12.0 nM. Furthermore, [18F]F-SARM3 is highly stable in phosphate-buffered saline and mouse blood (98.5% ± 1.2% and 98.6% ± 1.5% intact, respectively). The tracer's in vivo specificity was confirmed with the observed uptake in tumors and prostate glands of castrated mice, where uptake was blockable. In vivo specificity was not observed with [18F]FDHT. Conclusion: We developed a first-in-class SARM-based AR tracer that displays high affinity and selectivity for AR in vitro and in vivo. This represents a suitable PET tracer to image AR status in rodent models and provides a strong rationale for clinical translation of [18F]F-SARM3 as a high-affinity AR agonist PET imaging agent.

Bridging therapy (BT) is frequently administered during CD19 CAR T-cell manufacturing for relapsed or refractory large B-cell lymphoma (LBCL), and although disease status at infusion has been associated with outcomes, the prognostic relevance of response to BT, independent of BT modality, has been variably defined in real-world cohorts. To assess the impact of bridging response on clinical outcomes after CD19 CAR T-cell therapy in patients with LBCL, and to determine whether response to BT or BT regimen type are associated with progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. We conducted a retrospective multicenter study of 377 adults with relapsed/refractory LBCL treated with commercial CD19 CAR T-cell products (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel) between 2020 and 2024. BT was administered in 248 patients (66%) during the manufacturing period and categorized by regimen type. Response to BT and CAR T therapy were assessed using Lugano criteria. The primary endpoints were PFS and OS after CAR T infusion. Secondary endpoints included rates of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematologic toxicity. Multivariable Cox regression models adjusted for performance status, lactate dehydrogenase (LDH), CAR T product, and BT category were applied to evaluate associations. Among patients receiving BT, the overall response rate prior to CAR T infusion was 49%, including complete response (CR) in 12%. Patients achieving CR or partial response (PR) to BT had significantly longer PFS and OS compared with those with stable or progressive disease (SD/PD) (median PFS and OS not reached vs shorter durations; P < .01). In multivariable analysis, response to BT remained an independent predictor of both PFS (hazard ratio [HR] for SD/PD versus CR: 2.59, 95% confidence interval [CI] 1.28 to 5.22) and OS (HR: 4.53, 95% CI 1.64 to 12.5), while BT modality itself was not independently associated with survival outcomes. Patients with favorable BT responses demonstrated lower pre-infusion tumor burden and reduced systemic inflammatory markers. Rates of CRS and ICANS did not differ significantly by BT response category. Severe hematologic toxicity was more frequent following intensive chemotherapy-based BT regimens but was not independently associated with long-term outcomes. In this large observational real-world multicenter cohort, response to BT, rather than the specific BT modality, was strongly associated with improved survival outcomes after CD19 CAR T-cell therapy in LBCL. These findings emphasize the prognostic significance of pre-infusion disease control and support treatment strategies focused on achieving effective BT responses while balancing regimen toxicity.

Background HPV-associated oropharyngeal squamous cell carcinoma (HPV OPSCC) has excellent cure rates with standard high-dose radiation therapy (RT) and chemotherapy, but this comes at the cost of substantial long-term toxicity. De-escalation strategies aim to preserve oncologic outcomes while reducing treatment-related morbidity, with ¹⁸F-FMISO PET/CT emerging as a promising biomarker to guide patient selection based on tumour hypoxia. This study builds on prior pilot data to evaluate the feasibility and efficacy of ¹⁸F-FMISO-guided RT de-escalation in an independent healthcare setting and a distinct patient population. Methods DE-RADIATE is a phase II, non-randomised, uncontrolled, single institution prospective interventional study evaluating 18 F-FMISO PET-guided RT de-escalation in patients with AJCC 7th edition clinical stage T1-2N1-2b HPV OPSCC or carcinoma of unknown primary of presumed mucosal origin. After surgical resection of primary tumour, patients will commence RT. Patients will undergo 18 F-FMISO PET prior to RT and after two weeks of RT. Patients will be eligible for RT de-escalation (total prescribed dose 30 Gy in 15 fractions) with absence of hypoxia at baseline or resolution of hypoxia on intra-treatment PET. Remaining patients will receive standard of care RT to 70 Gy. All patients in both arms will receive concurrent high dose cisplatin chemotherapy. Patients in the de-escalated arm will undergo neck dissection from four months after RT to assess treatment response. Primary endpoint is pathologic complete response rate at neck surgery. Secondary endpoints include locoregional failure, overall- and progression-free survival, toxicities, patient-reported quality of life, and correlation of hypoxic regions on 18 F-FMISO PET with oxygen-enhanced MRI. Conclusion The results will inform the design of larger prospective trials of hypoxia-guided RT de-escalation and may help identify patients most likely to benefit from reduced treatment intensity.

The detection of biochemical recurrence (BCR) of prostate cancer remains challenging, as small-volume disease may fall below the sensitivity of standard imaging. Prostate-specific membrane antigen (PSMA) PET/CT is currently the most sensitive imaging modality for tumor detection at low prostate-specific antigen (PSA) levels, but recurrence continues to be difficult to detect. We evaluated whether routine delayed pelvic imaging at 90 min postinjection improves diagnosis of sites of recurrence in patients referred for BCR. Methods: We retrospectively analyzed 201 patients with prostate cancer undergoing dual-phase 68Ga-PSMA PET/CT for BCR of prostate cancer (median PSA, 0.52 ng/mL). Imaging of vertex to midthighs was acquired at approximately 60 min and delayed pelvic imaging at approximately 90 min postinjection. Two nuclear medicine physicians independently assessed whether delayed imaging improved diagnostic certainty or revealed additional 68Ga-PSMA-avid lesions. Results: Delayed pelvic imaging improved diagnostic certainty for 68 patients (34%) and revealed additional 68Ga-PSMA-avid lesions for 23 patients (11%). Of patients with additional lesions detected on delayed imaging, roughly one third-representing 3% of the total cohort-subsequently received focal radiation dose escalation during treatment planning. Improvements were primarily influenced by increased tracer uptake confirming subtle lesions, reduced bladder or ureteral interference, and differentiation of physiologic from pathologic uptake. All measurable lesions within the field of view of the delayed pelvic image were quantified. The median SUVmax for malignant lesions increased from 4.3 to 5.0, whereas benign lesions remained stable (median SUVmax of 2.7 on normal imaging and 2.6 on delayed imaging). Conclusion: Routine delayed pelvic imaging at 90 min postinjection enhanced lesion detection and diagnostic confidence in BCR of prostate cancer, particularly at low (<1 ng/mL) PSA levels. The addition of this additional acquisition into standard PSMA PET/CT protocols can improve staging accuracy and clinical decision-making.

PURPOSE:The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. METHODS:We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS:PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)-defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION:PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator-naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

To assess the performance of 68Ga-PSMA PET/CT in detecting biochemically recurrent prostate cancer and evaluate associations of PET imaging findings with alterations on genomic profiling. 68Ga-PSMA PET/CT scans of 603 prostate cancer patients with biochemical recurrence or persistently elevated PSA and without known metastatic disease were retrospectively included (mean PSA 1.0 ng/mL; range, 0.08-5). All scans were analysed for presence of recurrence by two experienced nuclear medicine physicians independently; discrepancies were resolved by an additional expert reader. A subset of patients (n = 239) had undergone tumour genetic profiling using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing assay. PET positivity and positive predictive value, inter-reader agreement, as well as associations between patient characteristics, location of recurrence, time to PET confirmed biochemical recurrence (PCBR), SUVmax, and most frequent gene alterations were investigated. The overall recurrence detection rate of 68Ga-PSMA PET/CT was 59.2

103 Background: We previously demonstrated favorable short-term outcomes in patients with human papillomavirus–associated oropharyngeal carcinoma (HPV+ OPC) treated with biologically selected major radiation dose de-escalation, guided by functional hypoxia imaging. We now report mature long-term outcomes from a substantially larger prospective cohort to evaluate the durability and long-term safety of this approach. Methods: We conducted a pre-specified integrated analysis of a series of three consecutive phase II trials, each trial representing a progressive refinement with the same therapeutic strategy, enrolling patients with T0–3/N1–2c HPV+ OPC from 10/1/2015 to 11/30/2023. 18 F-fluoromisonidazole positron emission tomography (FMISO PET) assessed intratumoral hypoxia to stratify treatment: patients without hypoxia received de-escalated chemoradiotherapy (CRT) to 30Gy, while those with intra-treatment hypoxia received standard CRT to 70Gy. The primary endpoint was 5-year overall survival (OS); secondary endpoints included local, regional, and distant failure, progression-free survival (PFS), treatment-related toxicities, and patient-reported outcomes (PROs). Time-to-event outcomes were analyzed using Kaplan-Meier method and cumulative incidence function. Results: A total of 430 patients were enrolled and received treatment. T, N stages were: T0/TX(51), T1(198), T2(173), T3(8); N1 (62), N2a (48), N2b (252), and N2c (68). 96 patients (22.3%) had >10 pack-years of smoking history. There were 323 patients (75%) who had no hypoxia on FMISO PET and received 30Gy while 107 patients (25%) had evidence of intra-treatment tumor hypoxia and received 70Gy. With a median follow-up of 4.05 years (range 1.27–10.03 years), the 5-year OS was 97% in both the 30Gy and 70Gy cohorts. All oncologic endpoints were equivalent in the 30Gy vs 70Gy cohorts: 5-year local failure (2.2% vs 1.9%, p=0.7), regional failure (6.2% vs 3.9%, p=0.4), and PFS (91% vs 89%, p=0.5). Notably, patients with intra-treatment hypoxia, who received 70Gy had higher distant failure rates versus those without intra-treatment hypoxia and received 30Gy (7.5% vs 1.3%, p=0.004). Detailed acute/late toxicities and PROs will be presented at the meeting. Conclusions: FMISO PET–guided biological and personalized major radiation dose de-escalation results in durable long-term outcomes, benefiting ~75% of the patients. These findings establish a precision-based paradigm for definitive CRT in HPV+ OPC, currently being validated in an on-going randomized phase III trial (NCT06563479, >1/3 randomized). Patients with intra-treatment hypoxia had a higher rate of distant metastasis where additional therapy can be considered in future trials. Clinical trial information: NCT03323463 , NCT05491512 .

In adult neuroendocrine malignancies, including small cell lung cancer, Delta-like ligand 3 (DLL3) is a validated therapeutic target. DLL3 is expressed in neuroblastoma, a pediatric cancer of neuroendocrine origin, but subcellular localization is incompletely defined, limiting clinical translation of DLL3-targeted therapies for neuroblastoma. Methods: DLL3 expression and localization were evaluated in human neuroblastoma tumors and preclinical models using RNA sequencing, immunohistochemistry, and flow cytometry. To assess in vivo tumor accessibility, DLL3-targeted PET imaging with [89Zr]Zr-deferoxamine-SC16.56 was performed in patient-derived xenograft (PDX) models and in 4 patients with neuroblastoma. Results: DLL3 was broadly expressed across neuroblastoma tumor samples and preclinical models. Although immunohistochemistry demonstrated variable protein expression, flow cytometry revealed near-universal DLL3 cell surface localization across clinical samples and PDX models, including tumors with low expression by immunohistochemistry. DLL3-targeted PET imaging demonstrated tumor-specific uptake in PDX models and in 4 patients with relapsed neuroblastoma, confirming in vivo accessibility of DLL3. Conclusion: DLL3 overexpression in neuroblastoma is associated with targetable cell surface localization, supporting DLL3 as a clinically actionable target for imaging and therapeutic strategies.

The approval of CD19 chimeric antigen receptor T-cell (CAR-T) therapy in the second-line (2L) setting for large B-cell lymphoma (LBCL) has reshaped treatment sequencing and the population at risk for post-CAR-T relapse; however, management after failure of early-line CAR-T therapy remains informed largely by later-line cohorts. We conducted an international, multicenter retrospective study of adults with LBCL treated with 2L or third-line (3L) CAR-T therapy to evaluate clinical characteristics, salvage strategies, and outcomes following relapse or progression. Among 545 patients, the 1-year cumulative incidence of relapse or progression after CAR-T was 40%. Of 235 patients who relapsed or progressed, 193 received salvage therapy, with an overall response rate (ORR) of 47%. One-year event-free survival (EFS) and overall survival (OS) after salvage were 18% and 44%, respectively. Outcomes were comparable after 2L and 3L CAR-T therapy, with no independent association between CAR-T line and EFS or OS in multivariable analyses. Relapse within 3 months of CAR-T infusion was strongly associated with inferior response and survival. Post-CAR-T salvage therapy consisted of heterogeneous regimens, most commonly polatuzumab-bendamustine-rituximab and CD20 × CD3 bispecific antibody monotherapy. Response rates and short-term survival varied across approaches, with bispecific antibody monotherapy having the highest ORR (65%) and favorable 1-year outcomes (OS 56%; EFS 43%). In this contemporary multicenter cohort, salvage therapy after CAR-T failure achieved objective but often short-lived responses, with outcomes driven by relapse timing after CAR-T infusion rather than the line of prior CAR-T therapy, supporting individualized treatment selection in this high-risk setting.

Background:DNA repair inhibitors may safely enhance targeted radiotherapy if they can be administered when radioisotope has cleared from critical normal tissues. We investigated whether the kinetics of [177Lu]Lu-PSMA-617 (Pluvicto) would be consistent with such a strategy in metastatic castrate resistant prostate cancer (mCRPC). Materials and Methods:Pluvicto effective t1/2 was measured for organs-at-risk (kidneys, parotid and submandibular glands) and lesions from 60 mCRPC patients. Based on this, a safe strategy for DDR inhibition was defined, and its potential benefit to the lesion was calculated, using published in vitro radiosensitivity data. Results:Pluvicto clearance is almost 3× faster in normal organs-at-risk compared to lesions. Using pre-clinical estimates of DDRi sensitization, a meaningful increase in lesion effective treatment dose could be achieved with minor additional risk to normal organs.

This study aimed to retrospectively characterize patients with biochemical failure and peritoneal metastases detected by PSMA PET/CT, describe the detectability of 18F-FDG PET/CT and conventional imaging; and assess patient outcome. We searched an institutional database for patients who underwent 68Ga-PSMA-11 or 18 F-DCFPyL PET/CT between 5/2016 and 9/2024 and measured the SUVmax of the most avid peritoneal lesion. We assessed correlative CT, MRI, or FDG PET/CT performed within 90 days and validated peritoneal metastases via composite reference. Survival was estimated with Kaplan-Meier analysis. Seven patients subsequently treated with 177Lu-PSMA-617 were analyzed. Of 9,877 screened patients, peritoneal metastases were confirmed in 57. Most had Gleason ≥ 4 + 3 (81

Rationale: Pretargeted radioimmunotherapy (PRIT), which combines systemic antibody-based targeting with ionizing radiation, is promising for treating liver metastases in patients with colorectal cancer (CRC). Previously, we established a three-step DOTA-PRIT regimen to deliver DOTA radiometal payloads to CRC using an anti-tumor/anti-DOTA bispecific antibody (BsAb) targeting cell surface glycoprotein A33 (GPA33), a tumor antigen target expressed on over 95% of primary and metastatic CRC; a clearing agent; and a monovalent 177Lu radiohapten called [177Lu]Lu-ABD. More recently, we developed a bivalent 177Lu radiohapten called [177Lu]Lu-Gemini to enhance tumor uptake and radiohapten retention. Here, we aimed to compare the efficacy and safety of bivalent vs. monovalent three-step DOTA-PRIT regimens in orthotopic CRC liver metastasis models, to mimic a clinical path forward. Methods: We established two orthotopic CRC liver metastasis models by inoculating either SW1222-luc (GPA33high) or LoVo (GPA33low) human CRC cells in athymic nude mice under ultrasonographic guidance. Tumor targeting efficacy and dosimetry of the radiohaptens were compared using ex vivo biodistribution studies, SPECT/CT, and quantitative autoradiography. We also performed a DOTA-PRIT experiment to compare the efficacy and safety profiles of bivalent (single-cycle [177Lu]Lu-Gemini, 48 h pretargeting interval) vs. monovalent (multicycle [177Lu]Lu-ABD, 24 h pretargeting interval) three-step DOTA-PRIT regimens, each designed to deliver comparable total radiation doses to tumors (around 50 Gy). Results: Both radiohaptens demonstrated efficient SW1222-luc tumor targeting, with [177Lu]Lu-Gemini showing superior targeting and tumor activity retention compared with [177Lu]Lu-ABD. In LoVo tumors, [177Lu]Lu-Gemini showed superior targeting, while [177Lu]Lu-ABD showed negligible targeting. Dosimetry estimates revealed higher SW1222-luc tumor mean absorbed doses for [177Lu]Lu-Gemini (119.88 cGy/MBq, 48 h pretargeting interval) compared with [177Lu]Lu-ABD (32.88 cGy/MBq, 24 h pretargeting interval), with more favorable blood and kidney therapeutic indices (50 and 9 for [177Lu]Lu-Gemini, and 15 and 5 for [177Lu]Lu-ABD, respectively). In the DOTA-PRIT experiment, both monovalent (injected activity: 3 × 44.4 MBq, 133.2 MBq total) and bivalent (injected activity: 44.4 MBq total) radiohapten regimens increased the median survival of treated mice compared with controls: 71 days for [177Lu]Lu-ABD-treated mice, 81 days for [177Lu]Lu-Gemini-treated mice, and 18 days for controls, without a statistical difference between treatment groups. Treatments were well tolerated, without significant weight loss or hematologic changes. Radiation-induced injuries were not identified histologically in the kidneys or bone marrow of mice submitted for necropsy. Conclusions: Our study demonstrates the exceptional benefit of a multivalent radiohapten strategy when treating an advanced model of CRC liver metastasis. Three-step GPA33 DOTA-PRIT with 177Lu-Gemini demonstrated that multivalency 1) improves PRIT therapeutic indices for blood and kidney and 2) has the potential to greatly reduce the administered activity without compromising the efficiency of the PRIT platform in clinically relevant models of target-rich and target-poor metastatic CRC.

Disease progression is a substantial challenge in patients with non-Hodgkin lymphoma (NHL) undergoing chimeric antigen receptor T cell (CAR-T) therapy. Here we present InflaMix (INFLAmmation MIXture Model), an unsupervised quantitative model integrating 14 pre-CAR-T infusion laboratory and cytokine measures capturing inflammation and end-organ function. Developed using a cohort of 149 patients with NHL, InflaMix revealed an inflammatory signature associated with a high risk of CAR-T treatment failure, including increased hazard of death or relapse (hazard ratio, 2.98; 95% confidence interval, 1.60–4.91; P < 0.001). Three independent cohorts comprising 688 patients with NHL from diverse treatment centers were used to validate our approach. InflaMix consistently and reproducibly identified patients with a higher likelihood of disease relapse and mortality, and it provided supplementary predictive value beyond established prognostic markers, including tumor burden. Moreover, InflaMix exhibited robust performance in cases with missing data, maintaining accuracy when considering only six readily available laboratory measures. These findings show that InflaMix is a valuable tool for point-of-care clinical decision-making in patients with NHL undergoing CAR-T therapy. A preinfusion circulatory inflammation biomarker-based signature predicts the likelihood of treatment failure in patients with non-Hodgkin lymphoma who were treated with CAR-T cell therapy, with an inflammatory cluster assignment being prognostic of clinical response and survival outcomes.