The aim of this study was to use image-derived dose metrics to predict the radiologic response of neuroendocrine tumors treated with [177Lu]Lu-DOTATATE. Particular focus was given to the evaluation of cyclic changes in absorbed dose per administered activity (AD/AA) as a potential prognostic factor. Methods: Data from 73 patients enrolled in the multicenter OZM-067 trial (NCT02743741) were analyzed. All patients who received 4 cycles of [177Lu]Lu-DOTATATE and underwent SPECT/CT imaging at 3 time points after each treatment were included. Tumor dosimetry was based on semiautomatic adaptive-threshold segmentations and recovery coefficient-based partial-volume correction; tumors smaller than 10 cm³ were excluded. If multiple tumors were segmented per patient, the mean absorbed dose (AD) and AD/AA were recorded at each cycle. Radiologic response was assessed using RECIST 1.1 criteria. Results: A significant decrease in AD/AA across cycles was observed, with a median decline of approximately 10% per cycle. Within this cohort, 28 patients had a partial response, 33 had stable disease, and 12 experienced disease progression. Responders exhibited a higher mean cumulative AD and greater decreases in AD/AA in successive cycles when compared with nonresponders. These metrics were uncorrelated predictors of response (P = 0.64). Notably, all 8 patients with an AD of at least 100 Gy and a decrease of at least 50% in AD/AA between cycles 1 and 4 were responders. Quantitative models combining AD and changes in AD/AA achieved an area under the receiver-operating-characteristic curve of 0.78. Conclusion: Both AD and changes in AD/AA were independently associated with radiologic response to [177Lu]Lu-DOTATATE in patients with neuroendocrine tumors. The consistent decrease in AD/AA over a course of therapy suggests a potential imaging biomarker that could inform adaptive treatment strategies, which should be further evaluated in a prospective setting and considered when designing dosimetry-guided [177Lu]Lu-DOTATATE trials.

Therapeutic resistance and limited brain penetration remain major challenges in high-grade gliomas. Protein-based nanocarriers, such as the heavy chain of human ferritin (FTH1), facilitate transferrin receptor-mediated transport across the blood-brain barrier. Here, we present multifunctional FTH1 nanocages as a unified nanoplatform for dual-drug chemotherapy and molecular imaging. The nanocages achieve > 98 % gallium-68 labeling efficiency and enable pH-responsive release of doxorubicin and paclitaxel. In isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant tumor models in ovo, FTH1 nanocages exhibit robust intracerebral distribution, tumor accumulation, and enhanced therapeutic efficacy. Dual-drug nanocages significantly reduce tumor growth (p < 0.001), with a stronger effect in the IDH-mutant model (p < 0.001), and improve embryo survival. Kinomic profiling reveals broad suppression of AGC and CMGC kinase families, consistent with attenuation of pro-survival and cell-cycle signaling, particularly in IDH-mutant models. These findings suggest treatment-associated kinase network adaptation linked to the IDH status of the models, consistent with increased therapeutic vulnerability, and support further evaluation of FTH1 nanocages as a platform for improved glioma treatment.

Supplementary Table S2. Tissue Microarray Metadata (merged data from 4 TMAs used in the study): Impact of stage, T-stage, N-stage, and tumor grade on c-MET positivity and H-score of EAC samples.

Supplementary Figure S5. Gross anatomy of mouse stomach.

Ex vivo fluorescence imaging of L2-IL1β mice: A, Representative white light and fluorescence images of the excised stomach taken from L2-IL1β mice. The white dotted line shows the SCJ, which is within the stomach in mice. A protruding, irregular lesion is visible at the EGJ and SCJ in the stomach taken from a high-score group mouse, with the corresponding fluorescence image below. B, Upregulation of c-MET in dysplastic lesions from the low-, intermediate-, and high-score groups. C, Correlation between dysplasia score and level of c-MET expression. D, Box-whisker plot of ROI analysis, which shows increasing fluorescence from low- to intermediate- to high-score lesions. E, Quantification of TBR in ex vivo IVIS fluorescence imaging. Range of box-whisker plots indicate minimum to maximum. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Eso, esophagus; H&E, hematoxylin and eosin; Max, maximum; Min, minimum; ns, not significant; Sbkg, signal intensities of the background; SJC, squamocolumnar junction; Slesion, signal intensities of the lesion.

Supplementary Figure S4. Fluorescence molecular endoscopy study schema.

Platinum-based cancer therapy remains a cornerstone of first-line treatment for several solid tumours such as ovarian, testicular, and non-small cell lung cancers, where it has received regulatory approval as both monotherapy and combination regimens. However, the inevitable emergence of resistance has necessitated extensive preclinical and clinical efforts to develop rational platinum-based combinations. The most appealing candidates for combination therapy are those that offer additive and/or synergistic effects without undesirable overlapping toxicities. Whilst early strategies focussed on co-administration with cytotoxic chemotherapies, recent advances have shifted towards combinations with targeted therapies and immunotherapies, offering improved efficacy and durability of response. In this review, we provide a comprehensive analysis of recent clinical trials evaluating platinum-based combination strategies (excluding radiotherapy) and give an overview of trial concepts that will lead to more refined therapies for cancer. We also highlight emerging dual-drug codelivery nanosystems, platinum-based antibody–drug conjugates (ADCs), and multi-targeted platinum compounds with promising preclinical and/or clinical evidence. Beyond traditional drug pairings, the improved design strategies of new platinum compounds such as their incorporation into ADCs offer enhanced targeting and reactivity. Whilst promising preclinical examples like trastuzumab-Pt(II) and cetuximab-C8Pt(IV) bring optimism to combinatorial approaches, significant challenges including stability and controlled payload release remain to be addressed before clinical translation. By integrating advances in molecular profiling and rational drug development, platinum-based therapies continue to evolve, offering renewed optimism for overcoming drug resistance and improving patient outcomes, although challenges such as biomarker identification, toxicity management, and treatment costs remain to be fully addressed.

Background:The impact of radiation dose escalation in locally advanced oesophageal cancer remains controversial. While higher doses may improve locoregional control, their effect on overall survival (OS) and progression-free survival (PFS) remains uncertain. The aim of this study was to thoroughly evaluate the impact of dose escalation on survival. Methods:A systematic search on Jan 4, 2025, identified studies evaluating definitive chemoradiotherapy (CRTx) for locally advanced oesophageal cancer stratified by radiation dose. Bayesian and frequentist meta-analyses assessed OS, PFS, and locoregional PFS (LRPFS). Meta-regression examined the influence of histology, tumour location, chemotherapy, and radiation techniques. Additional analyses included gene set enrichment analysis and immune infiltration estimation. This study is registered with PROSPERO, CRD42024538961. Findings:A total of 42 studies involving 8379 patients were included. High-dose radiotherapy significantly improved LRPFS, with the largest benefit observed at 1-year (median difference: 18.6%; 95% credible interval [CrI]: 10.7-26.1%). A modest improvement in OS was noted at 3-year (7.0%; 95% CrI: 0.01-13.9%), particularly in squamous cell carcinoma (SqCC). Meta-regression identified SqCC and taxane-based chemotherapy as key moderators, with high-dose conferring greater benefits in Asian populations. Genomic analysis revealed higher radiosensitivity and significant immune activation in Asian SqCC. Taxane-based chemotherapy regimens were the strongest predictors of 1-/2-year OS and PFS but diminished at 5-year. Any-grade pneumonitis was more common in high-dose, but frequencies of grade 3 or higher pneumonitis were similar. Modern techniques like intensity-modulated or volumetric-modulated radiotherapy were associated with higher complete response rate and a trend toward reduced toxicity. The study heterogeneity was moderate to high across pooled estimates but addressed through hierarchical modeling and subgroup/sensitivity analyses. Most included studies were retrospective with moderate risk of bias, and the certainty of evidence for primary outcomes was rated as low to high. Interpretation:Radiation dose escalation improves locoregional control and may enhance OS in SqCC, particularly in Asian populations, highlighting the need for histology- and region-specific therapeutic strategies. The choice of chemotherapy regimen may affect the interpretation of survival effects associated with high-dose. Furthermore, the genomic correlates of radiosensitivity and immune activation suggest potential for biologically guided dose personalization and combination with immunotherapy. Funding:None.

Supplementary Figure S3. Representative time course fluorescence imaging of the dual xenograft mouse model after EMI-137 injection.

Supplementary Information S1. Details of the Fluorescence Molecular Endoscopy (FME) System; Representative videos with screenshot of FME in L2-IL1b transgenic mice

Despite improvements in neuroblastoma treatment, survival figures lag behind those of many other childhood malignancies. New treatments, and better use of existing treatments, are essential to reduce mortality. Neuroblastoma expresses several molecular targets for radionuclide imaging and therapy, of which the most widely exploited is the norepinephrine transporter. [123I]metaiodobenzylguanidine (MIBG) imaging and [131I]MIBG treatment, which target this physiologic pathway, have been in clinical practice for 40 y. Although therapy outcomes have been favorable, [131I]MIBG use has not yet been optimized. Somatostatin receptors and the disialoganglioside are alternative targets, but their use remains experimental. The charity Children's Cancer Research Fund organized a workshop bringing together a broad range of scientists including radiochemists, radiobiologists, radiation physicists, clinical researchers including pediatric oncologists and nuclear medicine physicians, and patient advocates from the United Kingdom, United States, and continental Europe to share their experiences with molecular imaging and radiotherapy of neuroblastoma and discuss potential ways of improving treatment outcomes and access. These include development of alternative vectors targeting somatostatin receptors and disialoganglioside, isotopes such as α-particle and Auger electron emitters with different radiation characteristics, and combinations with external-beam radiotherapy, immunotherapy, and DNA damage repair inhibitors. Barriers to progress discussed included the unpredictable radioisotope supply, production of novel radiopharmaceuticals, lack of data regarding which are the best combination therapies, and insufficient clinical facilities. The aim was to stimulate the development and assessment of more effective treatments.

AbstractPurpose: Esophageal cancer carries a poor prognosis with a 5-year overall survival of less than 20%. Barrett’s esophagus increases the risk of esophageal adenocarcinoma. The aim of this study was to investigate the ability of EMI-137, a mesenchymal–epithelial transition factor (c-MET)-targeting optical imaging tracer, to detect dysplasia in Barrett’s esophagus. Experimental Design: c-MET expression in human esophageal tissue was investigated using Gene Expression Omnibus datasets, tissue microarrays, and Barrett’s esophagus biopsies. EMI-137 was tested in a dual xenograft mouse model bearing OE33 (c-MET high expression) and FLO-1 (c-MET low expression) tumors. Fluorescence molecular endoscopy was performed in a mouse model of Barrett’s-like metaplasia and dysplasia (L2-IL1β). Tumors and organs of interest were evaluated through ex vivo fluorescence imaging. Results: MET mRNA expression analyses and c-MET immunostaining confirmed upregulation of c-MET in Barrett’s esophagus and esophageal adenocarcinoma compared with normal epithelium. There was strong accumulation of EMI-137 in OE33 xenografts 3 hours after injection, decreasing by more than 50% on coinjection of a 10-fold molar excess of unlabeled EMI-137. The target-to-background ratio at 3 hours after injection for OE33 and FLO-1 tumors was 10.08 and 1.42, respectively. Fluorescence molecular endoscopy of L2-IL1β mice showed uptake of EMI-137 in dysplastic lesions within Barrett’s esophagus with a target-to-background ratio of 1.9 in vivo and greater than 2 in ex vivo fluorescence imaging. Conclusions: EMI-137 accumulates in dysplastic lesions within Barrett’s esophagus and also in c-MET–positive esophageal adenocarcinoma. EMI-137 imaging has potential as a screening and surveillance tool for patients with Barrett’s esophagus and as a means to detecting dysplasia and esophageal adenocarcinoma.

Details of L2-IL1β ex vivo IVIS experiment. Average radiant efficiencies of ROIs were calculated from ex vivo IVIS images: left and right squamocolumnar junctions, the junction between the forestomach and the cardiac/corpus of the stomach, and EGJ, with the corresponding background regions located in the corpus of the stomach.

c-MET is upregulated in Barrett’s esophagus and esophageal adenocarcinoma compared with normal epithelium: A and B, Upregulation of MET mRNA in Barrett’s esophagus and esophageal adenocarcinoma in two GEO databases in comparison with NSE. C, Representative immunostaining of normal epithelium, inflammation, hyperplasia, and esophageal adenocarcinoma. D, Analysis of human TMAs confirmed upregulation of c-MET protein in esophageal adenocarcinoma compared with NSE, inflammation, and hyperplasia (all P < 0.0001). E and F, Immunostaining of endoscopic human biopsy samples of NSE (n = 6) and Barrett’s esophagus (n = 5) showed an approximately 2-fold greater average H-score and percentage of c-MET positivity in Barrett’s esophagus compared with NSE. **, P < 0.01; ****, P < 0.0001.

BACKGROUND:Radiopharmaceutical therapy (RPT) has gained notable attention for its potential in treating difficult cancers, with [177Lu]Lu-DOTATATE being a notable example. However, the radiobiology of RPT is less understood compared to external beam radiotherapy (EBRT), and dosimetry protocols are not standardized. Organ dose limits and tumor dose-response correlations are often based on radiobiologically motivated equieffective doses (EQDX). On top of absorbed dose, these measures are also functions of the absorbed dose rate and radiobiological parameters that quantify tissue radiosensitivity and damage repair rate. Typically, the absorbed dose and repair rates are assumed to follow a monoexponential pattern, although describing the dose rate function often requires two or more phases to describe the data. PURPOSE:Here we present novel expressions for calculating the equieffective dose in 2 Gy fractions (EQD2) for RPT, considering various absorbed dose rate scenarios and the rate of sublethal DNA damage repair. We aimed to establish an approach that is scalable, robust, and can be used alongside various absorbed dose integration methods. METHODS:By assuming a simple exponential decay for DNA damage repair and employing a biexponential function for absorbed dose rate decay, we have re-established the solutions for EQDX in a concise analytical form. Additionally, we have devised a novel hybrid solution applicable to piecewise-defined absorbed dose-rate functions, leveraging both numerical and analytical methodologies. To validate these expressions, simulated measurements were utilized, and comparisons were made with a fully numerical approach. We also investigated the reliability of three methodologies-fully numerical, fully analytical, and a hybrid approach-when simplifying comprehensive dosimetry protocols. Utilizing publicly available clinical data from two patients undergoing [177Lu]Lu-DOTATATE therapy, we defined the baseline absorbed dose rate model based on the best biexponential fit to four post-injection SPECT measurements at the organ level. We then explored variations in EQD2 values resulting from the omission of the final measurement. RESULTS:The proposed expressions were found to be accurate and scalable, providing a reliable alternative to fully numerical methods. The results of the fully numerical method converged to our solutions with increasing accuracy as the extrapolation time after injection was increased. However, we found that to achieve an accuracy in EQD2 to within 2%, the numerical method had to extrapolate for up to 890 h in some cases, at which point overflow errors are likely to occur. Our hybrid method also achieved a significant decrease in computation time compared to the fully numerical method.Using data from two patients, we found that the numerical, hybrid, and analytical approaches underestimated the baseline EQD2 to tumors by 15.6 ± 9.4 %, 5.0 ± 4.2 %, and 1.5 ± 2.9 %, respectively. CONCLUSIONS:Comprehensive dosimetric studies are often preferred in RPT when increased measurement accuracy is desired. Correspondingly, it is vital for radiobiological models to maintain a level of accuracy commensurate with comprehensive studies. Our proposed methods are accurate, scalable, and suitable for radiobiologically motivated RPT dosimetry.

Supplementary Figure S2. Establishment of a dual xenograft mouse model for testing EMI-137.

Real-time FME imaging of L2-IL1β mouse after injection of EMI-137: A, Representative white-light, fluorescence, and overlay images of L2-IL1β mice with different lesion scores after EMI-137 injection. B, Normalized fluorescence signal intensities of the lesion and background in low- (n = 16 frames), intermediate- (n = 15 frames), and high-score (n = 8 frames) groups. C, Increased TBR in low-, intermediate- and high-score groups after EMI-137 injection compared with controls receiving PBS. ***, P < 0.001. AU, Arbitary unit; Sbkg, signal intensities of the background; Slesion, signal intensities of the lesion.

[177Lu]Lu-PSMA therapy has emerged as a promising option for metastatic prostate cancer (PCa). Many ongoing trials are exploring the combination of [177Lu]Lu-PSMA therapy with immunotherapy, highlighting the urgent need to identify potential biomarkers for this therapeutic approach. This study aims to investigate the immune effects of radionuclide therapy using [177Lu]Lu-PSMA-I&T in PCa.We used the RM1-PGLS cell line (a murine PCa cell line with a castration-resistant phenotype, stably transfected with human PSMA) to establish a syngeneic mouse model. RM1-PGLS tumor-bearing male C57BL/6 mice were treated with either 60 MBq of [177Lu]Lu-PSMA-I&T or 5 Gy of external beam radiotherapy (EBRT). Tumors were harvested on day 7 following treatment, and downstream profiling of immune responses was conducted using the NanoString Pancancer Immune panel.In vivo, immune responses were significantly activated on day 7, with 109 differentially expressed genes (DEGs) upregulated after [177Lu]Lu-PSMA-I&T therapy (accounting for 98.2% of all DEGs). Single sample Gene Set Enrichment Analysis revealed that 24 immune-related pathways (curated from MSigDB) were activated compared to the untreated control. Further analysis also showed significantly higher estimated infiltrations of macrophages, neutrophils, and CD56dim NK cells.Among the observed changes, Cxcl10 emerged as the most significantly upregulated gene for both therapies ([177Lu]Lu-PSMA-I&T: log2 fold change [FC] = 2.1, adjusted p = 0.0059; EBRT: log2FC = 2.3, adjusted p = 0.0025). Protein-protein interaction analysis revealed that Cxcl10 ranked among the top three genes with the highest number of interactions with other genes ([177Lu]Lu-PSMA-I&T: 71 edges, top 1; EBRT: 124 edges, top 3), indicating its critical role in the immune response.To investigate whether RM1-PGLS cells can express and release Cxcl10, we treated the cells with 1.2 MBq/ml of [177Lu]Lu-PSMA-I&T (equivalent to 5 Gy EBRT in vitro) and incubated them for 7 days, with the medium replaced every 2 days. Immunofluorescence images demonstrated a significant increase in Cxcl10 gene expression on day 7 (p < 0.001), while the Cxcl10 protein release peaked on day 2 (p < 0.05) but declined by days 4 and 6, showing no significant difference from baseline. These results suggest that RM1-PGLS cells can express and release Cxcl10 independent of immune cell involvement.Taken together, this study demonstrates that [177Lu]Lu-PSMA-I&T therapy induces a significant immune response characterized by Cxcl10 upregulation and activation of multiple immune pathways. Further studies are warranted to validate the therapeutic potential of these combinations in enhancing anti-tumor immunity and improving clinical outcomes for patients with PCa. Yang-Hong Dai, Gemma Dias, Carsten Kramer, Katherine A. Vallis. Exploration of immune effects of [Lu]Lu-PSMA therapy and rationale for combination with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 591.

EMI-137 binding affinity and specificity: A, Saturation binding assay showing the Kd value of EMI-137 is 8.72 nmol/L. B, Competitive binding assay of EMI-137 indicating the IC50 value of unlabeled EMI-137 is 25 nmol/L. C, Live-cell microscopy FLO-1 cells showing an absence of immunofluorescence staining for c-MET, whereas there is a strong signal in OE33 cells at 2 hours after the addition of EMI-137. Fluorescence in OE33 cells was markedly reduced when cells were exposed to a mixture of 100 nmol/L unlabeled EMI-137 with 10 nmol/L EMI-137. Scale bar, 50 μm. AU, Arbitary unit.

Supplementary Video S2. Low lesion score mouse: low to non-fluorescence was detected in normal, flat cardia whereas significant fluorescence was observed in protruding lesion of gastric cardia. Left, white light imaging; middle, fluorescence imaging; right, overlay imaging.