Vascular-targeted Photodynamic Therapy Research Articles

Abstract 6644: aPD1 treatment of urothelial cancers is synergistically enhanced by activating anti tumor immunity using vascular targeted photodynamic therapy

Abstract Background: Recurrence and progression rate following surgical treatment of locally advanced urothelial cancer is high, underscoring the unmet need to develop an effective, well tolerated treatment strategies, particularly for high grade upper tract urothelial cancer (HG-UTUC). The treatment success of low grade UTUC by vascular targeted photodynamic therapy (VTP) with WST11 (Padeliporfin) in phase I clinical trials led the FDA to approve Phase 3 trial in a fast track, orphan drug designation for low grade UTUC (ENLIGHT). Recently, treatment with immune checkpoint inhibitor (ICIs) of the PD1/PD-L1 axis has been approved for treatment of HG-UTUC. Yet, the failure rate of aPD1 therapy in HG-UTUC is high.We hypothesized that immune checkpoint inhibition needs to be complemented by the massive priming and accrual of newly activated anti-tumor immune cells through tumor immunogenic cell death. Early evidence indicated that WST11 VTP promotes anti-tumor immunity suggesting that VTP/aPD1 combinations may significantly improve the treatment success of HG-UTUC. Methods: Mice bearing s.c. MB49-Luc, were subjected to WST11 VTP at 14d post implantation at suboptimal dose of drug or partial area of illumination. 4 or 5 doses of aPD1 were intraperitonealy administrated every 3 days starting at 1d post VTP (aPD1+1), or every 3 days till 10 days post-treatment starting at 2 days before VTP (aPD1-2). Tumor progression was followed up to 90 days post treatment using IVIS. Hematoxylin-eosin staining, and multiplex immunohistochemistry (mIHC) were performed on controls and treated animals. Results: WST11 VTP with suboptimal drug dose, aPD1+1, and aPD1-2 resulted in 17%, 23% and 43% cure at day 90 post VTP. VTP at suboptimal drug dose combined with aPD1+1 or aPD1-2, resulted in 50% and 77% cure rate at 90 days, respectively. VTP with optimal drug dose (5mg/kg) but partial illumination resulted in 20% cure rate while combining this treatment modality with aPD1-2 resulted in 90% animal cure rate at day 90.At 24h post VTP mIHC showed a 2-3 fold increase of cytotoxic T cells, dendritic and NK cells, and a ~4 folds overexpression of PD1 and PD-L1 in the treated tumor tissue. At 2 days post aPD1-2 initiation, PD1 and PD-L1 apparent expression dropped to 0 and 2 folds higher than control, respectively. Following the combined VTP and aPD1-2 treatment, both PD1 and PDL-1 contents dropped down to zero and the CD8 content reached 3 folds enhancement compared to control. Conclusions: These observations indicate that elevating the content of anti-tumor immune cells in the tumor microenvironment by VTP in combination with ICI synergistically enhances the therapeutic effect providing a much higher complete cure compared with the individual therapies. The cure rate extent strongly depends on the synchronization of the two modalities providing guidelines for the clinical management of HG-UTUC treatment. Citation Format: Lilach Agemy, Keren Sasson, Tamar Yechezkel, Rachel Hamri, Raz Robas, David Kain, Avigdor Scherz. aPD1 treatment of urothelial cancers is synergistically enhanced by activating anti tumor immunity using vascular targeted photodynamic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6644.

Follow-up of vascular-targeted photodynamic therapy in a real-world setting

PurposeVascular-targeted photodynamic therapy (VTP) is an approved treatment option for unilateral low-risk prostate cancer (PCa).MethodsPatients with unilateral low- or intermediate-risk PCa undergoing hemiablation by VTP were evaluated in a real-world setting. Oncological outcome after VTP was measured by MRI-based re-biopsy at 12 and 24 months. Functional outcome after 1 year was investigated by IIEF-5 and IPSS questionnaires. Progression was defined as the evidence3 of ISUP ≥ 2 PCa.ResultsAt any control biopsy (n = 46) after VTP, only 37% of patients showed no evidence of PCa. Recurrence-free survival was 20 months (95% CI 4.9–45.5) and progression-free survival was 38.5 months (95% CI 33.5–43.6 months). In-field and out-field recurrent PCa occurs in 37% (55% ISUP ≥ 2 PCa) and 35% (56% ISUP ≥ 2 PCa). Seventy-nine percent of patients preserved erectile function, respectively. Ten percent of patients presented long-term bladder outlet obstruction. None of the patients presented incontinence.ConclusionDue to the high-recurrence in- and out-field recurrence rate in a mainly low-risk prostate cancer cohort, VTP has to be regarded critically as a therapy option in these patients. Pre-interventional diagnostic evaluation is the main issue before focal therapy to reduce the risk of tumor recurrence and progression.

Abstract LB_C05: A novel approach to convert non-resectable pancreatic cancer with major artery involvement using endovascular activation of Padeliporfin by vascular-targeted photodynamic therapy

Abstract Pancreatic cancer is a fatal disease: the patient usually has a very poor prognosis and limited treatment options. It is projected to be the second leading cause of cancer-related death by 2030. It is estimated that 80% of patients have metastatic or localized disease with vascular involvement at presentation, not amenable to surgery. Thus, a therapy that will convert unresectable, due to vascular involvement, tumors to resectable is an unmet medical need. We developed a novel treatment relying on endovascular activation of a photosensitizer Padeliporfin, by a vascular-targeted photodynamic therapy (VTP) to clear the artery from the encasing tumor enabling surgery. Padeliporfin is administered intravenously and activated locally by illumination via an optical fiber, deployed within the tumor encased artery by an angioplasty procedure under fluoroscopy. In a proof-of-concept study in normal swine model, treatment induced areas of ablation in normal pancreatic parenchyma while sparing the artery and other major structures in it’s vicinity. Drug and light doses used were proved effective in other solid tumors in preclinical and clinical studies. Safety was evaluated in a controlled study comprised of 12 pigs subjected to Padeliporfin VTP in a superior mesenteric artery (SMA). Two light doses were tested. Control groups received no drug or no illumination and drug. Follow up was 48 hours or seven days post treatment. Clinical observations and blood test results did not reveal any signs of decreased wellness without differences between treated and control groups. Lipase results were unchanged compared to the baseline. Amylase levels were within the normal range in all animals. Histopathology findings 48 hours post VTP in the SMA and surrounding tissues were similar in treated and control animals. Observed changes were manifested as small lesions consistent with angioplasty procedure impact, involving less than 25% of the media circumference. Small foci of coagulative necrosis were observed in the pancreatic parenchyma in the vicinity of SMA. In the seven-day samples, there was media pressure necrosis in occasional sections of the artery in all groups involving less than 25% of the circumference, attributed to the angioplasty procedure. Minimal fibrosis in a few samples, consisted of focal areas of fibroblast proliferation, indicating early regeneration, with no architectural or thickness changes of the arterial wall. The tissues surrounding SMA as well as organs downstream to the treated artery were mostly within normal ranges. Our results demonstrate that endovascular Padeliporfin VTP is feasible and has an acceptable safety profile together with evidence of ability to ablate pancreatic tumors encasing major abdominal arteries. The efficacy is further supported by our studies showing effective tumor ablations in orthotopic mouse models especially in combination with immune modulating therapies. A phase I trial (NCT5918783) aims to evaluate the potential of this approach for converting unresectable pancreatic cancer patients to amenable for surgery. Citation Format: Dina Preise, Yaniv Cohen, Genia Alpert, Zachary Sacks, Tamar Yechezkel, Natalia Kudinova, Eyal Morag, Ehud Willenz, Julia Rothman, Keren Brook, Inna Krasnopolskaya, Lilach Agemy, Sofia Zilber, Hooman Yarmohammadi, David Kelsen, David Perry, Avigdor Scherz. A novel approach to convert non-resectable pancreatic cancer with major artery involvement using endovascular activation of Padeliporfin by vascular-targeted photodynamic therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C05.

Vascular-targeted photodynamic therapy with glucose-conjugated chlorin e6 for dogs with spontaneously occurring tumours.

Photodynamic therapy (PDT) using photosensitisers is a minimally invasive treatment for malignant tumours. However, ideal photosensitisers are not yet established. Recently, we developed a new photosensitiser, glucose-conjugated chlorin e6 (G-Ce6). To evaluate the clinical efficacy of vascular-targeted PDT (VTP), a type of PDT utilising a short drug-light interval, using G-Ce6 to treat spontaneously occurring tumours in dogs. Five dogs with spontaneously occurring tumours (malignant melanoma: three; haemangiopericytoma: two; and squamous cell carcinoma: one) were subjected to VTP. These dogs were intravenously injected with G-Ce6 at doses of 1-3mg/kg 5min before laser irradiation. Tumours were superficially or interstitially irradiated using a 677-nm diode laser. Repeated VTP decreased tumour size, yielding complete remission in three dogs. Complications such as oedema surrounding normal tissues and fistulae were observed, and the oedema was self-limiting. The fistula was cured by debriding the necrotic tissues formed after VTP. Our findings demonstrate that VTP using G-Ce6 had antitumour effects in dogs with spontaneously occurring tumours.

Tissue optical clearing enhances efficacy of vascular targeted photodynamic therapy of mouse dorsal skin

Vascular-targeted photodynamic therapy (V-PDT) is an effective treatment for port wine stains (PWS). However, repeated treatment is usually needed to achieve optimal treatment outcomes, possibly due to the limited treatment light penetration depth in the PWS lesion. The optical clearing technique can increase light penetration in depth by reducing light scattering. This study aimed to investigate the V-PDT in combination with an optical clearing agent (OCA) for the therapeutic enhancement of V-PDT in the rodent skinfold window chamber model. Vascular responses were closely monitored with laser speckle contrast imaging (LSCI), optical coherence tomography angiography, and stereo microscope before, during, and after the treatment. We further quantitatively demonstrated the effects of V-PDT in combination with OCA on the blood flow and blood vessel size of skin microvasculature. The combination of OCA and V-PDT resulted in significant vascular damage, including vasoconstriction and the reduction of blood flow. Our results indicate the promising potential of OCA for enhancing V-PDT for treating vascular-related diseases, including PWS.

A phase 3 multicenter study to evaluate the safety and efficacy of padeliporfin vascular targeted photodynamic therapy (VTP) in treatment of low-grade (LG) upper tract urothelial cancer (UTUC).

TPS4613 Background: Padeliporfin VTP is a combination product: drug, padeliporfin is administered IV and a device, a laser light delivery system, includes a source of light (the laser) that emits near-infrared (NIR) light at 753 nm, and optic fiber that delivers the light to the target lesion(s) in the upper tract urothelium. In Phase 1 NCT03617003 study 19 patients(pts) received up to 2 endoscopic VTP treatments with 6 mos follow-up(FU). Pts with residual or recurrent UTUC (high grade(HG)or LG) who failed prior endoscopic treatment/unable/unwilling to undergo surgery were included. Primary endpoint, Maximum tolerated dose (MTD) of laser light fluence, was identified using dose escalation model with a modified continual reassessment method with increasing light fluence (100-200 mW/cm). Secondary endpoint was efficacy, defined by absence of visible tumor and negative urine cytology 30 days post-treatment. 14(74%) pts received the MTD of 200mW/cm, 2 (11%) of whom experienced DLTs (flank pain grade 2 and 3). Response rate at 30 days was 94% (50% CR, 44% partial). 8 pts received 2nd VTP, with a final observed 68% complete response (CR) rate. Most frequent adverse events: transient flank pain (79%) and hematuria (84%). No treatment-associated ureteral strictures were reported. All patients had preserved kidney at the 6-mos FU(Wesley Yip,2022). Methods: Padeliporfin VTP is being evaluated in a phase 3 study in patients with UTUC LG,100 patients are planned to be enrolled. Enrollment started in Mar 2021 and is ongoing in USA, EU&Israel,3 pts are enrolled. Pts are being treated with padeliporfin VTP in two phases: Induction and Maintenance treatment Phases (ITP and MTP). ITP consists of 1-3 VTPs every 28 days. If CR is not achieved after 1st VTP, up to 2 additional VTPs are allowed. If CR is achieved in the ITP, pts are allowed into the MTP (12 mos). In the MTP VTPs can be provided every 3 mos for pts with recurrent tumor that is deemed treatable, defined as LG with the largest tumor (index) 5 -15 mm, in up to 2 locations in the kidney or one ureter location ≤20 mm. Long Term FU Phase: Pts completing the MTP, will be followed for safety for 48 mos with no VTPs. Primary objective is to demonstrate efficacy and durability of effect of padeliporfin VTP treatment. Secondary objective-evaluation of padeliporfin VTP‐related safety and tolerability. Key inclusion criteria: Up to 2 biopsy-proven LG UTUC tumors with the largest tumor (index) 5-15 mm, located in the calyces, renal pelvis or in the ureter, with no HG cells. Ureter involvement in one location ≤ 20 mm. Key exclusion criteria: Current HG or muscle invasive urothelial bladder cancer . CIS current or previous in the upper urinary tract. History of ≥ T2 urothelial cancer in the past 2 years. DSMB last reviewed the trial in Sep 2022 and suggested the trial continue as planned. Clinical trial information: NCT04620239 .

Pyrrolopyrrole aza-BODIPY-based NIR-II fluorophores for in vivo dynamic vascular dysfunction visualization of vascular-targeted photodynamic therapy

Real-time monitoring vascular responses is crucial for evaluating the therapeutic effects of vascular-targeted photodynamic therapy (V-PDT). Herein, we developed a highly-stable and bright aggregation induced emission (AIE) fluorophore (PTPE3 NP) for dynamic fluorescence (FL) imaging of vascular dysfunction beyond 1300 nm window during V-PDT. The superior brightness (ϵmaxΦf>1000 nm ≈ 180.05 M−1 cm−1) and high resolution of PTPE3 NP affords not only high-clarity images of whole-body and local vasculature (hindlimbs, mesentery, and tumor) but also high-speed video imaging for tracking blood circulation process. By virtue of the NPs’ prolonged blood circulation time (t1/2 ≈ 86.5 min) and excellent photo/chemical (pH, RONS) stability, mesenteric and tumor vascular dysfunction (thrombosis formation, vessel occlusion, and hemorrhage) can be successfully visualized during V-PDT by FL imaging for the first time. Furthermore, the reduction of blood flow velocity (BFV) can be monitored in real time for precisely evaluating efficacy of V-PDT. These provide a powerful approach for assessing vascular responses during V-PDT and promote the development of advanced fluorophores for biological imaging.

Abstract 2421: WST-11 vascular-targeted photodynamic therapy induced immune modulation in upper tract urothelial cancer

Abstract Introduction: Vascular-targeted photodynamic therapy (VTP) with the photosensitizing agent padeliporfin (WST-11/TOOKAD Soluble; STEBA Biotech) has been approved for treating men with low-risk prostate cancer. A phase 1 trial of VTP evaluating treatment of upper tract urothelial carcinoma (UTUC) showed an acceptable safety profile with strong potential as an effective, kidney-sparing endoscopic management option. These results support a recently initiated multi-center Phase 3 trial (ENLIGHTED). Here we conducted a correlative study to assess immune modulatory activities of VTP and its potential association with treatment response. Methods: 19 patients with UTUC received up to two endoscopic VTP treatments in a phase I trial evaluating the safety of VTP. Treatment was applied by endoscopic illumination for 10 minutes at the involved site in the upper tract with three light fluence doses at 100 mW/cm, 150 mW/cm, or 200 mW/cm after intravenous injection of 4 mg/kg WST-11. Complete response was defined by absence of visible tumor and negative urine cytology at 30 days post treatment. To investigate the impact of VTP on the immune system, patient blood samples were collected and banked at 6 time points (base line, 4-6 hrs, 1 day, 1 week, 2 weeks, and 4 weeks post-treatment). Peripheral blood mononuclear cells (PBMCs) were subjected to flow cytometry analyses for T cell activation status and the abundance of myeloid derived suppressive cell (MDSC). Patient analyses were further stratified by complete responders (CR) and partial responders (PR). Mice bearing a murine bladder cell line MB49 or MB49 expressing ovalbumin (MB49-ova) was utilized for the assessment of efficacy and immune modulation by VTP. Results and Conclusions: An increase of the MDSC population in PBMC was observed immediately after VTP treatment (up to 24 hrs) in both CR and PR. However, the MDSC level returned close to pretreatment level in the majority of cases. The frequency of CD8 T cells among the total (CD3 positive) T cells in PBMC was increased immediately after VTP in both CR and PR. However, this increase was more prominent and durable among CR than PR, suggesting an association of treatment response with CD8 T cell driven immune modulation. Analysis of VTP induced antigen-specific immune responses using ovalbumin (ova) tetramers on MB49-ova model showed an increase in ova specific CD8 T cells in the blood and tumor samples at day 7 post VTP, indicating that VTP might induce tumor antigen specific adaptive response. Future analysis will be focused on the analysis of T cell receptor repertoire and immune correlation with clinical benefit. In summary, our pre-clinical and clinical data suggests that VTP induces antigen-specific CD8 T cell responses that may be durable. Citation Format: Kwanghee Kim, Sadna Budhu, Wesley Yip, Andrew Tracey, Andreas Aulitzky, Jasmine Thomas, Karan Nagar, Laura Alvim, Rebecca Dubrovsky, Caoimhe Ryan, Natalia Kudinova, Phillip Wong, Taha Merghoub, Avigdor Scherz, Jonathan Coleman. WST-11 vascular-targeted photodynamic therapy induced immune modulation in upper tract urothelial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2421.

Editorial Comment.

No AccessJournal of UrologyAdult Urology24 Feb 2023Editorial CommentThis article comments on the following:Final Results of a Phase I Trial of WST-11 (TOOKAD Soluble) Vascular-targeted Photodynamic Therapy for Upper Tract Urothelial Carcinoma Timothy D. Lyon, Ram A. Pathak, and Andrew J. Zganjar Timothy D. LyonTimothy D. Lyon Department of Urology, Mayo Clinic, Jacksonville, Florida More articles by this author , Ram A. PathakRam A. Pathak Department of Urology, Mayo Clinic, Jacksonville, Florida More articles by this author , and Andrew J. ZganjarAndrew J. Zganjar Department of Urology, Mayo Clinic, Jacksonville, Florida More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003202.01AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookLinked InTwitterEmail "Editorial Comment." The Journal of Urology, Publish Ahead of Print, pp. – REFERENCES 1. . Management of low-grade upper tract urothelial carcinoma: an unmet need. Rev Urol. 2020; 22(1):1-8. Medline, Google Scholar 2. . Robot-assisted laparoscopic ureteral reconstruction for malignant pathology: Single-center experience with analysis of perioperative, functional, and oncologic outcomes. J Endourol. 2023; 37(1):42-49. Crossref, Medline, Google Scholar 3. Final results of a phase I trial of WST-11 (TOOKAD Soluble) vascular-targeted photodynamic therapy for upper tract urothelial carcinoma. J Urol. 2023; 209(5):000. Google Scholar © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of Urology1 Feb 2023Final Results of a Phase I Trial of WST-11 (TOOKAD Soluble) Vascular-targeted Photodynamic Therapy for Upper Tract Urothelial Carcinoma Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Timothy D. Lyon Department of Urology, Mayo Clinic, Jacksonville, Florida More articles by this author Ram A. Pathak Department of Urology, Mayo Clinic, Jacksonville, Florida More articles by this author Andrew J. Zganjar Department of Urology, Mayo Clinic, Jacksonville, Florida More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract C016: New treatment modality for pancreatic cancer-Vascular Targeted Photodynamic therapy with WST11 (Padeliporfin) combined with endovascular light delivery

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Early detection and surgical removal of PDAC, when the cancer is localized with no clinical evidence for systemic spread, may be curative but tumor spread into the vicinity of major blood vessels, e.g. superior mesenteric artery (SMA), can be lethal and therefore avoid surgery. Here we show that Vascular Targeted Photodynamic therapy (VTP) with WST11 in combination with immune modulating chemotherapeutic agents allows PDAC tumors ablation while preserving large normal vessels and tissues in animal models. New endovascular illumination system recently developed by our group (1) provides the light needed for such ablation with no damage to the SMA and complete remodeling of the surrounding normal tissue. Methods: Two orthotopic models of pancreatic cancer (KPC-Luc-mcherry and non-labeled KPC tumors (NL-KPC)) in C57B mice were subjected to VTP, alongside intraperitoneal gemzar (GEM) or cyclophosphamide (CTX) treatment. multiplex immunohistochemistry (mIHC) and single analyses using 10X Genomics platform of tumor were performed for resolving the key factors in the therapeutic process. Results: Comparing the KPC-Luc-mcherry with the NL-KPC tumor, we found that non labeled KPC has the typical morphology of human PDAC, immunologically cold and is highly aggressive compared with KPC-Luc-mcherry. WST11-VTP results in high cure rate (~50%) of animals bearing small KPC-Luc-mcherry tumors, larger tumors required combinations with metronomic administration of GEM. High rate of complete necrosis (95-100%) was achieved also with the non-labled PDAC tumors but prolonged disease- free survival required combination with CTX. The mechanism of action for both tumor models involves co-generation of oxygen and NO radicals through local photoexcitation of WST11, followed by iNOS consumption and vascular break down. Infiltration of immune cells alarmed by HMGB1 and other DAMPs leads to annihilation of residual cancer cells and prolonged anticancer immunity. The administration of CTX amplifies and prolonged the VTP oxidative stress. Conclusion: WST11-VTP combination with immune modulating chemotherapeutic agents administrations, activated by endovascular illumination through the SMA, may provide solution to the unmet need of early stage diagnosed PDAC patients. (1) Franz E. Boas et al, “Downstaging Locally Advanced Pancreatic Cancer To Resectability: Perivascular Ablation Using An Intra-arterial Balloon Laser Catheter In Pigs”, Abstract Archives of the RSNA, RSNA 2021,SDR-IR-13- “Redefining radiology” 11/29-12/4, 2021 Citation Format: Lilach Agemy, Keren Sasson, Tamar Yechezkel, Dina Priese, Yaniv Cohen, Zachary Zacks, Gil Stelzer, David P. Kelsen, Hooman Yarmohammadi, Alice C. Wei, Stephen B. Solomon, Avidgor Scherz. New treatment modality for pancreatic cancer-Vascular Targeted Photodynamic therapy with WST11 (Padeliporfin) combined with endovascular light delivery [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C016.

Alternative- and focal therapy trends for prostate cancer: a total population analysis of in-patient treatments in Germany from 2006 to 2019

PurposeFocal therapy (FT) offers an alternative approach for prostate cancer (PCa) treatment in selected patients. However, little is known on its actual establishment in health care reality.Patients and methodsWe defined FT as high-intensity focused ultrasound (HIFU), hyperthermia ablation, cryotherapy, transurethral ultrasound ablation (TULSA) or vascular-targeted photodynamic therapy (VTP) TOOKAD®. We analyzed the nationwide German hospital billing database for a PCa diagnosis in combination with FT. For analyses on the hospital level, we used the reimbursement.INFO tool based on hospitals’ quality reports. The study period was 2006 to 2019.ResultsWe identified 23,677 cases of FT from 2006 to 2019. Considering all PCa cases with surgery, radiotherapy or FT, the share of FT was stable at 4%. The annual caseload of FT increased to a maximum of 2653 cases in 2008 (p < 0.001) and then decreased to 1182 cases in 2014 (p < 0.001). Since 2015, the cases of FT remained on a plateau around 1400 cases per year. The share of HIFU was stable at 92–96% from 2006 to 2017 and decreased thereafter to 75% in 2019 (p = 0.015). In 2019, VTP-TOOKAD® increased to 11.5% and TULSA to 6%. In 2006, 21% (62/299) of urological departments performed FT and 20 departments reached > 20 FT procedures. In 2019, 16% (58/368) of urological departments performed FT and 7 departments reached > 20 FT. In 2019, 25 urological departments offered FT other than HIFU: 5 centers hyperthermia ablation, 11 centers VTP TOOKAD®, 3 centers cryotherapy, 6 centers TULSA.ConclusionThe FT development in Germany followed the Gartner hype cycle. While HIFU treatment is the most commonly performed FT, the share of newer FT modalities such as VTP-TOOKAD® and TULSA is remarkably increasing.

Histological Characteristics of Port-Wine Stains with Complete Regression After Photodynamic Therapy Treatment: A 7-Year Follow-Up.

Background: Vascular-targeted photodynamic therapy (PDT) is an effective alternative treatment choice for port-wine stains (PWSs). The histological characteristics of PWSs after PDT treatment have not yet been reported. Objective: To investigate the morphological features of PWSs treated by PDT and define the histopathological characteristics of PWS that achieve clinical cure. Methods: Thirteen patients with facial PWSs, who presented with complete regressive PWS lesions after a mean of 4.38 (standard deviation = 4.907) sessions of PDT. Post-treatment biopsy samples were obtained from each patient. The number of blood vessels, vascular diameter, and depth were measured and compared in all samples of PDT-regressive sites, PDT-resistant sites, and normal skin. Results: Within the 7-year follow-up after PDT, there was no recurrence in the regression area of PDT. In the PDT-regressive sites, within 800 μm of the dermal-epidermal junction, the dilated vessels were occluded and remained fissure-like after PDT. Conclusions: When the vascular lesions within 800 μm of the dermal-epidermal junction were closed after PDT, a stable clinical cure (no recurrence) was achieved.

Zinc-Substituted Pheophorbide A Is a Safe and Efficient Antivascular Photodynamic Agent.

The present study focuses on the photodynamic activity of zinc-substituted pheophorbide a against human endothelial cells. Previously, zinc pheophorbide a has been shown to be a very potent photosensitizer but also a strong albumin binder. Binding to albumin significantly reduces its availability to cancer cells, which may necessitate the use of relatively high doses. Here we show that zinc pheophorbide a is very effective against vascular endothelial cells, even in its albumin-complexed form. Albumin complexation increases the lysosomal accumulation of the drug, thus enhancing its efficiency. Zinc pheophorbide a at nanomolar concentrations induces endothelial cell death via apoptosis, which in many cases is considered a desirable cell death mode because of its anti-inflammatory effect. Additionally, we demonstrate that in comparison to tumor cells, endothelial cells are much more susceptible to photodynamic treatment with the use of the investigated compound. Our findings demonstrate that zinc pheophorbide a is a very promising photosensitizer for use in vascular-targeted photodynamic therapy against solid tumors, acting as a vascular shutdown inducer. It can also possibly find application in the treatment of a range of vascular disorders. Numerous properties of zinc pheophorbide a are comparable or even more favorable than those of the well-known photosensitizer of a similar structure, palladium bacteriopheophorbide (TOOKAD®).

Current evidence for focal laser ablation and vascular-targeted photodynamic therapy for localized prostate cancer: review of literature published in the last 2 years.

Currently, a significant number of patients are diagnosed with unilateral and apparently unifocal low or intermediate-risk prostate cancer (PCa). These patients are suitable for focal therapy, thus preventing radical treatment side effects without affecting cancer control. Among focal therapy energy sources, laser-based technologies have shown promising outcomes. We aimed to summarize recent data on focal laser ablation (FLA) and vascular-targeted photodynamic therapy (VTP) for PCa. We selected eight studies reporting data on 1155 patients with PCa who underwent laser-based focal therapy. Five studies were on FLA and three on VTP (six prospective and two retrospective series); four reported both oncologic and functional outcomes whereas in three only oncologic and one only functional outcomes were discussed. Follow-up protocols and durations varied widely among the studies. PCa recurrence rates ranged between 20 and 56%. Urinary and erectile function were preserved after treatment, and complications were mild and transient. A lack of high-quality data on long-term oncological outcomes still remains, thus further highlighting the need for prospective controlled studies. FLA and VTP are well tolerated procedures with excellent functional outcomes. However, both procedures showed a significant rate of PCa recurrence, thus demonstrating a certain grade of oncologic control failure of the procedure and/or nonoptimal patients' selection.

Progress in Port-Wine Stains Lesion Structure and Its Optical Imaging Technique in Vascular-Targeted Photodynamic Therapy

Progress in Port-Wine Stains Lesion Structure and Its Optical Imaging Technique in Vascular-Targeted Photodynamic Therapy

Multi-step deep neural network for identifying subfascial vessels in a dorsal skinfold window chamber model.

Automatic segmentation of blood vessels in the dorsal skinfold window chamber (DWSC) model is a prerequisite for the evaluation of vascular-targeted photodynamic therapy (V-PDT) biological response. Recently, deep learning methods have been widely applied in blood vessel segmentation, but they have difficulty precisely identifying the subfascial vessels. This study proposed a multi-step deep neural network, named the global attention-Xnet (GA-Xnet) model, to precisely segment subfascial vessels in the DSWC model. We first used Hough transform combined with a U-Net model to extract circular regions of interest for image processing. GA step was then employed to obtain global feature learning followed by coarse segmentation for the entire blood vessel image. Secondly, the coarse segmentation of blood vessel images from the GA step and the same number of retinal images from the DRIVE datasets were combined as the mixing sample, inputted into the Xnet step to learn the multiscale feature predicting fine segmentation maps of blood vessels. The data show that the accuracy, sensitivity, and specificity for the segmentation of multiscale blood vessels in the DSWC model are 96.00%, 86.27%, 96.47%, respectively. As a result, the subfascial vessels could be accurately identified, and the connectedness of the vessel skeleton is well preserved. These findings suggest that the proposed multi-step deep neural network helps evaluate the short-term vascular responses in V-PDT.

Decision Regret and Quality of Life after Focal Therapy with Vascular-Targeted Photodynamic Therapy (TOOKAD®) for Localized Prostate Cancer

Purpose: The aim of the study was to assess quality of life (QoL), decision involvement, and decisional regret after treatment with vascular-targeted photodynamic therapy (VTP) (TOOKAD®) for unilateral low-risk prostate cancer. Methods: Validated questionnaires (EORTC QLQ-C30 and QLQ-PR25) capturing QoL post-treatment, involvement in decision-making (Control Preferences Scale) and decision regret (Decisional Regret Scale), were given to patients at the 12-month visit after undergoing VTP at our institution between May 2018 and February 2021. Results: Out of 44 patients, 36 patients were included in this study and 31 (86.1%) responded to the questionnaires. Mean overall health score capturing QoL at 12 months was 79.3 (standard deviation: ±18.1). 70.9% of the patients (n = 22) had no decision regret, and 67.8% of men (n = 21) had an active role in decision-making. In control biopsy at 12 months post-treatment, 19.4% of patients (n = 7) presented with local recurrence and progression to higher Gleason score (GS) was found in 13.8% of patients (n = 5). Patients (n = 3) presenting with tumor recurrence or progression to higher GS in control biopsy showed a significantly higher level of decision regret (p < 0.009). Conclusion: Only 9.7% of men (n = 3) felt a strong emotion of regret at 12 months after VTP. Level of decision regret was significantly higher in patients with local recurrence or tumor progression detected in control biopsy. QoL was stable after VTP.

A proposed scoring system for facial port-wine stain evaluation: Facial port-wine stain area and severity index.

Port-wine stain (PWS) is a congenital capillary malformation that often occurs on the face. Feasible and quantitative evaluation of facial port-wine stain (FPWS) can significantly impact its clinical management and aid in future research. To develop and validate an easy-to-use scoring system for FPWS evaluation. A facial port-wine stain area and severity index (FSASI) scoring system was proposed. To determine the FSASI score, the face was divided into four regions: forehead, right malar, left malar, and perioral. The severity of FPWS in each region was evaluated by three factors: percentage of the area affected, lesion color, and thickness. To evaluate the intra- and inter-rater reliability of FSASI, two separate FSASI assessments on 111clinical pictures were conducted by each rater in a one-week interval, and the results from 6 independent raters at different time points were compared. Validity of the FSASI scores was assessed by comparing it with physician global assessment (PGA) and traditional classification data. Validity of the area and color elements of FSASI was also determined. The changes in FSASI scores after vascular-targeted photodynamic therapy (V-PDT) were analyzed to evaluate the treatment effect. The FSASI scoring system showed good intra- and inter-rater reliability (ICC >0.75, p<0.001) and was found to be comparable to PGA scores (Spearman's r=0.752-0.907, p<0.001) and traditional classification data (Spearman's r=0.426-0.662, p<0.001). Efficacy analysis indicated that FSASI scores decreased after V-PDT treatment. The results of this study demonstrated the reliability and validity of FSASI, which may be applied to assess the severity of FPWS and to evaluate treatment effects in clinical practice and research.

Tumor irradiation combined with minimally invasive surgery (vascular-targeted photodynamic therapy) enhances anti-tumour effects in preclinical prostate cancer

Hanna T Sjoberg, Yiannis Philippou, Anette L Magnussen, Iain DC Tullis, Esther Bridges, Andrea Chatrian, Joel Loefebvre, Ka Ho Tam, Emma A Murphy, Jens Rittscher, Dina Preise, Lilach Agemy, Tamar Yechezkel, Sean C Smart, Paul Kinchesh, Stuart Gilchrist, Danny P Allen, David A Scheiblin, Stephen J Lockett, David A Wink, Alastair D Lamb, Ian G Mills, Adrian Harris, Ruth J Muschel, Boris Vojnovic, Avigdor Scherz, Freddie C Hamdy, Richard J Bryant.&#x0D; &#x0D; Introduction There is an important clinical need to improve the treatment of high risk localised and locally advanced prostate cancer (PCa), and to reduce the side effects of these treatments. We hypothesised that multi-modality therapy combining radiotherapy and vascular-targeted photodynamic therapy (VTP) could PCa tumour control compared against monotherapy with each of these treatments alone. This could provide proof-of-concept to take to the clinic. VTP is a minimally invasive focal surgical therapy for localised PCa, which rapidly destroys targeted tumours through vascular disruption. Tumour vasculature is characterised by vessel immaturity, increased permeability, aberrant branching and inefficient flow. Fractionated radiotherapy (FRT) alters the tumour microenvironment and promotes transient vascular normalisation.&#x0D; Materials and Methods We investigated whether sequential delivery of FRT followed by VTP 7 days later improves PCa tumour control compared to monotherapy with FRT or VTP alone.&#x0D; Results FRT induced vascular normalisation changes in PCa flank tumour allografts, improving vascular function as demonstrated using dynamic contrast enhanced magnetic resonance imaging. FRT followed by VTP significantly delayed tumour growth in flank PCa allograft pre-clinical models, compared with monotherapy with FRT or VTP alone, and improved overall survival.&#x0D; Conclusion Taken together, these results suggest that combining FRT and VTP could become a promising multimodal clinical strategy in PCa therapy. This provides proof-of-concept for this multi-modality therapy approach to take forward to early phase clinical trials.

PD37-09 INTERMITTENT WST-11 VASCULAR TARGET PHOTODYNAMIC THERAPY IN A MOUSE ORTHOTOPIC BLADDER MODEL

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I (PD37)1 Sep 2021PD37-09 INTERMITTENT WST-11 VASCULAR TARGET PHOTODYNAMIC THERAPY IN A MOUSE ORTHOTOPIC BLADDER MODEL Jie Chen, Jasmine Thomas, Karan Nagar, Lucas Nogueira, Peter Reisz, Kwanghee Kim, and Jonathan Coleman Jie ChenJie Chen More articles by this author , Jasmine ThomasJasmine Thomas More articles by this author , Karan NagarKaran Nagar More articles by this author , Lucas NogueiraLucas Nogueira More articles by this author , Peter ReiszPeter Reisz More articles by this author , Kwanghee KimKwanghee Kim More articles by this author , and Jonathan ColemanJonathan Coleman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002047.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Vascular targeted photodynamic therapy (VTP) is a non-surgical tumor ablation approach used to treat early-stage prostate cancer and may also be effective for urothelial cancer based on preclinical data in heterotopic models. While orthotopic models are valuable as they reproduce factors such as local tissue environment and cancer progression pathogenesis compared to ectopic implantation, its implementation is technically difficult. Herein we describe our work in developing an orthotopic murine model for bladder urothelial cancer using intermittent laser pulses to ensure mouse survival and local tumor control. METHODS: The MB-49 murine urothelial cancer line was used for all experiments after establishing stable luciferase expression. Tumors were implanted in 16 1C57BL-6 mice by surgical approach by direct injection of 1x105 MB49-Luc cells into the bladder. Successful tumor implantation was assessed by IVIS images 72 hours after implantation. Mice were divided in two groups: control and VTP treated. VTP was performed 96 hours after cell injection at a power of 100mW in 30 seconds pulses, with 30 seconds interval. Mouse bladders were harvested 13 days post implantation. Safety, tumor control, and histology parameters were assessed. RESULTS: Adequate tumor growth was observed in all mice, and no major toxicity was observed in both groups. Final tumor size was 71% smaller, and histological viability was decreased in VTP treated tumors when compared to controls (p <0.001, figure 1). CD31, Ki67 expression were decreased 2.75 and 1.87-fold respectively, and tunnel staining was increased 3.2-fold in control tumors when compared to VTP treated. (p <0.05, figure 2). CONCLUSIONS: A mouse orthotopic bladder urothelial model via injection of MB-49 cell line is feasible and displays a very high tumor take rates. Intermittent VTP treatment has an effect on mouse bladder tumors as shown by the decrease in tumor size, weight and change in histology. Additional refinement to the model may provide a means to establish an appropriate timeline and utility for future studies. Source of Funding: NIH/NCI (P30 CA008748) and the Thompson Family Foundation © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e658-e659 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jie Chen More articles by this author Jasmine Thomas More articles by this author Karan Nagar More articles by this author Lucas Nogueira More articles by this author Peter Reisz More articles by this author Kwanghee Kim More articles by this author Jonathan Coleman More articles by this author Expand All Advertisement Loading ...