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Purpose In this pilot study, DKI measures of diffusivity and kurtosis were compared in active tumor regions and correlated to radiologic response to radiotherapy after completion of 2 weeks of treatment to derive potential early measures of tumor response.Methods MRI and Magnetic Resonance Spectroscopic Imaging (MRSI) data were acquired before the beginning of RT (pre-RT) and 2 weeks after the initiation of treatment (during-RT) in 14 glioblastoma patients. The active tumor region was outlined as the union of the residual contrast-enhancing region and metabolically active tumor region. Average and standard deviation of mean, axial, and radial diffusivity (MD, AD, RD) and mean, axial, and radial kurtosis (MK, AK, RK) values were calculated for the active tumor VOI from images acquired pre-RT and during-RT and paired t-tests were executed to estimate pairwise differences. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the predictive capabilities of changes in diffusion metrics for progression-free survival (PFS).Results Analysis showed significant pairwise differences for AD (p= 0.035; Cohen’s d of 0.659) and AK (p= 0.019; Cohen’s d of 0.753) in diffusion measures after 2 weeks of RT. ROC curve analysis showed that percentage change differences in AD and AK between pre-RT and during-RT scans provided an Area Under the Curve (AUC) of 0.524 and 0.762, respectively, in discriminating responders (PFS>180 days) and non-responders (PFS<180 days).Conclusion This pilot study, although preliminary in nature, showed significant changes in AD and AK maps, with kurtosis derived AK maps showing an increased sensitivity in mapping early changes in the active tumor regions.

Radiation therapy (RT) plays a critical role in the overall management of many central nervous system (CNS) tumors. Advances in RT treatment planning, with techniques such as intensity modulated radiation therapy, volumetric modulated arc therapy, and stereotactic radiosurgery, now allow the delivery of highly conformal dose with great precision. These techniques rely on high-resolution 3-dimensional anatomical imaging modalities such as computed tomography or magnetic resonance imaging (MRI) scans to accurately and reliably define CNS targets and normal tissue avoidance structures. The integration of cross-sectional imaging into radiation oncology has directly translated into improvements in the therapeutic window of RT, and the union between radiation oncology and imaging is only expected to grow stronger. In addition, advanced imaging modalities including diffusion, perfusion, and spectroscopic MRIs as well as positron emission tomography (PET) scans with novel tracers are being utilized to provide additional insight into tumor biology and behavior beyond anatomy. Together, these standard and advanced imaging modalities hold significant potential to improve future RT delivery and response assessment. In this review, we will discuss the current utilization of standard/advanced imaging for CNS tumors from a radiation oncology perspective as well as the implications of novel MRI and PET modalities currently under investigation.

An increased understanding of the molecular biology of metastatic processes, including cell migration, blood–brain barrier penetration, angiogenesis and tumour proliferation, is providing new opportunities for the development of targeted therapiesAdvances in MRI, incorporating spectroscopy and perfusion techniques, and tracers unique to metastases, provide additional information on responses to treatment and enable the earlier detection of new tumoursImprovements in intraoperative tumour identification using MRI and fluorescent agents maximize the likelihood of complete tumour resection and minimize injury to normal tissueReduction of radiation-induced cerebral injury and cognitive decline through repeated use of stereotactic radiosurgery or hippocampal-avoidance whole-brain radiotherapy provide useful options for individuals with advanced cerebral metastatic diseaseTargeted therapy is beneficial in molecularly-selected tumours, including erlotinib in EGFR-mutant lung tumours, crizotinib in lung carcinomas with EML4–ALKtranslocations, trastuzumab in HER2+breast cancer and dabrafenib in BRAF-mutant melanoma

Abstract: Purpose: L-type amino acid transporter 1 (LAT1) is essential for the transport of large neutral amino acids. However, its role in breast cancer growth remains largely unknown. The purpose of the study is to investigate whether LAT1 is a potential biomarker for the diagnosis and treatment of breast cancer. Methods: LAT1 mRNA and protein levels in breast cancer cell lines and tissues were analyzed. In addition, the effects of targeting LAT1 for the inhibition of breast cancer cell tumorigenesis were assessed with soft agar assay. The imaging of xenograft with anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-[18F]FACBC) PET was assessed for its diagnostic biomarker potential. Results: Normal breast tissue or low malignant cell lines expressed low levels of LAT1 mRNA and protein, while highly malignant cancer cell lines and high-grade breast cancer tissue expressed high levels of LAT1. In addition, higher expression levels of LAT1 in breast cancer tissues were consistent with advanced-stage breast cancer. Furthermore, the blockade of LAT1 with its inhibitor, 2-amino-bicyclo[2.2.1]heptane-2-carboxylic acid (BCH), or the knockdown of LAT1 with siRNA, inhibited proliferation and tumorigenesis of breast cancer cells. A leucine analog, anti-[18F]FACBC, has been demonstrated to be an excellent PET tracer for the non-invasive imaging of malignant breast cancer using an orthotopic animal model. Conclusions: The overexpression of LAT1 is required for the progression of breast cancer. LAT1 represents a potential biomarker for therapy and diagnosis of breast cancer. Anti-[18F]FACBC that correlates with LAT1 function is a potential PET tracer for malignant breast tumor imaging.

Positron emission tomography (PET) is a noninvasive imaging technique that provides a functional or metabolic assessment of normal tissue or disease conditions. Fluorine 18–fluorodeoxyglucose PET imaging (FDG-PET) is widely used clinically for tumor imaging due to increased glucose metabolism in most types of tumors, and has been shown to improve the diagnosis and subsequent treatment of cancers. We review its use in cancer diagnosis, staging, restaging, and assessment of response to treatment. In addition, other metabolic PET imaging agents in pre-clinical research or clinical trial stages of development are discussed, including amino acid analogs based on increased protein synthesis, and choline, which is based on increased membrane lipid synthesis. Amino acid analogs and choline are more specific to tumor cells than FDG, so they play an important role in differentiating cancers from benign conditions and in the diagnosis of cancers with low FDG uptake or high background FDG uptake. For decades, researchers have shown that tumors display altered metabolic profiles with elevated uptake of glucose, amino acids, and lipids. This can be used for cancer diagnosis and monitoring of the therapeutic response with excellent signal-to-noise ratios.

Abstract: Molecular imaging is one of the fastest growing areas of medical imaging. Positron emission tomography (PET) has been widely used in the clinical management of patients with cancer. Nuclear imaging provides biological information at the cellular, subcellular, and molecular level in living subjects with non-invasive procedures. In particular, PET imaging takes advantage of traditional diagnostic imaging techniques and introduces positron-emitting probes to determine the expression of indicative molecular targets at different stages of cancer. 18F-fluorodeoxyglucose (18F-FDG), the only FDA approved oncological PET tracer, has been widely utilized in cancer diagnosis, staging, restaging, and even monitoring response to therapy; however, 18F-FDG is not a tumor-specific PET tracer. Over the last decade, many promising tumor-specific PET tracers have been developed and evaluated in preclinical and clinical studies. This review provides an overview of the current non-18F-FDG PET tracers in oncology that have been developed based on tumor characteristics such as increased metabolism, hyperproliferation, angiogenesis, hypoxia, apoptosis, and tumor-specific antigens and surface receptors.

We have identified a novel c-Myc-responsive gene, named JPO1, by representational difference analysis.JPO1responds to two inducible c-Myc systems and behaves as a direct c-Myc target gene. JPO1mRNA expression is readily detectable in the thymus, small intestine, and colon, whereas expression is relatively low in spleen, bone marrow, and peripheral leukocytes. We cloned a full-length JPO1cDNA that encodes a 47-kDa nuclear protein. To determine the role of JPO1 in Myc-mediated cellular phenotypes, stable Rat1a fibroblasts overexpressing JPO1 were tested and compared with transformed Rat1a-Myc cells. Although JPO1 has a diminished transforming activity as compared with c-Myc, JPO1 complements a transformation-defective Myc Box II mutant in the Rat1a transformation assay. This complementation provides evidence for a genetic link between c-Myc and JPO1. Similar to c-Myc, JPO1 overexpression enhances the clonogenicity of CB33 human lymphoblastoid cells in methylcellulose assays. These observations suggest that JPO1 participates in c-Myc-mediated transformation, supporting an emerging concept that c-Myc target genes constitute nodal points in a network of pathways that lead from c-Myc to various Myc-related phenotypes and ultimately to tumorigenesis.

Unlike normal mammalian cells, which use oxygen to generate energy, cancer cells rely on glycolysis for energy and are therefore less dependent on oxygen. We previously observed that the c-Myc oncogenic transcription factor regulates lactate dehydrogenase A and induces lactate overproduction. We, therefore, sought to determine whether c-Myc controls other genes regulating glucose metabolism. In Rat1a fibroblasts and murine livers overexpressing c-Myc, the mRNA levels of the glucose transporter GLUT1, phosphoglucose isomerase, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase were elevated. c-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.

Diffusion NMR spectroscopy was used to study intracellular volume and apparent water diffusion constants in different cell lines (DU145, human prostate cancer; AT3, rat prostate cancer; MCF‐7, human breast cancer; RIF‐1, mouse fibrosacroma). The cells were grown on various matrices (collagen sponge, collagen beads, polystyrene beads) which enabled continuous growth in perfused high density cell culture suitable for NMR studies. In perfused cell systems, the attenuation of the water signal versus the squared gradient strength was fitted by the sum of two decaying exponentials. For the slowly decaying component the apparent water diffusion constant at 37°C was 0.22 (±0.02) × 10−9s/m2for all cell lines at diffusion times > 100 ms. It continuously increased up to 0.47(±0.05) × 10−9s/m2when the diffusion time was decreased to 8 ms, indicating restricted diffusion. No significant effect of the matrices was observed. The fractional volume of the slow component as determined from the biexponential diffusion curve correlated with the relative intracellular volume, as obtained from the cell density in the sample and the cell size as measured by light microsocopy. Therefore, this simple NMR approach can be used to determine intracellular volume in perfused cell cultures suitable for NMR studies. Using this information in combination with spectroscopic data, changes in intracellular metabolite concentration can be detected even when the cellular volume is changing during the experiment. The apparent diffusion constant for the fast diffusing component varied with growth matrix, cell density and cell type and also showed the typical characteristics of restricted diffusion (increase of apparent diffusion constant with time).

A method is described for the isolation and purification of active oxygen-evolving photosystem II (PS II) membranes from the green alga Chlamydomonas reinhardtii. The isolation procedure is a modification of methods evolved for spinach (Berthold et al. 1981). The purity and integrity of the PS II preparations have been assesssed on the bases of the polypeptide pattern in SDS-PAGE, the rate of oxygen evolution, the EPR multiline signal of the S2 state, the room temperature chlorophyll a fluorescence yield, the 77 K emission spectra, and the P700 EPR signal at 300 K. These data show that the PS II characteristics are increased by a factor of two in PS II preparations as compared to thylakoid samples, and the PS I concentration is reduced by approximately a factor ten compared to that in thylakoids.

The ability of cancer cells to overproduce lactic acid aerobically was recognized by Warburg about seven decades ago, although its molecular basis has been elusive. Increases in glucose transport and hexokinase activity in cancer cells appear to account for the increased flux of glucose through the cancer cells. Herein we review current findings indicating that the c-Myc oncogenic transcription factor and hypoxia-inducible factor 1 (HIF-1) are able to bind the lactate dehydrogenase A promoter cisacting elements, which resemble the core carbohydrate response element (ChoRE), CACGTG. These and other observations suggest that the normal cell responds physiologically to changes in oxygen tension or the availability of glucose by altering glycolysis through the ChoRE, which hypothetically binds c-Myc, HIF-1, or related factors. The neoplastic cell is hypothesized to augment glycolysis by activation of ChoRE/ HIF-1 sites through direct interaction with c-Myc or through activation of HIF-1 or HIF-1 -like activity. We hypothesize that oncogene products either stimulate HIF-1 and related factors or, in the case of c-Myc, directly activate hypoxia/glucose responsive elements in glycolytic enzyme genes to increase the ability of cancer cells to undergo aerobic glycolysis.

The c-Myc protein is a helix-loop-helix leucine zipper oncogenic transcription factor that participates in the regulation of cell proliferation, differentiation, and apoptosis. The biochemical function of c-Myc has been well described, yet the identities of downstream effectors are just beginning to emerge. We describe the identification of a set of c-Myc-responsive genes in the Rat1a fibroblast through the application of cDNA representational difference analysis (RDA) to cDNAs isolated from nonadherent Rat1a and Rat1a-myc cells. In this system, c-Myc overexpression is sufficient to induce the transformed phenotype of anchorage-independent growth. We identified 20 differentially expressed cDNAs, several of which represent novel cDNA sequences. We further characterized one of the novel cDNAs identified in this screen, termed rcl. rclexpression is (i) directly stimulated by c-Myc; (ii) stimulated in the in vivo growth system of regenerating rat liver, as is c-myc; and (iii) elevated in human lymphoid cells that overexpress c-myc. By using an anti-Rcl antibody, immunoblot analysis, and immunofluorescence microscopy, the Rcl protein was found to be a 23-kDa nuclear protein. Ectopic expression of the protein encoded by the rclcDNA induces anchorage-independent growth in Rat1a fibroblasts, albeit to a diminished extent compared to ectopic c-Myc expression. These data suggest a role for rclduring cellular proliferation and c-Myc-mediated transformation.

Magnetic resonance spectroscopy (MRS) is a valuable tool for imaging brain tumors, primarily as an adjunct to conventional imaging and clinical presentation. MRS is useful in initial diagnosis of brain tumors, helping differentiate tumors from possible mimics such as metastatic disease, lymphoma, demyelination, and infection, as well as in the subsequent follow-up of patients after resection and chemoradiation. Unfortunately, the spectroscopic appearance of many pathologies can overlap, and ultimately follow-up or biopsy may be required to make a definitive diagnosis. Future developments may continue to increase the value of MRS for initial diagnosis, treatment planning, and early detection of recurrence.