History of Technological Advancements towards MR-Linac: The Future of Image-Guided Radiotherapy.

Image-guided radiotherapy (IGRT) enables optimal tumor targeting and sparing of organs-at-risk, which ultimately results in improved outcomes for patients. Magnetic resonance imaging (MRI) revolutionized diagnostic imaging with its superior soft tissue contrast, high spatiotemporal resolution, and freedom from ionizing radiation exposure. Over the past few years there has been burgeoning interest in MR-guided radiotherapy (MRgRT) to overcome current challenges in X-ray-based IGRT, including but not limited to, suboptimal soft tissue contrast, lack of efficient daily adaptation, and incremental exposure to ionizing radiation. In this review, we present an overview of the technologic advancements in IGRT that led to MRI-linear accelerator (MRL) integration. Our report is organized in three parts: (1) a historical timeline tracing the origins of radiotherapy and evolution of IGRT, (2) currently available MRL technology, and (3) future directions and aspirations for MRL applications.

Towards Accurate and Precise Image-Guided Radiotherapy: Clinical Applications of the MR-Linac.

Advances in image-guided radiotherapy have brought about improved oncologic outcomes and reduced toxicity. The next generation of image guidance in the form of magnetic resonance imaging (MRI) will improve visualization of tumors and make radiation treatment adaptation possible. In this review, we discuss the role that MRI plays in radiotherapy, with a focus on the integration of MRI with the linear accelerator. The MR linear accelerator (MR-Linac) will provide real-time imaging, help assess motion management, and provide online adaptive therapy. Potential advantages and the current state of these MR-Linacs are highlighted, with a discussion of six different clinical scenarios, leading into a discussion on the future role of these machines in clinical workflows.

Phase II trial of proton therapy versus photon IMRT for GBM: secondary analysis comparison of progression-free survival between RANO versus clinical assessment.

BACKGROUND: This secondary image analysis of a randomized trial of proton radiotherapy (PT) versus photon intensity-modulated radiotherapy (IMRT) compares tumor progression based on clinical radiological assessment versus Response Assessment in Neuro-Oncology (RANO). METHODS: Eligible patients were enrolled in the randomized trial and had MR imaging at baseline and follow-up beyond 12 weeks from completion of radiotherapy. "Clinical progression" was based on a clinical radiology report of progression and/or change in treatment for progression. RESULTS: Of 90 enrolled patients, 66 were evaluable. Median clinical progression-free survival (PFS) was 10.8 (range: 9.4-14.7) months; 10.8 months IMRT versus 11.2 months PT (P = .14). Median RANO-PFS was 8.2 (range: 6.9, 12): 8.9 months IMRT versus 6.6 months PT (P = .24). RANO-PFS was significantly shorter than clinical PFS overall (P = .001) and for both the IMRT (P = .01) and PT (P = .04) groups. There were 31 (46.3%) discrepant cases of which 17 had RANO progression more than a month prior to clinical progression, and 14 had progression by RANO but not clinical criteria. CONCLUSIONS: Based on this secondary analysis of a trial of PT versus IMRT for glioblastoma, while no difference in PFS was noted relative to treatment technique, RANO criteria identified progression more often and earlier than clinical assessment. This highlights the disconnect between measures of tumor response in clinical trials versus clinical practice. With growing efforts to utilize real-world data and personalized treatment with timely adaptation, there is a growing need to improve the consistency of determining tumor progression within clinical trials and clinical practice.

Detection of Glioblastoma Subclinical Recurrence Using Serial Diffusion Tensor Imaging.

Glioblastoma is an aggressive brain tumor with a propensity for intracranial recurrence. We hypothesized that tumors can be visualized with diffusion tensor imaging (DTI) before they are detected on anatomical magnetic resonance (MR) images. We retrospectively analyzed serial MR images from 30 patients, including the DTI and T1-weighted images at recurrence, at 2 months and 4 months before recurrence, and at 1 month after radiation therapy. The diffusion maps and T1 images were deformably registered longitudinally. The recurrent tumor was manually segmented on the T1-weighted image and then applied to the diffusion maps at each time point to collect mean FA, diffusivities, and neurite density index (NDI) values, respectively. Group analysis of variance showed significant changes in FA (p = 0.01) and NDI (p = 0.0015) over time. Pairwise t tests also revealed that FA and NDI at 2 months before recurrence were 11.2% and 6.4% lower than those at 1 month after radiation therapy (p < 0.05), respectively. Changes in FA and NDI were observed 2 months before recurrence, suggesting that progressive microstructural changes and neurite density loss may be detectable before tumor detection in anatomical MR images. FA and NDI may serve as non-contrast MR-based biomarkers for detecting subclinical tumors.

Detection of a Mammographically Occult Breast Cancer with a Challenging Clinical History.

Screening mammography has helped to identify countless incidences of breast cancer since its adoption in the 1960s. Over time, the screening guidelines and techniques have been refined to better detect malignancies and to avoid false positive results. However, weaknesses remain in mammography and represent an opportunity for improvement. The interference of natural breast tissue and glands can obscure the presence of occult breast malignancies. Additionally, the inability to differentiate breast tissue on the basis of depth, and the compounding of breast densities that occurs as a consequence of two-dimensional imaging, are setbacks when it comes to relying on mammography. User error and bias can also misguide the proper detection of underlying cancers during the radiological interpretation process. The following case represents a combination of these factors and others that culminated in a missed diagnosis of invasive ductal carcinoma in a young woman suffering from mastitis of the contralateral breast.

Upregulation of Cystathionine-ß-Synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis.

The trans-sulfuration enzyme cystathionine-ß-synthase (CBS) and its product hydrogen sulfide (H2S) are aberrantly upregulated in colorectal cancers, where they contribute to tumor growth and progression by both autocrine and paracrine mechanisms. However, it is unknown whether the CBS/H2S axis plays a role in colorectal carcinogenesis. Here, we report upregulation of CBS in human biopsies of precancerous adenomatous polyps and show that forced upregulation of CBS in an adenoma-like colonic epithelial cell line is sufficient to induce metabolic and gene expression profiles characteristic of colorectal cancer cells. Differentially expressed metabolites (65 increased and 20 decreased) clustered into the glycolytic pathway, nucleotide sugars, intermediates of the pentose phosphate pathway, and lipogenesis, including primarily phospholipids, sphingolipids, and bile acids. CBS upregulation induced broad changes in the NCM356 cell transcriptome with over 350 differentially expressed genes. These genes overlapped significantly with gene sets related to glycolysis, hypoxia, and a colon cancer cell phenotype, including genes regulated by NF-κB, KRAS, p53, and Wnt signaling, genes downregulated after E-cadherin knockdown, and genes related to increased extracellular matrix, cell adhesion, and epithelial-to-mesenchymal transition. The CBS-induced switch to an anabolic metabolism was associated with increased NCM356 cell bioenergetics, proliferation, invasion through Matrigel, resistance to anoikis, and CBS-dependent tumorigenesis in immunocompromised mice. Genetic ablation of CBS in CBS heterozygous mice (CBS+/- ) reduced the number of mutagen-induced aberrant colonic crypt foci. Taken together, these results establish that activation of the CBS/H2S axis promotes colon carcinogenesis. Cancer Res; 77(21); 5741-54. ©2017 AACR.