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Imaging of lymph node micrometastases using an oncolytic herpes virus and [F]FEAU PET.

Brader P, Kelly K, Gang S, Shah JP, Wong RJ, Hricak H, Blasberg RG, Fong Y, Gil Z - PLoS ONE (2009)

Bottom Line: Presence of virus-infected tumor cells was successfully imaged with [(18)F]FEAU-PET, that identified 8 out of 8 tumor-positive nodes.There was no overlap between radioactivity levels (lymph node to surrounding tissue ratio) of tumor-positive and tumor-negative lymph nodes.A new approach for imaging SLN metastases using NV1023 and [(18)F]FEAU-PET was successful in a murine model.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

ABSTRACT

Background: In patients with melanoma, knowledge of regional lymph node status provides important information on outlook. Since lymph node status can influence treatment, surgery for sentinel lymph node (SLN) biopsy became a standard staging procedure for these patients. Current imaging modalities have a limited sensitivity for detection of micrometastases in lymph nodes and, therefore, there is a need for a better technique that can accurately identify occult SLN metastases.

Methodology/principal findings: B16-F10 murine melanoma cells were infected with replication-competent herpes simplex virus (HSV) NV1023. The presence of tumor-targeting and reporter-expressing virus was assessed by [(18)F]-2'-fluoro-2'-deoxy-1-beta-D-beta-arabinofuranosyl-5-ethyluracil ([(18)F]FEAU) positron emission tomography (PET) and confirmed by histochemical assays. An animal foot pad model of melanoma lymph node metastasis was established. Mice received intratumoral injections of NV1023, and 48 hours later were imaged after i.v. injection of [(18)F]FEAU. NV1023 successfully infected and provided high levels of lacZ transgene expression in melanoma cells. Intratumoral injection of NV1023 resulted in viral trafficking to melanoma cells that had metastasized to popliteal and inguinal lymph nodes. Presence of virus-infected tumor cells was successfully imaged with [(18)F]FEAU-PET, that identified 8 out of 8 tumor-positive nodes. There was no overlap between radioactivity levels (lymph node to surrounding tissue ratio) of tumor-positive and tumor-negative lymph nodes.

Conclusion/significance: A new approach for imaging SLN metastases using NV1023 and [(18)F]FEAU-PET was successful in a murine model. Similar studies could be translated to the clinic and improve the staging and management of patients with melanoma.

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Related in: MedlinePlus

[18F]FEAU-PET imaging of mice with and without positive lymph node metastases.Representative coronal views of (A) a control animal with positive SLN injected with saline and (B) a mouse without tumor injected with NV1023, showing accumulation of radioactive signals in the gut, gallbladder and bladder. (C) A coronal view of a mouse with positive popliteal and inguinal lymph node metastases injected with NV1023. Positive PET signal was detected only in positive lymph nodes (white arrows). (D) The lymph node-to-surrounding tissue radioactivity ratios were measured in the PET scans; negative lymph nodes (blue column, n = 10), positive lymph nodes (orange column, n = 8).
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pone-0004789-g005: [18F]FEAU-PET imaging of mice with and without positive lymph node metastases.Representative coronal views of (A) a control animal with positive SLN injected with saline and (B) a mouse without tumor injected with NV1023, showing accumulation of radioactive signals in the gut, gallbladder and bladder. (C) A coronal view of a mouse with positive popliteal and inguinal lymph node metastases injected with NV1023. Positive PET signal was detected only in positive lymph nodes (white arrows). (D) The lymph node-to-surrounding tissue radioactivity ratios were measured in the PET scans; negative lymph nodes (blue column, n = 10), positive lymph nodes (orange column, n = 8).

Mentions: Region of interest (ROI) measurements from [18F]FEAU PET scans in mice injected with NV1023 identified all tumor-positive lymph nodes (with melanoma metastases) (n = 8). Conversely, all tumor-negative lymph nodes in mice injected with NV1023 (n = 5) and mice treated with saline (n = 5) had [18F]FEAU signal levels similar to background (Figure 5). The lymph node-to-surrounding tissue radioactivity ratio was significantly higher (P<0.001) for tumor-positive lymph nodes compared to tumor-negative nodes. Nucleoside analogs are not accumulated or trapped by mammalian tissue, as only virus-containing cells can induce phosphorylation of these tracers by the HSV1-tk reporter gene [8], [15], [16], [17]. Figure 5 shows a representative experiment of [18F]FEAU uptake in an animal with a lymph node metastasis injected with saline. The figure clearly demonstrates no radiotracer accumulation by mammalian tissue, aside from gallbladder uptake, where colonies of thymidine kinase forming bacteria may augment the background signal.


Imaging of lymph node micrometastases using an oncolytic herpes virus and [F]FEAU PET.

Brader P, Kelly K, Gang S, Shah JP, Wong RJ, Hricak H, Blasberg RG, Fong Y, Gil Z - PLoS ONE (2009)

[18F]FEAU-PET imaging of mice with and without positive lymph node metastases.Representative coronal views of (A) a control animal with positive SLN injected with saline and (B) a mouse without tumor injected with NV1023, showing accumulation of radioactive signals in the gut, gallbladder and bladder. (C) A coronal view of a mouse with positive popliteal and inguinal lymph node metastases injected with NV1023. Positive PET signal was detected only in positive lymph nodes (white arrows). (D) The lymph node-to-surrounding tissue radioactivity ratios were measured in the PET scans; negative lymph nodes (blue column, n = 10), positive lymph nodes (orange column, n = 8).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2651472&req=5

pone-0004789-g005: [18F]FEAU-PET imaging of mice with and without positive lymph node metastases.Representative coronal views of (A) a control animal with positive SLN injected with saline and (B) a mouse without tumor injected with NV1023, showing accumulation of radioactive signals in the gut, gallbladder and bladder. (C) A coronal view of a mouse with positive popliteal and inguinal lymph node metastases injected with NV1023. Positive PET signal was detected only in positive lymph nodes (white arrows). (D) The lymph node-to-surrounding tissue radioactivity ratios were measured in the PET scans; negative lymph nodes (blue column, n = 10), positive lymph nodes (orange column, n = 8).
Mentions: Region of interest (ROI) measurements from [18F]FEAU PET scans in mice injected with NV1023 identified all tumor-positive lymph nodes (with melanoma metastases) (n = 8). Conversely, all tumor-negative lymph nodes in mice injected with NV1023 (n = 5) and mice treated with saline (n = 5) had [18F]FEAU signal levels similar to background (Figure 5). The lymph node-to-surrounding tissue radioactivity ratio was significantly higher (P<0.001) for tumor-positive lymph nodes compared to tumor-negative nodes. Nucleoside analogs are not accumulated or trapped by mammalian tissue, as only virus-containing cells can induce phosphorylation of these tracers by the HSV1-tk reporter gene [8], [15], [16], [17]. Figure 5 shows a representative experiment of [18F]FEAU uptake in an animal with a lymph node metastasis injected with saline. The figure clearly demonstrates no radiotracer accumulation by mammalian tissue, aside from gallbladder uptake, where colonies of thymidine kinase forming bacteria may augment the background signal.

Bottom Line: Presence of virus-infected tumor cells was successfully imaged with [(18)F]FEAU-PET, that identified 8 out of 8 tumor-positive nodes.There was no overlap between radioactivity levels (lymph node to surrounding tissue ratio) of tumor-positive and tumor-negative lymph nodes.A new approach for imaging SLN metastases using NV1023 and [(18)F]FEAU-PET was successful in a murine model.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

ABSTRACT

Background: In patients with melanoma, knowledge of regional lymph node status provides important information on outlook. Since lymph node status can influence treatment, surgery for sentinel lymph node (SLN) biopsy became a standard staging procedure for these patients. Current imaging modalities have a limited sensitivity for detection of micrometastases in lymph nodes and, therefore, there is a need for a better technique that can accurately identify occult SLN metastases.

Methodology/principal findings: B16-F10 murine melanoma cells were infected with replication-competent herpes simplex virus (HSV) NV1023. The presence of tumor-targeting and reporter-expressing virus was assessed by [(18)F]-2'-fluoro-2'-deoxy-1-beta-D-beta-arabinofuranosyl-5-ethyluracil ([(18)F]FEAU) positron emission tomography (PET) and confirmed by histochemical assays. An animal foot pad model of melanoma lymph node metastasis was established. Mice received intratumoral injections of NV1023, and 48 hours later were imaged after i.v. injection of [(18)F]FEAU. NV1023 successfully infected and provided high levels of lacZ transgene expression in melanoma cells. Intratumoral injection of NV1023 resulted in viral trafficking to melanoma cells that had metastasized to popliteal and inguinal lymph nodes. Presence of virus-infected tumor cells was successfully imaged with [(18)F]FEAU-PET, that identified 8 out of 8 tumor-positive nodes. There was no overlap between radioactivity levels (lymph node to surrounding tissue ratio) of tumor-positive and tumor-negative lymph nodes.

Conclusion/significance: A new approach for imaging SLN metastases using NV1023 and [(18)F]FEAU-PET was successful in a murine model. Similar studies could be translated to the clinic and improve the staging and management of patients with melanoma.

Show MeSH
Related in: MedlinePlus