Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2023 Feb 7.
Published in final edited form as: Methods Mol Biol. 2022;2451:151–162. doi: 10.1007/978-1-0716-2099-1_11

In Vivo Models for Studying Interstitial Photodynamic Therapy of Locally Advanced Cancer

Gal Shafirstein 1, Emily Oakley 1, Sasheen Hamilton 1, Michael Habitzruther 1, Sarah Chamberlain 1, Sandra Sexton 2, Leslie Curtin 2, David A Bellnier 1
PMCID: PMC9904013  NIHMSID: NIHMS1861474  PMID: 35505016

Abstract

Interstitial photodynamic therapy (I-PDT) is a promising therapy considered for patients with locally advanced cancer. In I-PDT, laser fibers are inserted into the tumor for effective illumination and activation of the photosensitizer in a large tumor. The intratumoral light irradiance and fluence are critical parameters that affect the response to I-PDT. In vivo animal models are required to conduct light dose studies, to define optimal irradiance and fluence for I-PDT. Here we describe two animal models with locally advanced tumors that can be used to evaluate the response to I-PDT. One model is the C3H mouse bearing large subcutaneous SCCVII carcinoma (400–600 mm3). Using this murine model, multiple light regimens with one or two optical fibers with cylindrical diffuser ends (cylindrical diffuser fiber, CDF) can be used to study tumor response to I-PDT. However, tissue heating may occur when 630 nm therapeutic light is delivered through CDF at an intensity ≥60 mW/cm and energy ≥100 J/cm. These thermal effects can impact tumor response while treating locally advanced mice tumors. Magnetic resonance imaging and thermometry can be used to study these thermal effects. A larger animal model, New Zealand White rabbit with VX2 carcinoma (~5000 mm3) implanted in either the sternomastoid (neck implantation model) or the biceps femoris muscle (thigh implantation model), can be used to study I-PDT with image-based pretreatment planning using computed tomography. In the VX2 model, the light delivery can include the use of multiple laser fibers to test light dosimetry and delivery that are relevant for clinical use of I-PDT.

Keywords: Interstitial photodynamic therapy, Locally advanced cancer, SCCVII, VX2 carcinoma

1. Introduction

Cancer patients who failed to respond to surgery and chemoradiation therapy have high risk of developing large, locally advanced cancers (LAC). These patients have limited treatment options [1], and second- and third-line therapies, like the newest immunotherapies [2-4], result in relatively low response rates. In many cases, the LAC is adjacent to sensitive anatomy, so salvage surgery is not possible or too complex, and is associated with significant morbidity and low success rates [5, 6].

Interstitial photodynamic therapy (I-PDT) has shown promising results in achieving control of LAC [7-9]. In I-PDT, one or more optical fibers are inserted into the targeted LAC to provide intramural illumination. The goal of I-PDT is to provide complete ablation of the target tumor while sparing normal tissue and critical organs. I-PDT can be repeated, with no cumulative toxicity or development of therapy resistance, in order to extend patient disease-free interval.

The light irradiance and fluence (dosimetry) are key parameters that impact the response to I-PDT [7, 10-12]. Image-guided computer models are used to compute the light dosimetry in I-PDT. These models should be tested in animal models before translation into clinical studies [13, 14]. Here we describe a mouse model with subcutaneous and relatively large murine carcinoma, and a rabbit model with intramuscular cancerous tumor that can match the size of many LACs in patients. These animal models are suitable to test treatment planning methods, image-guided techniques, and light dosimetry to optimize I-PDT with clinically approved PS (porfimer sodium, Photofrin®), as recently described [15].

The first model is a murine syngeneic SCCVII squamous cell carcinoma, which is a widely accepted murine model for studying head and neck cancer [15, 16]. The locally advanced SCCVII is nonmetastatic and poorly immunogenic [16, 17]. We have reported little spontaneous necrosis or extensive hypoxia, and we have never observed spontaneous regression in the many 100 s of SCCVII tumors used in our studies [15]. For I-PDT light delivery, we use one or two cylindrical diffusing fiber optics (cylindrical diffuser fibers, CDFs), as shown in the sketches in Fig. 1. Noteworthy, in this mouse tumor and location, the red light (i.e., 630 nm) can induce significant tumor tissue heating that will result in complete response and cure when ≥60 mW/cm and 540 J/cm were administered through CDFs (porfimer sodium, Photofrin®) [15]. However, the addition of the photosensitizer (i.e., Photofrin®) resulted in significantly (p < 0.05) higher cure rate in comparison to light alone (no photosensitizer); for more details please see Shafirstein et al. (2018) [15]. The SCCVII tumor margins are readily defined in magnetic resonance imaging (MRI), and MR thermometry can be used to study tumor response and tissue heating during I-PDT.

Fig. 1.

Fig. 1

Open in a new tab

Drawings illustrate the administration of I-PDT in locally advanced SCCVII in mice. (a) A single catheter (18 G shielded IV catheter; Becton, Dickinson and Company, Franklin Lakes, NJ) is inserted through the center of the tumor, along its long axis, and parallel to the skin. (b) Two catheters are inserted at 6–7 mm apart, along the tumor long axis. The light is delivered through cylindrical diffuser fibers (CDFs): optical fibers with 0.98 mm diameter, 2 cm long cylindrical diffuser ends (e.g., RD 20, Medlight SA, Ecublens, Switzerland). During I-PDT, the tumor is slightly elevated (5–10 mm) above from the mouse body using a custom-made fixture

The second model discussed here is the locally advanced VX2 carcinoma established in New Zealand White rabbits. The rabbit VX2 tumor has been used extensively in studies of interstitial ablative therapies, including I-PDT [15, 18]. The New Zealand White (NZW) rabbit host allows support of tumors larger than those allowed in mice (≤2 cm at the longest axis) by most institutional Animal Care and Use Committees (IACUC). Tumors are initiated by implantation of a single piece of tumor previously harvested from a large VX2 tumor growing in a “donor” NZW rabbit. These 1 mm3 pieces are obtained only from tumors that show expected tumor growth patterns [19]. The VX2 tumor has a high frequency of spontaneous metastases.

We recently reported on the use of the NZW rabbit with VX2 to study light dosimetry in I-PDT in the treatment of LAHNC; see Shafirstein et al. (2018) [15]. Because of our interest in I-PDT of locally advanced head and neck cancer (LAHNC), we implanted the VX2 tumor in the sternomastoid muscle. This location allows us to determine tumor response as well as evaluate the risk of multiple catheter insertion-related complications and photodynamic damage to the surrounding tissues, vessels, and nerves in the head and neck region. In these tumors, multiple fibers can be implanted to study the effect of adjacent fibers on the response to I-PDT.

The VX2 is likely to metastasize once it reaches about 2–3 cm in its longest diameter (~5000 mm3). If implanted in the sternomastoid muscle, a ≥ 2 cm VX2 tumor shows a strong tendency to metastasize to the lungs [15]. Caliper measurements of VX2 tumors implanted intramuscularly often underestimate this tumor size. As such, it is recommended to image the VX2 tumor every week with non-contrast computed tomography (CT). These scans can also be used for pretreatment planning, as we recently described [15]. If implanted in the thigh muscle, the tumor could reach 2–2.5 cm before it is likely to metastasize.

2. Materials

2.1. Syngeneic SCCVII Squamous Cell Carcinoma Model

  1. The SCCVII cell line may be available through material transfer agreement with Roswell Park or other institutes. See also Note 1.

  2. RPMI-1640 medium.

  3. Fetal bovine serum (FBS).

  4. L-Glutamine, penicillin, and streptomycin.

  5. 0.25% Trypsin-EDTA.

  6. Phosphate-buffered saline (PBS).

  7. Hemocytometer.

  8. 1 mL Syringes with a 26-gauge needle.

  9. Isoflurane.

  10. Heating plate.

  11. Cylindrical diffuser fiber.

  12. IV catheter.

2.2. Rabbit VX2 Carcinoma

  1. The VX2 cell line (or frozen tumors) may be available through material transfer agreement with Roswell Park or other institutes. See also Note 1.

  2. Acepromazine.

  3. Cryoprotectant freezing media.

  4. Chlorhexidine.

  5. Isopropyl alcohol.

  6. Betadine.

  7. Vicryl suture.

  8. Sterile drapes.

  9. Isotropic detection fibers.

  10. CT-compatible surface fiducial markers.

  11. Buprenorphine.

  12. Meloxicam.

  13. Transparent closed-end sharp catheters.

  14. Enrofloxacin.

  15. Hypochlorous acid.

3. Methods

3.1. I-PDT in Murine Syngeneic SCCVII Squamous Cell Carcinoma

  1. SCCVII cells are grown in culture medium RPMI-1640 supplemented with 10% fetal bovine serum (FBS), 1× l-glutamine, and 100 units/mL penicillin and streptomycin in an atmosphere of 5% CO2 at 37 °C.

  2. Once confluent, the cells are trypsinized with 0.25% trypsin-EDTA and washed with 1× phosphate-buffered saline (PBS).

  3. Cell count is performed using a hemocytometer; cells are resuspended in 1× PBS to create a volume of one million (106) cells per 100 μL total volume for each inoculation.

  4. Using 1 mL syringes with a 26-gauge needle, the suspension of SCCVII cells is injected subcutaneously into the right upper shoulder region of each mouse. See Note 2 for additional information.

  5. Mice are followed few times a week, tumor size is measured with calipers, and tumor volumes are calculated as π/6 × L × W2 (L = length at longest axis, W = width orthogonal to L). See Note 3 for recommendations on animal feed for I-PDT experiments on these models.

  6. The mice were treated when the SCCVII tumors reach 400–600 mm3, which occurs at about 7–8 days postinoculation. Untreated tumors double their size within another 10–11 days.

  7. The I-PDT treatment is conducted while the mice are under gas anesthesia with isoflurane (2–3%) on a heating plate set at 38 °C. It is important to note that during I-PDT treatment we utilize a fixture to guide our insertion of laser fibers. The tumors are pulled away (5–10 mm) from the mouse body to reduce phototoxicity.

3.2. Post-procedure Follow-up and Treatment Assessment in the SCCVII/C3H Mice

  1. Generally, clinical signs of morbidity (as defined by the local IACUC) rarely occur following I-PDT. When any sign is present, institute veterinary staff should be contacted. Vigilance should then be increased for the remainder of the cohort.

  2. Tumors should be measured every 1–3 days after I-PDT.

  3. Significant edema may be observed at the tumor site within 1–2 days after I-PDT, and may last for several more days. Edema may complicate tumor measurement.

  4. A scab or eschar may form within 1–2 days, and may remain for 1–2 weeks. This may complicate tumor measurement.

  5. Mice should be humanely euthanized when tumors in control groups or tumors that failed therapy reach the maximum volume defined by the local IACUC.

  6. Treatment-related tumor regression occurs within 7–10 days. Cures may be defined as no manually palpable tumor at 60 or more days following I-PDT.

3.3. Acquisition and Maintenance of the Rabbit VX2 Carcinoma Model

Hereinafter are the specific steps for doing intramuscular implantation of a VX2 carcinoma in the neck or thigh in NZW rabbits of about 2–2.5 kg body weight. The veterinary staff at the Laboratory Animal Shared Resources (LASR) at Roswell Park provided the preparation of the VX2 tumor piece maintained in their cryopreserved tissue bank and the surgical procedures to implant the tumor in either the sternomastoid or the biceps femoris muscles of specific pathogen-free NZW rabbits.

  1. The VX2 carcinoma cannot be grown in cell culture and must be maintained via passage in live rabbits. The VX2 carcinoma is implanted in the biceps femoris thigh muscle of a donor rabbit for passage. Once the tumor grows to approximately 3 cm in its longest diameter, the donor rabbit is humanely euthanized, and the tumor is harvested aseptically, prepared into 2 mm x 2 mm pieces, frozen in cryoprotectant freezing media, and then stored in liquid nitrogen.

  2. To prepare the frozen VX2 carcinoma for implantation in an experimental rabbit, individual vials of frozen VX2 carcinoma are thawed in a 37 °C water bath, then placed in complete media, and centrifuged at 800 RPM for 5 min. The VX2 tumor pieces are then removed from the complete media and placed in phosphate-buffered saline, trimmed to the desired implantation size, and stored on wet ice until implantation occurs.

3.4. Implantation of the VX2 Model in Rabbits

  1. Rabbits are sedated with 0.3 mg/kg acepromazine intravenously (IV) and then anesthetized via facemask with 2% isoflurane in oxygen.

  2. The rabbit’s corneas are lubricated and the lateral neck or lateral thigh area is aseptically prepared by removing the hair with electric clippers, followed by a chemical depilatory, and then the skin is disinfected with chlorhexidine and isopropyl alcohol followed by betadine.

  3. The animal is then moved to the operating room, placed on warm water recirculating heating pad, and monitored during the surgical procedure via pulse oximetry, electrocardiogram (EKG), and core body temperature. The rabbit is draped with sterile drapes and sterile surgical instruments are used.

  4. A 2 cm incision in the skin is made over either the sternomastoid (neck implantation model) or the biceps femoris muscle (thigh implantation model), and with delicate blunt dissection the subcutaneous tissue is separated from the muscle fibers.

  5. Using small curved forceps, the delicate muscle fibers are separated to create a pocket in the muscle and the sterile 2 mm × 2 mm piece of VX2 carcinoma is then implanted in the pocket. One 6–0 Vicryl suture is used to close the pocket and then the skin is closed with 5–0 Vicryl suture or tissue glue.

  6. The animal is given fluids and analgesics subcutaneously and allowed to recover. The animals are monitored daily for tumor growth and signs of lung metastasis, and imaged weekly, with non-contrast CT, following the implantation of the tumor to determine the initiation of the I-PDT treatment. See Note 3 for recommendations on animal feed for I-PDT experiments on these models.

3.5. Pretreatment Planning

  1. Pretreatment non-contrast CT imaging is performed weekly to assess the growth of VX2 tumors. Once tumors are approximately 2 cm at the longest axis, CT scans of the NZW rabbits with CT-compatible surface fiducial markers are obtained. See Note 4 for additional information.

  2. Image visualization and segmentation: The CT scans are exported to image visualization and processing software, which is used to segment the tumor geometry along with any surrounding critical structures such as major blood vessels and surrounding tissues. The segmentations are individually smoothed using a Gaussian filter. Three-dimensional (3-D) computer-aided design (CAD) models are created from the smoothed segmentations.

  3. Treatment planning: The 3-D models are then exported to a finite element method (FEM) software, in which cylinders are virtually inserted within the tumor geometry to represent the sterilized plastic catheters through which the light diffusing optical fibers are placed during treatment. A tetrahedral mesh of approximately 600,000 elements is generated for the tumor geometry along with the surrounding critical structures and cylindrical catheters. We then apply a FEM solution to the light diffusion approximation of the equation for radiative transfer to simulate the light distribution within the tumor geometry during I-PDT. Our FEM has been previously described by Oakley et al. (2015) [20] and is used to determine the number, location, and light parameters of the source CDFs needed to deliver a prescribed light irradiance and fluence to 100% of the tumor volume.

3.6. Preparing the Rabbit and VX2 Tumor for I-PDT Treatment

  1. Twenty-four hours prior to the I-PDT treatment, the rabbit is sedated with 0.3 mg/kg acepromazine IV and then anesthetized via face mask with 2% isoflurane in oxygen. An IV catheter is placed in the auricular vein and the photosensitizer is injected slowly through the catheter. The catheter is then flushed with 0.9% saline and removed. The fiducial markers that were placed during the treatment planning CT scan are removed and tattoos are applied to permanently mark their location. This step is performed because the fiducial markers frequently fall off and can be lost prior to the I-PDT treatment.

  2. On the day of I-PDT, the rabbits are sedated with 0.3 mg/kg acepromazine IV and then anesthetized via face mask with 2% isoflurane in oxygen. It is important that the rabbit is in a surgical plane of anesthesia prior to implantation of the I-PDT fibers. An IV catheter is placed in the auricular vein for IV access.

  3. The rabbit’s corneas are lubricated and the skin overlying the tumor is aseptically prepared by removing the hair with electric clippers, followed by a chemical depilatory, and then the skin is disinfected with chlorhexidine and isopropyl alcohol followed by Betadine. Meticulous aseptic preparation of the I-PDT treatment area is critical to avoid posttreatment infection.

  4. The rabbit is placed on a warm water recirculating heating pad and draped with sterile paper drapes. Monitoring during the fiber insertion procedure includes assessment of respiratory rate, heart rate, pulse oximetry, and core body temperature. Aseptic technique is used while inserting the sterile I-PDT fibers.

  5. The rabbit is transported under isoflurane anesthesia to the CT scanner for imaging, which is used to verify correct placement of the fibers.

  6. The rabbit is then transported, under isoflurane anesthesia, to the PDT treatment room. During the I-PDT treatment the rabbit is placed on warm water recirculating heating pad for thermal support, and its vital signs (heart rate, EKG, pulse oximetry, respiratory rate, and core body temperature) are monitored every 10 min.

  7. I-PDT treatment: Sterilized transparent closed-end sharp catheters are inserted according to the treatment plan (see Subheading 3.5) using the surface fiducial markers as references. The use of these surface fiducial markers has been previously described by Oakley et al. (2017) [21]. The catheters may be inserted perpendicular and/or transverse to the body of the rabbit according to the treatment plan (see Fig. 2).

  8. Additional catheters are inserted at the margins of the tumor. Isotropic detection fibers are fed through these catheters and are used to monitor the light irradiance and fluence at the tumor margins to ensure that the prescribed light dose is delivered during treatment. Source CDFs are fed through the catheters based on the treatment plan (see Subheading 3.5). The I-PDT treatment can be performed in one session or multiple sessions of consecutive light administration depending on the maximum laser power output available. During I-PDT, intravenous fluids (0.9% normal saline) are given at a volume of 5 mL/kg/h. At the conclusion of treatment, opioid (0.05 mg/kg buprenorphine, subcutaneous) and NSAID (0.5 mg/kg meloxicam, orally) analgesics are given subcutaneously for pain relief, and the rabbit is recovered from anesthesia.

Fig. 2.

Fig. 2

Open in a new tab

CT scans obtained post-catheter insertion. The above figures show two different CT slices of a NZW rabbit with plastic cylindrical catheters inserted throughout the tumor volume. In this particular rabbit, cylindrical catheters were inserted both perpendicular and transverse to the body of the animal

3.7. Posttreatment Follow-up and Treatment Assessment in the Rabbit VX2 Model

  1. Post-procedural monitoring and care are critical for a successful outcome with this model. Rabbits must be monitored daily for post-procedure infection, tissue necrosis, and lung metastasis. Non-contrast CT imaging is performed once weekly to monitor for lung metastasis and local response to treatment. Rabbits receive meloxicam (0.5 mg/kg orally SID) and enrofloxacin (5 mg/kg orally SID) daily for analgesia and to prevent local infection at the PDT site. Tissue necrosis and sloughing at the treatment site are expected. The treatment area is examined daily and cleaned with 0.015% hypochlorous acid and treated topically with triple-antibiotic ointment. Necrotic tissue is debrided as needed. Secondary surgical debridement and closure of skin defects may be needed if skin and tissue sloughing are extensive.

  2. Posttreatment CT scans are performed weekly for 3 weeks to assess tumor response to treatment. If no tumor growth occurs within the first three weeks, tumor response is evaluated up to 12 weeks posttreatment. If at 12 weeks no tumor is observed on the CT scans, that rabbit will be considered a cure. In some cases, metastasis to the lungs occurs. If this happens, local control can be assessed through CT imaging.

4. Notes

  1. The Roswell Park mouse SCCVII cell line was confirmed to be of mouse origin, and tested for evidence of cross-species contamination (human, rat, Chinese hamster, and African green monkey). No contamination was found. Short tandem repeat (STR) testing was performed and the genetic profile obtained. The VX2 sample was confirmed to be of rabbit origin and no mammalian interspecies contamination was detected.

  2. Subcutaneous injection of as little as 100 SCCVII cells in 100 μl sterile PBS into the shoulder region of 8–12-week-old C3H mice will result in a tumor growth within 30 days postinjection.

  3. The diet used in the Roswell Park Laboratory Animal Shared Resource does not contain alfalfa, thus lowering the occurrence of natural phytoestrogens. Typical isoflavone concentrations (daidzein + genistein aglycone equivalents) range from 150 to 250 mg/kg. Exclusion of alfalfa reduces chlorophyll, improving optical imaging clarity.

  4. Image-based FEM pretreatment planning for mice with SCCVII can be performed using small animals’ MRI as described by Shafirstein et al. (2018) [15].

Acknowledgments

The authors would like to thank Diane Filippini for her assistance in obtaining the CT scans and Dr. Craig Hendler MD for conducting the diagnosis of CT scans, at the Department of Radiology at Roswell Park. This work was supported in part by National Cancer Institute of the National Institutes of Health under Award Number R01CA193610 to Gal Shafirstein, and by Roswell Park Comprehensive Cancer Center Support Grant P30CA16056. We thank Concordia Laboratories Inc. for providing the porfimer sodium (Photofrin) at no cost.

The authors would like to thank the staff of the shared resources at Roswell Park Comprehensive Cancer Center for their technical assistance in performing these studies: Laboratory Animal Shared Resource and Translational Imaging Shared Resource. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or Roswell Park Comprehensive Cancer Center.

Footnotes

Conflict of Interest

Gal Shafirstein, David Bellnier, and Emily Oakley are co-inventors in patent applications (owned by Roswell Park Comprehensive Cancer Center) of a light dosimetry system for interstitial and thermal photodynamic therapy. Gal Shafirstein acknowledges research grant support from Concordia Laboratories Inc. Gal Shafirstein acknowledges a service on the advisory board for Concordia International Corp. and Pinnacle Biologics, Inc. All other co-authors declare no potential conflicts of interest.

References

  • 1.McDonald MW, Lawson J, Garg MK, Quon H, Ridge JA, Saba N, Salama JK, Smith RV, Yeung AR, Yom SS et al. (2011) ACR appropriateness criteria retreatment of recurrent head and neck cancer after prior definitive radiation expert panel on radiation oncologyhead and neck cancer. Int J Radiat Oncol Biol Phys 80:1292–1298 [DOI] [PubMed] [Google Scholar]
  • 2.Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, Saba NF, Weiss J, Wirth L, Sukari A et al. (2017) Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J Clin Oncol 35:1542–1549 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C et al. (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375:1856–1867 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D et al. (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127 [DOI] [PubMed] [Google Scholar]
  • 5.Licitra L, Vermorken JB (2004) Is there still a role for neoadjuvant chemotherapy in head and neck cancer? Ann Oncol 15:7–11 [DOI] [PubMed] [Google Scholar]
  • 6.Khuri FR, Shin DM, Glisson BS, Lippman SM, Hong WK (2000) Treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck: current status and future directions. Semin Oncol 27:25–33 [PubMed] [Google Scholar]
  • 7.Shafirstein G, Bellnier D, Oakley E, Hamilton S, Potasek M, Beeson K, Parilov E (2017) Interstitial photodynamic therapy-a focused review. Cancers (Basel) 9(2):12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Karakullukcu B, Nyst HJ, van Veen RL, Hoebers FJ, Hamming-Vrieze O, Witjes MJ, de Visscher SA, Burlage FR, Levendag PC, Sterenborg HJ et al. (2012) mTHPC mediated interstitial photodynamic therapy of recurrent nonmetastatic base of tongue cancers: development of a new method. Head Neck 34:1597–1606 [DOI] [PubMed] [Google Scholar]
  • 9.Lou PJ, Jager HR, Jones L, Theodossy T, Bown SG, Hopper C (2004) Interstitial photodynamic therapy as salvage treatment for recurrent head and neck cancer. Br J Cancer 91:441–446 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Davidson SR, Weersink RA, Haider MA, Gertner MR, Bogaards A, Giewercer D, Scherz A, Sherar MD, Elhilali M, Chin JL et al. (2009) Treatment planning and dose analysis for interstitial photodynamic therapy of prostate cancer. Phys Med Biol 54:2293–2313 [DOI] [PubMed] [Google Scholar]
  • 11.Finlay JC, Zhu TC, Dimofte A, Stripp D, Malkowicz SB, Busch TM, Hahn SM (2006) Interstitial fluorescence spectroscopy in the human prostate during motexafin lutetium-mediated photodynamic therapy. Photochem Photobiol 82:1270–1278 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Johansson A, Axelsson J, Andersson-Engels S, Swartling J (2007) Realtime light dosimetry software tools for interstitial photodynamic therapy of the human prostate. Med Phys 34:4309–4321 [DOI] [PubMed] [Google Scholar]
  • 13.Du KL, Mick R, Busch TM, Zhu TC, Finlay JC, Yu G, Yodh AG, Malkowicz SB, Smith D, Whittington R et al. (2006) Preliminary results of interstitial motexafin lutetium-mediated PDT for prostate cancer. Lasers Surg Med 38:427–434 [DOI] [PubMed] [Google Scholar]
  • 14.Swartling J, Hoglund OV, Hansson K, Sodersten F, Axelsson J, Lagerstedt AS (2016) Online dosimetry for temoporfin-mediated interstitial photodynamic therapy using the canine prostate as model. J Biomed Opt 21:28002. [DOI] [PubMed] [Google Scholar]
  • 15.Shafirstein G, Bellnier DA, Oakley E, Hamilton S, Habitzruther M, Tworek L, Hutson A, Spernyak JA, Sexton S, Curtin L et al. (2018) Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer. Br J Cancer 119:1191–1199 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Khurana D, Martin EA, Kasperbauer JL, O’Malley BW Jr, Salomao DR, Chen L, Strome SE (2001) Characterization of a spontaneously arising murine squamous cell carcinoma (SCC VII) as a prerequisite for head and neck cancer immunotherapy. Head Neck 23:899–906 [DOI] [PubMed] [Google Scholar]
  • 17.Suit HD, Sedlacek RS, Silver G, Dosoretz D (1985) Pentobarbital anesthesia and the response of tumor and normal tissue in the C3Hf/sed mouse to radiation. Radiat Res 104:47–65 [PubMed] [Google Scholar]
  • 18.Elliott JT, Samkoe KS, Gunn JR, Stewart EE, Gardner TB, Tichauer KM, Lee TY, Hoopes PJ, Pereira SP, Hasan T et al. (2015) Perfusion CT estimates photosensitizer uptake and biodistribution in a rabbit orthotopic pancreatic cancer model: a pilot study. Acad Radiol 22:572–579 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Shafirstein G, Kaufmann Y, Hennings L, Siegel E, Griffin RJ, Novak P, Ferguson S, Moros EG (2009) Conductive interstitial thermal therapy (CITT) inhibits recurrence and metastasis in rabbit VX2 carcinoma model. Int J Hyperth 25:446–454 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Oakley E, Wrazen B, Bellnier DA, Syed Y, Arshad H, Shafirstein G (2015) A new finite element approach for near real-time simulation of light propagation in locally advanced head and neck tumors. Lasers Surg Med 47:60–67 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Oakley E, Bellnier DA, Hutson A, Wrazen B, Arshad H, Quon H, Shafirstein G (2017) Surface markers for guiding cylindrical diffuser fiber insertion in interstitial photodynamic therapy of head and neck cancer. Lasers Surg Med 49:599–608 [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES