Dose Threshold Values for Endovascular Photodynamic Therapy (PDT) in Normal Pig Pancreas and Human Pancreatic Cancer

Dose Threshold Values for Endovascular Photodynamic Therapy (PDT) in Normal Pig Pancreas and Human Pancreatic Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Dose Threshold Values for Endovascular Photodynamic Therapy (PDT) in Normal Pig Pancreas and Human Pancreatic Cancer Tina Saeidi, Alain Garcia Vazquez, Juan Verde, Fanélie Wanert, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7013948/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Dec, 2025 Read the published version in Photochemical & Photobiological Sciences → Version 1 posted 10 You are reading this latest preprint version Abstract Background Pancreatic cancers often involve major blood vessels, making complete surgical removal difficult or impossible. We are developing Endovascular Photodynamic Therapy (PDT) as a novel minimally invasive ablation method to clear tumours from these vessels, to enable potentially curative surgery. The goal is to determine the required endovascular irradiation times for effective treatment. Methods Threshold doses for PDT were estimated using Monte Carlo simulations, based on clinical data from previous Phase I/II studies involving Photodynamic Therapy of pancreatic cancer using interstitial needle-based irradiation. These thresholds were then compared to our recent in vivo study, which used endovascular catheter-based irradiation in normal pig pancreas. Using these dose thresholds, we estimated the PDT irradiation times needed to achieve necrotic tissue margins of 4 to 12 mm around blood vessels in pancreatic cancer patients, based on a fixed energy range and increasing doses of photosensitiser Results The threshold dose for Verteporfin-mediated PDT was determined to be 1.43 to 2.37 × 10¹⁷ hv∙cm⁻³ for human pancreatic cancer and 1.27 × 10¹⁸ hv∙cm⁻³ for normal pig pancreas. Based on these values, and assuming homogeneous tissue optical properties and a Verteporfin dose of 0.4 mg∙kg⁻¹, and an optical power of 300 mW∙cm -2 @ 690 nm, necrotic margins of circa 8 mm beyond the vessel adventitia can be anticipated in pancreatic cancer patients. The required irradiation times range from 337 to 636 seconds, inversely related to vessel diameters of 10 mm and 3 mm, respectively. Conclusions These findings suggest that PDT can potentially create a margin around major pancreatic blood vessels free of viable tumour tissue. The calculated dosimetry supports the feasibility of clinical application using the proposed Verteporfin dose and light delivery parameters, warranting further investigation in Clinical trials. Locally advanced pancreatic cancer Downstaging to enable surgery Endovascular photo-activated ablation of perivascular cancer Verteporfin Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction For Hepato-pancreatoiliary (HPB) cancers, surgery is currently the only potential cure for pancreatic adenocarcinoma, one of the most aggressive cancers. Annually, more than 500,000 patients are diagnosed with pancreatic cancer worldwide 1 ​. However, approximately 40% present with locally advanced pancreatic cancer (LAPC), frequently involving large blood vessels abutting or within the pancreas, preventing surgeons from achieving a complete resection of the malignancies 2 . Clinically downstaging these patients, that is, locally freeing vessels from abutting tumours, could make them eligible for surgery, and potentially extend their survival times. To become clinically relevant, such a procedure must induce rapid coagulative necrosis that matures within days and be minimally invasive, especially since patients would need to undergo the downstaging procedure and surgery within a short time period. Our group recently proposed that Endovascular Photodynamic Therapy (PDT) can be such a therapy, as necrosis occurs within 48 hrs. PDT is an innovative form of photodynamic therapy whereby irradiation occurs via the endovascular route to photoactivate the photosensitiser, Verteporfin, that was administered 60–90 minutes earlier. It can cause indiscriminate lipid and protein oxidation, leading to cell death, manifesting as apoptosis and coagulative necrosis 3 – 8 ​and has been investigated for pancreatic cancer over the past decades. In particular, Phase I/II clinical studies in 65 patients demonstrated that interstitial Photodynamic Therapy based on inserted optical fibres resulted in necrotic lesions in pancreatic tumours with 0.5–4.1 cm diameter ​ 9 , 10 ​. Photoactivated ablation via the endovascular route is not a novel concept and has been employed for vascular diseases, such as preventing angioplasty restenosis, using various photosensitizers (PSs) in pre-clinical studies 11 – 20 and clinical studies 21 – 24 . These experiments demonstrated that Photodynamic Therapy is well tolerated by large vessels. The studies did not result in vascular stenosis, thrombosis, aneurysms, or vessel rupture. Moreover, the supporting collagen and elastin, providing the structural integrity in the vascular wall, remain intact. However, these previous studies focused on treating the vasculature and primarily targeted the vascular wall. What is not known is whether necrosis outside the vascular wall in the perivascular tissue and surrounding organs is feasible, what devices and dose parameters are required, and if such a treatment can be carried out without unacceptable effects on the vasculature when surrounded by necrotic tumour tissue. Such ablation would have to be carried out within a clinically acceptable irradiation time, preferably faster than the maximum time permitted to block a vessel, thereby avoiding the compromise of downstream organs or tissues. To demonstrate the proof-of-concept and initial safety of this approach, our group recently developed a prototype near-infrared irradiating catheter and carried out a dose escalation study in a large animal model. Using verteporfin-mediated PDT in normal pig pancreas can generate a necrotic rim up to 15 mm wide around the vessel, while no immediate deterioration of the vein and artery was noted for the first 48 hours. To proceed to clinical trials, the required PDT dose parameters must be determined to generate the desired rim width of coagulation necrosis around the target blood vessels with an abutting or encasing tumour, within a clinically acceptable treatment time. Methods Dose Threshold Model In silico Monte Carlo calculations were utilised to quantify the interstitial photo-activated dose response, based on two prior clinical Phase I/II studies 9 , 10 and the pre-clinical endovascular catheter-mediated Photodynamic Therapy 9 , 10 . Using a dose threshold model, the PDT dose at position r is given by reactive oxygen species generated by Verteporfin, 0.77 25,26 , and the number of photons absorbed. Thus, the dose is given by the temporal integral over the light exposure time, T , of the photon density given by the fluence rate, \(\:\varphi\:(t,r)\) \(\:\lambda\:/hc\) , Verteporfin’s molar extinction coefficient, \(\:\epsilon\:\left(\lambda\:\right)\) and its concentration [PS], according to: $$\:{D}_{EPA}\left(r\right)={\int\:}_{0}^{T}\varphi\:\left(t,r\right)\frac{\lambda\:}{hc}\epsilon\:\left(\lambda\:\right)\left[PS\right]dt$$ with necrosis occurring when D PDT > T tissue , whereby T depends on the tissue, the PS, and PDT treatment conditions. The PDT dose depends on the D PDT , which is given in units of photons absorbed per unit volume or [hν∙cm − 3 ] after converting J into the number of photons based on the employed activation wavelength. In this simplest form, this PDT dose model assumes ubiquitous availability of oxygen and a constant Verteporfin concentration as a function of r. While photobleaching can be included in the equation, as shown by Kim et al. 27 , 28 , it is omitted here, given its low quantum yield of 5∙10 − 5 26 . The FullMonte light propagation simulations allow the extraction of the PDT dose Threshold, T, at the reported necrosis boundaries (r n ) in the work above 29 , 30 . Based on the derived threshold values, the dose range, in terms of administered photo-activated drug dose, optical power delivery, and illumination duration, was estimated to produce a 4-, 8-, or 12-mm margin of perivascular necrosis in human pancreatic cancer. Anatomical Model Simulations were performed within a basic cubic volume (4 × 4 × 5 cm³) representing pancreatic tissues. For the interstitial needle-based energy application used in the clinical studies, a 0.8 mm diameter optical fiber having a 1 cm cylindrical diffuser tip was positioned at the center of the tissue model. The tissue volume was divided equally, with one half representing pancreatic cancer and the other half representing normal pancreatic tissue. For the endovascular-based energy delivery used in the preclinical study, a centrally placed cylindrical tube within the cubical volume simulated a blood vessel. Arteries were modeled with an inner diameter of 3–6 mm and a three-layered wall (intima, media, and adventitia) totaling 1.3 mm in thickness. Veins were modeled with an inner diameter of 7–10 mm and a single-layer wall 0.5 mm thick. As in the interstitial model, the vessel was surrounded by pancreatic tissue, half cancerous and half normal. A near-infrared irradiating catheter was placed inside the vessel, featuring a centrally positioned 1 cm long cylindrical diffuser with a 0.8 mm diameter, located within a 3 cm long saline-filled balloon that matched the vessel’s inner diameter. Blood was assumed to be present in the vessel lumen beyond the proximal and distal ends of the balloon, corresponding to arterial and venous cases, respectively (see Fig. 1 ). The simulations to determine the threshold dose at the reported necrotic boundaries for the clinical and preclinical studies were executed using FullMonte’s 31 implementation for graphics processors FullMonteCUDA 30 . The optical properties for the tissues were selected from literature, including the three arterial wall layers at 690 nm 32 – 34 , and are listed in Table 1 . Saline and the optical diffusers are assumed to be optically neutral, with no absorption or scattering of light. Table 1 Tissue optical property assignments for simulation volumes representing different tissue structures at 690 nm. Tissues Absorption Coefficient µ a [mm − 1 ] Reduced Scattering Coefficient µ s [mm − 1 ] Scattering Anisotropy (g) Refractive Index (n) Pancreas 0.01 1.38 0.9 1.372 Pancreatic Cancer 0.01 1.38 0.9 1.372 Intima 0.2 0.3 0 1.38 Media 0.2333 3.37 0.9032 1.38 Adventitia 0.3825 3.062 0.8504 1.36 Input data for FullMonteCUDA simulations included: the molar absorption coefficient of 34,000 M − 1 ∙cm − 1 at 690 nm for Verteporfin, 718.8 g∙M − 1 molar weight, and a specific uptake ratio (SUR) of 0.6 for a drug light interval of 60–90 min post i.v. administration. The administered Verteporfin doses were 0.4 mg∙kg − 1 for the tumour and 0.4–3.2 mg∙kg − 1 for normal porcine pancreas, respectively. The clinical studies by Huggett et al. 10 and Hanada et al. 9 administered 0.4 mg∙kg − 1 Verteporfin i.v. and applied light energies escalation from 5 to 50 J∙cm − 1 diffuser length. The resulting radii of necrosis were calculated by assuming the reported necrosis volumes had a capsule shape, comprising a cylinder with hemispherical ends, and are summarized in Table 2 . The dose escalation in the porcine model by our group [Alain Garcia Vazquez, Tina Saeidi, Juan Verde, Fanélie Wanert, Irene Alexandra Spiridon, Axel Schmid, Lee Swanstrom, Stephen Bown, Lothar Lilge, and Arjen Bogaards “Downstaging Locally Advanced Pancreatic Cancer with Endovascular Photodynamic Therapy. A Proof-of-Concept Study in the Porcine Model”. Photochemistry and Photobiology Science. Under review] included variations to both the administered Verteporfin dose, a range factor of 8, from 0.4–3.2 mg∙kg − 1, and the much lower endovascular delivered light dose, with a range factor of 2, ranging from 188 to 395 J∙cm − 1 . The resulting radii or margins of necrosis that extend beyond the outer adventitia wall were measured from the hypointense regions seen on the CT images. All Data are listed in Table 3 . The threshold values were derived from the intersection of the FullMonte-derived light fluence as a function of the radial distance to the adventitia perpendicular to the diffuser centre and the measured radii of necrosis. Using the Verteporfin threshold values for human pancreatic and normal porcine pancreas, calculations based on in silico model simulations were performed to derive the irradiation times (in seconds) required to generate a 4-, 8-, or 12-mm tumour-free perivascular necrosis margin for arteries and veins with the aforementioned inner diameters. Times for high power delivery to the diffuser (1 W∙cm − 1 ) and when not exceeding 300 mW∙cm − 2 at the intima surface to prevent thermal damage to the vessel’s structural support, were determined as a function of the inner vessel diameter. Results Figure 2 shows an example of a hypodense contrast-enhanced CT image around the superior mesenteric artery, 24 hrs after administering 0.4 mg∙kg − 1 Verteporfin and 390 J∙cm − 1 . The hypodense signal, indicated by white arrows, at 24 hours was less pronounced, possibly due to not achieving mature necrosis, compared to the CT images at 48 hours in the other animals. Figures 3 show the resulting fluence [J∙cm − 2 ] in the mid-plane of the optical diffusers as a function of the radial distance from the emitter, based on the data provided in Huggett et al. 10 . Figure 4 shows the fluence for the cases presented by Garcia Vazquez et al. [Alain Garcia Vazquez, Tina Saeidi, Juan Verde, Fanélie Wanert, Irene Alexandra Spiridon, Axel Schmid, Lee Swanstrom, Stephen Bown, Lothar Lilge, and Arjen Bogaards Downstaging Locally Advanced Pancreatic Cancer with Endovascular Photodynamic Therapy. A Proof-of-Concept Study in the Porcine Model. Photochemistry and Photobiology Science. Under review] as a function of radial distance beyond the outer vessel surface, multiplied by the administered Verteporfin dose, to allow for comparison between the different animals. Both figures illustrate the ranges of observed necrosis radii for the various treatment conditions. Based on these simulations, the fluence at the boundary of necrosis and the administered Verteporfin concentrations, T tissue was calculated in units of [hv∙cm − 3 ] for human pancreatic tumours and normal porcine pancreas. Table 2 Verteporfin-mediated interstitial photo-activated conditions and necrosis imaging outcome according to the reports by Huggett et al. 10 . Patients all received 0.4 mg∙kg − 1 Verteporfin Patient # Delivered Light Dose [J∙cm -1 ] Volume Necrosis [cm 3 ] Radius Necrosis [mm] Fluence at Necrosis Radius [J∙cm -2 ] Photo- Activation Threshold 10 17 [hν∙cm -3 ] 1 10 0.931 1.72 0.56 0.552 2 10 0.434 1.18 1.47 1.45 3 10 0 0.00 > 11.54 > 11.4 4 20 0.311 1.00 2.94 2.89 5 20 2.36 2.74 0.74 0.725 6 20 0.745 1.54 0.80 0.785 7 40 5.09 4.03 1.14 1.13 8 40 2.61 2.88 1.24 1.22 9 40 2.67 2.92 1.24 1.22 10 80 5.34 2.92 1.96 1.93 The average threshold values based on the human data, excluding patient 3, given by Huggett et al. 10 is 1.43±0.76∙10 17 hv∙cm − 3 . For an administered Verteporfin dose of 0.4 mg∙kg − 1 and assuming a patient independent uptake ratio of 0.6 into the tumour tissue, the threshold is reached when delivering a fluence of 1.45±0.77 J∙cm − 2 . Hanada et al. 9 reported only summary results for the 5 patients in their trial with measurable necrotic volumes. The resulting threshold values for the 7.85 mm average necrotic tissue radius are 2.37∙10 17 hv∙cm − 3 or a fluence of 2.41 J∙cm − 2 for the same administered Verteporfin dose and a patient independent uptake ratio of 0.6 into the tumour tissue. Table 3 Verteporfin-mediated PDT conditions and necrosis CT imaging outcome according to Garcia Vazquez et al. in the normal porcine pancreas. Animal # Verteporfin [mg∙kg -1 ] Power [mW cm - 1 ] Time [sec] Light Dose [J∙cm -1 ] Target Vessel Diameter [mm] Necrosis depth range [mm] Min. -MAX threshold 10 18 [hν∙cm -3 ] 1 0.8 377 500 188.5 Splenic vein 8 0 - 2 0.4 260 1500 390 SMA 7 6–10 1.23–3.82 3 0.4 330 1500 495 Splenic artery 4 0–5 0.41–0.76 4 0.8 450 600 270 Splenic vein 8 6–10 0.43–0.79 5 1.6 450 690 310.5 Splenic vein 8 6–10 0.98–1.81 6 3.0 460 600 276 Splenic vein 10 11–15 0.76–1.27 7 3.2 535 600 321 Splenic vein 10 11–15 0.81–1.36 The exposure times to reach 4, 8, and 12 mm radii of necrosis were calculated for human pancreatic cancer patients and for the normal porcine pancreas. This is based on the administration of 0.4 mg∙kg -1 Verteporfin and the delivery of 690 nm light at 300 mW∙cm -2 at the intimal surface to limit potential thermal effects that could jeopardize the mechanical integrity of the blood vessel, as shown in Table 4 . The values presented in Table 4 b could be considered as Phase I/II dose ranges for future clinical studies in pancreatic cancer patients. Table 4 a-c . Calculated PDT dose parameters delivering 300 mW∙cm -2 . Table 5a presents the average fluence rate at the surface of the blood vessel intima and at radial distances of 0, 4, 8, and 12 mm. Table 5b provides the dose parameters for human pancreatic cancer tissues, listing the exposure times required to achieve perivascular necrotic margins of 4, 8, and 12 mm. Table 4 c provides the exposure times to reach the same necrosis radii in normal porcine pancreas. Blood vessel inner diameter [mm] 3 4 5 6 7 8 9 10 Table 4 a Fluence rate limited to an irradiance of 300 mW∙cm − 2 at the intima surface Power [W cm − 1 ] 0.25 0.32 0.37 0.45 0.54 0.61 0.69 0.79 Radial distance [mm] 0 0.30 0.30 0.30 0.30 0.30 0.30 0.30 0.30 4 0.066 0.073 0.081 0.085 0.097 0.10 0.11 0.11 8 0.030 0.035 0.039 0.042 0.048 0.050 0.054 0.057 12 0.016 0.018 0.020 0.023 0.026 0.028 0.030 0.032 Table 4 b Endovascular illumination time [sec] In human pancreatic cancer tissues, based on a dose threshold value of 0.14∙10 18 photons∙cm − 3 Necrosis Depth [mm] 4 316 273 258 232 205 194 196 175 8 636 553 504 460 406 382 357 337 12 1176 994 889 812 694 669 624 565 Table 4 c Endovascular illumination time [sec] In normal porcine pancreatic tissue, based on a dose threshold value of 1.27∙10 18 photons∙cm − 3 Necrosis Depth [mm] 4 2794 2412 2279 2049 1815 1713 1739 1553 8 5626 4894 4456 4066 3590 3379 3165 2979 12 10400 8789 7872 7191 6143 5925 5520 5001 Discussion In silico Monte Carlo simulations were performed based on input data from pancreatic cancer patients reported by Huggett et al. 10 and Hanada et al. 9 ​​ Using interstitial needle-based irradiation, the mean dose threshold to generate necrosis in human pancreatic cancer tissues was calculated to be 0.14 ± 0.08∙10 18 photons∙cm − 3 , which can be reached with ~ 190 J∙cm − 1 emitted from the light delivery fibre tip and a clinical Verteporfin dose of 0.4 mg∙kg − 1 and assuming an uptake ratio of 0.6. The threshold value calculated here is comparable to previously reported values. For example, in the rabbit cortex, the thresholds were 0.18∙10 18 and 0.5∙10 18 photons∙cm − 3 , using the photosensitiser 5-aminolevulinic acid or SnET 2 , respectively. For the VX2 tumour model, reported threshold values were 0.58∙10 18 and 0.5∙10 18 photons∙cm − 3 , respectively, for the same set of photosensitisers 35 ​​. Jermyn et al. 36 ​used the data from Huggett et al. 10 ​​and calculated the threshold values as 0.0105∙10 18 photons∙cm − 3 after correcting for spatial variations in the tissue optical properties. This is very low compared with previously reported values ​​ 35 ​​, and more than an order of magnitude lower compared to the value calculated in this work for the same data. Based on finite element analysis, a different methodology was employed to determine the fluence rate, where tissue optical properties were spatially resolved by segmenting blood vessels and pancreatic tissues, rather than using the homogeneous optical properties employed here. Yet, these reasons are insufficient to explain the differences and necessitate further investigation. The threshold values calculated herein for human pancreatic cancer are on the lower end of the spectrum compared to data previously reported in various animal models. This suggests that human pancreatic cancer tissues appear relatively sensitive to photodynamic damage, requiring a lower dose to achieve necrosis, compared to various animals, which typically require at least an order of magnitude higher dose to reach necrosis. To illustrate this, Ayaru et al. 37 reported a 3–4 mm radius of necrosis following a point illumination of the hamster pancreas sensitised with 2 mg∙kg − 1 Verteporfin, equivalent to a threshold value of 3.5∙10 18 photons∙cm − 3 . Similarly, Ferguson et al. 38 ​​ reported a threshold value of 2.3∙10 18 photons∙cm − 3 for breast cancer metastases in the rat spinal bone after administration of 0.8 mg∙kg − 1 Verteporfin. Likewise, for Photofrin administered at 2.5–10 mg∙kg − 1 , threshold values between 1.3–7.5∙10 18 photons∙cm − 3 were found in the rabbit VX2 model, white matter, and cortex 35 . Care is needed to distinguish between the extent of necrosis from point illumination (Ayaru) and illumination from a diffuser-tipped fibre where the light source is spread over a finite distance. For the same total energy, the maximum extent of the effect will be greater with the point source, but it will be confined to a smaller volume. For the seven porcine pancreases treated by our group. [Alain Garcia Vazquez, Tina Saeidi, Juan Verde, Fanélie Wanert, Irene Alexandra Spiridon, Axel Schmid, Lee Swanstrom, Stephen Bown, Lothar Lilge, and Arjen Bogaards Downstaging Locally Advanced Pancreatic Cancer with Endovascular Photodynamic Therapy. A Proof-of-Concept Study in the Porcine Model. Photochemistry and Photobiology Science. Under review], with endovascular irradiation, the calculated average PDT dose threshold was 1.27 ± 0.85∙10 18 photons∙cm − 3 . The threshold values remained relatively constant over the large dose range delivered here, as illustrated in Fig. 5 , indicating the robustness of this metric and the presented data. These values align with the above-mentioned data from other animals, yet are almost an order of magnitude higher than the threshold calculated for human pancreatic cancer patients. Currently, the underlying reasons for the differences in threshold values between animal models and human data remain unclear. Possible reasons include different uptake of verteporfin in normal porcine pancreas versus human pancreatic cancer tissues and varying administered doses of verteporfin. No tissue biopsies were available for Verteporfin uptake in the porcine study, as the minimally invasive approach was used for survival studies. While biopsies were available for the studies in human pancreatic cancers, insufficient detail was provided regarding Verteporfin uptake. Furthermore, blood is a dominant absorber at 690 nm, and the absorption coefficient in human pancreatic tumours may have been lower than considered in the tissue optical properties used here for the Monte Carlo simulations. A study by van Manen et al. demonstrated that the blood volume fraction in human pancreatic cancer (0.86%) was circa five times lower compared to the normal pancreas (4.49%), albeit with large interpatient variability ​ 39 ​. The low blood volume may also contribute to a lower pO 2 ; however, it does not appear to limit the efficacy of Verteporfin-mediated PDT, given the lower thresholds in the tumour versus the normal pancreatic tissue. Jermyn et al. 36 demonstrated that the necrotic lesion size effect can be more accurately predicted when the blood volume in pancreatic tissues, as measured with contrast-enhanced CT, is taken into account, highlighting the importance of blood volume in the target volume. The FullMonte simulations of the porcine data did not account for the increased absorption resulting from a higher photosensitizer concentration in some animals. This could lead to an overestimation of the fluence at the boundary of necrosis and, consequently, an overestimation of the PDT threshold values in animals exposed to higher drug-light combinations. Assuming a capsule-like necrotic volume for the clinical necrosis volumes is also an oversimplification, resulting only in a single threshold value and not a range, as shown in the porcine work. However, should this difference in thresholds between normal and cancerous pancreas be confirmed, it would suggest protection of normal pancreatic tissue during endovascular PDT. Conclusions Interstitial and endovascular light delivery as minimally invasive tissue therapy is feasible in pancreatic cancer patients. Only the endovascular route has the potential to downstage patients, that is, clearing tumours abutting major blood vessels, and thus providing tumour-free margins for the surgical removal of the remaining tumour. Considering the maximum time a blood vessel can be occluded, given clinical considerations, and the calculated exposure times indicated in Table 5b, when restricting the optical power not to exceed 300 mW∙cm − 2 , the attainable necrosis radius is limited, particularly for small-diameter vessels. These findings suggest that Endovascular Photodynamic Therapy (PDT) has the potential to create a necrotic tumour-free margin around pancreatic blood vessels, within clinically acceptable irradiation times. Based on our Monte Carlo calculations, assuming homogeneous tissue optical properties, a Verteporfin dose of 0.4 mg∙kg⁻¹ and an optical power of 300 mW∙cm − 2 @ 690 nm, necrotic margins of approximately 8 mm beyond the vessel adventitia can be anticipated in pancreatic cancer patients. The required irradiation times range from 337 to 636 seconds, inversely related to vessel diameters of 10 mm and 3 mm, respectively. These calculated dosimetry results support the feasibility of clinical application using the proposed Verteporfin dose and light delivery parameters, warranting further investigation in clinical trials. Declarations Funding This work benefited from state aid managed by the French National Research Agency (ANR) under the ‘‘investissements d’avenir’’ program with the reference ANR-10– IAHU-02, to the Institute of Image-Guided Surgery, IHU-Strasbourg, France. Salary support for (L.L. and T.S.) was provided through the Ontario Ministry of Economic Development and Trade under grant ORF 08-022 and the Princess Margaret Cancer Foundation. Authors' contributions A.G., T.S., J.V., L.S., L.L., and A.B. conceived and designed the study, developed the Methodology and interpreted results. A.G., T.S., J.V., F.W. ran simulations, executed the study, acquired the data or supported the data analysis. A.S. radiologically assessed the CT images. I.A.S. carried out the histopathological analysis. A.G., T.S., L.S., S.B., L.L., and A.B. discussed and interpreted the data and wrote and edited the manuscript. A.G., T.S., J.V., F.W., I.A.S., A.S., L.S., S.B., L.L., and A.B. reviewed and revised the manuscript. L.S., L.L. and A.B. supervised the study. Data availability The data supporting this study's findings are available from the corresponding author upon reasonable request. Acknowledgements We want to thank Ms. Amélie Gressier for project management and Ms. Cindy Vincent for coordinating the pre-clinical study. Vascular Oncology Biotechnologies B.V. kindly provided the laser device, light delivery prototypes, and Verteporfin. We thank Dr. Herbert Stepp and Prof. Dr. Ronald Sroka for granting us access to the equipment at the LIFE-Zentrum of the LMU Klinikum in Munich. Their support enabled us to cross-calibrate the wavelength and optical output power of the prototype devices developed herein against NIST-traceable standards. 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Inhibition of intimal hyperplasia in balloon injured arteries with adjunctive phthalocyanine sensitised photodynamic therapy. Eur J Vasc Endovasc Surg Off J Eur Soc Vasc Surg. 1996;11(1):19–28. doi: 10.1016/s1078-5884(96)80130-4 Ortu P, LaMuraglia GM, Roberts WG, Flotte TJ, Hasan T. Photodynamic therapy of arteries. A novel approach for treatment of experimental intimal hyperplasia. Circulation. 1992;85(3):1189–1196. doi: 10.1161/01.cir.85.3.1189 LaMuraglia GM, ChandraSekar NR, Flotte TJ, Abbott WM, Michaud N, Hasan T. Photodynamic therapy inhibition of experimental intimal hyperplasia: acute and chronic effects. J Vasc Surg . 1994;19(2):321–331. doi: 10.1016/s0741-5214(94)70107-5 Waksman R, McEwan PE, Moore TI, et al. PhotoPoint photodynamic therapy promotes stabilization of atherosclerotic plaques and inhibits plaque progression. J Am Coll Cardiol . 2008;52(12):1024–1032. doi: 10.1016/j.jacc.2008.06.023 Jenkins MP, Buonaccorsi GA, Raphael M, et al. Clinical study of adjuvant photodynamic therapy to reduce restenosis following femoral angioplasty. Br J Surg. 1999;86(10):1258–1263. doi: 10.1046/j.1365-2168.1999.01247.x Kereiakes DJ, Szyniszewski AM, Wahr D, et al. Phase I drug and light dose-escalation trial of motexafin lutetium and far red light activation (phototherapy) in subjects with coronary artery disease undergoing percutaneous coronary intervention and stent deployment: procedural and long-term results. Circulation. 2003;108(11):1310–1315. doi: 10.1161/01.CIR.0000087602.91755.19 Mansfield RJR, Jenkins MP, Pai ML, Bishop CCR, Bown SG, McEwan JR. Long-term safety and efficacy of superficial femoral artery angioplasty with adjuvant photodynamic therapy to prevent restenosis. Br J Surg. 2002;89(12):1538–1539. doi: 10.1046/j.1365-2168.2002.02269.x Usui M, Miyagi M, Fukasawa S, et al. A first trial in the clinical application of photodynamic therapy for the prevention of restenosis after coronary-stent placement. Lasers Surg Med. 2004;34(3):235–241. doi: 10.1002/lsm.20018 Nowak-Sliwinska P, Karocki A, Elas M, Pawlak A, Stochel G, Urbanska K. Verteporfin, photofrin II, and merocyanine 540 as PDT photosensitizers against melanoma cells. Biochem Biophys Res Commun. 2006;349(2):549–555. doi: 10.1016/j.bbrc.2006.08.060 Aveline B, Hasan T, Redmond RW. Photophysical and Photosensitizing Properties of Benzoporphyrin Derivative Monoacid Ring a (Bpd-Ma). Photochem Photobiol. 1994;59(3):328–335. doi: 10.1111/j.1751-1097.1994.tb05042.x Kim MM, Darafsheh A. Light Sources and Dosimetry Techniques for Photodynamic Therapy. Photochem Photobiol. 2020;96(2):280–294. doi: 10.1111/php.13219 Kim MM, Penjweini R, Zhu TC. Evaluation of singlet oxygen explicit dosimetry for predicting treatment outcomes of benzoporphyrin derivative monoacid ring A-mediated photodynamic therapy. J Biomed Opt. 2017;22(2):028002. doi: 10.1117/1.JBO.22.2.028002 Cassidy J, Betz V, Lilge L. Treatment plan evaluation for interstitial photodynamic therapy in a mouse model by Monte Carlo simulation with FullMonte. Front Phys. 2015;3. doi: 10.3389/fphy.2015.00006 Young-Schultz T, Brown S, Lilge L, Betz V. FullMonteCUDA: a fast, flexible, and accurate GPU-accelerated Monte Carlo simulator for light propagation in turbid media. Biomed Opt Express. 2019;10(9):4711–4726. doi: 10.1364/BOE.10.004711 Cassidy J, Nouri A, Betz V, Lilge L. High-performance, robustly verified Monte Carlo simulation with FullMonte. J Biomed Opt . 2018;23(8):1–11. doi: 10.1117/1.JBO.23.8.085001 Wilson RH, Chandra M, Scheiman J, et al. Optical spectroscopy detects histological hallmarks of pancreatic cancer. Opt Express . 2009;17(20):17502–17516. doi: 10.1364/OE.17.017502 Keijzer M, Richards-Kortum RR, Jacques SL, Feld MS. Fluorescence spectroscopy of turbid media: Autofluorescence of the human aorta. Appl Opt. 1989;28(20):4286–4292. doi: 10.1364/AO.28.004286 Lanka P, Bianchi L, Farina A, De Landro M, Pifferi A, Saccomandi P. Estimation of porcine pancreas optical properties in the 600–1100 nm wavelength range for light-based therapies. Sci Rep. 2022;12(1):1–11. doi: 10.1038/s41598-022-18277-7 Lilge L, Wilson BC. Photodynamic therapy of intracranial tissues: A preclinical comparative study of four different photosensitizers. J Clin Laser Med Surg. 1998;16(2):81–91. doi: 10.1089/clm.1998.16.81 Jermyn M, Davis SC, Dehghani H, et al. CT contrast predicts pancreatic cancer treatment response to verteporfin-based photodynamic therapy. Phys Med Biol. 2014;59(8):1911–1921. doi: 10.1088/0031-9155/59/8/1911 Ayaru L, Wittmann J, Macrobert AJ, Novelli M, Bown SG, Pereira SP. Photodynamic therapy using verteporfin photosensitization in the pancreas and surrounding tissues in the Syrian golden hamster. Pancreatol Off J Int Assoc Pancreatol. [et al]. 2007;7(1):20–27. doi: 10.1159/000101874 Ferguson D, Lo W, Molenhuis D, et al. Bpd-Ma Mediated PDT of Spinal Bone Metastases: Determining PDT Threshold Values. In:; 2019:1. doi: 10.1109/PN.2019.8819594 van Manen L, Schmidt I, Inderson A, et al. Single fiber reflectance spectroscopy for pancreatic cancer detection during endoscopic ultrasound guided fine needle biopsy: a prospective cohort study. Int J Med Sci . 2022;19(2):205–212. doi: 10.7150/ijms.65364 Additional Declarations Competing interest reported. A.B. owns shares in the start-up company Vascular Oncology Biotechnologies B.V. and is an inventor on a related patent application (WO2022218991A1). The other authors declare no competing interests. Cite Share Download PDF Status: Published Journal Publication published 03 Dec, 2025 Read the published version in Photochemical & Photobiological Sciences → Version 1 posted Editorial decision: Revision requested 01 Sep, 2025 Reviews received at journal 01 Sep, 2025 Reviews received at journal 26 Aug, 2025 Reviewers agreed at journal 21 Aug, 2025 Reviewers agreed at journal 12 Aug, 2025 Reviewers agreed at journal 28 Jul, 2025 Reviewers invited by journal 18 Jul, 2025 Editor assigned by journal 17 Jul, 2025 Submission checks completed at journal 16 Jul, 2025 First submitted to journal 30 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7013948","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":488142449,"identity":"fe87214e-41ff-4e0c-abc1-ac1098e7879f","order_by":0,"name":"Tina Saeidi","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Tina","middleName":"","lastName":"Saeidi","suffix":""},{"id":488142451,"identity":"372468b9-f955-4ebe-af8e-667cd4e983e5","order_by":1,"name":"Alain Garcia Vazquez","email":"","orcid":"","institution":"IHU Strasbourg","correspondingAuthor":false,"prefix":"","firstName":"Alain","middleName":"Garcia","lastName":"Vazquez","suffix":""},{"id":488142452,"identity":"16219149-239d-43eb-9ecf-e9df27f350ce","order_by":2,"name":"Juan Verde","email":"","orcid":"","institution":"IHU Strasbourg","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Verde","suffix":""},{"id":488142453,"identity":"1ebb0be5-82e0-49ae-8c16-12e30a491b8e","order_by":3,"name":"Fanélie Wanert","email":"","orcid":"","institution":"IHU Strasbourg","correspondingAuthor":false,"prefix":"","firstName":"Fanélie","middleName":"","lastName":"Wanert","suffix":""},{"id":488142454,"identity":"b1cbc9c9-036f-4539-bee7-056e88bcda4e","order_by":4,"name":"Irene Alexandra Spiridon","email":"","orcid":"","institution":"IHU Strasbourg","correspondingAuthor":false,"prefix":"","firstName":"Irene","middleName":"Alexandra","lastName":"Spiridon","suffix":""},{"id":488142455,"identity":"59a4993e-352a-4008-8460-d5153c9623cd","order_by":5,"name":"Axel Schmid","email":"","orcid":"","institution":"University Hospital Erlangen","correspondingAuthor":false,"prefix":"","firstName":"Axel","middleName":"","lastName":"Schmid","suffix":""},{"id":488142456,"identity":"42ec93f0-34c5-40e3-a9a2-68738f3a98fa","order_by":6,"name":"Lee Swanstrom","email":"","orcid":"","institution":"IHU Strasbourg","correspondingAuthor":false,"prefix":"","firstName":"Lee","middleName":"","lastName":"Swanstrom","suffix":""},{"id":488142457,"identity":"6d812e4a-2d15-448d-add7-735fc78aba46","order_by":7,"name":"Stephen Bown","email":"","orcid":"","institution":"University Health Network","correspondingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"","lastName":"Bown","suffix":""},{"id":488142458,"identity":"da4b4ac7-d587-41d4-95e5-3fbbaa9b61d6","order_by":8,"name":"Lothar Lilge","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYBACPgYGNhAtw8YOJD8wHCCshY2BGayFh42ZgYFxBklaGIBamHmI0sLef+zBzz0MPHzM7Bcf27bdyWNgP/wAvxaew+yGPc9ADuMpNs5te1bMwJNmgF+LRDKbBM8BsJY06dy2w4kNEgyEtUj+gWhJ/20J1sL+gaAWaYgt7MeYGcFaeAjYwnPYTFrmgATIFmbJnnOHE9t4cgrwauFnb3wm+eaAjZx8e/vDDz/KDif2sx/fgFcLFEgAMdQ9bMSohwL2ByQoHgWjYBSMgpEEAGblN95teeSlAAAAAElFTkSuQmCC","orcid":"","institution":"University of Toronto","correspondingAuthor":true,"prefix":"","firstName":"Lothar","middleName":"","lastName":"Lilge","suffix":""},{"id":488142459,"identity":"eaa9eb37-8953-4c65-8ee2-d14e91c6a155","order_by":9,"name":"Arjen Bogaards","email":"","orcid":"","institution":"Vascular Oncology Biotechnologies B.V.,","correspondingAuthor":false,"prefix":"","firstName":"Arjen","middleName":"","lastName":"Bogaards","suffix":""}],"badges":[],"createdAt":"2025-06-30 20:23:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7013948/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7013948/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s43630-025-00791-y","type":"published","date":"2025-12-03T15:58:15+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87384366,"identity":"02add6b4-58c6-4a4b-983c-05444b376c59","added_by":"auto","created_at":"2025-07-23 08:49:17","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":93681,"visible":true,"origin":"","legend":"\u003cp\u003eModels for FullMonte simulation space for top row clinically placed interstitial diffusers and bottom row pre-clinically placed endovascular diffusers.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7013948/v1/fa692bea2c3c7c95df150de6.jpg"},{"id":87383122,"identity":"8ab949d5-6dd3-4b83-ba5d-9d45cabf0571","added_by":"auto","created_at":"2025-07-23 08:41:17","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":56199,"visible":true,"origin":"","legend":"\u003cp\u003eshows an example of a hypodense contrast-enhanced CT image around the superior mesenteric artery, 24 hrs after administering 0.4 mg∙kg\u003csup\u003e-1\u003c/sup\u003e Verteporfin and 390 J∙cm\u003csup\u003e-1\u003c/sup\u003e. The hypodense signal, indicated by white arrows, at 24 hours was less pronounced, possibly due to not achieving mature necrosis, compared to the CT images at 48 hours in the other animals.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7013948/v1/481958c6e05a448fd9559e08.jpg"},{"id":87383117,"identity":"330b4973-0484-4f81-a12c-f65624fe08c2","added_by":"auto","created_at":"2025-07-23 08:41:17","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":38314,"visible":true,"origin":"","legend":"\u003cp\u003eClinical data given a Verteporfin dose of 0.4 mg kg\u003csup\u003e-1\u003c/sup\u003e, the light-activated drug absorbed fluence as a function of radius from the interstitial diffuser for 10 J∙cm\u003csup\u003e-1\u003c/sup\u003e (blue), 20 J∙cm\u003csup\u003e-1 \u003c/sup\u003e(green), 40 J∙cm\u003csup\u003e-1 \u003c/sup\u003e(yellow), Photo-activated activation light as employed by Huggett et al.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7013948/v1/33b0610831c823e0f9c291a7.jpg"},{"id":87383118,"identity":"ec2eda7e-b6fa-491c-8107-d24be1156c7e","added_by":"auto","created_at":"2025-07-23 08:41:17","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":65257,"visible":true,"origin":"","legend":"\u003cp\u003eThe fluence rate absorbed by Verteporfin in seven porcine, by PDT utilizing endovascular-based irradiation as a function of radial distance from the vessel wall (adventitia) #1 (blue azure), #2 (light blue), #3 (green), #4 (yellow), #5 (orange), #6 (light red), and #7 (dark red). The vertical colour boxes indicate the range of measured tissue necrosis, as seen in Table 2. The horizontal, red-shaded area indicates the range of administered PDT doses required to cause pancreatic tissue necrosis.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7013948/v1/d0e84cbad105456e71443ca1.jpg"},{"id":87386414,"identity":"b7fc536f-ab90-44c2-9df7-36f6b9620da1","added_by":"auto","created_at":"2025-07-23 08:57:17","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":35319,"visible":true,"origin":"","legend":"\u003cp\u003eMinimum (open symbols) and maximum (solid symbols) Verteporfin PDT threshold values as a function of the delivered Photosensitizer and endovascular light dose product in the normal porcine pancreas. The threshold values are largely independent of the delivered PDT dose.\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7013948/v1/fdbf332c60f8abbdadb240fc.jpg"},{"id":97724119,"identity":"40e961d4-d74f-439f-b54e-e8167c11e039","added_by":"auto","created_at":"2025-12-08 16:12:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1349699,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7013948/v1/3ac83225-3fbf-4a55-906f-6ed6390c5ab0.pdf"}],"financialInterests":"Competing interest reported. A.B. owns shares in the start-up company Vascular Oncology Biotechnologies B.V. and is an inventor on a related patent application (WO2022218991A1). The other authors declare no competing interests.","formattedTitle":"Dose Threshold Values for Endovascular Photodynamic Therapy (PDT) in Normal Pig Pancreas and Human Pancreatic Cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFor Hepato-pancreatoiliary (HPB) cancers, surgery is currently the only potential cure for pancreatic adenocarcinoma, one of the most aggressive cancers. Annually, more than 500,000 patients are diagnosed with pancreatic cancer worldwide\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e​. However, approximately 40% present with locally advanced pancreatic cancer (LAPC), frequently involving large blood vessels abutting or within the pancreas, preventing surgeons from achieving a complete resection of the malignancies \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Clinically downstaging these patients, that is, locally freeing vessels from abutting tumours, could make them eligible for surgery, and potentially extend their survival times.\u003c/p\u003e\u003cp\u003eTo become clinically relevant, such a procedure must induce rapid coagulative necrosis that matures within days and be minimally invasive, especially since patients would need to undergo the downstaging procedure and surgery within a short time period.\u003c/p\u003e\u003cp\u003eOur group recently proposed that Endovascular Photodynamic Therapy (PDT) can be such a therapy, as necrosis occurs within 48 hrs. PDT is an innovative form of photodynamic therapy whereby irradiation occurs via the endovascular route to photoactivate the photosensitiser, Verteporfin, that was administered 60–90 minutes earlier. It can cause indiscriminate lipid and protein oxidation, leading to cell death, manifesting as apoptosis and coagulative necrosis \u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e–\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e ​and has been investigated for pancreatic cancer over the past decades. In particular, Phase I/II clinical studies in 65 patients demonstrated that interstitial Photodynamic Therapy based on inserted optical fibres resulted in necrotic lesions in pancreatic tumours with 0.5–4.1 cm diameter ​\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e​.\u003c/p\u003e\u003cp\u003ePhotoactivated ablation via the endovascular route is not a novel concept and has been employed for vascular diseases, such as preventing angioplasty restenosis, using various photosensitizers (PSs) in pre-clinical studies \u003csup\u003e\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e–\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e and clinical studies \u003csup\u003e\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e–\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. These experiments demonstrated that Photodynamic Therapy is well tolerated by large vessels. The studies did not result in vascular stenosis, thrombosis, aneurysms, or vessel rupture. Moreover, the supporting collagen and elastin, providing the structural integrity in the vascular wall, remain intact. However, these previous studies focused on treating the vasculature and primarily targeted the vascular wall. What is not known is whether necrosis outside the vascular wall in the perivascular tissue and surrounding organs is feasible, what devices and dose parameters are required, and if such a treatment can be carried out without unacceptable effects on the vasculature when surrounded by necrotic tumour tissue. Such ablation would have to be carried out within a clinically acceptable irradiation time, preferably faster than the maximum time permitted to block a vessel, thereby avoiding the compromise of downstream organs or tissues.\u003c/p\u003e\u003cp\u003eTo demonstrate the proof-of-concept and initial safety of this approach, our group recently developed a prototype near-infrared irradiating catheter and carried out a dose escalation study in a large animal model. Using verteporfin-mediated PDT in normal pig pancreas can generate a necrotic rim up to 15 mm wide around the vessel, while no immediate deterioration of the vein and artery was noted for the first 48 hours.\u003c/p\u003e\u003cp\u003eTo proceed to clinical trials, the required PDT dose parameters must be determined to generate the desired rim width of coagulation necrosis around the target blood vessels with an abutting or encasing tumour, within a clinically acceptable treatment time.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eDose Threshold Model\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eIn silico\u003c/em\u003e Monte Carlo calculations were utilised to quantify the interstitial photo-activated dose response, based on two prior clinical Phase I/II studies \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e and the pre-clinical endovascular catheter-mediated Photodynamic Therapy\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Using a dose threshold model, the PDT dose at position \u003cem\u003er\u003c/em\u003e is given by reactive oxygen species generated by Verteporfin, 0.77 \u003csup\u003e25,26\u003c/sup\u003e, and the number of photons absorbed. Thus, the dose is given by the temporal integral over the light exposure time, \u003cem\u003eT\u003c/em\u003e, of the photon density given by the fluence rate, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\varphi\\:(t,r)\\)\u003c/span\u003e\u003c/span\u003e \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\lambda\\:/hc\\)\u003c/span\u003e\u003c/span\u003e, Verteporfin’s molar extinction coefficient, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\epsilon\\:\\left(\\lambda\\:\\right)\\)\u003c/span\u003e\u003c/span\u003e and its concentration [PS], according to:\u003c/p\u003e\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:{D}_{EPA}\\left(r\\right)={\\int\\:}_{0}^{T}\\varphi\\:\\left(t,r\\right)\\frac{\\lambda\\:}{hc}\\epsilon\\:\\left(\\lambda\\:\\right)\\left[PS\\right]dt$$\u003c/div\u003e\u003c/div\u003e\u003cp\u003ewith necrosis occurring when \u003cem\u003eD\u003c/em\u003e\u003csub\u003e\u003cem\u003ePDT\u003c/em\u003e\u003c/sub\u003e \u0026gt;\u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003etissue\u003c/em\u003e\u003c/sub\u003e, whereby \u003cem\u003eT\u003c/em\u003e depends on the tissue, the PS, and PDT treatment conditions. The PDT dose depends on the \u003cem\u003eD\u003c/em\u003e\u003csub\u003e\u003cem\u003ePDT\u003c/em\u003e,\u003c/sub\u003e which is given in units of photons absorbed per unit volume or [hν∙cm\u003csup\u003e− 3\u003c/sup\u003e] after converting J into the number of photons based on the employed activation wavelength. In this simplest form, this PDT dose model assumes ubiquitous availability of oxygen and a constant Verteporfin concentration as a function of r. While photobleaching can be included in the equation, as shown by Kim et al. \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, it is omitted here, given its low quantum yield of 5∙10\u003csup\u003e− 5 26\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe FullMonte light propagation simulations allow the extraction of the PDT dose Threshold, T, at the reported necrosis boundaries (r\u003csub\u003en\u003c/sub\u003e) in the work above\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eBased on the derived threshold values, the dose range, in terms of administered photo-activated drug dose, optical power delivery, and illumination duration, was estimated to produce a 4-, 8-, or 12-mm margin of perivascular necrosis in human pancreatic cancer.\u003c/p\u003e\u003cp\u003e\u003cem\u003eAnatomical Model\u003c/em\u003e\u003c/p\u003e\u003cp\u003eSimulations were performed within a basic cubic volume (4 × 4 × 5 cm³) representing pancreatic tissues. For the interstitial needle-based energy application used in the clinical studies, a 0.8 mm diameter optical fiber having a 1 cm cylindrical diffuser tip was positioned at the center of the tissue model. The tissue volume was divided equally, with one half representing pancreatic cancer and the other half representing normal pancreatic tissue.\u003c/p\u003e\u003cp\u003eFor the endovascular-based energy delivery used in the preclinical study, a centrally placed cylindrical tube within the cubical volume simulated a blood vessel. Arteries were modeled with an inner diameter of 3–6 mm and a three-layered wall (intima, media, and adventitia) totaling 1.3 mm in thickness. Veins were modeled with an inner diameter of 7–10 mm and a single-layer wall 0.5 mm thick. As in the interstitial model, the vessel was surrounded by pancreatic tissue, half cancerous and half normal. A near-infrared irradiating catheter was placed inside the vessel, featuring a centrally positioned 1 cm long cylindrical diffuser with a 0.8 mm diameter, located within a 3 cm long saline-filled balloon that matched the vessel’s inner diameter. Blood was assumed to be present in the vessel lumen beyond the proximal and distal ends of the balloon, corresponding to arterial and venous cases, respectively (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe simulations to determine the threshold dose at the reported necrotic boundaries for the clinical and preclinical studies were executed using FullMonte’s \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e implementation for graphics processors FullMonteCUDA \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. The optical properties for the tissues were selected from literature, including the three arterial wall layers at 690 nm \u003csup\u003e\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e–\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, and are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Saline and the optical diffusers are assumed to be optically neutral, with no absorption or scattering of light.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTissue optical property assignments for simulation volumes representing different tissue structures at 690 nm.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTissues\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAbsorption Coefficient\u003c/p\u003e\u003cp\u003eµ\u003csub\u003ea\u003c/sub\u003e [mm\u003csup\u003e− 1\u003c/sup\u003e]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReduced Scattering Coefficient\u003c/p\u003e\u003cp\u003eµ\u003csub\u003es\u003c/sub\u003e [mm\u003csup\u003e− 1\u003c/sup\u003e]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eScattering Anisotropy\u003c/p\u003e\u003cp\u003e(g)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRefractive Index\u003c/p\u003e\u003cp\u003e(n)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePancreas\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.372\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePancreatic Cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.372\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntima\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.2333\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.9032\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdventitia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.3825\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.062\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.8504\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eInput data for FullMonteCUDA simulations included: the molar absorption coefficient of 34,000 M\u003csup\u003e− 1\u003c/sup\u003e∙cm\u003csup\u003e− 1\u003c/sup\u003e at 690 nm for Verteporfin, 718.8 g∙M\u003csup\u003e− 1\u003c/sup\u003e molar weight, and a specific uptake ratio (SUR) of 0.6 for a drug light interval of 60–90 min post i.v. administration. The administered Verteporfin doses were 0.4 mg∙kg\u003csup\u003e− 1\u003c/sup\u003e for the tumour and 0.4–3.2 mg∙kg\u003csup\u003e− 1\u003c/sup\u003e for normal porcine pancreas, respectively.\u003c/p\u003e\u003cp\u003eThe clinical studies by Huggett et al.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e and Hanada et al.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e administered 0.4 mg∙kg\u003csup\u003e− 1\u003c/sup\u003e Verteporfin i.v. and applied light energies escalation from 5 to 50 J∙cm\u003csup\u003e− 1\u003c/sup\u003e diffuser length. The resulting radii of necrosis were calculated by assuming the reported necrosis volumes had a capsule shape, comprising a cylinder with hemispherical ends, and are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The dose escalation in the porcine model by our group [Alain Garcia Vazquez, Tina Saeidi, Juan Verde, Fanélie Wanert, Irene Alexandra Spiridon, Axel Schmid, Lee Swanstrom, Stephen Bown, Lothar Lilge, and Arjen Bogaards “Downstaging Locally Advanced Pancreatic Cancer with Endovascular Photodynamic Therapy. A Proof-of-Concept Study in the Porcine Model”. Photochemistry and Photobiology Science. Under review] included variations to both the administered Verteporfin dose, a range factor of 8, from 0.4–3.2 mg∙kg\u003csup\u003e− 1,\u003c/sup\u003e and the much lower endovascular delivered light dose, with a range factor of 2, ranging from 188 to 395 J∙cm\u003csup\u003e− 1\u003c/sup\u003e. The resulting radii or margins of necrosis that extend beyond the outer adventitia wall were measured from the hypointense regions seen on the CT images. All Data are listed in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eThe threshold values were derived from the intersection of the FullMonte-derived light fluence as a function of the radial distance to the adventitia perpendicular to the diffuser centre and the measured radii of necrosis.\u003c/p\u003e\u003cp\u003eUsing the Verteporfin threshold values for human pancreatic and normal porcine pancreas, calculations based on in silico model simulations were performed to derive the irradiation times (in seconds) required to generate a 4-, 8-, or 12-mm tumour-free perivascular necrosis margin for arteries and veins with the aforementioned inner diameters. Times for high power delivery to the diffuser (1 W∙cm\u003csup\u003e− 1\u003c/sup\u003e) and when not exceeding 300 mW∙cm\u003csup\u003e− 2\u003c/sup\u003e at the intima surface to prevent thermal damage to the vessel’s structural support, were determined as a function of the inner vessel diameter.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows an example of a hypodense contrast-enhanced CT image around the superior mesenteric artery, 24 hrs after administering 0.4 mg∙kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e Verteporfin and 390 J∙cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. The hypodense signal, indicated by white arrows, at 24 hours was less pronounced, possibly due to not achieving mature necrosis, compared to the CT images at 48 hours in the other animals.\u003c/p\u003e\u003cp\u003eFigures \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e show the resulting fluence [J∙cm\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e] in the mid-plane of the optical diffusers as a function of the radial distance from the emitter, based on the data provided in Huggett et al.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the fluence for the cases presented by Garcia Vazquez et al. [Alain Garcia Vazquez, Tina Saeidi, Juan Verde, Fan\u0026eacute;lie Wanert, Irene Alexandra Spiridon, Axel Schmid, Lee Swanstrom, Stephen Bown, Lothar Lilge, and Arjen Bogaards Downstaging Locally Advanced Pancreatic Cancer with Endovascular Photodynamic Therapy. A Proof-of-Concept Study in the Porcine Model. Photochemistry and Photobiology Science. Under review] as a function of radial distance beyond the outer vessel surface, multiplied by the administered Verteporfin dose, to allow for comparison between the different animals. Both figures illustrate the ranges of observed necrosis radii for the various treatment conditions.\u003c/p\u003e\u003cp\u003eBased on these simulations, the fluence at the boundary of necrosis and the administered Verteporfin concentrations, \u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003etissue\u003c/em\u003e\u003c/sub\u003e was calculated in units of [hv∙cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e] for human pancreatic tumours and normal porcine pancreas.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eVerteporfin-mediated interstitial photo-activated conditions and necrosis imaging outcome according to the reports by Huggett et al. \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Patients all received 0.4 mg∙kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e Verteporfin\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient\u003c/p\u003e\u003cp\u003e#\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDelivered\u003c/p\u003e\u003cp\u003eLight Dose\u003c/p\u003e\u003cp\u003e[J∙cm\u003csup\u003e-1\u003c/sup\u003e]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eVolume Necrosis\u003c/p\u003e\u003cp\u003e[cm\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRadius Necrosis\u003c/p\u003e\u003cp\u003e[mm]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFluence at Necrosis\u003c/p\u003e\u003cp\u003eRadius\u003c/p\u003e\u003cp\u003e[J∙cm\u003csup\u003e-2\u003c/sup\u003e]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePhoto-\u003c/p\u003e\u003cp\u003eActivation\u003c/p\u003e\u003cp\u003eThreshold\u003c/p\u003e\u003cp\u003e10\u003csup\u003e17\u003c/sup\u003e [hν∙cm\u003csup\u003e-3\u003c/sup\u003e]\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.931\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.552\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.434\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;11.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;11.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.311\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.89\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.725\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.745\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.785\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.22\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.22\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.93\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe average threshold values based on the human data, excluding patient 3, given by Huggett et al.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e is 1.43\u0026plusmn;0.76∙10\u003csup\u003e17\u003c/sup\u003e hv∙cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e. For an administered Verteporfin dose of 0.4 mg∙kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and assuming a patient independent uptake ratio of 0.6 into the tumour tissue, the threshold is reached when delivering a fluence of 1.45\u0026plusmn;0.77 J∙cm\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e. Hanada et al.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e reported only summary results for the 5 patients in their trial with measurable necrotic volumes. The resulting threshold values for the 7.85 mm average necrotic tissue radius are 2.37∙10\u003csup\u003e17\u003c/sup\u003e hv∙cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e or a fluence of 2.41 J∙cm\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e for the same administered Verteporfin dose and a patient independent uptake ratio of 0.6 into the tumour tissue.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eVerteporfin-mediated PDT conditions and necrosis CT imaging outcome according to Garcia Vazquez et al. in the normal porcine pancreas.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnimal #\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVerteporfin\u003c/p\u003e\u003cp\u003e[mg∙kg\u003csup\u003e-1\u003c/sup\u003e]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePower\u003c/p\u003e\u003cp\u003e[mW cm\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTime\u003c/p\u003e\u003cp\u003e[sec]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLight\u003c/p\u003e\u003cp\u003eDose\u003c/p\u003e\u003cp\u003e[J∙cm\u003csup\u003e-1\u003c/sup\u003e]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTarget\u003c/p\u003e\u003cp\u003eVessel\u003c/p\u003e\u003cp\u003eDiameter\u003c/p\u003e\u003cp\u003e[mm]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNecrosis depth\u003c/p\u003e\u003cp\u003erange\u003c/p\u003e\u003cp\u003e[mm]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMin. -MAX\u003c/p\u003e\u003cp\u003ethreshold\u003c/p\u003e\u003cp\u003e10\u003csup\u003e18\u003c/sup\u003e [hν∙cm\u003csup\u003e-3\u003c/sup\u003e]\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e377\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e500\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e188.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSplenic\u003c/p\u003e\u003cp\u003evein\u003c/p\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e260\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1500\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e390\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSMA\u003c/p\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6\u0026ndash;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.23\u0026ndash;3.82\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e330\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1500\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e495\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSplenic\u003c/p\u003e\u003cp\u003eartery\u003c/p\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u0026ndash;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.41\u0026ndash;0.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e450\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e600\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e270\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSplenic\u003c/p\u003e\u003cp\u003evein\u003c/p\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6\u0026ndash;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.43\u0026ndash;0.79\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e450\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e690\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e310.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSplenic\u003c/p\u003e\u003cp\u003evein\u003c/p\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6\u0026ndash;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.98\u0026ndash;1.81\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e460\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e600\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e276\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSplenic\u003c/p\u003e\u003cp\u003evein\u003c/p\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e11\u0026ndash;15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.76\u0026ndash;1.27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e535\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e600\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e321\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSplenic\u003c/p\u003e\u003cp\u003evein\u003c/p\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e11\u0026ndash;15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.81\u0026ndash;1.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe exposure times to reach 4, 8, and 12 mm radii of necrosis were calculated for human pancreatic cancer patients and for the normal porcine pancreas. This is based on the administration of 0.4 mg∙kg\u003csup\u003e-1\u003c/sup\u003e Verteporfin and the delivery of 690 nm light at 300 mW∙cm\u003csup\u003e-2\u003c/sup\u003e at the intimal surface to limit potential thermal effects that could jeopardize the mechanical integrity of the blood vessel, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The values presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb could be considered as Phase I/II dose ranges for future clinical studies in pancreatic cancer patients.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003ea-c\u003c/b\u003e. Calculated PDT dose parameters delivering 300 mW∙cm\u003csup\u003e-2\u003c/sup\u003e. Table\u0026nbsp;5a presents the average fluence rate at the surface of the blood vessel intima and at radial distances of 0, 4, 8, and 12 mm. Table\u0026nbsp;5b provides the dose parameters for human pancreatic cancer tissues, listing the exposure times required to achieve perivascular necrotic margins of 4, 8, and 12 mm. Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec provides the exposure times to reach the same necrosis radii in normal porcine pancreas.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"19\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c17\" colnum=\"17\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c18\" colnum=\"18\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c19\" colnum=\"19\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"18\" nameend=\"c19\" namest=\"c2\"\u003e\u003cp\u003eBlood vessel inner diameter [mm]\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c15\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c18\" namest=\"c16\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c19\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"18\" nameend=\"c19\" namest=\"c2\"\u003e\u003cp\u003eFluence rate limited to an irradiance of 300 mW∙cm\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e at the intima surface\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePower [W cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e0.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e0.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003e0.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003e0.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e0.79\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003eRadial distance [mm]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.066\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e0.073\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e0.081\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003e0.085\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003e0.097\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003e0.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.030\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e0.035\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e0.039\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003e0.042\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003e0.048\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003e0.050\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.054\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e0.057\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e0.018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e0.020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003e0.023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003e0.026\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003e0.028\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.030\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e0.032\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"18\" nameend=\"c19\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eEndovascular illumination time [sec]\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eIn human pancreatic cancer tissues, based on a dose threshold value of\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e0.14∙10\u003c/b\u003e\u003csup\u003e\u003cb\u003e18\u003c/b\u003e\u003c/sup\u003e \u003cb\u003ephotons∙cm\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026minus;\u0026thinsp;3\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eNecrosis\u003c/p\u003e\u003cp\u003eDepth\u003c/p\u003e\u003cp\u003e[mm]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e316\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e273\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e258\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003e232\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003e205\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003e194\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e196\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e175\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e636\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e553\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e504\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003e460\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003e406\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003e382\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e357\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e337\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1176\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e994\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e889\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003e812\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003e694\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003e669\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e624\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e565\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"18\" nameend=\"c19\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eEndovascular illumination time [sec]\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eIn normal porcine pancreatic tissue, based on a dose threshold value of\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e1.27∙10\u003c/b\u003e\u003csup\u003e\u003cb\u003e18\u003c/b\u003e\u003c/sup\u003e \u003cb\u003ephotons∙cm\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026minus;\u0026thinsp;3\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eNecrosis\u003c/p\u003e\u003cp\u003eDepth\u003c/p\u003e\u003cp\u003e[mm]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2794\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e2412\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e2279\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003e2049\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003e1815\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003e1713\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e1739\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e1553\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5626\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e4894\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e4456\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003e4066\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003e3590\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003e3379\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e3165\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e2979\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10400\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e8789\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e7872\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003e7191\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003e6143\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c16\" namest=\"c14\"\u003e\u003cp\u003e5925\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e5520\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c19\" namest=\"c18\"\u003e\u003cp\u003e5001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cem\u003eIn silico\u003c/em\u003e Monte Carlo simulations were performed based on input data from pancreatic cancer patients reported by Huggett et al.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e and Hanada et al. \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e​​ Using interstitial needle-based irradiation, the mean dose threshold to generate necrosis in human pancreatic cancer tissues was calculated to be 0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08∙10\u003csup\u003e18\u003c/sup\u003e photons∙cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e, which can be reached with ~\u0026thinsp;190 J∙cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e emitted from the light delivery fibre tip and a clinical Verteporfin dose of 0.4 mg∙kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and assuming an uptake ratio of 0.6. The threshold value calculated here is comparable to previously reported values. For example, in the rabbit cortex, the thresholds were 0.18∙10\u003csup\u003e18\u003c/sup\u003e and 0.5∙10\u003csup\u003e18\u003c/sup\u003e photons∙cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e, using the photosensitiser 5-aminolevulinic acid or SnET\u003csub\u003e2\u003c/sub\u003e, respectively. For the VX2 tumour model, reported threshold values were 0.58∙10\u003csup\u003e18\u003c/sup\u003e and 0.5∙10\u003csup\u003e18\u003c/sup\u003e photons∙cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e, respectively, for the same set of photosensitisers\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e ​​. Jermyn et al.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e ​used the data from Huggett et al.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e ​​and calculated the threshold values as 0.0105∙10\u003csup\u003e18\u003c/sup\u003e photons∙cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e after correcting for spatial variations in the tissue optical properties. This is very low compared with previously reported values ​​\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e​​, and more than an order of magnitude lower compared to the value calculated in this work for the same data. Based on finite element analysis, a different methodology was employed to determine the fluence rate, where tissue optical properties were spatially resolved by segmenting blood vessels and pancreatic tissues, rather than using the homogeneous optical properties employed here. Yet, these reasons are insufficient to explain the differences and necessitate further investigation.\u003c/p\u003e\u003cp\u003eThe threshold values calculated herein for human pancreatic cancer are on the lower end of the spectrum compared to data previously reported in various animal models. This suggests that human pancreatic cancer tissues appear relatively sensitive to photodynamic damage, requiring a lower dose to achieve necrosis, compared to various animals, which typically require at least an order of magnitude higher dose to reach necrosis.\u003c/p\u003e\u003cp\u003eTo illustrate this, Ayaru et al.\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e reported a 3\u0026ndash;4 mm radius of necrosis following a point illumination of the hamster pancreas sensitised with 2 mg∙kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e Verteporfin, equivalent to a threshold value of 3.5∙10\u003csup\u003e18\u003c/sup\u003e photons∙cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e. Similarly, Ferguson et al.\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e​​ reported a threshold value of 2.3∙10\u003csup\u003e18\u003c/sup\u003e photons∙cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e for breast cancer metastases in the rat spinal bone after administration of 0.8 mg∙kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e Verteporfin. Likewise, for Photofrin administered at 2.5\u0026ndash;10 mg∙kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, threshold values between 1.3\u0026ndash;7.5∙10\u003csup\u003e18\u003c/sup\u003e photons∙cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e were found in the rabbit VX2 model, white matter, and cortex \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Care is needed to distinguish between the extent of necrosis from point illumination (Ayaru) and illumination from a diffuser-tipped fibre where the light source is spread over a finite distance. For the same total energy, the maximum extent of the effect will be greater with the point source, but it will be confined to a smaller volume.\u003c/p\u003e\u003cp\u003eFor the seven porcine pancreases treated by our group. [Alain Garcia Vazquez, Tina Saeidi, Juan Verde, Fan\u0026eacute;lie Wanert, Irene Alexandra Spiridon, Axel Schmid, Lee Swanstrom, Stephen Bown, Lothar Lilge, and Arjen Bogaards Downstaging Locally Advanced Pancreatic Cancer with Endovascular Photodynamic Therapy. A Proof-of-Concept Study in the Porcine Model. Photochemistry and Photobiology Science. Under review], with endovascular irradiation, the calculated average PDT dose threshold was 1.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.85∙10\u003csup\u003e18\u003c/sup\u003e photons∙cm\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e. The threshold values remained relatively constant over the large dose range delivered here, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, indicating the robustness of this metric and the presented data. These values align with the above-mentioned data from other animals, yet are almost an order of magnitude higher than the threshold calculated for human pancreatic cancer patients.\u003c/p\u003e\u003cp\u003eCurrently, the underlying reasons for the differences in threshold values between animal models and human data remain unclear. Possible reasons include different uptake of verteporfin in normal porcine pancreas versus human pancreatic cancer tissues and varying administered doses of verteporfin. No tissue biopsies were available for Verteporfin uptake in the porcine study, as the minimally invasive approach was used for survival studies. While biopsies were available for the studies in human pancreatic cancers, insufficient detail was provided regarding Verteporfin uptake. Furthermore, blood is a dominant absorber at 690 nm, and the absorption coefficient in human pancreatic tumours may have been lower than considered in the tissue optical properties used here for the Monte Carlo simulations. A study by van Manen et al. demonstrated that the blood volume fraction in human pancreatic cancer (0.86%) was circa five times lower compared to the normal pancreas (4.49%), albeit with large interpatient variability ​\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e​. The low blood volume may also contribute to a lower pO\u003csub\u003e2\u003c/sub\u003e; however, it does not appear to limit the efficacy of Verteporfin-mediated PDT, given the lower thresholds in the tumour versus the normal pancreatic tissue. Jermyn et al.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e demonstrated that the necrotic lesion size effect can be more accurately predicted when the blood volume in pancreatic tissues, as measured with contrast-enhanced CT, is taken into account, highlighting the importance of blood volume in the target volume. The FullMonte simulations of the porcine data did not account for the increased absorption resulting from a higher photosensitizer concentration in some animals. This could lead to an overestimation of the fluence at the boundary of necrosis and, consequently, an overestimation of the PDT threshold values in animals exposed to higher drug-light combinations.\u003c/p\u003e\u003cp\u003eAssuming a capsule-like necrotic volume for the clinical necrosis volumes is also an oversimplification, resulting only in a single threshold value and not a range, as shown in the porcine work. However, should this difference in thresholds between normal and cancerous pancreas be confirmed, it would suggest protection of normal pancreatic tissue during endovascular PDT.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eInterstitial and endovascular light delivery as minimally invasive tissue therapy is feasible in pancreatic cancer patients. Only the endovascular route has the potential to downstage patients, that is, clearing tumours abutting major blood vessels, and thus providing tumour-free margins for the surgical removal of the remaining tumour.\u003c/p\u003e\u003cp\u003eConsidering the maximum time a blood vessel can be occluded, given clinical considerations, and the calculated exposure times indicated in Table\u0026nbsp;5b, when restricting the optical power not to exceed 300 mW∙cm\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e, the attainable necrosis radius is limited, particularly for small-diameter vessels.\u003c/p\u003e\u003cp\u003eThese findings suggest that Endovascular Photodynamic Therapy (PDT) has the potential to create a necrotic tumour-free margin around pancreatic blood vessels, within clinically acceptable irradiation times. Based on our Monte Carlo calculations, assuming homogeneous tissue optical properties, a Verteporfin dose of 0.4 mg∙kg⁻\u0026sup1; and an optical power of 300 mW∙cm\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e @ 690 nm, necrotic margins of approximately 8 mm beyond the vessel adventitia can be anticipated in pancreatic cancer patients. The required irradiation times range from 337 to 636 seconds, inversely related to vessel diameters of 10 mm and 3 mm, respectively.\u003c/p\u003e\u003cp\u003eThese calculated dosimetry results support the feasibility of clinical application using the proposed Verteporfin dose and light delivery parameters, warranting further investigation in clinical trials.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work benefited from state aid managed by the French National Research Agency (ANR) under the ‘‘investissements d’avenir’’ program with the reference ANR-10– IAHU-02, to the Institute of Image-Guided Surgery, IHU-Strasbourg, France.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSalary support for (L.L. and T.S.) was provided through the Ontario Ministry of Economic Development and Trade under grant ORF 08-022 and the Princess Margaret Cancer Foundation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA.G., T.S., J.V., L.S., L.L., and A.B. conceived and designed the study, developed the\u003c/p\u003e\n\u003cp\u003eMethodology and interpreted results. A.G., T.S., J.V., F.W. ran simulations, executed the study, acquired the data or supported the data analysis. A.S. radiologically assessed the CT images. I.A.S. carried out the histopathological analysis. A.G., T.S., L.S., S.B., L.L., and A.B. discussed and interpreted the data and wrote and edited the manuscript. A.G., T.S., J.V., F.W., I.A.S., A.S., L.S., S.B., L.L., and A.B. reviewed and revised the manuscript. L.S., L.L. and A.B. supervised the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting this study's findings are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe want to thank Ms. Amélie Gressier for project management and Ms. Cindy Vincent for coordinating the pre-clinical study. Vascular Oncology Biotechnologies B.V. kindly provided the laser device, light delivery prototypes, and Verteporfin. We thank Dr. Herbert Stepp and Prof. Dr. Ronald Sroka for granting us access to the equipment at the LIFE-Zentrum of the LMU Klinikum in Munich. Their support enabled us to cross-calibrate the wavelength and optical output power of the prototype devices developed herein against NIST-traceable standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe porcine studies referred to were conducted and reported in accordance with the ARRIVE 2.0 guidelines for animal research. Animal experiments were reviewed and approved by the local Ethical Committee and authorised by the French Ministry of Education and Research under Protocol notification #28599-2020121012122760. 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Single fiber reflectance spectroscopy for pancreatic cancer detection during endoscopic ultrasound guided fine needle biopsy: a prospective cohort study. \u003cem\u003eInt J Med Sci\u003c/em\u003e. 2022;19(2):205\u0026ndash;212. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7150/ijms.65364\u003c/span\u003e\u003cspan address=\"10.7150/ijms.65364\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"photochemical-and-photobiological-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ppss","sideBox":"Learn more about [Photochemical \u0026 Photobiological Sciences](https://link.springer.com/journal/43630)","snPcode":"43630","submissionUrl":"https://www.editorialmanager.com/ppss/","title":"Photochemical \u0026 Photobiological Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Locally advanced pancreatic cancer, Downstaging to enable surgery, Endovascular, photo-activated, ablation of perivascular cancer, Verteporfin","lastPublishedDoi":"10.21203/rs.3.rs-7013948/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7013948/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePancreatic cancers often involve major blood vessels, making complete surgical removal difficult or impossible. We are developing Endovascular Photodynamic Therapy (PDT) as a novel minimally invasive ablation method to clear tumours from these vessels, to enable potentially curative surgery. The goal is to determine the required endovascular irradiation times for effective treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThreshold doses for PDT were estimated using Monte Carlo simulations, based on clinical data from previous Phase I/II studies involving Photodynamic Therapy of pancreatic cancer using interstitial needle-based irradiation. These thresholds were then compared to our recent \u003cem\u003ein vivo\u003c/em\u003e study, which used endovascular catheter-based irradiation in normal pig pancreas. Using these dose thresholds, we estimated the PDT irradiation times needed to achieve necrotic tissue margins of 4 to 12 mm around blood vessels in pancreatic cancer patients, based on a fixed energy range and increasing doses of photosensitiser\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe threshold dose for Verteporfin-mediated PDT was determined to be 1.43 to 2.37 × 10¹⁷ hv∙cm⁻³ for human pancreatic cancer and 1.27 × 10¹⁸ hv∙cm⁻³ for normal pig pancreas.\u003c/p\u003e\n\u003cp\u003eBased on these values, and assuming homogeneous tissue optical properties and a Verteporfin dose of 0.4 mg∙kg⁻¹, and an optical power of 300 mW∙cm\u003csup\u003e-2\u003c/sup\u003e @ 690 nm, necrotic margins of circa 8 mm beyond the vessel adventitia can be anticipated in pancreatic cancer patients. The required irradiation times range from 337 to 636 seconds, inversely related to vessel diameters of 10 mm and 3 mm, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese findings suggest that PDT can potentially create a margin around major pancreatic blood vessels free of viable tumour tissue. The calculated dosimetry supports the feasibility of clinical application using the proposed Verteporfin dose and light delivery parameters, warranting further investigation in Clinical trials.\u003c/p\u003e","manuscriptTitle":"Dose Threshold Values for Endovascular Photodynamic Therapy (PDT) in Normal Pig Pancreas and Human Pancreatic Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 08:41:12","doi":"10.21203/rs.3.rs-7013948/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-01T12:55:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-01T12:49:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-26T14:59:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"93459083137105157417485732158558658654","date":"2025-08-21T09:50:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"141616530887854057996790748341018971573","date":"2025-08-12T13:40:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"314539851884750022869429125251503506615","date":"2025-07-28T14:48:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-18T18:28:02+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-17T06:56:03+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-16T17:18:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"Photochemical \u0026 Photobiological Sciences","date":"2025-06-30T20:08:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"photochemical-and-photobiological-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ppss","sideBox":"Learn more about [Photochemical \u0026 Photobiological Sciences](https://link.springer.com/journal/43630)","snPcode":"43630","submissionUrl":"https://www.editorialmanager.com/ppss/","title":"Photochemical \u0026 Photobiological Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"329be1da-1852-45fe-9298-45a743cd5bc6","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-08T16:07:30+00:00","versionOfRecord":{"articleIdentity":"rs-7013948","link":"https://doi.org/10.1007/s43630-025-00791-y","journal":{"identity":"photochemical-and-photobiological-sciences","isVorOnly":false,"title":"Photochemical \u0026 Photobiological Sciences"},"publishedOn":"2025-12-03 15:58:15","publishedOnDateReadable":"December 3rd, 2025"},"versionCreatedAt":"2025-07-23 08:41:12","video":"","vorDoi":"10.1007/s43630-025-00791-y","vorDoiUrl":"https://doi.org/10.1007/s43630-025-00791-y","workflowStages":[]},"version":"v1","identity":"rs-7013948","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7013948","identity":"rs-7013948","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}