Fluoromisonidazole Positron Emission Tomography Research Articles

Assessment of tumor hypoxia in spontaneous canine tumors after treatment with OMX, a novel H-NOX oxygen carrier, with [18F]FMISO PET/CT

BackgroundHypoxia is a detrimental factor in solid tumors, leading to aggressiveness and therapy resistance. OMX, a tunable oxygen carrier from the heme nitric oxide/oxygen-binding (H-NOX) protein family, has the potential to reduce tumor hypoxia. [18F]Fluoromisonidazole ([18F]FMISO) positron emission tomography (PET) is the most widely used and investigated method for non-invasive imaging of tumor hypoxia. In this study, we used [18F]FMISO PET/CT (computed tomography) to assess the effect of OMX on tumor hypoxia in spontaneous canine tumors.ResultsThirteen canine patients with various tumors (n = 14) were randomly divided into blocks of two, with the treatment groups alternating between receiving intratumoral (IT) OMX injection (OMX IT group) and intravenous (IV) OMX injection (OMX IV group). Tumors were regarded as hypoxic if maximum tumor-to-muscle ratio (TMRmax) was greater than 1.4. In addition, hypoxic volume (HV) was defined as the region with tumor-to-muscle ratio greater than 1.4 on [18F]FMISO PET images. Hypoxia was detected in 6/7 tumors in the OMX IT group and 5/7 tumors in the OMX IV injection group. Although there was no significant difference in baseline hypoxia between the OMX IT and IV groups, the two groups showed different responses to OMX. In the OMX IV group, hypoxic tumors (n = 5) exhibited significant reductions in tumor hypoxia, as indicated by decreased TMRmax and HV in [18F]FMISO PET imaging after treatment. In contrast, hypoxic tumors in the OMX IT group (n = 6) displayed a significant increase in [18F]FMISO uptake and variable changes in TMRmax and HV.Conclusions[18F]FMISO PET/CT imaging presents a promising non-invasive procedure for monitoring tumor hypoxia and assessing the efficacy of hypoxia-modulating therapies in canine patients. OMX has shown promising outcomes in reducing tumor hypoxia, especially when administered intravenously, as evident from reductions in both TMRmax and HV in [18F]FMISO PET imaging.

NIMG-33. [18F]-FLUOROMISONIDAZOLE RELATIVE PET INFLUX RATE IMPROVES DIAGNOSTIC ACCURACY FOR GLIOBLASTOMA PROGRESSION FROM THERAPY-INDUCED NEUROINFLAMMATORY PSEUDOPROGRESSION

Abstract Glioblastoma is the most common and aggressive form of primary brain tumor in adults. Standard of care gadolinium-enhanced MRI (Gd-MRI) fails to capture hypoxia, a disease-defining feature of glioblastoma. Hypoxia potentiates resistance to chemo-radiation therapy (CRT) but is not extensively observed with therapy-induced pseudoprogression (PSP). This neuroinflammatory response to CRT occurs in approximately 40% of patients and is indistinguishable from disease progression by Gd-MRI, potentially causing unnecessary termination of effective therapy in patients with PSP. Additionally, delayed second line-therapy can occur in patients with resistance to CRT. This research evaluated whether [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET), a noninvasive metric of tissue hypoxia, improves diagnostic accuracy in this context. Clinically, PET quantification employs the standardized uptake value (SUV), representing summed counts over an acquisition period. To add accuracy to this assessment, static 40-minute PET data acquired starting 90 minutes after FMISO injection was reconstructed into 20x2-minute frames and a relative Patlak model was applied. This technique forgoes blood sampling and extensive examination times required by traditional dynamic PET studies. The model produces two parameters that separately characterize the FMISO relative influx rate (Ki') and blood volume (VB'). In a cohort of 16 patients (3 IDH-mutated) imaged at a time of presumed disease progression, results showed that Ki' within the Gd-MRI enhancing lesion predicts future diagnosis of true progression (n = 11) or inflammation (n =5 ) with a sensitivity and specificity of 91% and 80% respectively. This outperforms diagnosis made with Gd-MRI alone, achieving ~70% for the same metrics. A t-test assuming unequal variance of cohort-wide mean Ki' tended toward significance (p = 0.07) for differentiating progressive disease (0.0036 ± 0.0016 min-1) from PSP (0.0011 ± 0.0017 min-1). RESULTS: from this study suggest relative Patlak analysis adds specificity to Gd-MRI and provides clinically relevant information regarding disease status.

Predicting response to combination evofosfamide and immunotherapy under hypoxic conditions in murine models of colon cancer.

The goal of this study is to develop a mathematical model that captures the interaction between evofosfamide, immunotherapy, and the hypoxic landscape of the tumor in the treatment of tumors. Recently, we showed that evofosfamide, a hypoxia-activated prodrug, can synergistically improve treatment outcomes when combined with immunotherapy, while evofosfamide alone showed no effects in an in vivo syngeneic model of colorectal cancer. However, the mechanisms behind the interaction between the tumor microenvironment in the context of oxygenation (hypoxic, normoxic), immunotherapy, and tumor cells are not fully understood. To begin to understand this issue, we develop a system of ordinary differential equations to simulate the growth and decline of tumors and their vascularization (oxygenation) in response to treatment with evofosfamide and immunotherapy (6 combinations of scenarios). The model is calibrated to data from in vivo experiments on mice implanted with colon adenocarcinoma cells and longitudinally imaged with [18F]-fluoromisonidazole ([18F]FMISO) positron emission tomography (PET) to quantify hypoxia. The results show that evofosfamide is able to rescue the immune response and sensitize hypoxic tumors to immunotherapy. In the hypoxic scenario, evofosfamide reduces tumor burden by $ 45.07 \pm 2.55 $%, compared to immunotherapy alone, as measured by tumor volume. The model accurately predicts the temporal evolution of five different treatment scenarios, including control, hypoxic tumors that received immunotherapy, normoxic tumors that received immunotherapy, evofosfamide alone, and hypoxic tumors that received combination immunotherapy and evofosfamide. The average concordance correlation coefficient (CCC) between predicted and observed tumor volume is $ 0.86 \pm 0.05 $. Interestingly, the model values to fit those five treatment arms was unable to accurately predict the response of normoxic tumors to combination evofosfamide and immunotherapy (CCC = $ -0.064 \pm 0.003 $). However, guided by the sensitivity analysis to rank the most influential parameters on the tumor volume, we found that increasing the tumor death rate due to immunotherapy by a factor of $ 18.6 \pm 9.3 $ increases CCC of $ 0.981 \pm 0.001 $. To the best of our knowledge, this is the first study to mathematically predict and describe the increased efficacy of immunotherapy following evofosfamide.

Abstract 3990: Imaging molecular alterations during tucatinib response in preclinical models of HER2+ breast cancer

Abstract Introduction: Human epidermal growth factor receptor 2 (HER2) is overexpressed in 25% of breast cancers. Tucatinib, a small molecule HER2 inhibitor, was FDA approved for inoperable or metastatic HER2+ breast cancer. As many of these patients have inoperable tumors, there is a need to identify imaging metrics that can characterize response to tucatinib. Positron emission tomography (PET) imaging can quantify changes in the tumor microenvironment that precede changes in tumor size through imaging with radiopharmaceuticals that target proliferation (fluorothymidine, [18F]-FLT), hypoxia (fluoromisonidazole, [18F]-FMISO) and HER2 expression ([89Zr]-Pertuzumab). The goal of this study is to use advanced PET imaging to non-invasively monitor response to tucatinib in HER2+ primary breast cancer and quantify the subsequent tumor microenvironment modulation. Methods: HER2+ cell line (BT474) and patient derived xenograft (BCM 3472) tumor models were engrafted and developed to 270 ± 166.4 mm3 before being enrolled into experiments. Mice were treated with 50 mg/kg tucatinib via PO and were imaged with [18F]-FLT PET (N = 8) on days 0, 3 and 7, [18F]-FMISO PET (N = 6) on days 0, 3 and 7, or [89Zr]-Pertuzumab PET (N = 5) on days 0 and 14. Intratumoral proliferation, hypoxia and HER2 expression were quantified with standardized uptake value (SUV). Following the final imaging timepoint, tumors were excised for immunohistochemistry against Ki-67 (proliferation), pimonidazole (hypoxia), and HER2. A non-parametric T-test was used to assess for significance. Results: Tucatinib treated BT474 and BCM3472 tumors had a 2.07 and 2.63 fold decrease in tumor volume, respectively (p<0.01). Tucatinib treated BT474 and BCM3472 tumors had significantly decreased hypoxia and proliferation, relative to control tumors (p<0.05). Tucatinib treated BT474 tumors had significantly decreased HER2 expression (p<0.05); however, no significant change in HER2 expression was observed in tucatinib treated BCM3472 tumors. Conclusion: Tucatinib significantly decreases tumor volume and decreases intratumoral proliferation and hypoxia in both cell-line and patient-derived xenograft models of HER2+ breast cancer. Our data suggests molecular imaging may drive understanding of and predict response to tucatinib therapy. Acknowledgements: Tucatinib was provided by Seagen Inc. Bothell, Washington, USA. Citation Format: Patrick Song, Ameer Mansur, Anna Sorace. Imaging molecular alterations during tucatinib response in preclinical models of HER2+ breast cancer. [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 3990.

Visualization of tumor hypoxia and re-oxygenation after stereotactic body radiation therapy in early peripheral lung cancer: A prospective study

Background and purposeIn this study, fluoromisonidazole positron emission tomography (F-MISO PET/CT) was used to evaluate tumor hypoxia and re-oxygenation in patients with lung tumors treated with stereotactic body radiation therapy (SBRT). Materials and methodsPatients with T1-2 N0 lung cancer were included in this study. The prescribed dose was 48–52 Gy in four fractions. F-MISO PET/CT was performed twice, before SBRT and 1–3 days after the first irradiation. The maximum standardized uptake value (SUVmax) and tumor/muscle ratio (TMR) were evaluated as indicators of hypoxia. The threshold for hypoxia was defined as a TMR of 1.30 or more. ResultsBetween 2016 and 2021, 15 patients were included. Pre-treatment tumor hypoxia was observed in nine tumors (60 %). TMR in all six tumors without pre-treatment hypoxia rose after single high-dose irradiation. In contrast, TMR in six of nine tumors with pre-treatment hypoxia dropped after irradiation, suggesting re-oxygenation. Although no local recurrence was noted, regional and/or distant relapses were seen in four patients (27 %). Of these, three had tumors with abnormal F-MISO uptake. The remaining patient had a tumor without signs of hypoxia on pre-treatment PET/CT. The 2-year progression free survival of patients with tumors with and without pre-treatment hypoxia were 30 % and 63 %, respectively (p = 0.319). ConclusionTumor hypoxia reduced after single high-dose irradiation. Tumor with F-MISO uptake seems to be an unfavorable prognostic factor in lung SBRT.

Molecular Imaging of Oxygenation Changes during Immunotherapy in Combination with Paclitaxel in Triple Negative Breast Cancer.

Hypoxia is a common feature of the tumor microenvironment, including that of triple-negative breast cancer (TNBC), an aggressive breast cancer subtype with a high five-year mortality rate. Using [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) imaging, we aimed to monitor changes in response to immunotherapy (IMT) with chemotherapy in TNBC. TNBC-tumor-bearing mice received paclitaxel (PTX) ± immune checkpoint inhibitors anti-programmed death 1 and anti-cytotoxic T-lymphocyte 4. FMISO-PET imaging was performed on treatment days 0, 6, and 12. Max and mean standard uptake values (SUVmax and SUVmean, respectively), histological analyses, and flow cytometry results were compared. FMISO-PET imaging revealed differences in tumor biology between treatment groups prior to tumor volume changes. 4T1 responders showed SUVmean 1.6-fold lower (p = 0.02) and 1.8-fold lower (p = 0.02) than non-responders on days 6 and 12, respectively. E0771 responders showed SUVmean 3.6-fold lower (p = 0.001) and 2.7-fold lower (p = 0.03) than non-responders on days 6 and 12, respectively. Immunohistochemical analyses revealed IMT plus PTX decreased hypoxia and proliferation and increased vascularity compared to control. Combination IMT/PTX recovered the loss of CD4+ T-cells observed with single-agent therapies. PET imaging can provide timely, longitudinal data on the TNBC tumor microenvironment, specifically intratumoral hypoxia, predicting therapeutic response to IMT plus chemotherapy.

Magnetic resonance imaging of hypoxia in acute stroke compared with fluorine-18 fluoromisonidazole-positronemissiontomography:Across-validationstudy?

Acute ischemic stroke results in an ischemic core surrounded by a tissue at risk, named the penumbra, which is potentially salvageable. One way to differentiate the tissues is to measure the hypoxia status. The purpose of the current study is to correlate the abnormal brain tissue volume derived from magnetic resonance-based imaging of brain oxygen saturation (St O2 -MRI) to the fluorine-18 fluoromisonidazole ([18 F]FMISO) positron emission tomography (PET) volume for hypoxia imaging validation, and to analyze the ability of St O2 -MRI to depict the different hypoxic tissue types in the acute phase of stroke. In a pertinent model of stroke in the rat, the volume of tissue with decreased St O2 -MRI signal and that with increased uptake of [18 F]FMISO were equivalent and correlated (r = 0.706; p = 0.015). The values of St O2 in the tissue at risk were significantly greater than those quantified in the core of the lesion, and were less than those for healthy tissue (52.3% ± 2.0%; 43.3% ± 1.9%, and 67.9 ± 1.4%, respectively). A threshold value for St O2 of ≈60% as the cut-off for the identification of the tissue at risk was calculated. Tissue volumes with reduced St O2 -MRI correlated with the final lesion (r = 0.964, p < 0.0001). The findings show that the St O2 -MRI approach is sensitive for the detection of hypoxia and for the prediction of the final lesion after stroke. Once validated in acute clinical settings, this approach might be used to enhance the stratification of patients for potential therapeutic interventions.

Tumor Volume Predicts for Baseline Hypoxia Status in HPV Related Oropharyngeal Carcinomas (OPC) that Underwent Major Radiation De-escalation: The 30 Reduction in Oropharyngeal Cancer Trial

<h3>Purpose/Objective(s)</h3> The 30 ROC Trial utilizes functional imaging, specifically pre-treatment (Tx) and intra-Tx fluorine-18-labeled fluoromisonidazole positron emission tomography (18F-FMISO PET) to select appropriate human papillomavirus positive (HPV+) OPC patients for major de-escalation to 30 Gy. In this trial, patients also underwent pre-Tx and weekly multiparametric magnetic resonance imaging (MRI) scans to correlate with hypoxia status. The aim of the present study was to assess the value of MRI tumor volume to predict baseline hypoxia status in HPV+OPC patients who underwent major dose de-escalation. <h3>Materials/Methods</h3> A total (N = 158) patients with cT0-2,N1-2b (AJCC 7^th ed.) p16+ OPC were enrolled. All patients had pre-Tx 18F-FMISO PET scans to assess baseline hypoxia status, and only those with baseline hypoxia underwent a repeat intra-Tx scan. Pre-Tx and weekly intra-Tx MRI scans were acquired on technology company's 3T MRI scanner using a neurovascular phased array coil. Radiation oncologists delineated gross nodal disease as regions of interest on T₂w images. Tumor volume (cm³) was calculated in ITK SNAP for each patient using the segmentation software. All standard statistical analyses were performed on RStudio 2021.09.2. <h3>Results</h3> Of the 158 patients, N=95 patients had analyzable pre-Tx and weekly on-Tx MRI scans. Based on pre-Tx 18F-FMISO PET results, increased tumor volume was associated with baseline nodal hypoxia (N=69, median 18.55 cm³, range: 3.15- 60.62) compared to initially non-hypoxic tumors (N= 26, median 6.44 cm³, range: 0.48 – 47.74, p<0.001). After the intra-Tx 18F-FMISO PET result, patients were further stratified into converted negative (N= 57), persistently hypoxic (N=12), and never hypoxic (N=26). We found that the median pre-Tx nodal volume for the persistently hypoxic (median 17.75 cm³, range 5.54- 42.93, p=0.006) and converted negative (median 18.55 cm³, range 3.15 – 60.62, p<0.001) groups was significantly (P= <0.05) increased compared to the initially hypoxia negative patients (6.44 cm³, range 0.48 – 47.74). We performed further assessment of this pattern with intra-Tx MRIs (weeks 1-4) and found that this correlation of groups with baseline hypoxia (converted negative and persistently hypoxic) continued to exhibit larger nodal volume compared to the never hypoxic group. <h3>Conclusion</h3> Pre-Tx nodal volume on MRI correlates with pre-Tx hypoxia status where the larger the volume, the higher the likelihood of hypoxia. This correlation continued throughout radiation Tx as evidenced by the weekly MRI scans.

18F-FMISO PET/CT detects hypoxic lesions of cardiac and extra-cardiac involvement in patients with sarcoidosis

Background18F-fluoromisonidazole (FMISO) is a hypoxia positron emission tomography (PET) tracer. Here, we evaluated cardiac and extra-cardiac sarcoidosis using both FMISO and 18F-fluorodeoxyglucose (FDG) PET/CT in a prospective cohort of patients with sarcoidosis. MethodsTen consecutive sarcoidosis patients with suspected cardiac involvement were prospectively enrolled. Each patient fasted overnight (for ≥ 18 hours) preceded by a low-carbohydrate diet before FDG PET/CT but not given special dietary instructions before the FMISO PET/CT scan. We visually and semiquantitatively assessed the uptakes of FMISO and FDG using the maximal standardized uptake value (SUVmax). The metabolic volume (MV) of FDG was calculated as the volume within the boundary determined by the threshold (mean SUV of blood pool × 1.5). ResultsNine patients showed focal FDG uptake in the myocardium and were diagnosed with cardiac sarcoidosis. Among the patients with extra-cardiac lesions, FDG uptake was seen in 8 lymph nodes and 3 lung lesions. FMISO uptake was seen in the 7 cardiac (77.8%) and 6 extra-cardiac (54.5%) lesions. None of the patients showed physiological FMISO uptake in the myocardium. The SUVmax values of the lesions with FMISO uptake were higher than those of the lesions without FMISO uptake in both the cardiac (SUVmax: 9.9, IQR: 8.4-10.0 vs 7.3, IQR: 6.3-8.2) and non-cardiac lesions (SUVmax: 17.6, IQR: 14.5-19.3 vs 6.1, IQR: 5.9-6.2; P = 0.006). The MV values of the lesions with FMISO uptake were significantly higher than those of the lesions without FMISO uptake (111.3, IQR: 78.3-135.7 vs 6.4, IQR: 1.9-23.3; P = 0.0009). ConclusionsFMISO showed no physiological myocardial uptake and did not require special preparation. FMISO PET has the potential to detect hypoxic lesions in patients with sarcoidosis.

Quantitative Longitudinal Imaging Reveals that Inhibiting Hedgehog Activity Alleviates the Hypoxic Tumor Landscape.

Metastases account for the majority of mortalities related to breast cancer. The onset and sustained presence of hypoxia strongly correlates with increased incidence of metastasis and unfavorable prognosis in patients with breast cancer. The Hedgehog (Hh) signaling pathway is dysregulated in breast cancer, and its abnormal activity enables tumor progression and metastasis. In addition to programming tumor cell behavior, Hh activity enables tumor cells to craft a metastasis-conducive microenvironment. Hypoxia is a prominent feature of growing tumors that impacts multiple signaling circuits that converge upon malignant progression. We investigated the role of Hh activity in crafting a hypoxic environment of breast cancer. We used radioactive tracer [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) to image tumor hypoxia. We show that tumors competent for Hh activity are able to establish a hypoxic milieu; pharmacologic inhibition of Hh signaling in a syngeneic mammary tumor model mitigates tumor hypoxia. Furthermore, in hypoxia, Hh activity is robustly activated in tumor cells and institutes increased HIF signaling in a VHL-dependent manner. The findings establish a novel perspective on Hh activity in crafting a hypoxic tumor landscape and molecularly navigating the tumor cells to adapt to hypoxic conditions. IMPLICATIONS: Importantly, we present a translational strategy of utilizing longitudinal hypoxia imaging to measure the efficacy of vismodegib in a preclinical model of triple-negative breast cancer.

Hypoxia and glucose metabolism assessed by FMISO and FDG PET for predicting IDH1 mutation and 1p/19q codeletion status in newly diagnosed malignant gliomas

BackgroundTumor hypoxia and glycolysis have been recognized as determinant factors characterizing tumor aggressiveness in malignant gliomas. To clarify in vivo hypoxia and glucose metabolism in relation to isocitrate dehydrogenase (IDH) mutation and chromosome 1p and 19q (1p/19q) codeletion status, we retrospectively analyzed hypoxia as assessed by positron emission tomography (PET) with [18F]-fluoromisonidazole (FMISO) and glucose metabolism as assessed by PET with [18F]-fluoro-2-deoxy-d-glucose (FDG) in newly diagnosed malignant gliomas.MethodsIn total, 87 patients with newly diagnosed supratentorial malignant (WHO grade III and IV) gliomas were enrolled in this study. They underwent PET studies with FMISO and FDG before surgery. The molecular features and histopathological diagnoses based on the 2016 WHO classification were determined using surgical specimens. Maximal tumor-to-normal ratio (TNR) was calculated for FDG PET, and maximal tumor-to-blood SUV ratio (TBR) was calculated for FMISO PET. The PET uptake values in relation to IDH mutation and 1p/19q codeletion status were statistically analyzed.ResultsIn all tumors and malignant astrocytomas, the median FMISO TBR in IDH-wildtype tumors was significantly higher than that in IDH-mutant tumors (P < 0.001 and P < 0.01, respectively). In receiver operating characteristic (ROC) analysis, the area under the curve showed that the sensitivity for the discrimination was moderate (0.7–0.8) and the specificity was low (0.65–0.68). In the same population, the median FDG TNR in IDH-wildtype tumors tended to be higher than that in IDH-mutant tumors, but the difference was not statistically significant. In WHO grade III anaplastic astrocytomas, there were no significant differences in median FMISO TBR or FDG TNR between IDH-mutant and IDH-wildtype tumors. In IDH-mutant WHO grade III anaplastic gliomas, there were no significant differences in median FMISO TBR or FDG TNR between anaplastic astrocytomas and anaplastic oligodendrogliomas.ConclusionsTumor hypoxia as assessed by FMISO PET was informative for prediction of the IDH mutation status in newly diagnosed malignant gliomas. However, the accuracy of the discrimination was not satisfactory for clinical application. On the other hand, glucose metabolism as assessed by FDG PET could not differentiate the IDH-mutant status. Moreover, PET studies using FMISO and FDG could not predict IDH mutation and 1p/19q codeletion status in WHO grade III tumors.

IMG-02. USEFUL DIAGNOSIS OF PEDIATRIC CYSTIC BRAIN TUMORS USING MULTIPLE POSITRON EMISSION TOMOGRAPHY STUDIES

OBJECTIVEPediatric brain tumors are primarily diagnosed using MRI or CT examination; however, determining the correct diagnosis using only morphological MRI can sometimes be challenging. Positron emission tomography (PET) uses radiotracers for metabolic and molecular imaging. We examined the accumulation of multiple PET (FDG, MET, FLT, and FMISO) studies for diagnosing pediatric cystic brain tumors.METHODSWe performed PET scans for eight pediatric patients (five pilocytic astrocytoma, one pleomorphic xanthoastrocytoma, one diffuse astrocytoma with IDH1 mutation, one ganglioglioma) from April 2010 to December 2019. The resulting studies were compared by measuring the tumor-to-normal lesion (T/N) ratio of FDG, MET, and FLT and the tumor-to-blood value (T/B) ratio of FMISO between each pediatric cystic brain tumor.RESULTSAll pediatric brain tumors showed tumor uptake of FDG, MET, and FLT. We could not examine FMISO PET for one diffuse astrocytoma with IDH1 mutation. The T/N ratios of FDG, MET, and FLT and the T/B ratio of FMISO were 1.07, 2.76, 4.6, and 1.12 for pilocytic astrocytoma; 0.65, 4.6, 7.67, and 1.38 for pleomorphic xanthoastrocytoma; 0.61, 2.14, and 3.82 for diffuse astrocytoma with IDH1 mutation; and 0.79, 1.78, 5, and 1.49 for ganglioglioma, respectively. The T/N ratios of MET and FLT for pleomorphic xanthoastrocytoma were high, but the Ki-67 labeling index was 1%. In the ganglioglioma, the T/N ratio of FLT was high, but the T/N ratio of MET was low.CONCLUSIONSpecialized multiple PET accumulation patterns for tumors are useful for discriminating each tumor.

Correlation of Tumor Hypoxia Metrics Derived from 18F-Fluoromisonidazole Positron Emission Tomography and Pimonidazole Fluorescence Images of Optically Cleared Brain Tissue.

18F-fluoromisonidazole (FMISO) positron emission tomography (PET) is a widely used noninvasive imaging modality for assessing hypoxia. We describe the first spatial comparison of FMISO PET with an ex vivo reference standard for hypoxia across whole tumor volumes. Eighteen rats were orthotopically implanted with C6 or 9L brain tumors and made to undergo FMISO PET scanning. Whole brains were excised, sliced into 1-mm-thick sections, optically cleared, and fluorescently imaged for pimonidazole using an in vivo imaging system. FMISO maximum tumor uptake, maximum tumor-to-cerebellar uptake (TCmax), and hypoxic fraction (extracted 110 minutes after FMISO injection) were correlated with analogous metrics derived from pimonidazole fluorescence images. FMISO SUVmax was not significantly different between C6 and 9L brain tumors (P = .70), whereas FMISO TCmax and hypoxic fraction were significantly greater for C6 tumors (P < .01). FMISO TCmax was significantly correlated with the maximum tumor pimonidazole intensity (ρ = 0.76, P < .01), whereas FMISO SUVmax was not. FMISO tumor hypoxic fraction was significantly correlated with the pimonidazole-derived hypoxic fraction (ρ = 0.78, P < .01). Given that FMISO TCmax and tumor hypoxic fraction had strong correlations with the pimonidazole reference standard, these metrics may offer more reliable measures of tumor hypoxia than conventional PET uptake metrics (SUVmax). The voxel-wise correlation between FMISO uptake and pimonidazole intensity for a given tumor was strongly dependent on the tumor’s TCmax (ρ = 0.81, P < .01) and hypoxic fraction (ρ = 0.85, P < .01), indicating PET measurements within individual voxels showed greater correlation with pimonidazole reference standard in tumors with greater hypoxia.

Targeting Hypoxia Using Evofosfamide and Companion Hypoxia Imaging of FMISO-PET in Advanced Biliary Tract Cancer.

PurposeHypoxia is widely known as one of the mechanisms of chemoresistance and as an environmental condition which triggers invasion and metastasis of cancer. Evofosfamide is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard conjugated with 2-nitroimidazole. Biliary tract cancer (BTC) is known to contain large hypoxic area. This study evaluated the efficacy and safety of evofosfamide as a second-line treatment of advanced BTC.Materials and MethodsPatients received evofosfamide at a dose of 340 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Primary end-point was progression-free survival (PFS) rate at 4-months (4m-PFSR). Secondary end-points included overall survival (OS), PFS, disease control rate (DCR), metabolic response by 18F-fluorodeoxyglucose positron emission tomography (PET), hypoxic parameters evaluated by 18F-fluoromisonidazole (FMISO) PET and toxicity.ResultsTwenty patients were treated with evofosfamide, with 16 response-evaluable patients. There was no objective response; stable disease was observed in nine patients, with a DCR of 56.25%. 4m-PFSR was 40.6%. Median PFS was 3.60 months (95% confidence interval [CI], 1.68 to 5.52). Median OS was 6.37 months (95% CI, 3.94 to 8.79). Reduction of tumor metabolic activity was observed in eight of 15 patients (53.3%). High baseline hypoxic parameters were associated with poor PFS. Change of hypoxic parameters between pretreatment and post-treatment reflected hypoxic-activated drug response. There was no treatment-related death.ConclusionEvofosfamide as second-line treatment of advanced BTC showed acceptable safety and comparable efficacy to other agents. Changes in volumetric parameters measured with FMISO PET, showing the degree of tumor hypoxia, reflected the response to evofosfamide based on the mode of action.

Abstract 6189: Identifying efficacy of targeted HER2 antibodies in sensitization of HER2+ breast cancer to fractionated radiation

Abstract Background: Radiation therapy is one component of standard-of-care therapy for patients with breast cancer; however, treatment is often associated with patient toxicity. Fractionated radiation has emerged as an alternative to single dose radiation; although, there have been limited studies investigating it in combination with other therapies. Positron emission tomography (PET) imaging allows for detection of biological and molecular alternations. In this study, we utilized [18F]-fluoromisonidazole (FMISO)-PET imaging to monitor changes in tumor hypoxia to quantify tumor response to combination targeted plus radiation therapy. Methods: To assess for cell death, breast cancer cells (BT474, SKBR3, MDA MB 361, and MCF-7) were treated with 1 ug/mL trastuzumab (anti-HER2 targeted therapy) and radiation therapy and assessed for cell death four days later (N = 4 replicates per group). To assess for DNA double strand breaks (DSB), cells were probed for γ-H2AX with flow cytometry 30 minutes post treatment. For in vivo studies, 107 BT474 cells were subcutaneously injected into athymic nude mice (N = 3 for control and trastuzumab treated, N = 4 for radiation and combination therapy). Mice were treated with trastuzumab (4 mg/kg) on days 0 and 3 and radiation (6/3 Gy) on days 1, 2 and 3. Controls included single agent therapies and saline treated. Changes in hypoxia were assessed with FMISO PET imaging on days 0, 3 and 7. Mean and standard error of standardized uptake value (SUV) was quantified at each time point. Treatment synergy and statistical significance were assessed with Bliss test of independence and non-parametric T-test, respectively. Results: In vitro cell death assay revealed that trastuzumab or radiation treated groups exhibited 19% ± 2% or 50% ± 9% cell death respectively, while trastuzumab prior to radiation exhibited 76% ± 5.3% cell death (p = 0.01) in BT474 cells. Analysis of γ-H2AX flow cytometry showed that trastuzumab prior to radiation exhibited 40.8% ± 11% DSB, which significantly increased from trastuzumab (0.5% ± 0.4%) or radiation only groups (9% ± 7.2%) (p = 0.01). Bliss test of independence confirmed synergy of trastuzumab and fractionated radiation. In vivo data revealed that BT474 tumors treated with trastuzumab and radiation experienced a 45.8% ± 9.1% decrease in volume, while radiation only experienced a 23.2% ± 13.3% decrease from day 0 to 7 (p = 0.26). FMISO PET imaging indicated that tumors treated with trastuzumab and radiation therapy experienced a 20.5% ± 4% decrease in [18F]-FMISO tumor:muscle SUV, while radiation only tumors experience a 61.2% ± 33.3% increase in tumor:muscle SUV from day 0 to 7 (p = 0.01). Conclusions: Preliminary data reveals that treatment of cancer cells with trastuzumab synergistically increases the efficacy of fractionated radiation in vitro and in vivo. FMISO PET imaging may provide insight regarding the optimal treatment window of radiation therapy. Citation Format: Patrick Song, Yun Lu, Sharon Samuel, Anna Sorace. Identifying efficacy of targeted HER2 antibodies in sensitization of HER2+ breast cancer to fractionated radiation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6189.

Individual patient data meta-analysis of FMISO and FAZA hypoxia PET scans from head and neck cancer patients undergoing definitive radio-chemotherapy

Background and purposeTumor hypoxia plays an important role in head and neck squamous cell carcinomas (HNSCC). Various positron emission tomography (PET) tracers promise non-invasive assessment of tumor hypoxia. So far, the applicability of hypoxia PET is hampered by monocentric imaging trials with few patients. Materials and methodsMulticenter individual patient data based meta-analysis of the original PET data from four prospective imaging trials was performed. All patients had localized disease and were treated with curatively intended radio(-chemo)therapy. Hypoxia PET imaging was performed with 18F-Fluoromisonidazole (FMISO, 102 patients) or 18F-Fluoroazomycin-arabinoside (FAZA, 51 patients). Impact of hypoxia PET parameters on loco-regional control (LRC) and overall survival (OS) was analyzed by uni- and multivariable Cox regression. ResultsBaseline characteristics between participating centers differed significantly, especially regarding T stage (p < 0.001), tumor volume (p < 0.001) and p16 status (p = 0.009). The commonly used hypoxia parameters, maximal tumor-to-muscle ratio (TMRmax) and hypoxic volume with 1.6 threshold (HV1.6), showed a strong association with LRC (p = 0.001) and OS (p < 0.001). These findings were irrespective of the radiotracer and the same cut-off values could be applied for FMISO and FAZA (TMRmax > 2.0 or HV1.6 > 1.5 ml). The effect size of TMRmax was similar for subgroups of patients defined by radiotracer, p16 status and FDG-PET parameters for LRC and OS, respectively. ConclusionPET measured hypoxia is robust and has a strong impact on LRC and OS in HNSCC. The most commonly investigated tracers FMISO and FAZA can probably be used equivalently in multicenter trials. Optimal strategies to improve the dismal outcome of hypoxic tumors remain elusive.

Mechanism-Based Modeling of Tumor Growth and Treatment Response Constrained by Multiparametric Imaging Data.

Multiparametric imaging is a critical tool in the noninvasive study and assessment of cancer. Imaging methods have evolved over the past several decades to provide quantitative measures of tumor and healthy tissue characteristics related to, for example, cell number, blood volume fraction, blood flow, hypoxia, and metabolism. Mechanistic models of tumor growth also have matured to a point where the incorporation of patient-specific measures could provide clinically relevant predictions of tumor growth and response. In this review, we identify and discuss approaches that use multiparametric imaging data, including diffusion-weighted magnetic resonance imaging, dynamic contrast-enhanced magnetic resonance imaging, diffusion tensor imaging, contrast-enhanced computed tomography, [18F]fluorodeoxyglucose positron emission tomography, and [18F]fluoromisonidazole positron emission tomography to initialize and calibrate mechanistic models of tumor growth and response. We focus the discussion on brain and breast cancers; however, we also identify three emerging areas of application in kidney, pancreatic, and lung cancers. We conclude with a discussion of the future directions for incorporating multiparametric imaging data and mechanistic modeling into clinical decision making for patients with cancer.

The Roles of Hypoxia Imaging Using 18F-Fluoromisonidazole Positron Emission Tomography in Glioma Treatment.

Glioma is the most common malignant brain tumor. Hypoxia is closely related to the malignancy of gliomas, and positron emission tomography (PET) can noninvasively visualize the degree and the expansion of hypoxia. Currently, 18F-fluoromisonidazole (FMISO) is the most common radiotracer for hypoxia imaging. The clinical usefulness of FMISO PET has been established; it can distinguish glioblastomas from lower-grade gliomas and can predict the microenvironment of a tumor, including necrosis, vascularization, and permeability. FMISO PET provides prognostic information, including survival and treatment response information. Because hypoxia decreases a tumor’s sensitivity to radiation therapy, dose escalation to an FMISO-positive volume is an attractive strategy. Although this idea is not new, an insufficient amount of evidence has been obtained regarding this concept. New tracers for hypoxia imaging such as 18F-DiFA are being tested. In the future, hypoxia imaging will play an important role in glioma management.

Biodistribution and radiation dosimetry of the novel hypoxia PET probe [18F]DiFA and comparison with [18F]FMISO

BackgroundTo facilitate hypoxia imaging in a clinical setting, we developed 1-(2,2-dihydroxymethyl-3-[18F]-fluoropropyl)-2-nitroimidazole ([18F]DiFA) as a new tracer that targets tumor hypoxia with its lower lipophilicity and efficient radiosynthesis. Here, we evaluated the radiation dosage, biodistribution, human safety, tolerability, and early elimination after the injection of [18F]DiFA in healthy subjects, and we performed a preliminary clinical study of patients with malignant tumors in a comparison with [18F]fluoromisonidazole ([18F]FMISO).ResultsThe single administration of [18F]DiFA in 8 healthy male adults caused neither adverse events nor abnormal clinical findings. Dynamic and sequential whole-body scans showed that [18F]DiFA was rapidly cleared from all of the organs via the hepatobiliary and urinary systems. The whole-body mean effective dose of [18F]DiFA estimated by using the medical internal radiation dose (MIRD) schema with organ level internal dose assessment/exponential modeling (OLINDA/EXM) computer software 1.1 was 14.4 ± 0.7 μSv/MBq. Among the organs, the urinary bladder received the largest absorbed dose (94.7 ± 13.6 μSv/MBq). The mean absorbed doses of the other organs were equal to or less than those from other hypoxia tracers. The excretion of radioactivity via the urinary system was very rapid, reaching 86.4 ± 7.1% of the administered dose. For the preliminary clinical study, seven patients were subjected to [18F]FMISO and [18F]DiFA positron emission tomography (PET) at 48-h intervals to compare the two tracers’ diagnostic ability for tumor hypoxia. The results of the tumor hypoxia evaluation by [18F]DiFA PET at 1 h and 2 h were not significantly different from those obtained with [18F]FMISO PET at 4 h ([18F]DiFA at 1 h, p = 0.32; [18F]DiFA at 2 h, p = 0.08). Moreover, [18F]DiFA PET at both 1 h (k = 0.68) and 2 h (k = 1.00) showed better inter-observer reproducibility than [18F]FMISO PET at 4 h (k = 0.59).Conclusion[18F]DiFA is well tolerated, and its radiation dose is comparable to those of other hypoxia tracers. [18F]DiFA is very rapidly cleared via the urinary system. [18F]DiFA PET generated comparable images to [18F]FMISO PET in hypoxia imaging with shorter waiting time, demonstrating the promising potential of [18F]DiFA PET for hypoxia imaging and for a multicenter trial.

Multivariate Regularized Newton and Levenberg-Marquardt methods: a comparison on synthetic data of tumor hypoxia in a kinetic framework

Abstract In this paper we propose a new algorithm to optimize the parameters of a compartmental problem describing tumor hypoxia. The method is based on a multivariate Newton approach, with Tikhonov regularization, and can be easily applied to data with diverse statistical distributions. Here we simulate [18 F]−fluoromisonidazole Positron Emission Tomography dynamic data of hypoxia of a neck tumor and describe the tracer flow inside tumor with a two-compartments compartmental model. We perform optimization on the parameters of the model via the proposed Multivariate Regularized Newton method and validate it against results obtained with a standard Levenberg-Marquardt approach. The proposed algorithm returns parameters that are closer to the ground truth while preserving the statistical distribution of the data.