Tumor Volume Measurements Research Articles

P15.02.A EVALUATION OF [68GA]GA-PSMA-617 PET AS A DIAGNOSTIC AGENT IN RECURRENT GLIOBLASTOMA PATIENTS: RESULTS OF THE GENESIS GBM 001 PHASE I/II STUDY

Abstract BACKGROUND PSMA is a cell-surface protein that is highly expressed in the endothelium of the tumour neovasculature of several solid tumours, including glioblastoma (GBM), making it an excellent target for antibody-drug conjugates or peptide receptor radionuclide therapy. Several [68Ga]Ga-PSMA-based radioligands have shown utility in the diagnosis and treatment response assessment of primary GBM patients in a number of case studies. The small-molecule ligand [68Ga]Ga-PSMA-617 has the advantage of being suitable for radiolabelling with different radioisotopes, including 68Ga, 177Lu, 111In and 90Y, which raised the possibility of using it in a theranostic application in glioblastoma. The aim of this phase I/II prospective study was to evaluate the potential of [68Ga]Ga-PSMA-617 as a PET imaging biomarker and as a candidate ligand for targeted radionuclide therapy in patients with recurrent GBM. MATERIAL AND METHODS Ten patients with recurrent glioblastoma were recruited for the study between October 2018 and September 2021. Patients underwent [68Ga]Ga-PSMA-617 and [18F]F-FET PET brain scans done on two separate days. Two patients had full-body [68Ga]Ga-PSMA-617 scans. Tumour selectivity of [68Ga]Ga-PSMA-617 was assessed by measuring tumour volume on [68Ga]Ga-PSMA-617 PET scans and comparing it with tumour volume measured on [18F]F-FET PET scans, which are more widely used clinically. Tumour specificity of [68Ga]Ga-PSMA-617 was assessed by comparing its standard uptake value (SUV) and tumour-to-brain-ratio (TBR) with those of [18F]F-FET TBR, and by measuring [68Ga]Ga-PSMA-617 tumour-to-liver ratio (TLR). RESULTS PSMA-defined tumour volume was on average 1.87±1.10 times larger than the FET-defined tumour volume (p=0.084), and the two volumes had a DICE similarity coefficient of 0.578±0.175. Mean and maximum TBR was significantly (p=0.002) higher (~10x) for PSMA than for FET. Mean SUV in the tumour was significantly higher for FET than for PSMA (p=0.002), while maximum SUV was slightly higher for PSMA than for FET (p=0.08). For the two patients with full-body [68Ga]Ga-PSMA PET scan available, PSMA mean TLR was 0.91 and 0.68, and maximum TLR was 1.20 and 1.07, respectively. CONCLUSION [68Ga] Ga-PSMA PET delineates a larger tumour volumes compared to [18F]F-FET PET, suggesting there are areas of the tumour with emerging tumour neovasculature that are not yet metabolically active. The poor spatial overlap between PSMA and FET tumour volume suggests the complementary diagnostic role of the two tracers. The higher TBR of PSMA compared to FET demonstrates the higher tumour specificity of the former, and thus its potential ability as a diagnostic agent for recurrent tumour volume delineation. Relatively low values of PSMA SUV and TLR suggest that PSMA specific uptake is not sufficient to use this ligand for targeted radionuclide therapy in glioblastoma when conjugated to [177Lu].

Prognostic impact of highly solid component in early-stage solid lung adenocarcinoma.

Based on computed tomography (CT) findings of lung cancer, solid nodules have a much worse prognosis than subsolid nodules, even if the nodules are subcentimeter in size. There is, however, no systematic method for determining the prognosis of solid tumors on CT. This study aimed to discover the prognostic factor of early-stage solid lung adenocarcinoma using three-dimensional CT volumetry. Patients with pathological stage I solid lung adenocarcinoma who underwent complete resection between 2007 and 2012 were selected in this retrospective study. Clinicopathological data and preoperative multidetector CT findings, such as tumor size on the two-dimensional axial image, three-dimensional tumor volume between -600 and 199 HU, and three-dimensional solid volume between 0 and 199 HU, which corresponded to highly solid components, were compared between recurrence and non-recurrence. Furthermore, these radiological values were compared to pathological invasive volume (PIV). During this time, 709 patients had their lung cancer completely removed. From this cohort, 90 patients with pathological stage I solid lung adenocarcinoma were selected. In addition, recurrence was found in 26 patients (28.9%). Although two-dimensional axial image, serum carcinoembryonic antigen (CEA) level, and SUVmax on 18F fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) did not differ statistically between recurrent and non-recurrent patients, three-dimensional tumor and solid tumor volume did. Multivariate analysis indicated that three-dimensional solid tumor volume [hazard ratio: 2.440; 95% confidence interval (CI): 1.110-5.361, P=0.026] and epidermal growth factor receptor (EGFR) mutation (hazard ratio: 4.307; 95% CI: 1.328-13.977, P=0.015) were significantly associated with disease-free survival (DFS). When three-dimensional tumor and solid tumor volume were compared to PIV, three-dimensional solid tumor volume (3,091 mm3 on average) showed a highly similar value with PIV (2,930 mm3 on average), whereas three-dimensional tumor volume (6,175 mm3 on average) was significantly larger than PIV (P<0.001). In patients with early-stage solid lung adenocarcinoma, the measurement of three-dimensional solid tumor volume, which is correlated with PIV, accurately predicted the postoperative outcome.

RECIST 1.1 Target Lesion Categorical Response in Metastatic Renal Cell Carcinoma: A Comparison of Conventional versus Volumetric Assessment.

Purpose To investigate Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) approximations of target lesion tumor burden by comparing categorical treatment response according to conventional RECIST versus actual tumor volume measurements of RECIST target lesions. Materials and Methods This is a retrospective cohort study of individuals with metastatic renal cell carcinoma enrolled in a clinical trial (from 2003 to 2017) and includes individuals who underwent baseline and at least one follow-up chest, abdominal, and pelvic CT study and with at least one target lesion. Target lesion volume was assessed by (a) Vmodel, a spherical model of conventional RECIST 1.1, which was extrapolated from RECIST diameter, and (b) Vactual, manually contoured volume. Volumetric responses were determined by the sum of target lesion volumes (Vmodel-sum TL and Vactual-sum TL, respectively). Categorical volumetric thresholds were extrapolated from RECIST. McNemar tests were used to compare categorical volume responses. Results Target lesions were assessed at baseline (638 participants), week 9 (593 participants), and week 17 (508 participants). Vmodel-sum TL classified more participants as having progressive disease (PD), compared with Vactual-sum TL at week 9 (52 vs 31 participants) and week 17 (57 vs 39 participants), with significant overall response discordance (P < .001). At week 9, 25 (48%) of 52 participants labeled with PD by Vmodel-sum TL were classified as having stable disease by Vactual-sum TL. Conclusion A model of RECIST 1.1 based on a single diameter measurement more frequently classified PD compared with response assessment by actual measured tumor volume. Keywords: Urinary, Kidney, Metastases, Oncology, Tumor Response, Volume Analysis, Outcomes Analysis ClinicalTrials.gov registration no. NCT01865747 © RSNA, 2023 Supplemental material is available for this article.

Analysis of correlation of pre-therapeutic assessment and the final diagnosis in endometrial cancer: role of tumor volume in the magnetic resonance imaging.

To evaluate whether the introduction of tumor volume as new parameter in the MRI assessment could improve both concordance between preoperative and postoperative staging, and the identification of histological findings. A retrospective observational study with 127 patients with endometrial cancer (EC) identified between 2016 and 2021 at the Juan Ramon Jimenez University Hospital, Huelva (Spain) was carried out. Tumor volume was measured in three ways. Analyses of Receiver Operating Characteristic (ROC) curve and the area under the curve (AUC) were performed. Although preoperative MRI had an 89.6% and 66.7% sensitivity for the detection of deep mucosal invasion and cervical stroma infiltration, preoperative assessment had an intraclass correlation coefficient of 0.517, underestimating tumor final stage in 12.6% of cases, with a poor agreement between preoperative MRI and postoperative staging (κ=0.082) and low sensitivity (14.3%) for serosa infiltration. The cut-off values for all three volume parameters had good/excellent AUC (0.73-0.85), with high sensitivity (70-83%) and specificity (64-84%) values for all histopathological variables. Excellent/good agreement was found all volume parameters for the identification of deep myometrial invasion (0.71), cervical stroma infiltration (0.80), serosa infiltration (0.81), and lymph node metastases (0.81). Tumor volume measurements have good predictive capacity to detect histopathological findings that affect final tumor staging and might play a crucial role in the preoperative assessment of patients with endometrial cancer in the future.

Automated 2-Dimensional Measurement of Vestibular Schwannoma: Validity and Accuracy of an Artificial Intelligence Algorithm.

Validation of automated 2-dimensional (2D) diameter measurements of vestibular schwannomas on magnetic resonance imaging (MRI). Retrospective validation study using 2 data sets containing MRIs of vestibular schwannoma patients. University Hospital in The Netherlands. Two data sets were used, 1 containing 1 scan per patient (n = 134) and the other containing at least 3 consecutive MRIs of 51 patients, all with contrast-enhanced T1 or high-resolution T2 sequences. 2D measurements of the maximal extrameatal diameters in the axial plane were automatically derived from a 3D-convolutional neural network compared to manual measurements by 2 human observers. Intra- and interobserver variabilities were calculated using the intraclass correlation coefficient (ICC), agreement on tumor progression using Cohen's kappa. The human intra- and interobserver variability showed a high correlation (ICC: 0.98-0.99) and limits of agreement of 1.7 to 2.1 mm. Comparing the automated to human measurements resulted in ICC of 0.98 (95% confidence interval [CI]: 0.974; 0.987) and 0.97 (95% CI: 0.968; 0.984), with limits of agreement of 2.2 and 2.1 mm for diameters parallel and perpendicular to the posterior side of the temporal bone, respectively. There was satisfactory agreement on tumor progression between automated measurements and human observers (Cohen's κ = 0.77), better than the agreement between the human observers (Cohen's κ = 0.74). Automated 2D diameter measurements and growth detection of vestibular schwannomas are at least as accurate as human 2D measurements. In clinical practice, measurements of the maximal extrameatal tumor (2D) diameters of vestibular schwannomas provide important complementary information to total tumor volume (3D) measurements. Combining both in an automated measurement algorithm facilitates clinical adoption.

Early MRI Predictors of Relapse in Primary Central Nervous System Lymphoma Treated with MATRix Immunochemotherapy.

Primary Central Nervous System Lymphoma (PCNSL) is a highly malignant brain tumour. We investigated dynamic changes in tumour volume and apparent diffusion coefficient (ADC) measurements for predicting outcome following treatment with MATRix chemotherapy in PCNSL. Patients treated with MATRix (n = 38) underwent T1 contrast-enhanced (T1CE) and diffusion-weighted imaging (DWI) before treatment, after two cycles and after four cycles of chemotherapy. Response was assessed using the International PCNSL Collaborative Group (IPCG) imaging criteria. ADC histogram parameters and T1CE tumour volumes were compared among response groups, using one-way ANOVA testing. Logistic regression was performed to examine those imaging parameters predictive of response. Response after two cycles of chemotherapy differed from response after four cycles; of the six patients with progressive disease (PD) after four cycles of treatment, two (33%) had demonstrated a partial response (PR) or complete response (CR) after two cycles. ADCmean at baseline, T1CE at baseline and T1CE percentage volume change differed between response groups (0.005 < p < 0.038) and were predictive of MATRix treatment response (area under the curve: 0.672-0.854). Baseline ADC and T1CE metrics are potential biomarkers for risk stratification of PCNSL patients early during remission induction therapy with MATRix. Standard interim response assessment (after two cycles) according to IPCG imaging criteria does not reliably predict early disease progression in the context of a conventional treatment approach.

Fractional calculus in mathematical oncology

Even though, nowadays, cancer is one of the leading causes of death, too little is known about the behavior of this disease due to its unpredictability from one patient to another. Classical mathematical models of tumor growth have shaped our understanding of cancer and have broad practical implications for treatment scheduling and dosage. However, improvements are still necessary on these models. The primary objective of the present research is to prove the efficiency of fractional order calculus in mathematical oncology, more specifically in tumor growth modeling. For this, a generalization of the four most used differential equation models in tumor volume measurements fitting is realized, using the corresponding fractional order equivalent. Are established the fractional order Exponential, Logistic, Gompertz, General Bertalanffy-Pütter and Classical Bertalanffy-Pütter models for a treated and untreated dataset. The obtained results are compared by Mean Squared Error (MSE) with the integer order correspondent of each model. The results prove the superiority of the fractional order models. The MSE of fractional order models are reduced at least at half in comparison with the MSE of the integer order equivalent. It is demonstrated in this way that fractional order deterministic models can offer a good starting point in finding a proper mathematical model for tumor evolution prediction. Fractional calculus is a suitable method in this case due to its memory property, aspect that particularly characterizes biological processes.

Salvia mitiorrhiza Bunge aqueous extract attenuates infiltration of tumor-associated macrophages and potentiates anti-PD-L1 immunotherapy in colorectal cancer through modulating Cox2/PGE2 cascade

Ethnopharmacological relevanceBased on the notion of traditional Chinese medicine, the theory of invigorating the circulation of blood is a prominent treatment for cancer in clinic. Therefore, Salvia miltiorrhiza Bunge, as a representative of Chinese medicine of invigorating the circulation of blood, has been proved to be an effective medicinal herb for treating cancer. Aim of the studyTo clarify the anti-cancer effect of Salvia miltiorrhiza Bunge aqueous extract (SMAE) on colorectal cancer (CRC) and investigate whether the therapeutic effect of SMAE was mediated by attenuating the infiltration of tumor-associated macrophages (TAMs) into the tumor microenvironment (TME). Materials and methodsHigh-performance liquid chromatography (HPLC) was used for determined the main compounds of SMAE. MC38 cells were subcutaneously injected into the mice to establish the mouse model of CRC. Tumor growth curve was detected by tumor volume measurement. The model group received distilled water irrigation once a day. SMAE-treated group received 5 g/kg or 10 g/kg SMAE once a day. Anti-PD-L1 treated group received 5 mg/kg anti-PD-L1 once every three days. Protein expression of Cox2 and PD-L1 was determined by Western blot assay. The secretion levels of PGE2, IL-1β, IL-6, MCP-1, and GM-CSF were evaluated through ELISA. The mRNA expression of CSF1, CCL2, CXCL1, CXCL2, and CXCL3 was measured by using RT-qPCR. Staining of Ki67, TUNEL and Caspase3 was used to investigate cell proliferation and apoptosis. Immunohistochemical staining was used to determine CD8+ T cell distribution. H&E staining was used to confirm histopathological changes. The expressions of F4/80 and CD68 were measured by flow cytometry to identify macrophages in tumors and lymph nodes. The number of CD8+ T cells and the expression of PD-1, IFN-γ, and Granzyme B (GZMB) were determined by flow cytometry. ResultsSMAE significantly retarded the growth of MC38 mouse colorectal cancer. SMAE strikingly inhibited the expression of Cox2 and impaired the secretion of PGE2 in tumors, contributing to the attenuated intra-tumoral infiltration of TAMs via Cox2/PGE2 cascade. Meanwhile, SMAE augmented anti-tumor immunity by the elevated proportion of IFN-γ+ CD8+ T cells and GZMB+ CD8+ T cells, which decreased the tumor load. Furthermore, the combination of SMAE and anti-PD-L1 showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in MC38 xenograft model. ConclusionsSMAE attenuated the infiltration of TAMs into tumors and synergized with anti-PD-L1 to treat CRC via modulating Cox2/PGE2 cascade.

Functional precision oncology for follicular lymphoma with patient‐derived xenograft in avian embryos

Introduction: Follicular lymphoma (FL) is an incurable type of B-cell malignancy that accounts for 25 percent of all lymphomas. Although most patients achieve remission with immuno-chemotherapy, almost all of them will experience multiple relapses after treatment. The prognosis is especially poor for around 20 percent of FL patients who relapse within two years after treatment initiation. The understanding of the heterogeneity of treatment responses is limited by the absence of in vitro or in vivo experimental models, mainly due to the strong dependence of tumor cells on their surrounding environment to survive. The aim of this project is to develop a primary FL cell xenograft model in chicken embryos to capture treatment response heterogeneity and analyze the mechanisms of response to immune-chemotherapy. Methods: The FL-AVI-PDXTM model was developed by transplanting primary FL cells into chicken embryos. We transplanted 20 biopsy samples, including good (n = 11) and poor clinical responders (POD24, n = 9), and treated each set of embryos with either RCHOP or vehicle intravenously. The effects of treatment were evaluated 24 hours later with tumor volume measurement by light-sheet microscopy and transcriptomic analysis at the single-cell level (scRNAseq). Results: All samples engrafted successfully in the aorto-gonado-mesonephros of chicken embryos. Tumor volume reduction achieved with RCHOP in the avian embryo was strongly correlated to patient's clinical outcome (mean tumor volume decreased by 35% in the good responders (n = 11) compared to an increase of 2% in the poor responders (n = 9), p < 0.05). Transcriptomic analysis of individual cells was conducted on 14 patients in three different conditions (before and after transplantation with RCHOP or vehicle treatment). We found a robust signature of 21 genes whose expression increased after exposure to RCHOP in all the patients. Among these genes was BAX, a key effector of the mitochondrial outer membrane permeabilization (MOMP), whose inactivation (by CRISPR-CAS9) conferred resistance to RCHOP in cell lines. Furthermore, venetoclax, a BCL2 inhibitor that lowers the threshold of BAX level required for MOMP, had synergistic effects with RCHOP in cell lines and primary samples in vivo, validating the findings in the model. Encore Abstract - previously submitted to regional or national meetings (up to <1’000 attendees) Encore Abstract - previously submitted to EHA 2023 Keywords: Indolent non-Hodgkin lymphoma, Patient-Derived Xenograft (PDX) Models, Tumor Biology and Heterogeneity Conflicts of interests pertinent to the abstract. C. Costechareyre Employment or leadership position: CC, is employed by Oncofactory SAS. VC and CB are co-founders of Oncofactory SAS. L. Jarrosson Employment or leadership position: LJ is employed by Oncofactory SAS. VC and CB are co-founders of Oncofactory SAS. R. Teinturier Employment or leadership position: RT is employed by Oncofactory SAS. VC and CB are co-founders of Oncofactory SAS. V. Castellani Employment or leadership position: VC is co-founders of Oncofactory SAS. C. Delloye-Bourgeois Employment or leadership position: CB is co-founders of Oncofactory SAS.

Association of biophysics-based biomarker with tumor volumetric response in breast cancer treated with immunotherapy.

608 Background: The treatment landscape of triple negative breast cancer (TNBC) has rapidly changed in recent years, with immuno-oncology (IO) therapies, such as immune checkpoint inhibitors, leading to improvement in patient outcomes. However, the number of patients who benefit is less than 15%, and the therapy itself can prompt severe immune-related adverse events. Breast cancer tumor volume measurements derived from magnetic resonance imaging (MRI) have proven to be a strong predictor of outcome (survival) in patients who either achieve pathological complete response (pCR) or have residual cancer burden (RCB) (ACRIN6657/CALGB150007 I-SPY1). Using an integrative computational approach, we developed both the TumorIO biomarker and the TumorIO Score to predict response to IO therapy in breast cancer patients. Here, we assess the volumetric response in IO-treated patients and its relationship with the TumorIO Score. Methods: We assessed the relationship between breast tumor volumetric response to IO therapy and the TumorIO Score, a previously developed metric that relates probability of IO responsiveness to spatially-resolved tumor biology. We grouped patients into TumorIO Score high vs. low populations, and compared final volumes assessed by MRI and percent response to therapy between groups. Results: We analyzed the volumetric response of IO-treated patients from the I-SPY2 trial and from an independent cohort (total n = 67). Over 96% of the IO-treated patients in the I-SPY2 trial (n = 55) had a greater than 90% volumetric response, while in the independent cohort (n = 12) only 50% of patients had greater than 90% volumetric response. Across both cohorts, 95.8% of patients with a high TumorIO Score achieved &gt; 90% reduction in tumor volume. Additionally, we identified three patients in our cohort that appeared not to respond to IO therapy, who were later classified as progressor, pseudo-progressor, and non-responder patients. The TumorIO biomarker was able to differentiate these three patients, as it associates a unique distinctive biological phenomenon with either response or lack of response. Conclusions: The TumorIO Score provides a novel technology to address several challenges in neoadjuvant IO therapy, namely: predicting which patients are likely to have pCR in response to IO therapy, as well as identifying patients likely to have a substantial volumetric response to IO. Additionally, this method may facilitate subcategorizing patients likely to show radiological pseudo-progression prior to IO administration, although a larger cohort is needed to validate these findings.

Circular RNA-AnnexinA7 accelerates cisplatin resistance in non-small cell lung cancer via modulating microRNA-545-3p to mediate Cyclin D1

Objective: To explore the mechanism of circular RNA (circRNA)-AnnexinA7 (ANXA7) in non-small cell lung cancer (NSCLC) cisplatin (DDP) resistance through microRNA (miR)-545-3p to target Cyclin D1 (CCND1). Methods: DDP-resistant and non-resistant NSCLC tissues and normal tissues were collected. DDP-resistant cells (A549/DDP and H460/DDP) were constructed. circ-ANXA7, miR-545-3p, CCND1, P-Glycoprotein, and glutathione S-transferase-π in tissues and cells were measured. Analysis of circ-ANXA7 ring structure was performed, as well as detection of circ-ANXA7 distribution in cells. Cell proliferation was detected by MTT and colony formation assay, apoptosis rate was detected by flow cytometry, and cell migration and invasion were evaluated by Transwell assay. The targeting relationship between circ-ANXA7, miR-545-3p and CCND1 was verified. Measurement of tumor volume and quality in mice was performed. Results: Circ-ANXA7 and CCND1 were elevated, while miR-545-3p was suppressed in DDP-resistant NSCLC tissues and cells. Circ-ANXA7 combined with miR-545-3p, which targeted CCND1 to expedite A549/DDP cell proliferation, migration, invasion, DDP resistance, but inhibited cell apoptosis. Conclusion: Circ-ANXA7 enhances DDP resistance in NSCLC via absorbing miR-545-3p to target CCND1 and might be a latent therapeutic target for NSCLC.

An in-vivo study of the combined therapeutic effects of pulsed non-thermal focused ultrasound and radiation for prostate cancer

Purpose The purpose of this study was to investigate the in vivo combined effects of pulsed focused ultrasound (pFUS) and radiation (RT) for prostate cancer treatment. Materials and Methods An animal prostate tumor model was developed by implanting human LNCaP tumor cells in the prostates of nude mice. Tumor-bearing mice were treated with pFUS, RT or both (pFUS + RT) and compared with a control group. Non-thermal pFUS treatment was delivered by keeping the body temperature below 42 °C as measured real-time by MR thermometry and using a pFUS protocol (1 MHz, 25 W focused ultrasound; 1 Hz pulse rate with a 10% duty cycle for 60 sec for each sonication). Each tumor was covered entirely using 4–8 sonication spots. RT treatment with a dose of 2 Gy was delivered using an external beam (6 MV photon energy with dose rate 300MU/min). Following the treatment, mice were scanned weekly with MRI for tumor volume measurement. Results The results showed that the tumor volume in the control group increased exponentially to 142 ± 6%, 205 ± 12%, 286 ± 22% and 410 ± 33% at 1, 2, 3 and 4 weeks after treatment, respectively. In contrast, the pFUS group was 29% (p < 0.05), 24% (p < 0.05), 8% and 9% smaller, the RT group was 7%, 10%, 12% and 18% smaller, and the pFUS + RT group was 32%, 39%, 41% and 44% (all with p < 0.05) smaller than the control group at 1, 2, 3, and 4 weeks post treatment, respectively. Tumors treated by pFUS showed an early response (i.e. the first 2 weeks), while the RT group showed a late response. The combined pFUS + RT treatment showed consistent response throughout the post-treatment weeks. Conclusions These results suggest that RT combined with non-thermal pFUS can significantly delay the tumor growth. The mechanism of tumor cell killing between pFUS and RT may be different. Pulsed FUS shows early tumor growth delay, while RT contributes to the late effect on tumor growth delay. The addition of pFUS to RT significantly enhanced the therapeutic effect for prostate cancer treatment.

Intravesical Contrast-Enhanced MRI: A Potential Tool for Bladder Cancer Surveillance and Staging.

This review article gives an overview of the current state of the art of bladder cancer imaging and then discusses in depth the scientific and technical merit of a novel imaging approach, tracing its evolution from murine cancer models to cancer patients. While the poor resolution of soft tissue obtained by widely available imaging options such as abdominal sonography and radiation-based CT leaves them only suitable for measuring the gross tumor volume and bladder wall thickening, dynamic contrast-enhanced magnetic resolution imaging (DCE MRI) is demonstrably superior in resolving muscle invasion. However, major barriers still exist in its adoption. Instead of injection for DCE-MRI, intravesical contrast-enhanced MRI (ICE-MRI) instills Gadolinium chelate (Gadobutrol) together with trace amounts of superparamagnetic agents for measurement of tumor volume, depth, and aggressiveness. ICE-MRI leverages leaky tight junctions to accelerate passive paracellular diffusion of Gadobutrol (604.71 Daltons) by treading the paracellular ingress pathway of fluorescein sodium and of mitomycin (<400 Daltons) into bladder tumor. The soaring cost of diagnosis and care of bladder cancer could be mitigated by reducing the use of expensive operating room resources with a potential non-surgical imaging option for cancer surveillance, thereby reducing over-diagnosis and over-treatment and increasing organ preservation.

Abstract 5045: NTSR1-targeted alpha therapeutic [Ac-225]-FPI-2059 induces growth inhibition in a preclinical colorectal tumor model

Abstract Background: Neurotensin receptor 1 (NTSR1) is overexpressed in multiple cancer indications that include pancreatic, colorectal and prostate cancers, all of which have limited therapeutic treatment options and unmet medical need. Fusion is developing novel targeted alpha therapeutics (TATs) that enable the specific delivery of high energy alpha particles (actinium-225; [225Ac]) to tumor cells while sparing surrounding normal tissues. The alpha radiation released by TATs causes cell damage through the induction of multiple double-stranded DNA breaks leading to tumor cell death. Here, we describe the therapeutic efficacy of an [225Ac]-conjugated, NTSR1 targeting small molecule in a colorectal cancer tumor model. Materials and Methods: CT26 colorectal cancer cells overexpressing murine NTSR1 (mNTSR1) were generated by lentiviral transduction. Selected cells were evaluated for stable mNTSR1 expression by an in vitro radioligand binding assay and subsequently implanted subcutaneously into Balb/c mice for in vivo evaluations. FPI-2056 (parent compound) was radiolabeled with either lutetium-177 ([177Lu]-FPI-2057) or actinium-225 ([225Ac]-FPI-2059). Biodistribution assessment studies were conducted in mice bearing CT26-mNTSR1 tumors dosed intravenously with [177Lu]-FPI-2057. Therapeutic efficacy studies were conducted by intravenous administration of single doses of 0.185 - 5.55 MBq/kg of [225Ac]-FPI-2059 (0.1-3 µCi) to animals bearing CT26-mNTSR1 tumors, followed by tumor growth monitoring for 50 days. Study endpoints included tumor volume measurements and impact on animal health status. Results: Evaluation of [177Lu]-FPI-2057 biodistribution and excretion revealed rapid renal clearance via urine with a clearance from the blood by 24 h. Uptake of [177Lu]-FPI-2057 was detected in the CT26-mNTSR1 tumors with a maximum concentration of 7.0 %ID/g at 6 h post-injection, dropping to 4.6 and 2.8 %ID/g at 24 and 48 h post-injection, with 20-fold higher uptake in the tumor vs. blood levels at both 24 and 48h time points. Therapeutic administration of a single dose of [225Ac]-FPI-2059 resulted in dose-dependent tumor growth inhibition at doses above 1.85 MBq/kg of [225Ac]-FPI-2059 (1 μCi), which translated into increased survival compared to control animals. Conclusion: These results demonstrate that targeted delivery of [225Ac]-FPI-2059 to NTSR1 expressing tumors results in significant growth inhibition and enhanced survival, thereby providing promising preclinical evidence to support the clinical development of [225Ac]-FPI-2059. Citation Format: Saleemulla Mahammad, Jaline Broqueza, Brigitte L. Theriault, John Forbes, Christopher P. Leamon, John Valliant. NTSR1-targeted alpha therapeutic [Ac-225]-FPI-2059 induces growth inhibition in a preclinical colorectal tumor model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5045.

Abstract 1100: 4-1BBL agonist targeted to fibroblast activation protein α synergizes with radiotherapy in murine breast tumor

Abstract Background. Ionizing radiation (IR) is a double-edge sword for immunotherapy as it may cause both immunosuppressive and immunostimulatory effects. The interactions of IR with the tumor microenvironment (TME) is a key factor for this balance. Fibroblast activation protein (FAP) is expressed on the surface of CAFs in many cancer types and its presence is associated with poor immune response to immune checkpoint blockade in patients. We hypothesize that IR increases FAP expression in CAFs, therefore the combination of IR with targeted immunomodulators such as an agonistic FAP-41BBL bispecific antibody-like fusion protein could enhance the immune-mediated antitumoral effect of these treatments given in combination. Methods: Murine transplantable tumor cells lines (TSA and MC38) were used to investigate increases in FAP expression on CAFs in tumors under irradiation using IHQ and qPCR. Established orthotopic transplanted models were used. We treated bilateral tumor-bearing mice in which only one of the lesions was locally irradiated (2×6Gy) given alone or in combination with a systemic administration of the FAP-41BBL agonistic bispecific construct. Tumor sizes were followed over time and in the cellular composition microenvironment (TME) was assessed by immunochemistry and multiplex tissue immunofluorescence. Selective depletions of immune cell populations were used to delineate the immune system requirements for efficacy.We measured the changes in FAP expression following radiotherapy in engrafted syngeneic TSA and MC38 models using immunohistochemistry (IHC) and qPCR. TSA cells and CAFs were coinjected orthotopically creating bilateral tumor-bearing models, which were irradiated (2x6Gy) only inone of the lesions, either as a single treatment intervention or in combination with systemic administrations of FAP-41BBL. Treatment efficacy was evaluated measuring tumor volume and changes in the TME. Anti -D8 and a neutralizing anti-type-I IFN mAbs were used to define requirements for the efficacy of the radioimmunotherapy combination. Results. Irradiation of TSA-breast cancer tumors showed clear increases of FAP expression levels after local irradiation. The suboptimal radiotherapy regimen chosen failed to control TSA-derived tumors in in which TSA-breast cancer cells had been co-engrafted with CAF. The combination of irradiation and FAP-41BBL resulted in more prominent increases of FAP expression after local irradiation and, importantly, induced durable complete responses in more than 50% of the mice treated with the combination. A role in the therapeutic effect for CD8+ T cells and type-I IFN was uncovered. Robust immune memory was observed in re-challenge experiments. Conclusion. Our data provides a proof-of-concept and mechanistic insights pertaining the therapeutic efficacy of the bispecific FAP-41BBL fusion protein combined with local radiotherapy. Citation Format: Eneko Garate-Soraluze, Irantzu Serrano-Mendioroz, Carlos E de Andrea, Toni Rullan, Christina Claus, Pablo Umana, Christian klein, Ignacio Melero, Maria E. Rodriguez-Ruiz. 4-1BBL agonist targeted to fibroblast activation protein α synergizes with radiotherapy in murine breast tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1100.

The Impact of an Electromagnetic Seed Localization Device Versus Wire Localization on Breast-Conserving Surgery: A Matched-Pair Analysis.

For breast-conserving surgery (BCS), several alternatives to wire localization (WL) have been developed. The newest, electromagnetic seed localization (ESL), provides three-dimensional navigation using the electrosurgical tool. This study assessed operative times, specimen volumes, margin positivity, and re-excision rates for ESL and WL. Patients who had ESL-guided breast-conserving surgery between August 2020 and August 2021 were reviewed and matched one-to-one with patients who had WL based on surgeon, procedure type, and pathology. Variables were compared between ESL and WL using Wilcoxon rank-sum and Fisher's exact tests. The study matched 97 patients who underwent excisional biopsy (n = 20) or partial mastectomy with (n = 53) or without (n = 24) sentinel lymph node biopsy (SLNB) using ESL. The median operative time for ESL versus WL for lumpectomy was 66 versus 69 min with SLNB (p = 0.76) and 40 versus 34.5 min without SLNB (p = 0.17). The median specimen volume was 36 cm3 using ESL versus 55 cm3 using WL (p = 0.001). For the patients with measurable tumor volume, excess tissue was greater using WL versus ESL (median, 73.2 vs. 52.5 cm3; p = 0.017). The margins were positive for 10 (10 %) of the 97 ESL patients and 18 (19 %) of the 97 WL patients (p = 0.17). In the ESL group, 6 (6 %) of the 97 patients had a subsequent re-excision compared with 13 (13 %) of the 97 WL patients (p = 0.15). Despite similar operative times, ESL is superior to WL, as evidenced by decreased specimen volume and excess tissue excised. Although the difference was not statistically significant, ESL resulted in fewer positive margins and re-excisions than WL. Further studies are needed to confirm that ESL is the most advantageous of the two methods.

Radiologic versus Segmentation Measurements to Quantify Wilms Tumor Volume on MRI in Pediatric Patients.

Wilms tumor is a common pediatric solid tumor. To evaluate tumor response to chemotherapy and decide whether nephron-sparing surgery is possible, tumor volume measurements based on magnetic resonance imaging (MRI) are important. Currently, radiological volume measurements are based on measuring tumor dimensions in three directions. Manual segmentation-based volume measurements might be more accurate, but this process is time-consuming and user-dependent. The aim of this study was to investigate whether manual segmentation-based volume measurements are more accurate and to explore whether these segmentations can be automated using deep learning. We included the MRI images of 45 Wilms tumor patients (age 0-18 years). First, we compared radiological tumor volumes with manual segmentation-based tumor volume measurements. Next, we created an automated segmentation method by training a nnU-Net in a five-fold cross-validation. Segmentation quality was validated by comparing the automated segmentation with the manually created ground truth segmentations, using Dice scores and the 95th percentile of the Hausdorff distances (HD95). On average, manual tumor segmentations result in larger tumor volumes. For automated segmentation, the median dice was 0.90. The median HD95 was 7.2 mm. We showed that radiological volume measurements underestimated tumor volume by about 10% when compared to manual segmentation-based volume measurements. Deep learning can potentially be used to replace manual segmentation to benefit from accurate volume measurements without time and observer constraints.

Spatiotemporally confined assembly of radiosensitizers for synergistic radio-chemodynamic therapy on deep tumor of rabbit

The controllable assembly of nanoparticles significantly improves their biological effects in vivo. However, it is difficult to realize the assembly regulation of nanomaterials under complex physiological conditions. Herein, endogenous glutathione (GSH)-triggered vesicles with spatiotemporally confined aggregation of gold nanogapped nanoparticles (AuNNPs) within vesicles were developed. These vesicles had excellent photoacoustic (PA) imaging capability in the near-infrared second window (NIR-II) for precise localization of deep tumors, measuring tumor volume, and making deep tumors more sensitive to radiotherapy and chemodynamic therapy (CDT). The vesicles were prepared via self-assembly of MnO2-coated AuNNPs that were functionalized by phosphate-polystyrene and bovine serum albumin (AuNNP@MnO2 Ve@BSA). The MnO2 shell was etched when AuNNP@MnO2 Ve@BSA vesicle was exposed to GSH, the gap between intra-vesicular AuNNP@MnO2 NPs was reduced. This significantly enhanced the plasmonic coupling effect between AuNNP@MnO2 NPs, giving it excellent NIR-II PA imaging capability, and thus can be used to delineate the boundary and volume of deep-seated tumors. Meanwhile, the Mn2+-mediated CDT released after the etching of the MnO2 shell interacted with GSH-responsive AuNNP@MnO2 Ve@BSA and significantly inhibited tumor growth due to enhanced radiosensitization effect. This unique strategy provides new perspectives and methods for designing and applying biomedical nanomaterials.

Thiram, an inhibitor of 11ß-hydroxysteroid dehydrogenase type 2, enhances the inhibitory effects of hydrocortisone in the treatment of osteosarcoma through Wnt/β-catenin pathway

BackgroundThe anti-osteosarcoma effects of hydrocortisone and thiram, an inhibitor of type 2 11ß-hydroxysteroid dehydrogenase (11HSD2), have not been reported. The purpose of this study was to investigate the effects of hydrocortisone alone or the combination of hydrocortisone with thiram on osteosarcoma and the molecular mechanism, and determine whether they can be as new therapeutic agents for osteosarcoma.MethodsNormal bone cells and osteosarcoma cells were treated with hydrocortisone or thiram alone or in combination. The cell proliferation, migration, cell cycle and apoptosis were detected by using CCK8 assay, wound healing assay, and flow cytometry, respectively. An osteosarcoma mouse model was established. The effect of drugs on osteosarcoma in vivo was assessed by measuring tumor volume. Transcriptome sequencing, bioinformatics analysis, RT–qPCR, Western blotting (WB), enzymelinked immunosorbent assay (ELISA) and siRNA transfection were performed to determine the molecular mechanisms.ResultsHydrocortisone inhibited the proliferation and migration, and induced apoptosis and cell cycle arrest of osteosarcoma cells in vitro. Hydrocortisone also reduced the volume of osteosarcoma in mice in vivo. Mechanistically, hydrocortisone decreased the levels of Wnt/β-catenin pathway-associated proteins, and induced the expression of glucocorticoid receptor α (GCR), CCAAT enhancer-binding protein β (C/EBP-beta) and 11HSD2, resulting in a hydrocortisone resistance loop. Thiram inhibited the activity of the 11HSD2 enzyme, the combination of thiram and hydrocortisone further enhanced the inhibition of osteosarcoma through Wnt/β-catenin pathway.ConclusionsHydrocortisone inhibits osteosarcoma through the Wnt/β-catenin pathway. Thiram inhibits 11HSD2 enzyme activity, reducing hydrocortisone inactivation and promoting the effect of hydrocortisone through the same pathway.

Survivin (BIRC5) Peptide Vaccine in the 4T1 Murine Mammary Tumor Model: A Potential Neoadjuvant T Cell Immunotherapy for Triple Negative Breast Cancer: A Preliminary Study

A triple negative breast cancer model using the murine 4T1 tumor cell line was used to explore the efficacy of an adjuvanted survivin peptide microparticle vaccine using tumor growth as the outcome metric. We first performed tumor cell dose titration studies to determine a tumor cell dose that resulted in sufficient tumor takes but allowed multiple serial measurements of tumor volumes, yet with minimal morbidity/mortality within the study period. Later, in a second cohort of mice, the survivin peptide microparticle vaccine was administered via intraperitoneal injection at the study start with a second dose given 14 days later. An orthotopic injection of 4T1 cells into the mammary tissue was performed on the same day as the administration of the second vaccine dose. The mice were followed for up to 41 days with subcutaneous measurements of tumor volume made every 3-4 days. Vaccination with survivin peptides was associated with a peptide antigen-specific gamma interferon enzyme-linked immunosorbent spot response in the murine splenocyte population but was absent from the control microparticle group. At the end of the study, we found that vaccination with adjuvanted survivin peptide microparticles resulted in statistically significant slower primary tumor growth rates in BALB/c mice challenged with 4T1 cells relative to the control peptideless vaccination group. These studies suggest that T cell immunotherapy specifically targeting survivin might be an applicable neoadjuvant immunotherapy therapy for triple negative breast cancer. More preclinical studies and clinical trials are needed to explore this concept further.