The objective of this review article is to summarize current knowledge of blood flow and perfusion-related parameters, which usually go hand in hand and in turn define the cellular metabolic microenvironment of human malignancies. A compilation of available data from the literature on blood flow, oxygen and nutrient supply, and tissue oxygen and pH distribution in human tumors is presented. Whenever possible, data obtained for human tumors are compared with the respective parameters in normal tissues, isotransplanted or spontaneous rodent tumors, and xenografted human tumors. Although data on human tumors in situ are scarce and there may be significant errors associated with the techniques used for measurements, experimental evidence is provided for the existence of a compromised and anisotropic blood supply to many tumors. As a result, O2-depleted areas develop in human malignancies which coincide with nutrient and energy deprivation and with a hostile metabolic microenvironment (e.g., existence of severe tissue acidosis). Significant variations in these relevant parameters must be expected between different locations within the same tumor, at the same location at different times, and between individual tumors of the same grading and staging. Furthermore, this synopsis will attempt to identify relevant pathophysiological parameters and other related areas future research of which might be most beneficial for designing individually tailored treatment protocols with the goal of predicting the acute and/or long-term response of tumors to therapy.

https://cancerres.aacrjournals.org/content/canres/49/23/6449.full.pdf

Blood Flow, Oxygen and Nutrient Supply, and Metabolic Microenvironment of Human Tumors: A Review

PURPOSEWe assessed the feasibility of noninvasive metabolic monitoring of cancer chemohormonotherapy using sequential quantitative positron emission tomographic (PET) scans of tumor glucose metabolism with the glucose analog 2-[18F]-fluoro-2-deoxy-D-glucose (FDG).PATIENTS AND METHODSEleven women with newly diagnosed primary breast cancers larger than 3 cm in diameter beginning a chemohormonotherapy program underwent a baseline and four follow-up quantitative PET scans during the first three cycles of treatment (days 0 to 63). Tumor response was sequentially determined clinically, radiographically, and then pathologically after nine treatment cycles.RESULTSEight patients had partial or complete pathologic responses. Their maximal tumor uptake of FDG assessed by PET decreased promptly with treatment to the following: day 8, 78 +/- 9.2% (P < .03); day 21, 68.1 +/- 7.5% (P < .025); day 42, 60 +/- 5.1% (P < .001); day 63, 52.4 +/- 4.4% (P < .0001) of the basal values. Tumor diameter did not decrease significan...

Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: initial evaluation.

“Functional” tumor treatment response parameters have been developed to measure treatment induced biochemical changes in the entire tumor mass, using positron emission tomography (PET) and [F-18] fludeoxyglucose (FDG). These new parameters are intended to measure global changes in tumor glycolysis. The response parameters are determined by comparing the pre- and posttreatment PET-FDG images either visually from the change in image appearance in the region of the tumor, or quantitatively based on features of the calibrated digital PET image. The visually assessed parameters are expressed as a visual response score (VRS), or visual response index (VRI), as the estimated percent response of the tumor. Visual Response Score (VRS) is recorded on a 5 point response scale (0–4): 0: no response or progression; 1: 1–33%; 2: >33%–66%; 3: >66%–99%; and 4: >99%, estimated response, respectively. The quantitative changes are expressed as total lesion glycolysis TLG or as the change in TLG during treatment, also called δTLG or Larson-Ginsberg Index (LGI), expressed as percent response. The volume of the lesion is determined from the PET-FDG images by an adaptive thresholding technique. This response index is computed as, δTLG (LGI) = {[(SUVave)1 * (Vol)1 – (SUVave)2 * (Vol)2]/[(SUVave)1 * (Vol)1]} * 100. Where “1” and “2” denote the pre- and posttreatment PET-FDG, scans respectively. Pre- and posttreatment PET-FDG scans were performed on a group of 41 locally advanced lung (2), rectal (17), esophageal (16) and gastric (6) cancers. These patients were treated before surgery with neoadjuvant chemo-radiation. Four experienced PET readers determined individual VRS and VRI blinded to each other as well as to the clinical history. Consensus VRS was obtained based on a discussion. The interobserver variability captured by intraclass correlation coefficient was 89.7%. In addition, reader reliability was assessed for the categorized VRS using Kendall's coefficient of concordance for ordinal data and was found to be equal to 85% This provided assurance that these response parameters were highly reproducible. The correlation of δTLG with % change in SUVave and % change in SUVmax, as widely used parameters of response, were 0.73 and 0.78 (P

Tumor Treatment Response Based on Visual and Quantitative Changes in Global Tumor Glycolysis Using PET-FDG Imaging. The Visual Response Score and the Change in Total Lesion Glycolysis.

Positron emission tomography (PET) is now primarily used in oncological indication owing to the successful application of fluorine-18 fluorodeoxyglucose (FDG) in an increasing number of clinical indications at different stages of diagnosis, and for staging and follow-up. This review first considers the biological characteristics of FDG and then discusses methodological considerations regarding its use. Clinical indications are considered, and the results achieved in respect of various organs and tumour types are reviewed in depth. The review concludes with a brief consideration of the ways in which clinical PET might be improved.

/pdf/oncological-applications-of-positron-emission-tomography-1qoet8uhon.pdf

Oncological applications of positron emission tomography with fluorine-18 fluorodeoxyglucose.

Positron emission tomography (PET) is an analytical imaging technique that provides a way of making in vivo measurements of the anatomical distribution and rates of specific biochemical reactions. This ability of PET to measure and image dynamic biochemistry builds a bridge between the basic and clinical neurosciences founded on the commonality of the types of measurements made. Clinical findings with PET in humans are suggesting hypotheses that can be tested rigorously in the basic science laboratory.

https://science.sciencemag.org/content/sci/228/4701/799.full.pdf

Positron emission tomography: human brain function and biochemistry

Five patients who had undergone radiation therapy for cerebral tumors and whose conditions were deteriorating were examined by means of positron emission tomography (PET) with [18F] fluorodeoxyglucose. All five cases had similar clinical and computed tomographic findings. Using the PET technique the two cases of radiation necrosis were distinguished from the three recurrent tumors. In the two cases of radiation necrosis the rate of glucose utilization in the lesion was markedly reduced compared with the normal brain parenchyma. In the recurrent gliomas, however, the glucose metabolic rate was elevated. All five diagnoses were confirmed by biopsy or autopsy.

Work in progress: [18F] fluorodeoxyglucose and positron emission tomography in the evaluation of radiation necrosis of the brain

Seventeen patients with intracranial meningiomas were studied with positron emission tomography and fluorine-18-2-fluorodeoxyglucose (PET-FDG) to assess the glucose utilization of these tumors. Four meningiomas followed for 3-5 years after PET-FDG and surgery showed no evidence of recurrence. These tumors had significantly lower glucose utilization rates (1.9 mg/dl/min +/- 1.0) than 11 recurrent or regrowing meningiomas (4.5 mg/dl/min +/- 1.96) (P less than .01). The glucose metabolic rates of meningiomas correlated with tumor growth, as estimated from changes in tumor size on repeated computed tomographic scans. Histopathologically, a syncytial (atypical) meningioma had the highest glucose utilization rate, followed by a papillary meningioma and an angioblastic meningioma. Individual transitional and syncytial (typical) meningiomas showed marked differences in glucose metabolism despite similar microscopic appearance. Glucose utilization rate appears to be at least as reliable as histologic classification and other proposed criteria for predicting the behavior and recurrence of intracranial meningiomas.

Glucose utilization by intracranial meningiomas as an index of tumor aggressivity and probability of recurrence: a PET study.

The management of low-grade gliomas represents a challenge to the physician as a significant proportion may undergo malignant degeneration to a high-grade tumor. We present the positron emission tomography (PET) scans, using [18F] fluorodeoxyglucose (FDG), of 12 patients who have histological and/or clinical evidence of malignant degeneration of a low-grade glioma. Each scan displays a focal area of hypermetabolism similar to that of malignant gliomas which arise de novo. Three patients also underwent PET scanning prior to malignant degeneration. When the initial scan is compared with the postmalignant degeneration study, a difference in tumoral glucose uptake can be recognized. A region previously shown to be hypometabolic develops focal hypermetabolism as malignant changes evolve. This study displays the utility of FDG-PET in the evaluation of malignant degeneration of low-grade gliomas. The knowledge that a neoplasm has altered its biological behavior may influence subsequent therapeutic options. If these findings can be confirmed in larger series and by other investigators, it is possible that FDG-PET may be adopted as one of the diagnostic tools for guiding the management of low-grade gliomas.

H V Rizzoli

Papers

Work in progress: [18F] fluorodeoxyglucose and positron emission tomography in the evaluation of radiation necrosis of the brain

Glucose utilization by intracranial meningiomas as an index of tumor aggressivity and probability of recurrence: a PET study.

Positron emission tomography in the detection of malignant degeneration of low-grade gliomas.