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Nathan Goodyear

How We Read Oncologic FDG PET/CT | Cancer Imaging | Full Text - 0 views

cancerimagingjournal.biomedcentral.com/...s40644-016-0091-3

PET_CT PET scan CT cancer

shared by Nathan Goodyear on 20 Feb 18 - No Cached
  • In early PET literature focusing on analysis of solitary pulmonary nodules, some researchers defined malignancy based on a SUVmax threshold of greater than 2.5
  • We contend that SUV analysis has virtually no role in this setting.
  • tumours grow as spheres, whereas inflammatory processes are typically linear
  • ...35 more annotations...
  • Far more important than the SUVmax is the pattern rather than intensity of metabolic abnormality and the correlative CT findings
  • Descriptively, we define SUV < 5 as “low intensity”, 5–10 as “moderate”, 10–15 as “intense” and >15 as “very intense”
  • Evolving literature suggests that intensity of uptake is an independent prognostic factor and in some tumour subtypes superior to histopathologic characterisation.
  • aerobic glycolysis
  • Our practice of thresholding the grey and colour scale to liver as detailed above results in similar image intensity to a fixed upper SUV threshold of 8 to 10
  • The advantage of using the liver as a reference tissue is also aided by this organ having rather low variability in metabolic activity
  • When the liver is abnormal and cannot be used as a reference organ, we use the default SUV setting of an upper SUV threshold of 8
  • One of the most challenging aspects of oncologic FDG PET/CT review, however, is to recognise all the patterns of metabolic activity that are not malignant and which consequently confound interpretation
  • Many benign and inflammatory processes are also associated with high glycolytic activity
  • Future articles in the “How I Read” series will address the specific details of reading PET/CT in various cancers
  • The intensity of uptake in metastases usually parallels that in the primary site of disease
  • For example, discordant low-grade activity in an enlarged lymph node in the setting of intense uptake in the primary tumour suggests it is unlikely malignant and more likely inflammatory or reactive
  • By CT criteria the enlarged node is ‘pathologic’ but the discordantly low metabolic signature further characterises this is as non-malignant since such a node is not subject to partial volume effects and therefore the intensity of uptake should be similar to the primary site
  • The exception is when the lymph node is centrally necrotic as a small rim of viable tumour is subject to partial volume effects with expectant lower intensity of uptake; integrating the CT morphology is therefore critical to reaching an accurate interpretation
  • Small nodes that are visualised on PET are conversely much more likely to be metastatic as such nodes are subject to partial volume effects.
  • The exception to this rule is tumours with a propensity for tumour heterogeneity at different sites
  • The combination of FDG and a more specific tracer, which visualises the well-differentiated disease can be very useful to characterise this phenomenon
  • “metabolic signature”
  • For the majority of malignant processes, the intensity of metabolic abnormality correlates with degree of aggressiveness or proliferative rate.
  • a negative PET/CT study in a patient with biopsy proven malignancy would be considered false-negative
  • Warburg effect
  • There, however, are a significant minority of tumours that utilise substrates other glucose such as glutamine or fatty acids as a source of the carbon atoms required for growth and proliferation
  • This includes a subset of diffuse gastric adenocarcinomas, signet cell colonic adenocarcinomas and some sarcomas, particularly liposarcoma
  • There may be a role for other radiotracers such as fluorothymidine (FLT) or amino acid substrates in this setting.
  • Some tumours harbour mutations that result in defective aerobic mitochondrial energy metabolism, effectively simulating the Warburg effect
  • patients with hereditary paraganglioma and pheochromocytoma highlight this phenomenon
  • These have intense uptake on FDG PET/CT despite often having low proliferative rate.
  • Uterine fibroids, hepatic adenomas, fibroadenomas of the breast and desmoid tumours are benign or relatively benign lesions that can have quite high FDG-avidity.
  • Metabolic activity switches off rapidly following initiation of therapy
  • Common examples where patients have commenced active therapy but the referrer is requesting “staging” includes hormonal therapy (eg. tamoxifen) in breast cancer, oral capecitabine in colorectal cancer or high dose steroids in Hodgkin’s lymphoma
  • It is therefore critical to perform PET staging before commencement of anti-tumour therapy
  • The potential advantage of routine diagnostic CT is improved anatomic localisation and definition
  • Without intravenous contrast, additional identification of typical oncologic complications such as pulmonary embolism or venous thrombosis cannot be identified
  • If the study is performed as an “interim” restaging study after commencement of therapy but before completion, in order to reach a valid or clinically useful conclusion findings must be interpreted in the context of known changes that occur at a specific timing and type of therapy
  • The most well studied use of interim PET is in Hodgkin’s lymphoma where repeat PET after two cycles of ABVD-chemotherapy provides powerful prognostic information and may improve outcomes by enabling early change of management
  • Nathan Goodyear on 20 Feb 18
     
    good read on the PET/CT scan reading.  They mention that tumors are spheres and inflammation is linear, yet inflammation coexists with cancer; hard to simply delineate these on simple terms. I do agree aon the metabolic signature of the PET/CT scan
Nathan Goodyear

High-Dose Vitamin C for Cancer Therapy - PMC - 0 views

www.ncbi.nlm.nih.gov/...PMC9231292

vitamin C cancer

shared by Nathan Goodyear on 27 Jul 22 - No Cached
  • diabetes [8], atherosclerosis [9], the common cold [10], cataracts [11], glaucoma [12], macular degeneration [13], stroke [14], heart disease [15], COVID-19 [16], and cancer.
  • 1–5% of the Vit-C inside the human cells
  • interaction between Fe(II) and H2O2 produces OH− through the Fenton reaction
  • ...35 more annotations...
  • metabolic activity, oxygen transport, and DNA synthesis
  • Iron is found in the human body in the form of haemoglobin in red blood cells and growing erythroid cells.
  • macrophages contain considerable quantities of iron
  • iron is taken up by the majority of cells in the form of a transferrin (Tf)-Fe(III) complex that binds to the cell surface receptor transferrin receptor 1 (TfR1)
  • excess iron is retained in the liver cells
  • the endosomal six transmembrane epithelial antigen of the prostate 3 (STEAP3) reduces Fe(III) (ferric ion) to Fe(II) (ferrous ion), which is subsequently transferred across the endosomal membrane by divalent metal transporter 1 (DMT1)
  • labile iron pool (LIP)
  • LIP is toxic to the cells owing to the production of massive amounts of ROS.
  • DHA is quickly converted to Vit-C within the cell, by interacting with reduced glutathione (GSH) [45,46,47]. NADPH then recycles the oxidized glutathione (glutathione disulfide (GSSG)) and converts it back into GSH
  • Fe(II) catalyzes the formation of OH• and OH− during the interaction between H2O2 and O2•− (Haber–Weiss reaction)
  • Ascorbate can efficiently reduce free iron, thus recycling the cellular Fe(II)/Fe(III) to produce more OH• from H2O2 than can be generated during the Fenton reaction, which ultimately leads to lipid, protein, and DNA oxidation
  • Vit-C-stimulated iron absorption
  • reduce cellular iron efflux
  • high-dose Vit-C may elevate cellular LIP concentrations
  • ascorbate enhanced cancer cell LIP specifically by generating H2O2
  • Vit-C produces H2O2 extracellularly, which in turn inhibits tumor cells immediately
  • tumor cells have a need for readily available Fe(II) to survive and proliferate.
  • Tf has been recognized to sequester most labile Fe(II) in vivo
  • Asc•− and H2O2 were generated in vivo upon i.v Vit-C administration of around 0.5 g/kg of body weight and that the generation was Vit-C-dose reliant
  • free irons, especially Fe(II), increase Vit-C autoxidation, leading to H2O2 production
  • iron metabolism is altered in malignancies
  • increase in the expression of various iron-intake pathways or the downregulation of iron exporter proteins and storage pathways
  • Fe(II) ion in breast cancer cells is almost double that in normal breast tissues
  • macrophages in the cancer microenvironment have been revealed to increase iron shedding
  • Advanced breast tumor patients had substantially greater Fe(II) levels in their blood than the control groups without the disease
  • increased the amount of LIP inside the cells through transferrin receptor (TfR)
  • Warburg effect, or metabolic reprogramming,
  • Warburg effect is aided by KRAS or BRAF mutations
  • Vit-C is supplied, it oxidizes to DHA, and then is readily transported by GLUT-1 in mutant cells of KRAS or BRAF competing with glucose [46]. DHA is quickly converted into ascorbate inside the cell by NADPH and GSH [46,107]. This decrease reduces the concentration of cytosolic antioxidants and raises the intracellular ROS amounts
  • increased ROS inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH)
  • ROS activates poly (ADP-ribose) polymerase (PARP), which depletes NAD+ (a critical co-factor of GAPDH); thus, further reducing the GAPDH associated with a multifaceted metabolic rewiring
  • Hindering GAPDH can result in an “energy crisis”, due to the decrease in ATP production
  • high-dose Vit-C recruited metabolites and increased the enzymatic activity in the pentose phosphate pathway (PPP), blocked the tri-carboxylic acid (TCA) cycle, and increased oxygen uptake, disrupting the intracellular metabolic balance and resulting in irreversible cell death, due to an energy crisis
  • mega-dose Vit-C influences energy metabolism by producing tremendous amounts of H2O2
  • Due to its great volatility at neutral pH [76], bolus therapy with mega-dose DHA has only transitory effects on tumor cells, both in vitro and in vivo.
Nathan Goodyear

Metformin and breast cancer risk: a ... [Breast Cancer Res Treat. 2012] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...22847511

breast cancer metformin post-menopause menopause glucose

shared by Nathan Goodyear on 23 Jul 13 - No Cached
  • Nathan Goodyear on 23 Jul 13
     
    Studies like this surprise me. This study lauds the benefit of metformin as a breast cancer protective in postmenopuasal womb.  Their focus is on the bandaid--the prescription drug.  They completely ignore the cause--glucose.  The Warburg effect in cancer is well known.  Limit simple sugar intake and support oxidative phosphorylation will do the same.  That is treating the cause.
Nathan Goodyear

Home: Cell PressInhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells - 0 views

www.cell.com/...S1535-6108(18)30471-9

Cancer cancer stem cells CSC

shared by Nathan Goodyear on 24 Nov 18 - No Cached
  • Nathan Goodyear on 24 Nov 18
     
    Cancer Stem cells are not tied to the Warburg effect.
Nathan Goodyear

The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of brain cancer | Nutrition & Metabolism | Full Text - 0 views

nutritionandmetabolism.biomedcentral.com/...s12986-015-0009-2

cancer GKI glucose ketone index ketogenic diet nutrition

shared by Nathan Goodyear on 02 Apr 18 - No Cached
  • The ‘Glucose Ketone Index’ (GKI) was created to track the zone of metabolic management for brain tumor management
  • The GKI is a biomarker that refers to the molar ratio of circulating glucose over β-OHB, which is the major circulating ketone body.
  • We present evidence showing that the GKI can predict success for brain cancer management in humans and mice using metabolic therapies that lower blood glucose and elevate blood ketone levels
  • ...14 more annotations...
  • The GKI can be useful in determining the success of dietary therapies that shift glucose- and lactate-based metabolism to ketone-based metabolism
  • Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, chronic inflammatory disease, and epilepsy
  • The zone of metabolic management is likely entered with GKI values between 1 and 2 for humans
  • Optimal management is predicted for values approaching 1.0, and blood glucose and ketone values should be measured 2–3 hours postprandial, twice a day if possible
    • Nathan Goodyear
      Nathan Goodyear on 09 May 18
       
      check GKI 2-3 hr postprandial twice daily
  • Preclinical studies have demonstrated a clear linkage between GKI and therapeutic efficacy
  • the Warburg effect (aerobic fermentation of glucose) is a common metabolic malady expressed in nearly all neoplastic cells of these and other malignant tumors
  • Aerobic fermentation (Warburg effect) is necessary to compensate for the insufficiency of mitochondrial oxidative phosphorylation in the cells of most tumors
  • Normal brain cells gradually transition from the metabolism of glucose to the metabolism of ketone bodies (primarily β-hydroxybutyrate and acetoacetate) for energy when circulating glucose levels become limiting
  • Ketone bodies bypass the glycolytic pathway in the cytoplasm and are metabolized directly to acetyl CoA in the mitochondria
  • Tumor cells are less capable than normal cells in metabolizing ketone bodies for energy due to their mitochondrial defects
  • daily activities and emotional stress can cause blood glucose levels to vary making it difficult for some people to enter the predicted zone of metabolic management
  • a clear association of the GKI to the therapeutic action of calorie restriction against distal invasion, proliferation, and angiogenesis in the VM-M3 model of glioblastoma
  • The results suggest that GKI levels that approach 1.0 are therapeutic for managing brain tumor growth
  • Therapeutic efficacy of the KD or calorie restriction is greater with lower GKI values than with higher values
  • Nathan Goodyear on 02 Apr 18
     
    The glucose ketone index shown to predict dietary metabolic success. In humans with brain cancer-- the target is 1.  The glucose and ketone (betahydroxybutyrate) should be measured 2-3 hours postprandial twice daily.
Nathan Goodyear

Chicken or the egg: Warburg effect and mitochondrial dysfunction - 1 views

www.ncbi.nlm.nih.gov/...PMC4447048

cancer Warburg effect mitochondria

shared by Nathan Goodyear on 11 Jun 20 - No Cached
  • Nathan Goodyear on 11 Jun 20
     
    good review of the relationship between cancer and mitochondria.
Nathan Goodyear

Oncotarget | Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer - 0 views

www.oncotarget.com/index.php

vitamin C IV vitamin C cancer warburg effect colon cancer

shared by Nathan Goodyear on 02 Jul 18 - No Cached
  • Nathan Goodyear on 02 Jul 18
     
    To be read article on Vitamin C
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