Models using comprehensive, lesion-level, longitudinal [68Ga]Ga-DOTA-TATE PET-derived features lead to superior outcome prediction in neuroendocrine tumor patients treated with [177Lu]Lu-DOTA-TATE.

PURPOSE: Somatostatin receptor (SSTR) imaging features are predictive of treatment outcome for neuroendocrine tumor (NET) patients receiving peptide receptor radionuclide therapy (PRRT). However, comprehensive (all metastatic lesions), longitudinal (temporal variation), and lesion-level measured features have never been explored. Such features allow for capturing the heterogeneity in disease response to treatment. Furthermore, models combining these features are lacking. In this work we evaluated the predictive power of comprehensive, longitudinal, lesion-level 68GA-SSTR-PET features combined with a multivariate linear regression (MLR) model. METHODS: This retrospective study enrolled NET patients treated with [177Lu]Lu-DOTA-TATE and imaged with [68Ga]Ga-DOTA-TATE at baseline and post-therapy. All lesions were segmented, anatomically labeled, and longitudinally matched. Lesion-level uptake and variation in uptake were measured. Patient-level features were engineered and selected for modeling of progression-free survival (PFS). The model was validated via concordance index, patient classification (ROC analysis), and survival analysis (Kaplan-Meier and Cox proportional hazards). The MLR was benchmarked against single feature predictions. RESULTS: Thirty-six NET patients were enrolled and stratified into poor and good responders (PFS ≥ 25 months). Four patient-level features were selected, the MLR concordance index was 0.826, and the AUC was 0.88 (0.85 specificity, 0.81 sensitivity). Survival analysis led to significant patient stratification (p<.001) and hazard ratio (3⨯10-5). Lastly, in a benchmark study, the MLR modeling approach outperformed all the single feature predictors. CONCLUSION: Comprehensive, lesion-level, longitudinal 68GA-SSTR-PET analysis, combined with MLR modeling, leads to excellent predictions of PRRT outcome in NET patients, outperforming non-comprehensive, patient-level, and single time-point feature predictions. MESSAGE: Neuroendocrine tumor, peptide receptor radionuclide therapy, Somatostatin Receptor Imaging, Outcome Prediction, Treatment Response Assessment.

Nuclear Medicine Imaging Techniques in Glioblastomas.

Glioblastomas are the most common primary malignant grade 4 tumors of the central nervous system (CNS). The treatment and management of such tumors requires a multidisciplinary approach and nuclear medicine techniques play an important role in this process. Glioblastoma, which recurs despite current treatments and becomes resistant to treatments, is among the tumors with the lowest survival rate, with a survival rate of approximately 8 months. Currently, the standard treatment of glioblastoma is adjuvant chemoradiotherapy after surgical resection. There have been many recent advances in the field of Nuclear Medicine in glioblastoma. PET scans are critical in determining tumor localization, pre-surgical planning, evaluation of post-treatment response and detection of recurrence. Advances in the treatment of glioblastoma and a better understanding of the biological characteristics of the disease have contributed to the development of nuclear medicine techniques. This review, in addition to other studies, is intended as a general imaging summary guide and includes some new expressions discovered in glioblastoma. This review discusses recent advances in nuclear medicine in glioblastoma.

Machine learning-based response assessment in patients with rectal cancer after neoadjuvant chemoradiotherapy: radiomics analysis for assessing tumor regression grade using T2-weighted magnetic resonance images.

PURPOSE: This study aimed to assess tumor regression grade (TRG) in patients with rectal cancer after neoadjuvant chemoradiotherapy (NCRT) through a machine learning-based radiomics analysis using baseline T2-weighted magnetic resonance (MR) images. MATERIALS AND METHODS: In total, 148 patients with locally advanced rectal cancer(T2-4 or N+) who underwent MR imaging at baseline and after chemoradiotherapy between January 2010 and May 2021 were included. A region of interest for each tumor mass was drawn by a radiologist on oblique axial T2-weighted images, and main features were selected using principal component analysis after dimension reduction among 116 radiomics and three clinical features. Among eight learning models that were used for prediction model development, the model showing best performance was selected. Treatment responses were classified as either good or poor based on the MR-assessed TRG (mrTRG) and pathologic TRG (pTRG). The model performance was assessed using the area under the receiver operating curve (AUROC) to classify the response group. RESULTS: Approximately 49% of the patients were in the good response (GR) group based on mrTRG (73/148) and 26.9% based on pTRG (28/104). The AUCs of clinical data, radiomics models, and combined radiomics with clinical data model for predicting mrTRG were 0.80 (95% confidence interval [CI] 0.73, 0.87), 0.74 (95% CI 0.66, 0.81), and 0.75(95% CI 0.68, 0.82), and those for predicting pTRG was 0.62 (95% CI 0.52, 0.71), 0.74 (95% CI 0.65, 0.82), and 0.79 (95% CI 0.71, 0.87). CONCLUSION: Radiomics combined with clinical data model using baseline T2-weighted MR images demonstrated feasible diagnostic performance in predicting both MR-assessed and pathologic treatment response in patients with rectal cancer after NCRT.

Predictive value on advance hodgkin lymphoma treatment outcome of end-of treatment FDG PET/CT in the HD0607 clinical trial.

The Lugano classification for response assessment in lymphoma recommends the use of the 5-point-scale Deauville Score (DS) to assess response evaluation of end-of-treatment FDG-PET/CT (eotPET) in Hodgkin Lymphoma (HL); nevertheless, there is a paucity of data on its accuracy and reproducibility. We focus here on the cohort of advanced stage IIb-IV HL patients enrolled in the HD0607 clinical trial (NCT identifier 00795613) that having had a negative interim PET performed 6 cycles of ABVD (Doxorubicin, Vinblastine, Vincristine and Dacarbazine) and then performed an eotPET. Negative patients were randomized to radiotherapy and no further treatment while positive patients were treated based on local policies. eotPET was re-evaluated independently by two readers evaluated and progression free survival was analysed (PFS). eotPET of 254 patients were analysed. The median follow-up was 43 months. The best receiver operator characteristics cut-off values to distinguish positive and negative patients was 4. The area-under-the-curve was 0.81 (95%CI, 0.70-0.91). Three-years PFS was 0.95 (95% CI 0.90-0.97) in eotPET negative and 0.22 (95% CI 0.11-0.43) in eotPET positive. DS demonstrated a good reproducibility of positivity/negativity between the readers consensus and local site evaluation where the agreement occurred on 95.0% of patients. The present study demonstrates that eotPET is an accurate tool to predict treatment outcome in HL and confirms the appropriateness of the Lugano classification for eotPET evaluation.

Updates on LI-RADS Treatment Response Criteria for Hepatocellular Carcinoma: Focusing on MRI.

As the incidence of hepatocellular carcinoma (HCC) and subsequent treatments with liver-directed therapies rise, the complexity of assessing lesion response has also increased. The Liver Imaging Reporting and Data Systems (LI-RADS) treatment response algorithm (LI-RADS TRA) was created to standardize the assessment of response after locoregional therapy (LRT) on contrast-enhanced CT or MRI. Originally created based on expert opinion, these guidelines are currently undergoing revision based on emerging evidence. While many studies support the use of LR-TRA for evaluation of HCC response after thermal ablation and intra-arterial embolic therapy, data suggest a need for refinements to improve assessment after radiation therapy. In this manuscript, we review expected MR imaging findings after different forms of LRT, clarify how to apply the current LI-RADS TRA by type of LRT, explore emerging literature on LI-RADS TRA, and highlight future updates to the algorithm. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Model-free dynamic contrast-enhanced MRI analysis: differentiation between active tumor and necrotic tissue in patients with glioblastoma.

OBJECTIVE: Treatment response assessment in patients with high-grade gliomas (HGG) is heavily dependent on changes in lesion size on MRI. However, in conventional MRI, treatment-related changes can appear as enhancing tissue, with similar presentation to that of active tumor tissue. We propose a model-free data-driven method for differentiation between these tissues, based on dynamic contrast-enhanced (DCE) MRI. MATERIALS AND METHODS: The study included a total of 66 scans of patients with glioblastoma. Of these, 48 were acquired from 1 MRI vendor and 18 scans were acquired from a different MRI vendor and used as test data. Of the 48, 24 scans had biopsy results. Analysis included semi-automatic arterial input function (AIF) extraction, direct DCE pharmacokinetic-like feature extraction, and unsupervised clustering of the two tissue types. Validation was performed via (a) comparison to biopsy result (b) correlation to literature-based DCE curves for each tissue type, and (c) comparison to clinical outcome. RESULTS: Consistency between the model prediction and biopsy results was found in 20/24 cases. An average correlation of 82% for active tumor and 90% for treatment-related changes was found between the predicted component and population-based templates. An agreement between the predicted results and radiologist's assessment, based on RANO criteria, was found in 11/12 cases. CONCLUSION: The proposed method could serve as a non-invasive method for differentiation between lesion tissue and treatment-related changes.

[Advances in Molecular Targeted Ultrasound Contrast Agents].

In real-time ultrasound,molecular targeted contrast agent is introduced into the blood circulation through peripheral intravenous injection to enhance the imaging signal of target lesions after binding to the corresponding intravascular receptors,which can realize early diagnosis,staging of diseases,assessment of treatment response,and targeted treatment.In addition,molecular targeted ultrasound contrast agents provide a platform for the delivery of drugs and genes via microbubbles,and nanoscale contrast agents can be infiltrated through vascular endothelium into the interstitial space of the lesion for imaging or treatment.The available studies of molecular targeted ultrasound contrast agents mainly focus on the preclinical trials.Some clinical trials have been conducted in humans and preliminarily confirm the safety and feasibility of targeted ultrasound contrast agents.The molecular targeted ultrasound contrast agents enjoy a broad prospect in clinical application.

Predicting treatment response of patients with extranodal natural killer/T-cell lymphoma based on levels of PD-L1 mRNA and soluble PD-L1.

Appropriate biomarkers may help predict patient response to treatment for extranodal natural killer/T-cell lymphoma (ENKTL), a subtype of non-Hodgkin's lymphoma in China. Programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) have been investigated in various tumors. However, few studies have addressed expression of PD-1/PD-L1 in peripheral blood of ENKTL patients. To identify novel peripheral blood biomarkers for diagnosis and treatment of ENKTL, we retrospectively examined 89 healthy volunteers, 49 patients with ENKTL and 74 patients with diffuse large B-cell lymphoma treated at West China Hospital from September 2017 to September 2018. Both patient groups showed significantly higher expression of PD-1 and PD-L1 on CD4+ T cells, higher levels of PD-L1 mRNA in peripheral blood mononuclear cells (PBMCs) and higher levels of soluble PD-L1 in plasma than healthy volunteers (P < .05). In ENKTL patients, levels of PD-L1 mRNA and soluble PD-L1 were related to disease stage, level of lactate dehydrogenase, lymphocyte count, and copies of Epstein-Barr genome in blood. Levels of PD-L1 mRNA and soluble PD-L1 were similar between healthy volunteers and ENKTL patients who showed complete remission after treatment, and uni- and multivariate analyses identified soluble PD-L1 as a predictor of treatment response in ENKTL patients. Our results suggest that the levels of PD-L1 mRNA in PBMCs and soluble PD-L1 in plasma are useful for ENKTL staging and prediction of treatment response.

Magnetic resonance imaging after external beam radiotherapy and concurrent chemotherapy for locally advanced cervical cancer helps to identify patients at risk of recurrence.

OBJECTIVE: Tumor volume and regression after external beam radiotherapy have been shown to be accurate parameters to assess treatment response via magnetic resonance imaging (MRI). The aim of the study was to evaluate the prognostic value of tumor size reduction rate after external beam radiotherapy and chemotherapy prior to brachytherapy. METHODS: Patients with locally advanced cervical cancer treated at two French comprehensive cancer centers between 1998 and 2010 were included. Treatment was pelvic external beam radiotherapy with platinum based chemotherapy followed by brachytherapy. Records were reviewed for demographic, clinical, imaging, treatment, and follow-up data. Anonymized linked data were used to ascertain the association between pre-external and post-external beam radiotherapy MRI results, and survival data. RESULTS: 185 patients were included in the study. Median age at diagnosis was 45 years (range 26-72). 77 patients (41.6%) were International Federation of Gynecology and Obstetrics stage IB2-IIA disease and 108 patients (58.4%) were stage IIB-IVA. Median tumor size after external beam radiotherapy and chemotherapy was 2.0 cm (range 0.0-8.0) and median tumor size reduction rate was 62.4% (range 0.0-100.0%). Tumor size and tumor reduction rate at 45 Gy external beam radiotherapy MRI were significantly associated with local recurrence free survival (P<0.001), disease free survival, and overall survival (P<0.05). Tumor reduction rate ≥60% was significantly associated with a decreased risk of relapse and death (HR (95% CI) 0.21 (0.09 to 0.50), P=0.001 for local recurrence free survival; 0.48 (0.30 to 0.77) P=0.002 for disease free survival; and 0.51 (0.29 to 0.88), P=0.014 for overall survival). CONCLUSIONS: Tumor size reduction rate >60% between pre-therapeutic and post-therapeutic 45 Gy external beam radiotherapy with concurrent chemotherapy was associated with improved survival. Future studies may help to identify patients who may ultimately benefit from completion surgery, adjuvant chemotherapy, and closer follow-up.

An artificial neural networks approach for assessment treatment response in oncological patients using PET/CT images.

BACKGROUND: Positron Emission Tomography - Computed Tomography (PET/CT) imaging is the basis for the evaluation of response-to-treatment of several oncological diseases. In practice, such evaluation is manually performed by specialists, which is rather complex and time-consuming. Evaluation measures have been proposed, but with questionable reliability. The usage of before and after-treatment image descriptors of the lesions for treatment response evaluation is still a territory to be explored. METHODS: In this project, Artificial Neural Network approaches were implemented to automatically assess treatment response of patients suffering from neuroendocrine tumors and Hodgkyn lymphoma, based on image features extracted from PET/CT. RESULTS: The results show that the considered set of features allows for the achievement of very high classification performances, especially when data is properly balanced. CONCLUSIONS: After synthetic data generation and PCA-based dimensionality reduction to only two components, LVQNN assured classification accuracies of 100%, 100%, 96.3% and 100% regarding the 4 response-to-treatment classes.

¹8F-FDG PET/CT in the early prediction of pathological response in aggressive subtypes of breast cancer: review of the literature and recommendations for use in clinical trials.

Early assessment of response to neoadjuvant chemotherapy (NAC) might be helpful in avoiding the toxicity of ineffective chemotherapy and allowing refinement of treatment. We conducted a review of the literature regarding the applicability of (18)F-FDG PET/CT to the prediction of an early pathological response in different subgroups of breast cancer. Clinical research in this field has intensified in the last few years. Early studies by various groups have shown the potential of (18)F-FDG PET/CT in the early assessment of response to NAC. However, interim PET/CT in breast cancer has not yet gained wide acceptance compared to its use in other settings such as lymphomas. This is in part due to a lack of consensus that early evaluation of response can be used to direct change in therapy in the neoadjuvant breast cancer setting, and only limited data showing that response-adaptive therapy leads to improved outcomes. However, one major element that has hampered the use of (18)F-FDG PET/CT in directing neoadjuvant therapy is its evaluation in populations with mixed subtypes of breast cancer. However, major improvements have occurred in recent years. Pilot studies have highlighted the need for considering breast cancer subtype and the type of treatment, and have offered criteria for the use of PET/CT for the early prediction of response in specific settings. (18)F-FDG PET/CT has considerable potential for the early prediction of pathological complete response to NAC in aggressive subtypes such as triple-negative or HER2-positive breast cancers. The results of a multicentre trial that used early metabolic response on (18)F-FDG PET/CT as a means to select poor responders to adapt neoadjuvant treatment have recently been published. Other trials are ongoing or being planned.

Digital "flipbooks" for enhanced visual assessment of simple and complex brain tumors.

Typical longitudinal radiographic assessment of brain tumors relies on side-by-side qualitative visualization of serial magnetic resonance images (MRIs) aided by quantitative measurements of tumor size. However, when assessing slowly growing tumors and/or complex tumors, side-by-side visualization and quantification may be difficult or unreliable. Whole-brain, patient-specific "digital flipbooks" of longitudinal scans are a potential method to augment radiographic side-by-side reads in clinical settings by enhancing the visual perception of changes in tumor size, mass effect, and infiltration across multiple slices over time. In this approach, co-registered, consecutive MRI scans are displayed in a slide deck, where one slide displays multiple brain slices of a single timepoint in an array (eg, 3 × 5 "mosaic" view of slices). The flipbooks are viewed similarly to an animated flipbook of cartoons/photos so that subtle radiographic changes are visualized via perceived motion when scrolling through the slides. Importantly, flipbooks can be created easily with free, open-source software. This article describes the step-by-step methodology for creating flipbooks and discusses clinical scenarios for which flipbooks are particularly useful. Example flipbooks are provided in Supplementary Material.

Treatment response assessment of acute pyelonephritis: A multi-reader DWI-based MRI approach.

PURPOSE: To evaluate the diagnostic accuracy of a structured reporting score (SRS) in treatment response assessment for acute pyelonephritis (APN) using a diffusion-weighted imaging (DWI) -based MRI approach. Additionally, we explored the influence of reader experience on the interpretation of SRS and DWI, including lesion conspicuity and measurements of Apparent Diffusion Coefficient (ADC) maps. METHODS: Follow-up DWI-based MRIs of 36 patients treated for APN between September 2021 and June 2023 were retrospectively reviewed by three readers. Follow-up blood inflammatory markers were used as reference standard. Treatment response was assessed using a structured reporting score (SRS). Each reader assigned a score from 1 to 3 to the "conspicuity" of the residual disease on DWI. Quantitative ADC measurements were compared with the Mann-Whitney U test. Descriptive statistics and Intraclass Correlation Coefficient (ICC) were calculated. RESULTS: The diagnostic accuracy of SRS was 80.6 %, 76.9 %, and 72.2 % for the Reader 1, 2, and 3 respectively. ICC decreased from 0.82 (Reader 1 and 2), to 0.68 when considering all readers. The average conspicuity varied between 2.3 and 2.7. ADC values were significantly higher in complete responders for Reader 1 and 2 (153.5-154.5 vs 107.7-116.2, p < 0.001). The ICC was good (0.89) for Reader 1 and 2 and moderate (0.60) when considering all readers. CONCLUSIONS: Treatment response of pyelonephritis can be accurately assessed by a DWI-based MRI, potentially avoiding unnecessary contrast agent administration and radiation exposure. SRS and DWI analysis showed a good inter-observer agreement but a certain learning curve may be necessary for less expert readers.

Cholangiocarcinoma imaging: from diagnosis to response assessment.

Cholangiocarcinoma (CCA), a highly aggressive primary liver cancer arising from the bile duct epithelium, represents a substantial proportion of hepatobiliary malignancies, posing formidable challenges in diagnosis and treatment. Notably, the global incidence of intrahepatic CCA has seen a rise, necessitating a critical examination of diagnostic and management strategies, especially due to presence of close imaging mimics such as hepatocellular carcinoma (HCC) and combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA). Hence, it is imperative to understand the role of various imaging modalities such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), elucidating their strengths, and limitations in diagnostic precision and staging accuracy. Beyond conventional approaches, there is emerging significance of functional imaging tools including positron emission tomography (PET)-CT and diffusion-weighted (DW)-MRI, providing pivotal insights into diagnosis, therapeutic assessment, and prognostic evaluation. This comprehensive review explores the risk factors, classification, clinical features, and role of imaging in the holistic spectrum of diagnosis, staging, management, and restaging for CCA, hence serving as a valuable resource for radiologists evaluating CCA.

[18F]FDG PET/CT Integration in Evaluating Immunotherapy for Lung Cancer: A Clinician's Practical Approach.

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment paradigm of lung cancer, resulting in notable enhancements in patient survival. Nevertheless, evaluating treatment response in patients undergoing immunotherapy poses distinct challenges due to unconventional response patterns like pseudoprogressive disease (PPD), dissociated response (DR), and hyperprogressive disease (HPD). Conventional response criteria such as the RECIST 1.1 may not adequately address these complexities. To tackle this issue, novel response criteria such as the iRECIST and imRECIST have been proposed, enabling a more comprehensive assessment of treatment response by incorporating additional scans and considering the best overall response even after radiologic progressive disease evaluation. Additionally, [18F]FDG PET/CT imaging has emerged as a valuable modality for evaluating treatment response, with various metabolic response criteria such as the PERCIMT, imPERCIST, and iPERCIST developed to overcome the limitations of traditional criteria, particularly in detecting pseudoprogression. A multidisciplinary approach involving oncologists, radiologists, and nuclear medicine specialists is crucial for effectively navigating these complexities and enhancing patient outcomes in the era of immunotherapy for lung cancer. In this review, we delineate the key components of these guidelines, summarizing essential aspects for radiologists and nuclear medicine physicians. Furthermore, we provide insights into how imaging can guide the management of individual lung cancer patients in real-world multidisciplinary settings.

An automated methodology for whole-body, multimodality tracking of individual cancer lesions.

Objective. Manual analysis of individual cancer lesions to assess disease response is clinically impractical and requires automated lesion tracking methodologies. However, no methodology has been developed for whole-body individual lesion tracking, across an arbitrary number of scans, and acquired with various imaging modalities.Approach. This study introduces a lesion tracking methodology and benchmarked it using 2368Ga-DOTATATE PET/CT and PET/MR images of eight neuroendocrine tumor patients. The methodology consists of six steps: (1) alignment of multiple scans via image registration, (2) body-part labeling, (3) automatic lesion-wise dilation, (4) clustering of lesions based on local lesion shape metrics, (5) assignment of lesion tracks, and (6) output of a lesion graph. Registration performance was evaluated via landmark distance, lesion matching accuracy was evaluated between each image pair, and lesion tracking accuracy was evaluated via identical track ratio. Sensitivity studies were performed to evaluate the impact of lesion dilation (fixed versus automatic dilation), anatomic location, image modalities (inter- versus intra-modality), registration mode (direct versus indirect registration), and track size (number of time-points and lesions) on lesion matching and tracking performance.Main results. Manual contouring yielded 956 lesions, 1570 lesion-matching decisions, and 493 lesion tracks. The median residual registration error was 2.5 mm. The automatic lesion dilation led to 0.90 overall lesion matching accuracy, and an 88% identical track ratio. The methodology is robust regarding anatomic locations, image modalities, and registration modes. The number of scans had a moderate negative impact on the identical track ratio (94% for 2 scans, 91% for 3 scans, and 81% for 4 scans). The number of lesions substantially impacted the identical track ratio (93% for 2 nodes versus 54% for ≥5 nodes).Significance. The developed methodology resulted in high lesion-matching accuracy and enables automated lesion tracking in PET/CT and PET/MR.

Investigating the role of delayed contrast magnetic resonance imaging (MRI) to differentiate radiation necrosis from tumour recurrence in brain metastases after stereotactic radiosurgery.

INTRODUCTION: The incidence of radionecrosis (RN) after stereotactic radiosurgery (SRS) to brain metastases is increasing. An overlap in the conventional MRI appearances of RN and tumour recurrence (TR) is diagnostically challenging. Delayed contrast MRI compares contrast enhancement over two time periods to create treatment response assessment maps (TRAMs). We aim to assess the utility of TRAMs in brain metastases patients. METHODS: Delayed contrast MRI scans were performed on ten brain metastases patients, previously treated with SRS, who developed equivocal lesion(s) on routine MRI follow-up. T1-weighted images were obtained five minutes and 60-75 min after contrast injection, followed by Brain Lab software analysis to create TRAMs. TRAMs patterns were then compared with the patient's clinical status, subsequent imaging, and histology results. RESULTS: We identified three regions on TRAMs: central, peripheral, and surrounding. Each region could be described either as contrast accumulation (red colour and representing non-tumour tissue) or contrast clearance (blue colour and representing tumour tissue). Our analysis demonstrated similarities in the TRAMs pattern between TR and RN, though to varying degrees. CONCLUSION: In conclusion, the TRAMs appearances of RN and TR overlap. Our findings suggest that the previously-described correlation between contrast clearance and TR is at least partially attributable to more solid initial enhancement, rather than convincingly a difference in the underlying tissue properties, and the additional diagnostic value of TRAMs may be limited. Thus, further research on TRAMs is necessary prior to incorporating it into routine clinical management after SRS for brain metastases.

The MANGO study: a prospective investigation of oxygen enhanced and blood-oxygen level dependent MRI as imaging biomarkers of hypoxia in glioblastoma.

Background: Glioblastoma (GBM) is the most aggressive type of brain cancer, with a 5-year survival rate of ~5% and most tumours recurring locally within months of first-line treatment. Hypoxia is associated with worse clinical outcomes in GBM, as it leads to localized resistance to radiotherapy and subsequent tumour recurrence. Current standard of care treatment does not account for tumour hypoxia, due to the challenges of mapping tumour hypoxia in routine clinical practice. In this clinical study, we aim to investigate the role of oxygen enhanced (OE) and blood-oxygen level dependent (BOLD) MRI as non-invasive imaging biomarkers of hypoxia in GBM, and to evaluate their potential role in dose-painting radiotherapy planning and treatment response assessment. Methods: The primary endpoint is to evaluate the quantitative and spatial correlation between OE and BOLD MRI measurements and [18F]MISO values of uptake in the tumour. The secondary endpoints are to evaluate the repeatability of MRI biomarkers of hypoxia in a test-retest study, to estimate the potential clinical benefits of using MRI biomarkers of hypoxia to guide dose-painting radiotherapy, and to evaluate the ability of MRI biomarkers of hypoxia to assess treatment response. Twenty newly diagnosed GBM patients will be enrolled in this study. Patients will undergo standard of care treatment while receiving additional OE/BOLD MRI and [18F]MISO PET scans at several timepoints during treatment. The ability of OE/BOLD MRI to map hypoxic tumour regions will be evaluated by assessing spatial and quantitative correlations with areas of hypoxic tumour identified via [18F]MISO PET imaging. Discussion: MANGO (Magnetic resonance imaging of hypoxia for radiation treatment guidance in glioblastoma multiforme) is a diagnostic/prognostic study investigating the role of imaging biomarkers of hypoxia in GBM management. The study will generate a large amount of longitudinal multimodal MRI and PET imaging data that could be used to unveil dynamic changes in tumour physiology that currently limit treatment efficacy, thereby providing a means to develop more effective and personalised treatments.

Influence of MRI Follow-Up on Treatment Decisions during Standard Concomitant and Adjuvant Chemotherapy in Patients with Glioblastoma: Is Less More?

MRI is the gold standard for treatment response assessments for glioblastoma. However, there is no consensus regarding the optimal interval for MRI follow-up during standard treatment. Moreover, a reliable assessment of treatment response is hindered by the occurrence of pseudoprogression. It is unknown if a radiological follow-up strategy at 2-3 month intervals actually benefits patients and how it influences clinical decision making about the continuation or discontinuation of treatment. This study assessed the consequences of scheduled follow-up scans post-chemoradiotherapy (post-CCRT), after three cycles of adjuvant chemotherapy [TMZ3/6], and after the completion of treatment [TMZ6/6]), and of unscheduled scans on treatment decisions during standard concomitant and adjuvant treatment in glioblastoma patients. Additionally, we evaluated how often follow-up scans resulted in diagnostic uncertainty (tumor progression versus pseudoprogression), and whether perfusion MRI improved clinical decision making. Scheduled follow-up scans during standard treatment in glioblastoma patients rarely resulted in an early termination of treatment (2.3% post-CCRT, 3.2% TMZ3/6, and 7.8% TMZ6/6), but introduced diagnostic uncertainty in 27.7% of cases. Unscheduled scans resulted in more major treatment consequences (30%; p < 0.001). Perfusion MRI caused less diagnostic uncertainty (p = 0.021) but did not influence treatment consequences (p = 0.871). This study does not support the current pragmatic follow-up strategy and suggests a more tailored follow-up approach.

Standardized brain tumor imaging protocols for clinical trials: current recommendations and tips for integration.

Standardized MRI acquisition protocols are crucial for reducing the measurement and interpretation variability associated with response assessment in brain tumor clinical trials. The main challenge is that standardized protocols should ensure high image quality while maximizing the number of institutions meeting the acquisition requirements. In recent years, extensive effort has been made by consensus groups to propose different "ideal" and "minimum requirements" brain tumor imaging protocols (BTIPs) for gliomas, brain metastases (BM), and primary central nervous system lymphomas (PCSNL). In clinical practice, BTIPs for clinical trials can be easily integrated with additional MRI sequences that may be desired for clinical patient management at individual sites. In this review, we summarize the general concepts behind the choice and timing of sequences included in the current recommended BTIPs, we provide a comparative overview, and discuss tips and caveats to integrate additional clinical or research sequences while preserving the recommended BTIPs. Finally, we also reflect on potential future directions for brain tumor imaging in clinical trials.