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NETosis is a special form of programmed cell death in neutrophils, which is characterized by the extrusion of DNA, histones, and antimicrobial proteins in a web-like structure known as neutrophil extracellular traps (NETs)

increased generation of reactive oxygen species (ROS) is a crucial intracellular process that causes NETosis

Another indirect route of SARS-CoV-2-induced NET production is platelet activation

When NETs are activated in the circulation, they can also induce hypercoagulability and thrombosis

In COVID-19, major NET protein cargos of NETs (i.e., NE, MPO, and histones) are significantly elevated.

SARS-CoV-2 can also infect host cells through noncanonical receptors such as C-type lectin receptors

Immunopathological manifestations, including cytokine storms and impaired adaptive immunity, are the primary drivers behind COVID-19, with neutrophil infiltration being suggested as a significant cause

NETosis and NETs are increasingly recognized as causes of vascular injury

SARS-CoV-2 and its components (e.g., spike proteins and viral RNA) attach to platelets and increase their activation and aggregation in COVID-19, resulting in vascular injury and thrombosis, both of which are linked to NET formation

NET formation may be caused by activated platelets rather than SARS-CoV-2 itself

NETosis, leading to aberrant immunity such as cytokine storms, autoimmune disorders, and immunosuppression.

early bacterial coinfections were more prevalent in COVID-19 patients than those infected with other viruses

NETosis and NETs may also have a role in the development of post COVID-19 syndromes, including lung fibrosis, neurological disorders, tumor growth, and worsening of concomitant disease

NETs and other by-products of NETosis have been shown to act as direct inflammation amplifiers. Hyperinflammation

“cytokine storm”

SARS-CoV-2 drives NETosis and NET formation to allow for the release of free DNA and by-products (e.g., elastases and histones). This may trigger surrounding macrophages and endothelial cells to secrete excessive proinflammatory cytokines and chemokines, which, in turn, enhance NET formation and form a positive feedback of cytokine storms in COVID-19

NET release enables self-antigen exposure and autoantibody production, thereby increasing the autoinflammatory response

patients with COVID-19 who have higher anti-NET antibodies are more likely to be detected with positive autoantibodies [e.g., antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA)]

COVID-19 NETs may act as potential inducers for autoimmune responses

have weakened adaptive immunity as well as a high level of inflammation

tumor-associated NETosis and NETs promote an immunosuppressive environment in which anti-tumor immunity is compromised

NETs have also been shown to enhance macrophage pyroptosis in sepsis

facilitating an immunosuppressive microenvironment

persistent immunosuppression may result in bacterial co-infection or secondary infection

can enhance this process by interacting with neutrophils through toll-like receptor 4 (TLR4), platelet factor 4 (PF4), and extracellular vesicle-dependent processes

NET-induced immunosuppression in COVID-19 in the context of co-existing bacterial infection

Following initial onset of COVID-19, an estimated 50% or more of COVID-19 survivors may develop multi-organ problems (e.g., pulmonary dysfunction and neurologic impairment) or have worsening concomitant chronic illness

NETs in the bronchoalveolar lavage fluid of severe COVID-19 patients cause EMT in lung epithelial cells

decreased E-cadherin (an epithelial marker) expression

COVID-19 also has a long-term influence on tumor progression

Patients with tumors have been shown to be more vulnerable to SARS-CoV-2 infection and subsequent development of severe COVID-19

patients who have recovered from COVID-19 may have an increased risk of developing cancer or of cancer progression and metastasis

awaken cancer cells

NETs have been shown to change the tumor microenvironment

enhance tumor progression and metastasis

vitamin C has been tested in phase 2 clinical trials aimed at reducing COVID-19-associated mortality by reducing excessive activation of the inflammatory response

vitamin C is an antioxidant that significantly attenuates PMA-induced NETosis in healthy neutrophils by scavenging ROS

vitamin C may also inhibit NETosis and NET production in COVID-19

Metformin

Vitamin C

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