PMC4373706_01
Clinical course of in situ Ad-REIC gene therapy. The patient received two scheduled injections into metastatic left obturator LN and additional 13 injections into metastatic LNs using cGMP Ad-REIC (1.0 x 1012 vp/1.2 mL). The procedure was carried out by using a set of 21G long needles and an injection machine that can control the injection speed and solution volume under CT guidance. Dynamic changes in metastatic LNs and PSA levels over two years are demonstrated. Green represents viable LNs and gray represents nonviable LNs.
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From August 2012, he received five cycles of chemotherapy with decetaxel 75 mg/m2 every 3-4 weeks at another regional core hospital (Fig. 1). Ad-REIC is summarized in Figure 1. Based on these clinical findings, an additional four Ad-REIC injections were administered (Fig. 2C), leading to complete control of pelvic LNs with further PSA decline (5.02 ng/mL), as shown in Figures 1 and 3. Next, additional six Ad-REIC injections were administered into para-aortic metastatic LNs (Figs. 1 and 4), resulting in remarkable PSA decline (2.57 ng/mL), and necrotic changes in the targeted LNs were detected by
Needle biopsy and Ad-REIC injection under CT guidance. (A) Pretreatment biopsy of left obturator LN, showing a metastatic adenocarcinoma with a Gleason score of 9 (5 + 4), H&E staining, reduced from x 40. (B) Biopsy of left obturator LN after two scheduled Ad-REIC treatments, showing almost complete necrosis (H&E, x 40). (C) Schematic representation and radiological imaging of scheduled and additional Ad-REIC injections into metastatic pelvic LNs.
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Subsequently, he underwent a CT-guided needle biopsy of the left obturator LN, which showed a metastatic adenocarcinoma with a Gleason score of 9 (5 + 4) (Fig. 2A), while ultrasound-guided transrectal 10-core prostate biopsy showed no cancer cells. Ad-REIC (1.0 x 1012 vp/1.2 mL) was directly injected into the left obturator LN (more than 30 mL in volume) under CT guidance. After two scheduled injections, a significant decrease in serum PSA level (31.27 56.08 17.23 ng/mL) and almost complete necrosis within the injected LN was observed by CT and histological examinations (Fig. 2B). Based on these clinical findings, an additional four Ad-REIC injections were administered (Fig. 2C), leading to complete control of pelvic LNs with further PSA decline (5.02 ng/mL), as shown in Figures 1 and 3.
Changes in CT findings of pelvic LN metastases. Before injection, multiple metastatic pelvic LNs were observed. After the third injection, almost complete necrosis of the injected lt. obturator LN was observed, illustrating Ad-REIC induced powerful direct effects. Similar necrotic changes of non-injected external and common iliac LNs were observed, illustrating the induction of strong indirect effects of Ad-REIC. After the sixth injection, cytoreductive effects were clearly seen and external and common iliac LNs were not detected after the 15th injection.
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Based on these clinical findings, an additional four Ad-REIC injections were administered (Fig. 2C), leading to complete control of pelvic LNs with further PSA decline (5.02 ng/mL), as shown in Figures 1 and 3. Two injections into the upper part and one into lower part of the LNs resulted in adequate control of the whole of the metastatic LNs (Figs. 3 and 6B) with PSA decline (2.25 ng/mL).
Schematic representation and radiological imaging of Ad-REIC injections into para-aortic metastatic LNs. In the treatment of metastatic para-aortic LNs, three main LNs were treated separately and four injections were administered into lt. para-aortic node.
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Next, additional six Ad-REIC injections were administered into para-aortic metastatic LNs (Figs. 1 and 4), resulting in remarkable PSA decline (2.57 ng/mL), and necrotic changes in the targeted LNs were detected by
Changes in CT findings of para-aortic LN metastases including histological examination. (A) Before Ad-REIC injection, no para-aortic LN metastases were detected. Before the seventh injection, apparent LN metastases were observed, as indicated by arrows. After the ninth injection, right and central para-aortic LNs showed necrotic changes, but left para-aortic LN (LPN) showed enlargement. After the 12th injection, LPN showed cytoreductive effects with necrotic change. (B) Schematic representation of biopsy procedure and histology of LPN showing complete necrosis after 12th injection (H&E, x40).
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CT and histological examination (Fig. 5). Consequently, the patient was treated successfully for one year by 12 injections at an average four weeks' interval.
Histological examination and CT changes of re-enlarged LPN. (A) Before the 13th injection, biopsy of LPN showed clusters of viable cancer cells (H&E, x100). (B) LPN appeared to have gourd-shaped growth. After the 14th injection, the upper part showed lobulated shrinkage with necrosis but the lower part showed enlargement. After the 15th injection, the lower part ceased to grow.
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In the following year, three therapeutic Ad-REIC injections were administered into newly enlarged, gourd-shaped left para-aortic LNs, after a biopsy specimen from the upper part of the left para-aortic LNs showed clusters of viable cancer cells (Fig. 6A). Two injections into the upper part and one into lower part of the LNs resulted in adequate control of the whole of the metastatic LNs (Figs. 3 and 6B) with PSA decline (2.25 ng/mL).