Tumour evolution and microenvironment interactions in 2D and 3D space.

To study the spatial interactions among cancer and non-cancer cells1, we here examined a cohort of 131 tumour sections from 78 cases across 6 cancer types by Visium spatial transcriptomics (ST). This was combined with 48 matched single-nucleus RNA sequencing samples and 22 matched co-detection by indexing (CODEX) samples. To describe tumour structures and habitats, we defined 'tumour microregions' as spatially distinct cancer cell clusters separated by stromal components. They varied in size and density among cancer types, with the largest microregions observed in metastatic samples. We further grouped microregions with shared genetic alterations into 'spatial subclones'. Thirty five tumour sections exhibited subclonal structures. Spatial subclones with distinct copy number variations and mutations displayed differential oncogenic activities. We identified increased metabolic activity at the centre and increased antigen presentation along the leading edges of microregions. We also observed variable T cell infiltrations within microregions and macrophages predominantly residing at tumour boundaries. We reconstructed 3D tumour structures by co-registering 48 serial ST sections from 16 samples, which provided insights into the spatial organization and heterogeneity of tumours. Additionally, using an unsupervised deep-learning algorithm and integrating ST and CODEX data, we identified both immune hot and cold neighbourhoods and enhanced immune exhaustion markers surrounding the 3D subclones. These findings contribute to the understanding of spatial tumour evolution through interactions with the local microenvironment in 2D and 3D space, providing valuable insights into tumour biology.

NCCN Guidelines® Insights: Prostate Cancer, Version 3.2024.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

Oncogenic Gq/11 signaling acutely drives and chronically sustains metabolic reprogramming in uveal melanoma.

Metabolic reprogramming has been shown to occur in uveal melanoma (UM), the most common intraocular tumor in adults. Mechanisms driving metabolic reprogramming in UM are poorly understood. Elucidation of these mechanisms could inform development of new therapeutic strategies for metastatic UM, which has poor prognosis because existing therapies are ineffective. Here, we determined whether metabolic reprogramming is driven by constitutively active mutant α-subunits of the heterotrimeric G proteins Gq or G11 (Gq/11), the oncogenic drivers in ∼90% of UM patients. Using PET-computed tomography imaging, microphysiometry, and GC/MS, we found that inhibition of oncogenic Gq/11 with the small molecule FR900359 (FR) attenuated glucose uptake by UM cells in vivo and in vitro, blunted glycolysis and mitochondrial respiration in UM cell lines and tumor cells isolated from patients, and reduced levels of several glycolytic and tricarboxylic acid cycle intermediates. FR acutely inhibited glycolysis and respiration and chronically attenuated expression of genes in both metabolic processes. UM therefore differs from other melanomas that exhibit a classic Warburg effect. Metabolic reprogramming in UM cell lines and patient samples involved protein kinase C and extracellular signal-regulated protein kinase 1/2 signaling downstream of oncogenic Gq/11. Chronic administration of FR upregulated expression of genes involved in metabolite scavenging and redox homeostasis, potentially as an adaptive mechanism explaining why FR does not efficiently kill UM tumor cells or regress UM tumor xenografts. These results establish that oncogenic Gq/11 signaling is a crucial driver of metabolic reprogramming in UM and lay a foundation for studies aimed at targeting metabolic reprogramming for therapeutic development.

Prostate Cancer, Version 4.2023, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions regarding the workup of patients with prostate cancer, risk stratification and management of localized disease, post-treatment monitoring, and treatment of recurrence and advanced disease. The Guidelines sections included in this article focus on the management of metastatic castration-sensitive disease, nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). Androgen deprivation therapy (ADT) with treatment intensification is strongly recommended for patients with metastatic castration-sensitive prostate cancer. For patients with nonmetastatic CRPC, ADT is continued with or without the addition of certain secondary hormone therapies depending on prostate-specific antigen doubling time. In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, the presence or absence of visceral disease, symptoms, and potential side effects.

Low-Field-Strength Body MRI: Challenges and Opportunities at 0.55 T.

Advances in MRI technology have led to the development of low-field-strength (hereafter, "low-field") (0.55 T) MRI systems with lower weight, fewer shielding requirements, and lower cost than those of traditional (1.5-3 T) systems. The trade-offs of lower signal-to-noise ratio (SNR) at 0.55 T are partially offset by patient safety and potential comfort advantages (eg, lower specific absorption rate and a more cost-effective larger bore diameter) and physical advantages (eg, decreased T2* decay, shorter T1 relaxation times). Image reconstruction advances leveraging developing technologies (such as deep learning-based denoising) can be paired with traditional techniques (such as increasing the number of signal averages) to improve SNR. The overall image quality produced by low-field MRI systems, although perhaps somewhat inferior to 1.5-3 T MRI systems in terms of SNR, is nevertheless diagnostic for a broad variety of body imaging applications. Effective low-field body MRI requires (a) an understanding of the trade-offs resulting from lower field strengths, (b) an approach to modifying routine sequences to overcome SNR challenges, and (c) a workflow for carefully selecting appropriate patients. The authors describe the rationale, opportunities, and challenges of low-field body MRI; discuss important considerations for low-field imaging with common body MRI sequences; and delineate a variety of use cases for low-field body MRI. The authors also include lessons learned from their preliminary experience with a new low-field MRI system at a tertiary care center. Finally, they explore the future of low-field MRI, summarizing current limitations and potential future developments that may enhance the clinical adoption of this technology. ©RSNA, 2023 Supplemental material is available for this article. Quiz questions for this article are available through the Online Learning Center. See the invited commentary by Venkatesh in this issue.

High visceral fat to subcutaneous fat ratios portend a poor prognosis in patients with advanced endometrial cancer.

OBJECTIVES: Visceral adiposity has been established as a predictor of outcomes in various cancers. We aimed to determine the association of radiographic measurements of visceral fat with clinical outcomes in patients with endometrial cancer. METHODS: A retrospective review of patients with stage III-IV endometrial cancer who underwent surgery between 2004 and 2014 was performed. Visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and total adipose tissue (TAT;VAT+SAT) were assessed on preoperative computed tomography (CT) scans. Exploratory analysis was performed to establish the optimal cut-off values for VAT, SAT, and TAT to identify patients with poor prognostic body composition. Survival rates were analyzed using Kaplan-Meier analysis, log-rank tests, and cox-regression. RESULTS: Eighty-three patients were included. Forty-two (51%) patients had a low VAT/SAT ratio (<0.45) and 41 (49.4%) had a high VAT/SAT ratio (>0.45). There were no significant differences in demographics between the groups. The mean VAT, SAT, and TAT were 176.3 cm2, 379.3 cm2, and 555.3 cm2 respectively. Compared to patients with low VAT/SAT ratios, patients with high VAT/SAT ratios had a shorter recurrence-free survival (median 29.6 vs 32.3 months, P = 0.01) and shorter overall survival (median 56 vs 93.7 months, P = 0.03). CONCLUSIONS: Visceral fat measurements are predictive of outcomes in patients with advanced stage endometrial cancer. Specifically, VAT to SAT ratios are predictive of overall survival. Future studies should be pursued to identify potential therapeutic targets and biological mechanisms that underlie obesity's relationship with endometrial cancer.

NCCN Guidelines® Insights: Prostate Cancer, Version 1.2023.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, recurrent, and metastatic disease. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. These NCCN Guidelines Insights summarizes much of the panel's discussions for the 4.2022 and 1.2023 updates to the guidelines regarding systemic therapy for metastatic prostate cancer.

Prostate MRI in Stereotactic Body Radiation Treatment Planning and Delivery for Localized Prostate Cancer.

Prostate MRI is increasingly being used to make diagnoses and guide management for patients receiving definitive radiation treatment for prostate cancer. Radiologists should be familiar with the potential uses of prostate MRI in radiation therapy planning and delivery. Radiation therapy is an established option for the definitive treatment of localized prostate cancer. Stereotactic body radiation therapy (SBRT) is an external-beam radiation therapy method used to deliver a high dose of radiation to an extracranial target in the body, often in five or fewer fractions. SBRT is increasingly being used for prostate cancer treatment and has been recognized by the National Comprehensive Cancer Network as an acceptable definitive treatment regimen for low-, intermediate-, and high-risk prostate cancer. MRI is commonly used to aid in prostate radiation therapy. The authors review the uses of prostate MRI in SBRT treatment planning and delivery. Specific topics discussed include the use of prostate MRI for identification of and dose reduction to the membranous and prostatic urethra, which can decrease the risk of acute and late toxicities. MRI is also useful for identification and appropriate dose coverage of the prostate apex and areas of extraprostatic extension or seminal vesicle invasion. In prospective studies, prostate MRI is being validated for identification of and dose intensification to dominant intraprostatic lesions, which potentially can improve oncologic outcomes. It also can be used to evaluate the placement of fiducial markers and hydrogel spacers for radiation therapy planning and delivery. ©RSNA, 2022.

Comparison of hyperpolarized 13 C and non-hyperpolarized deuterium MRI approaches for imaging cerebral glucose metabolism at 4.7 T.

PURPOSE: The purpose of this study was to directly compare two isotopic metabolic imaging approaches, hyperpolarized (HP) 13 C MRI and deuterium metabolic imaging (DMI), for imaging specific closely related segments of cerebral glucose metabolism at 4.7 T. METHODS: Comparative HP-13 C and DMI neuroimaging experiments were conducted consecutively in normal rats during the same scanning session. Localized conversions of [1-13 C]pyruvate and [6,6-2 H2 ]glucose to their respective downstream metabolic products were measured by spectroscopic imaging, using an identical 2D-CSI sequence with parameters optimized for the respective experiments. To facilitate direct comparison, a pair of substantially equivalent 2.5-cm double-tuned X/1 H RF surface coils was developed. For improved results, multidimensional low-rank reconstruction was applied to denoise the raw DMI data. RESULTS: Localized conversion of HP [1-13 C]pyruvate to [1-13 C]lactate, and [6,6-2 H2 ]glucose to [3,3-2 H2 ]lactate and Glx-d (glutamate and glutamine), was detected in rat brain by spectroscopic imaging at 4.7 T. The SNR and spatial resolution of HP-13 C MRI was superior to DMI but limited to a short time window, whereas the lengthy DMI acquisition yielded maps of not only lactate, but also Glx production, albeit with relatively poor spectral discrimination between metabolites at this field strength. Across the individual rats, there was an apparent inverse correlation between cerebral production of HP [1-13 C]lactate and Glx-d, along with a trend toward increased [3,3-2 H2 ]lactate. CONCLUSION: The HP-13 C MRI and DMI methods are both feasible at 4.7 T and have significant potential for metabolic imaging of specific segments of glucose metabolism.

NCCN Guidelines Insights: Prostate Cancer, Version 1.2021.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel's discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.

Correction to: Inhibition of the key metabolic pathways, glycolysis and lipogenesis, of oral cancer by bitter melon extract.

Following publication of the original article [1], it was reported that Fig. 1c was not entirely readable due to overlapping Fig. 1d. The publishers apologise for this error.

Inhibition of the key metabolic pathways, glycolysis and lipogenesis, of oral cancer by bitter melon extract.

BACKGROUND: Metabolic reprogramming is one of the hallmarks of cancer which favours rapid energy production, biosynthetic capabilities and therapy resistance. In our previous study, we showed bitter melon extract (BME) prevents carcinogen induced mouse oral cancer. RNA sequence analysis from mouse tongue revealed a significant modulation in "Metabolic Process" by altering glycolysis and lipid metabolic pathways in BME fed group as compared to cancer group. In present study, we evaluated the effect of BME on glycolysis and lipid metabolism pathways in human oral cancer cells. METHODS: Cal27 and JHU022 cells were treated with BME. RNA and protein expression were analysed for modulation of glycolytic and lipogenesis genes by quantitative real-time PCR, western blot analyses and immunofluorescence. Lactate and pyruvate level was determined by GC/MS. Extracellular acidification and glycolytic rate were measured using the Seahorse XF analyser. Shotgun lipidomics in Cal27 and JHU022 cell lines following BME treatment was performed by ESI/ MS. ROS was measured by FACS. RESULTS: Treatment with BME on oral cancer cell lines significantly reduced mRNA and protein expression levels of key glycolytic genes SLC2A1 (GLUT-1), PFKP, LDHA, PKM and PDK3. Pyruvate and lactate levels and glycolysis rate were reduced in oral cancer cells following BME treatment. In lipogenesis pathway, we observed a significant reduction of genes involves in fatty acid biogenesis, ACLY, ACC1 and FASN, at the mRNA and protein levels following BME treatment. Further, BME treatment significantly reduced phosphatidylcholine, phosphatidylethanolamine, and plasmenylethanolamine, and reduced iPLA2 activity. Additionally, BME treatment inhibited lipid raft marker flotillin expression and altered its subcellular localization. ER-stress associated CHOP expression and generation of mitochondrial reactive oxygen species were induced by BME, which facilitated apoptosis. CONCLUSION: Our study revealed that bitter melon extract inhibits glycolysis and lipid metabolism and induces ER and oxidative stress-mediated cell death in oral cancer. Thus, BME-mediated metabolic reprogramming of oral cancer cells will have important preventive and therapeutic implications along with conventional therapies.

Current Status of MRI and PET in the NCCN Guidelines for Prostate Cancer.

Prostate cancer (PCa) represents a significant source of morbidity and mortality for men in the United States, with approximately 1 in 9 being diagnosed with PCa in their lifetime. The role of imaging in the evaluation of men with PCa has evolved and currently plays a central role in diagnosis, treatment planning, and evaluation of recurrence. Appropriate use of multiparametric MRI (mpMRI) and MRI-guided transrectal ultrasound (MR-TRUS) biopsy increases the detection of clinically significant PCa while decreasing the detection of clinically insignificant PCa. This process may help patients with clinically insignificant PCa avoid the adverse effects of unnecessary therapy. In the setting of a known PCa, patients with low-grade disease can be observed using active surveillance, which often includes a combination of prostate-specific antigen (PSA) testing, serial mpMRI, and, if indicated, follow-up systematic and targeted TRUS-guided tissue sampling. mpMRI can provide important information in the posttreatment setting, but PET/CT is creating a paradigm shift in imaging standards for patients with locally recurrent and metastatic PCa. This article examines the strengths and limitations of mpMRI for initial PCa diagnosis, active surveillance, recurrent disease evaluation, and image-guided biopsies, and the use of PET/CT imaging in men with recurrent PCa. The goal of this review is to provide a rational basis for current NCCN Clinical Practice Guidelines in Oncology for PCa as they pertain to the use of these advanced imaging modalities.

Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.

Synergy of Sex Differences in Visceral Fat Measured with CT and Tumor Metabolism Helps Predict Overall Survival in Patients with Renal Cell Carcinoma.

Purpose To determine if sex differences in abdominal visceral fat composition, measured by using computed tomography (CT), and tumor glucose metabolism, measured by gene expression, can help predict outcomes in patients with clear cell renal cell carcinoma (RCC). Materials and Methods This retrospective cohort study included 222 patients with clear cell RCC from The Cancer Imaging Atlas. By using CT, body fat was segmented into subcutaneous fat and visceral fat areas (VFAs) and normalized to total fat to obtain the relative VFA (rVFA) and relative subcutaneous fat area. Multivariate Cox proportional hazard regression models were performed to identify effects of rVFA on sex-specific survival. Expression profiles for 39 glycolytic genes in tumors from these patients were obtained from The Cancer Genome Atlas to determine sex differences in metabolism and compared with rVFA. Key mutations in clear cell RCC were analyzed for association with rVFA and tumor glycolytic profiles. Results Women with rVFA greater than 30.9% had an increased risk of death (hazard ratio, 3.66 [95% confidence interval: 1.64, 8.19]) for women vs 1.13 ([95% confidence interval: 0.58, 2.18] for men, P = .028). Glycolytic gene expression stratified both men and women, and the combination of low rVFA and low glycolysis identified 19 women with excellent overall survival (P < .001). SETD2 and BAP1 mutations were uniquely enriched in female tumors with high glycolysis (P = .036 and .001, respectively). No significant differences were identified in tumor mutations between patients with high and low rVFA. Conclusion Sex differences in visceral fat and tumor glucose metabolism may provide a new risk-stratification system for patients with clear cell RCC. © RSNA, 2018 Online supplemental material is available for this article.

Prostate cancer PET tracers: essentials for the urologist.

INTRODUCTION: In the past, positron emission tomography (PET) has played a relatively limited role in prostate cancer imaging. However, in recent years, several new PET tracers have emerged, offering potential improvements in diagnostic performance for both the detection of prostate cancer metastases at initial staging and the localization of recurrent disease. MATERIALS AND METHODS: We reviewed the literature for prostate cancer PET tracers that are either being used for patient management or being evaluated in clinical research trials. For each tracer, we compiled clinically relevant background information and evidence supporting clinical use, with the intention of providing a high-yield primer for urologists managing patients with prostate cancer. RESULTS: 18F-FDG, 18F-NaF, ¹¹C-choline, and 18F-fluciclovine have all proven useful for prostate cancer imaging, though the utility of each of these tracers is limited to targeted management questions and particular clinical settings. In contrast, the newer prostate-specific membrane antigen (PSMA) agents may prove useful as general purpose PET tracers for prostate cancer imaging. Numerous other novel PET tracers have shown promising results in pre-clinical studies. CONCLUSION: Basic knowledge of these PET tracers, specifically their strengths, weaknesses, and indications for use, is essential to urologists and other physicians caring for patients with prostate cancer.

Imaging in Prostate Cancer: Magnetic Resonance Imaging and Beyond.

Imaging is becoming critical for guiding management decisions in prostate cancer (PCa) both at initial diagnosis and at recurrence. Multiparametric magnetic resonance imaging (mpMRI) and positron emission tomography (PET) of the prostate have proven valuable in the detection and localization of aggressive disease. Therefore, understanding the indications for mpMRI, imaging techniques and interpretation, limitations of current imaging approaches, and utility of PET and simultaneous PET/MRI has become increasingly important.

Beyond Seed and Soil: Understanding and Targeting Metastatic Prostate Cancer; Report From the 2016 Coffey-Holden Prostate Cancer Academy Meeting.

INTRODUCTION: The 2016 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Beyond Seed and Soil: Understanding and Targeting Metastatic Prostate Cancer," was held from June 23 to June 26, 2016, in Coronado, California. METHODS: For the 4th year in a row, the Prostate Cancer Foundation (PCF) hosted the CHPCA Meeting, a think tank-structured scientific conference, which focuses on a specific topic of critical unmet need on the biology and treatment of advanced prostate cancer. The 2016 CHPCA Meeting was attended by 71 investigators from prostate cancer and other fields, who discussed the biology, study methodologies, treatment strategies, and critical unmet needs concerning metastatic prostate cancer, with the ultimate goal of advancing strategies to treat and eliminate this disease. RESULTS: The major topics of discussion included: the molecular landscape and molecular heterogeneity of metastatic prostate cancer, the role of the metastatic microenvironment, optimizing immunotherapy in metastatic prostate cancer, learning from exceptional responders and non-responders, targeting DNA repair deficiency in advanced prostate cancer, developing and applying novel biomarkers and imaging techniques, and potential roles for the microbiome in prostate cancer. DISCUSSION: This article reviews the topics presented and discussions held at the CHPCA Meeting, with a focus on the unknowns and next steps needed to advance our understanding of the biology and most effective treatment strategies for metastatic prostate cancer. Prostate 77:123-144, 2017. © 2016 Wiley Periodicals, Inc.

Radiogenomics of High-Grade Serous Ovarian Cancer: Multireader Multi-Institutional Study from the Cancer Genome Atlas Ovarian Cancer Imaging Research Group.

Purpose To evaluate interradiologist agreement on assessments of computed tomography (CT) imaging features of high-grade serous ovarian cancer (HGSOC), to assess their associations with time-to-disease progression (TTP) and HGSOC transcriptomic profiles (Classification of Ovarian Cancer [CLOVAR]), and to develop an imaging-based risk score system to predict TTP and CLOVAR profiles. Materials and Methods This study was a multireader, multi-institutional, institutional review board-approved, HIPAA-compliant retrospective analysis of 92 patients with HGSOC (median age, 61 years) with abdominopelvic CT before primary cytoreductive surgery available through the Cancer Imaging Archive. Eight radiologists from the Cancer Genome Atlas Ovarian Cancer Imaging Research Group developed and independently recorded the following CT features: characteristics of primary ovarian mass(es), presence of definable mesenteric implants and infiltration, presence of other implants, presence and distribution of peritoneal spread, presence and size of pleural effusions and ascites, lymphadenopathy, and distant metastases. Interobserver agreement for CT features was assessed, as were univariate and multivariate associations with TTP and CLOVAR mesenchymal profile (worst prognosis). Results Interobserver agreement for some features was strong (eg, α = .78 for pleural effusion and ascites) but was lower for others (eg, α = .08 for intraparenchymal splenic metastases). Presence of peritoneal disease in the right upper quadrant (P = .0003), supradiaphragmatic lymphadenopathy (P = .0004), more peritoneal disease sites (P = .0006), and nonvisualization of a discrete ovarian mass (P = .0037) were associated with shorter TTP. More peritoneal disease sites (P = .0025) and presence of pouch of Douglas implants (P = .0045) were associated with CLOVAR mesenchymal profile. Combinations of imaging features contained predictive signal for TTP (concordance index = 0.658; P = .0006) and CLOVAR profile (mean squared deviation = 1.776; P = .0043). Conclusion These results provide some evidence of the clinical and biologic validity of these image features. Interobserver agreement is strong for some features, but could be improved for others. © RSNA, 2017 Online supplemental material is available for this article.