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1.  Motexafin lutetium-photodynamic therapy of prostate cancer: Short and long term effects on PSA 
The time course of serum PSA response to photodynamic therapy (PDT) of prostate cancer was measured.
Experimental Design:
Seventeen patients were treated in a Phase I trial of motexafin lutetium-PDT. PDT dose was calculated in each patient as the product of the ex vivo-measured pre-PDT photosensitizer level and the in situ-measured light dose. Serum PSA level was measured within two months prior to PDT (baseline), and at day 1; weeks 1-3; months 1, 2 and 3; months 4-6 and months 7-11 after PDT.
At 24h after PDT, serum PSA increased by 98±36% (mean ± SE) relative to baseline levels (p=0.007). When patients were dichotomized based on median PDT dose, those who received high PDT dose demonstrated a 119±52% increase in PSA compared to a 54±27% increase in patients treated at low PDT dose. Patients treated with high vs. low PDT dose demonstrated a median biochemical delay of 82 vs. 43 days (p=0.024), with biochemical delay defined as the length of time between PDT and a nonreversible increase in PSA to a value ≥baseline.
Results show PDT to induce large, transient increases in serum PSA levels. Patients who experienced high PDT dose demonstrated greater short-term increase in PSA and a significantly more durable PSA response (biochemical delay). These data strongly promote the need for individualized delivery of PDT dose and assessment of treatment effect in PDT of prostate cancer. Information gained from such patient-specific measurements could facilitate the introduction of multiple PDT sessions in patients who would benefit.
PMCID: PMC2680073  PMID: 18676760
motexafin lutetium; prostate; PSA; PDT dose; photosensitizer concentration
2.  Choline PET for Monitoring Early Tumor Response to Photodynamic Therapy 
Photodynamic therapy (PDT) is a relatively new therapy that has shown promise for treating various cancers in both preclinical and clinical studies. The present study evaluated the potential use of PET with radiolabeled choline to monitor early tumor response to PDT in animal models.
Two human prostate cancer models (PC-3 and CWR22) were studied in athymic nude mice. A second-generation photosensitizer, phthalocyanine 4 (Pc 4), was delivered to each animal by a tail vein injection 48 h before laser illumination. Small-animal PET images with 11C-choline were acquired before PDT and at 1, 24, and 48 h after PDT. Time–activity curves of 11C-choline uptake were analyzed before and after PDT. The percentage of the injected dose per gram of tissue was quantified for both treated and control tumors at each time point. In addition, Pc 4-PDT was performed in cell cultures. Cell viability and 11C-choline uptake in PDT-treated and control cells were measured.
For treated tumors, normalized 11C-choline uptake decreased significantly 24 and 48 h after PDT, compared with the same tumors before PDT (P < 0.001). For the control tumors, normalized 11C-choline uptake increased significantly. For mice with CWR22 tumors, the prostate-specific antigen level decreased 24 and 48 h after PDT. Pc 4-PDT in cell culture showed that the treated tumor cells, compared with the control cells, had less than 50% 11C-choline activity at 5, 30, and 45 min after PDT, whereas the cell viability test showed that the treated cells were viable longer than 7 h after PDT.
PET with 11C-choline is sensitive for detecting early changes associated with Pc 4-PDT in mouse models of human prostate cancer. Choline PET has the potential to determine whether a PDT-treated tumor responds to treatment within 48 h after therapy.
PMCID: PMC2999358  PMID: 20008981
small-animal PET; choline molecular imaging; photodynamic therapy (PDT); prostate cancer; tumor response
3.  5-Aminolevulinic acid photodynamic therapy versus argon plasma coagulation for ablation of Barrett’s oesophagus: a randomised trial 
Gut  2004;53(6):785-790.
Background: Photochemical and thermal methods are used for ablating Barrett’s oesophagus (BO). The aim of this study was to compare 5-aminolevulinic acid induced photodynamic therapy (ALA-PDT) with argon plasma coagulation (APC) with respect to complete reversal of BO.
Methods: Patients with BO (32 no dysplasia and eight low grade dysplasia) were randomised to one of three treatments: (a) ALA-PDT as a single dose of 100 J/cm2 at four hours (PDT100; n = 13); (b) ALA-PDT as a fractionated dose of 20 and 100 J/cm2 at one and four hours, respectively (PDT20+100; n = 13); or (c) APC at a power setting of 65 W in two sessions (APC; n = 14). If complete elimination of BO was not achieved by the designated treatment, the remaining BO was treated by a maximum of two sessions of APC.
Results: Mean endoscopic reduction of BO at six weeks was 51% (range 20–100%) in the PDT100 group, 86% (range 0–100%) in the PDT20+100 group, and 93% (range 40–100%) in the APC group (PDT100 v PDT20+100, p<0.005; PDT100 v APC, p<0.005; and PDT20+100 v APC, NS) with histologically complete ablation in 1/13 (8%) patients in the PDT100 group, 4/12 (33%) in the PDT20+100 group, and 5/14 (36%) in the APC group (NS). Remaining BO was additionally treated with APC in 23/40 (58%) patients. Histological examination at 12 months revealed complete ablation in 9/11 (82%) patients in the PDT100 group, in 9/10 (90%) patients in the PDT20+100 group, and in 8/12 (67%) patients in the APC group (NS). At 12 months, no dysplasia was detected. Side effects (that is, pain (p<0.01), and nausea and vomiting (p<0.05)) and elevated liver transaminases (p<0.01) were more common after PDT than APC therapy. One patient died three days after treatment with PDT, presumably from cardiac arrhythmia.
Conclusion: APC alone or ALA-PDT in combination with APC can lead to complete reversal of Barrett’s epithelium in at least two thirds of patients when administered in multiple treatment sessions. As the goal of treatment should be complete reversal of Barrett’s epithelium, we do not recommend these techniques for the prophylactic ablation of BO.
PMCID: PMC1774080  PMID: 15138203
Barrett’s oesophagus; dysplasia; 5-aminolevulinic acid; photodynamic therapy; argon plasma coagulation; oesophageal cancer
4.  Photodynamic Therapy with 3-(1’-hexyloxyethyl) pyropheophorbide a (HPPH) for Cancer of the Oral Cavity 
The primary objective was to evaluate safety of 3-(1’-hexyloxyethyl)pyropheophorbide-a (HPPH) photodynamic therapy (HPPH-PDT) for dysplasia and early squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives were the assessment of treatment response and reporters for an effective PDT reaction.
Experimental Design
Patients with histologically proven oral dysplasia, carcinoma in situ (CiS ) or early stage HNSCC were enrolled in two sequentially conducted dose escalation studies with an expanded cohort at the highest dose level. These studies employed an HPPH dose of 4 mg/m2 and light doses from 50 to 140 J/cm2. Pathologic tumor responses were assessed at 3 months. Clinical follow up range was 5 to 40 months. PDT induced cross-linking of signal transducer and activator of transcription 3 (STAT3) were assessed as potential indicators of PDT effective reaction.
Forty patients received HPPH-PDT. Common adverse events were pain and treatment site edema. Biopsy proven complete response rates were 46% for dysplasia and CiS, and 82% for SCCs lesions at 140 J/cm2. The responses in the CiS/dysplasia cohort are not durable. The PDT induced STAT3 cross-links is significantly higher (P=0.0033) in SCC than in CiS/dysplasia for all light-doses.
HPPH-PDT is safe for the treatment of CiS/dysplasia and early stage cancer of the oral cavity. Early stage oral HNSCC appears to respond better to HPPH-PDT in comparison to premalignant lesions. The degree of STAT3 cross-linking is a significant reporter to evaluate HPPH-PDT mediated photoreaction.
PMCID: PMC3911775  PMID: 24088736
5.  Increased killing of SCCVII squamous cell carcinoma cells after the combination of Pc 4 photodynamic therapy and dasatinib is associated with enhanced caspase-3 activity and ceramide synthase 1 upregulation 
International Journal of Oncology  2013;43(6):2064-2072.
Photodynamic therapy (PDT) is not always effective as an anticancer treatment, therefore, PDT is combined with other anticancer agents for improved efficacy. The combination of dasatinib and PDT with the silicone phthalocyanine photosensitizer Pc 4 was assessed for increased killing of SCCVII mouse squamous cell carcinoma cells, a preclinical model of head and neck squamous cell carcinoma, using apoptotic markers and colony formation as experimental end-points. Because each of these treatments regulates the metabolism of the sphingolipid ceramide, their effects on mRNA levels of ceramide synthase, a ceramide-producing enzyme, and the sphingolipid profile were determined. PDT + dasatinib induced an additive loss of clonogenicity. Unlike PDT alone or PDT + dasatinib, dasatinib induced zVAD-fmk-dependent cell killing. PDT or dasatinib-induced caspase-3 activation was potentiated after the combination. PDT alone induced mitochondrial depolarization, and the effect was inhibited after the combination. Annexin V+ and propidium iodide+ cells remained at control levels after treatments. In contrast to PDT alone, dasatinib induced upregulation of ceramide synthase 1 mRNA, and the effect was enhanced after the combination. Dasatinib induced a modest increase in C20:1-and C22-ceramide but had no effect on total ceramide levels. PDT increased the levels of 12 individual ceramides and total ceramides, and the addition of dasatinib did not affect these increases. PDT alone decreased substantially sphingosine levels and inhibited the activity of acid ceramidase, an enzyme that converts ceramide to sphingosine. The data suggest that PDT-induced increases in ceramide levels do not correlate with ceramide synthase mRNA levels but rather with inhibition of ceramidase. Cell killing was zVAD-fmk-sensitive after dasatinib but not after either PDT or the combination and enhanced cell killing after the combination correlated with potentiated caspase-3 activation and upregulation of ceramide synthase 1 mRNA but not the production of ceramide. The data imply potential significance of the combination for cancer treatment.
PMCID: PMC3834346  PMID: 24126464
apoptosis; ceramide; ceramide synthase; ceramidase; dasatinib; PDT; sphingolipids; sphingosine
6.  Photodynamic therapy and tumor imaging of hypericin-treated squamous cell carcinoma 
Conventional cancer therapy including surgery, radiation, and chemotherapy often are physically debilitating and largely ineffective in previously treated patients with recurrent head and neck squamous cell carcinoma (SCC). A natural photochemical, hypericin, could be a less invasive method for laser photodynamic therapy (PDT) of these recurrent head and neck malignancies. Hypericin has powerful photo-oxidizing ability, tumor localization properties, and fluorescent imaging capabilities as well as minimal dark toxicity. The current study defined hypericin PDT in vitro with human SCC cells before the cells were grown as tumor transplants in nude mice and tested as a model for hypericin induced tumor fluorescence and PDT via laser fiberoptics.
SNU squamous carcinoma cells were grown in tissue culture, detached from monolayers with trypsin, and incubated with 0.1 μg to 10 μg/ml of hypericin before exposure to laser light at 514, 550, or 593 nm to define optimal dose, time, and wavelength for PDT of tumor cells. The SCC cells also were injected subcutaneously in nude mice and grown for 6–8 weeks to form tumors before hypericin injection and insertion of fiberoptics from a KTP532 surgical laser to assess the feasibility of this operating room instrument in stimulating fluorescence and PDT of tumors.
In vitro testing revealed a hypericin dose of 0.2–0.5 μg/ml was needed for PDT of the SCC cells with an optimal tumoricidal response seen at the 593 nm light absorption maximum. In vivo tumor retention of injected hypericin was seen for 7 to10 days using KTP532 laser induced fluorescence and biweekly PDT via laser fiberoptics led to regression of SCC tumor transplants under 0.4 cm2 diameter, but resulted in progression of larger size tumors in the nude mice.
In this preclinical study, hypericin was tested for 514–593 nm dye laser PDT of human SCC cells in vitro and for KTP532 surgical laser targeting of SCC tumors in mice. The results suggest hypericin is a potent tumor imaging agent using this surgical laser that may prove useful in defining tumor margins and possibly in sterilizing post-resection margins. Deeply penetrating pulsed infrared laser emissions will be needed for PDT of larger and more inaccessible tumors.
PMCID: PMC1762016  PMID: 17147827
7.  Comparative Study of Photodynamic Therapy with Topical Methyl Aminolevulinate versus 5-Aminolevulinic Acid for Facial Actinic Keratosis with Long-Term Follow-Up 
Annals of Dermatology  2014;26(3):321-331.
Few studies have compared the efficacy, cosmetic outcomes, and adverse events between 5-aminolevulinic acid photodynamic therapy (ALA-PDT) and methyl aminolevulinate-PDT (MAL-PDT) for actinic keratoses (AKs) in Asian ethnic populations with dark-skin.
We retrospectively compared the long-term efficacy, recurrence rates, cosmetic outcomes, and safety of ALA-PDT versus MAL-PDT for facial AKs in Koreans.
A total of 222 facial AKs in 58 patients were included in this study. A total of 153 lesions (29 patients) were treated with 5-ALA, and 69 lesions (29 patients) with MAL. ALA and MAL creams were applied for 6 hours and 3 hours, respectively; the lesions were then illuminated with a halogen lamp at 150 J/cm2 for ALA-PDT and a diode lamp at 37 J/cm2 for MAL-PDT.
The complete response rates of ALA-PDT and MAL-PDT were 56.9% and 50.7%, respectively, with no significant difference at 12 months after treatment. No significant difference in recurrence rates was observed between the 2 PDT modalities at either 6 or 12 months after treatment. There was no significant difference in the cosmetic outcomes between the 2 treatment modalities at 12 months after PDT. However, ALA-PDT caused significantly more painful than MAL-PDT (p=0.005). The adverse events were mild to moderate, transient, and self-limiting for both modalities.
MAL-PDT was similar to ALA-PDT in terms of long-term efficacy, recurrence rates, cosmetic outcomes, and adverse events; however, it was a significantly less painful procedure than ALA-PDT in our study.
PMCID: PMC4069642  PMID: 24966631
Long-term efficacy; Methyl aminolevulinate; Multiple actinic keratoses; Photodynamic therapy; 5-aminolevulinic acid
8.  Photodynamic therapy activated signaling from epidermal growth factor receptor and STAT3 
Cancer Biology & Therapy  2012;13(14):1463-1470.
Patients with serosal (pleural or peritoneal) spread of malignancy have few definitive treatment options and consequently have a very poor prognosis. We have previously shown that photodynamic therapy (PDT) can be an effective treatment for these patients, but that the therapeutic index is relatively narrow. Here, we test the hypothesis that EGFR and STAT3 activation increase survival following PDT, and that inhibiting these pathways leads to increased PDT-mediated direct cellular cytotoxicity by examining BPD-PDT in OvCa and NSCLC cells. We found that BPD-mediated PDT stimulated EGFR tyrosine phosphorylation and nuclear translocation, and that EGFR inhibition by erlotinib resulted in reduction of PDT-mediated EGFR activation and nuclear translocation. Nuclear translocation and PDT-mediated activation of EGFR were also observed in response to BPD-mediated PDT in multiple cell lines, including OvCa, NSCLC and head and neck cancer cells, and was observed to occur in response to porfimer sodium-mediated PDT. In addition, we found that PDT stimulates nuclear translocation of STAT3 and STAT3/EGFR association and that inhibiting STAT3 signaling prior to PDT leads to increased PDT cytotoxicity. Finally, we found that inhibition of EGFR signaling leads to increased PDT cytotoxicity through a mechanism that involves increased apoptotic cell death. Taken together, these results demonstrate that PDT stimulates the nuclear accumulation of both EGFR and STAT3 and that targeting these survival pathways is a potentially promising strategy that could be adapted for clinical trials of PDT for patients with serosal spread of malignancy.
PMCID: PMC3542238  PMID: 22986230
PDT; EGFR; STAT3; lung cancer; ovarian cancer; pleural; peritoneal
9.  Comparison of foveal-sparing with foveal-involving photodynamic therapy for myopic choroidal neovascularization 
Eye  2013;28(1):17-22.
To evaluate the visual outcomes of choroidal neovascularization (CNV) secondary to pathological myopia in eyes treated with photodynamic therapy (PDT), and to determine the effect of lesion location and foveal involvement on visual prognosis.
Interventional case series of 24 consecutive patients with myopic CNV treated with PDT. The main outcome measure was final LogMAR visual acuity (VA).
Of 24 eyes, the CNV lesion was subfoveal in 11 and extrafoveal in 13. Overall, the mean LogMAR VA at 24 months was 0.72. Extrafoveal CNV lesions achieved significantly better final VA compared with subfoveal CNV (LogMAR 0.45 vs 1.05, P=0.012). Eyes with extrafoveal CNV lesions were subdivided into foveal-sparing PDT (where the PDT laser spot did not involve the foveal center) and foveal-involved PDT (where the PDT laser covered the fovea). At all time points, the group with foveal-sparing PDT had significantly better VA compared with the foveal-involved group. The final LogMAR VA for the foveal-sparing PDT group was 0.26 compared with 1.00 for the foveal-involved PDT group (P=0.003). At 24 months, 77.8% of foveal-sparing PDT cases achieved VA of ≥20/40, compared with 25% of foveal-involved PDT cases and 9.1% of subfoveal CNV lesions (P=0.006).
For patients with myopic CNV, foveal-sparing PDT results in significantly better long-term visual outcomes compared with those with foveal-involved PDT. Foveal-sparing PDT may be of value for treatment of myopic CNV patients who are not suitable for treatment with anti-vascular endothelial growth factor injections.
PMCID: PMC3890748  PMID: 24051405
myopic choroidal neovascularization; pathologic myopia; photodynamic therapy; visual acuity; foveal sparing
10.  Photodynamic therapy (PDT) in early central lung cancer: a treatment option for patients ineligible for surgical resection 
Thorax  2006;62(5):391-395.
To review the Yorkshire Laser Centre experience with bronchoscopic photodynamic therapy (PDT) in early central lung cancer in subjects not eligible for surgery and to discuss diagnostic problems and the indications for PDT in such cases.
Of 200 patients undergoing bronchoscopic PDT, 21 had early central lung cancer and were entered into a prospective study. Patients underwent standard investigations including white light bronchoscopy in all and autofluorescence bronchoscopy in 12 of the most recent cases. Indications for bronchoscopic PDT were recurrence/metachronous endobronchial lesions following previous treatment with curative intent in 10 patients (11 lesions), ineligibility for surgery because of poor cardiorespiratory function in 8 patients (9 lesions) and declined consent to operation in 3 patients. PDT consisted of intravenous administration of Photofrin 2 mg/kg followed by bronchoscopic illumination 24–48 h later.
29 treatments were performed in 21 patients (23 lesions). There was no procedure‐related or 30 day mortality. One patient developed mild skin photosensitivity. All patients expressed satisfaction with the treatment and had a complete response of variable duration. Six patients died at 3–103 months (mean 39.3), three of which were not as a result of cancer. Fifteen patients were alive at 12–82 months.
Bronchoscopic PDT in early central lung cancer can achieve long disease‐free survival and should be considered as a treatment option in those ineligible for resection. Autofluorescence bronchoscopy is a valuable complementary investigation for identification of synchronous lesions and accurate illumination in bronchoscopic PDT.
PMCID: PMC2117198  PMID: 17090572
11.  Diffusion-Weighted MRI for Monitoring Tumor Response to Photodynamic Therapy 
To examine diffusion-weighted MRI (DW-MRI) for assessing the early tumor response to photodynamic therapy (PDT).
Materials and Methods
Subcutaneous tumor xenografts of human prostate cancer cells (CWR22) were initiated in athymic nude mice. A second-generation photosensitizer, Pc 4, was delivered to each animal by a tail vein injection 48 h before laser illumination. A dedicated high-field (9.4 Tesla) small animal MR scanner was used to acquire diffusion-weighted MR images pre-PDT and 24 h after the treatment. DW-MRI and apparent diffusion coefficients (ADC) were analyzed for 24 treated and 5 control mice with photosensitizer only or laser light only. Tumor size, prostate specific antigen (PSA) level, and tumor histology were obtained at different time points to examine the treatment effect.
Treated mice showed significant tumor size shrinkage and decrease of PSA level within 7 days after the treatment. The average ADC of the 24 treated tumors increased 24 h after PDT (P < 0.001) comparing with pre-PDT. The average ADC was 0.511 ± 0.119 × 10−3 mm2/s pre-PDT and 0.754 ± 0.181 × 10−3 mm2/s 24 h after the PDT. There is no significant difference in ADC values pre-PDT and 24 h after PDT in the control tumors (P = 0.20).
The change of tumor ADC values measured by DW-MRI may provide a noninvasive imaging marker for monitoring tumor response to Pc 4-PDT as early as 24 h.
PMCID: PMC3076282  PMID: 20677270
diffusion-weighted MRI; prostate cancer; photodynamic therapy; apparent diffusion coefficients (ADC); efficacy assessment; treatment monitoring
12.  How to access photodynamic therapy for bile duct carcinoma 
Photodynamic therapy (PDT) is a promising treatment option for local control of remnant cancer after surgical resection or biliary stenosis by the unresectable tumor in patients with bile duct carcinomas (BDC). To achieve effective tumor necrosis, an appropriate approach to laser irradiation is necessary.
The efficacy of endoscopy-guided PDT using porfimer (n=12) or talaporfin sodium (n=13) was investigated by evaluating the transhepatic biliary routes and endoscopic retrograde biliary (ERB) routes in 25 patients with BDC.
Diseases included perihilar intrahepatic cholangiocarcinoma (ICC) in four patients, extrahepatic BDCs in 19 and ampular carcinoma (AC) in two patients. Adjuvant PDT after surgical resection was performed in 18 patients, and PDT for tumor biliary stenosis was performed in seven. In patients undergoing surgical resections, the mean period between the operation and PDT was 87±42 days. In patients who underwent prior surgical resections, the transhepatic route was used in five (28%), the jejunal loop was used in 11 (61%), the T-tube route was used in one, and the endoscopic retrograde cholangiography (ERC) route via papilla Vater was used in one. In unresectable BDC, the ERC route was used in four patients (57%), and the transhepatic biliary route was used in three (43%). Endoscopic-guided PDT could not be performed in one patient because of a technical failure. Except for the complication of photosensitivity, endoscopy-related complications were not observed in any patients. Patients undergoing PDT with porfimer sodium had a significantly longer admission period compared to patients undergoing PDT with talaporfin sodium (36 vs. 5 days, respectively) (P<0.01).
PDT was safely and definitively performed using the endoscopy-guided approach via the transhepatic or ERC route. By considering the disadvantages of both routes, PDT must be adequately achieved for local control of BDC.
PMCID: PMC4200623  PMID: 25332999
Photodynamic therapy (PDT); endoscopy; transhepatic; transpapillary; transjejunal; bile duct carcinoma (BDC); access route
13.  High-Field Magnetic Resonance Imaging of the Response of Human Prostate Cancer to Pc 4-Based Photodynamic Therapy in an Animal Model 
Lasers in surgery and medicine  2007;39(9):723-730.
High-field magnetic resonance imaging (MRI) is an emerging technique that provides a powerful, non-invasive tool for in vivo studies of cancer therapy in animal models. Photodynamic therapy (PDT) is a relatively new treatment modality for prostate cancer, the second leading cause of cancer mortality in American males. The goal of this study was to evaluate the response of human prostate tumor cells growing as xenografts in athymic nude mice to Pc 4-sensitized PDT.
Materials and Methods
PC-3, a cell line derived from a human prostate malignant tumor, was injected intradermally on the back flanks of athymic nude mice. Two tumors were initiated on each mouse. One was treated and the other served as the control. A second-generation photosensitizing drug Pc 4 (0.6 mg/kg body weight) was delivered to each animal by tail vein injection 48 hours before laser illumination (672 nm, 100 mW/cm2, 150 J/cm2). A dedicated high-field (9.4 T) small-animal MR scanner was used for image acquisitions. A multi-slice multi-echo (MSME) technique, permitting noninvasive in vivo assessment of potential therapeutic effects, was used to measure the T2 values and tumor volumes. Animals were scanned immediately before and after PDT and 24 hours after PDT. T2 values were computed and analyzed for the tumor regions.
For the treated tumors, the T2 values significantly increased (P < 0.002) 24 hours after PDT (68.2 ± 8.5 milliseconds), compared to the pre-PDT values (55.8 ± 6.6 milliseconds). For the control tumors, there was no significant difference (P = 0.53) between the pre-PDT (52.5 ± 6.1 milliseconds) and 24-hour post-PDT (54.3 ± 6.4 milliseconds) values. Histologic analysis showed that PDT-treated tumors demonstrated necrosis and inflammation that was not seen in the control.
Changes in tumor T2 values measured by multi-slice multi-echo MR imaging provide an assay that could be useful for clinical monitoring of photodynamic therapy of prostate tumors.
PMCID: PMC2719260  PMID: 17960753
photodynamic therapy; magnetic resonance imaging (MRI); prostate cancer; efficacy assessment; multi-slice multi-echo; tumor treatment monitoring
14.  Long-Term Survival Following Endoscopic and Surgical Treatment of High-Grade Dysplasia in Barrett’s Esophagus 
Gastroenterology  2007;132(4):1226-1233.
Background & Aims
Photodynamic therapy (PDT) for high-grade dysplasia (HGD) in Barrett’s esophagus is a Food and Drug Administration–approved alternative to esophagectomy. Critical information regarding overall survival of patients followed up long-term after these therapies is lacking. Our aim was to compare the long-term survival of patients treated with PDT with patients treated with esophagectomy.
We reviewed records of patients with HGD seen at our institution between 1994 and 2004. PDT was performed 48 hours following the intravenous administration of a photosensitizer using light at 630 nm. Esophagectomy was performed by either transhiatal or transthoracic approaches by experienced surgeons. We excluded all patients with evidence of cancer on biopsy specimens. Vital status and death date information was queried using an institutionally approved Internet research and location service. Statistical analysis was performed using Kaplan–Meier curves and Cox proportional hazards ratios.
A total of 199 patients were identified. A total of 129 patients (65%) were treated with PDT and 70 (35%) with esophagectomy. Overall mortality in the PDT group was 9% (11/129) and in the surgery group was 8.5% (6/70) over a median follow-up period of 59 ± 2.7 months for the PDT group and 61 ± 5.8 months for the surgery group. Overall survival was similar between the 2 groups (Wilcoxon test = 0.0924; P = .76). Treatment modality was not a significant predictor of mortality on multivariate analysis.
Overall mortality and long-term survival in patients with HGD treated with PDT appears to be comparable to that of patients treated with esophagectomy.
PMCID: PMC2646409  PMID: 17408660
15.  Photodynamic Therapy with 5-Aminolevulinic acid (ALA) Impairs Tumor Initiating and Chemo-Resistance Property in Head and Neck Cancer-Derived Cancer Stem Cells 
PLoS ONE  2014;9(1):e87129.
Head and neck cancer (HNC) ranks the fourth leading malignancy and cancer death in male population in Taiwan. Despite recent therapeutic advances, the prognosis for HNC patients is still dismal. New strategies are urgently needed to improve the chemosensitization to conventional chemotherapeutic drugs and clinical responses of HNC patients. Studies have demonstrated that topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is being used in the treatment of various human premalignant and malignant lesions with some encouraging clinical outcomes. However, the molecular mechanisms of ALA-PDT in the therapeutic effect in HNC tumorigenesis and whether ALA-PDT as chemosensitizer for HNC treatment remain unclear. Accumulating data support cancer stem cells (CSCs) contributes chemo-resistance in HNC. Based on the previous studies, the purpose of the study is to investigate the effect of ALA-PDT on CSCs and chemosensitization property in HNC.
Methodology/Principal Finding
CSCs marker ALDH1 activity of HNC cells with ALA-PDT treatment as assessed by the Aldefluor assay flow cytometry analysis. Secondary Sphere-forming self-renewal, stemness markers expression, and invasiveness of HNC-CSCs with ALA-PDT treatment were presented. We observed that the treatment of ALA-PDT significantly down-regulated the ALDH1 activity and CD44 positivity of HNC-CSCs. Moreover, ALA-PDT reduced self-renewal property and stemness signatures expression (Oct4 and Nanog) in sphere-forming HNC-CSCs. ALA-PDT sensitized highly tumorigenic HNC-CSCs to conventional chemotherapies. Lastly, synergistic effect of ALA-PDT and Cisplatin treatment attenuated invasiveness/colongenicity property in HNC-CSCs.
Our results provide insights into the clinical prospect of ALA-PDT as a potential chemo-adjuvant therapy against head and neck cancer through eliminating CSCs property.
PMCID: PMC3901774  PMID: 24475244
16.  Phase I study of photodynamic therapy using talaporfin sodium and diode laser for local failure after chemoradiotherapy for esophageal cancer 
Photodynamic therapy (PDT) is a less invasive and effective salvage treatment for local failure after chemoradiotherapy (CRT) for esophageal cancer, however it causes a high rate of skin phototoxicity and requires a long sun shade period. Talaporfin sodium is a rapidly cleared photosensitizer that is expected to have less phototoxicity. This study was undertaken to clarify the optimum laser fluence rate of PDT using talaporfin sodium and a diode laser for patients with local failure after CRT or radiotherapy (RT) for esophageal cancer.
This phase I, laser dose escalation study used a fixed dose (40 mg/m2) of intravenous talaporfin sodium administered 4 to 6 hours before irradiation in patients with local failure limited to T2 after CRT or RT (≥ 50 Gy). The primary endpoint was to assess the dose limiting toxicity (DLT) of PDT, and the secondary endpoints were to evaluate the adverse events and toxicity related to PDT. The starting fluence of the 664 nm diode laser was 50 J/cm2, with an escalation plan to 75 J/cm2 and 100 J/cm2.
9 patients with local failure after CRT or RT for ESCC were enrolled and treated in groups of 3 individuals to the third fluence level. No DLT was observed at any fluence level. Phototoxicity was not observed, but one subject had grade 1 fever, three had grade 1 esophageal pain, and 1 had grade 1 dysphagia. Five of 9 patients (55.6%) achieved a complete response after PDT.
PDT using talaporfin sodium and a diode laser was safe for local failure after RT in patients with esophageal cancer. The recommended fluence for the following phase II study is 100 J/cm2.
PMCID: PMC3410784  PMID: 22824179
Photodynamic therapy; Esophageal cancer; Talaporfin sodium; Salvage treatment; Phase I study
17.  Photodynamic Therapy With YAG-OPO Laser for Early Stage Lung Cancer 
Photodynamic therapy (PDT) utilizing Photofrin is proving to be effective for the treatment of early stage lung cancers. The effect of PDT utilizing YAG-OPO laser as new light source was evaluated in 26 patients (29 lesions) with early stage lung cancers. YAG-OPO laser is solid state tunable laser which is easy to change wavelength between 620 and 670 nm exciting various kinds of photosensitizers. Moreover, YAG-OPO laser is more reliable, smaller and has less consumables than argon-dye laser or excimer-dye laser. As the result of PDT with YAG-OPO laser, complete remission (CR) was obtained in 82.6% of the 29 lesions, partial remission (PR) in 13.8% and no change (NC) was obtained in 3.4%. We conclude that PDT utilizing YAG-OPO laser is efficacious in the treatment of early stage lung cancers and can achieve complete remission.
PMCID: PMC2362591  PMID: 18493456
18.  Combined Benzoporphyrin Derivative Monoacid Ring A Photodynamic Therapy and Pulsed Dye Laser for Port Wine Stain Birthmarks 
Pulsed dye laser (PDL) is a commonly utilized treatment for port wine stain birthmarks (PWS) in the United States; however, results are variable and few patients achieve complete removal. Photodynamic therapy (PDT) is commonly used in China, but treatment associated photosensitivity lasts several weeks and scarring may occur. We propose an alternative treatment option, combined PDT+PDL and performed a proof-of-concept preliminary clinical trial.
Subjects with non-facial PWS were studied. Each subject had four test sites: control, PDL alone, PDT alone (benzoporphyrin derivative monoacid ring A photosensitizer with 576 nm light), and PDT+PDL. Radiant exposure time for PDT was increased in increments of 15 J/cm2. Authors evaluated photographs and chromametric measurements before and 12 weeks post-treatment.
No serious adverse events were reported; epidermal changes were mild and self-limited. No clinical blanching was noted in control or PDT-alone sites. At PDT radiant exposures of 15 and 30 J/cm2, equivalent purpura and blanching was observed at PDL and PDT+PDL sites. At PDT radiant exposures over 30 J/cm2, greater purpura was noted at PDT+PDL sites as compared to PDL alone. Starting at 75 J/cm2, improved blanching was noted at PDT+PDL sites.
Preliminary results indicate that PDT+PDL is safe and may offer improved PWS treatment efficacy. Additional studies are warranted.
PMCID: PMC2784424  PMID: 19932451
Port wine stain birthmarks; pulsed dye laser; photodynamic therapy; vascular birthmarks
19.  Photodynamic Therapy with the Phthalocyanine Photosensitizer Pc 4 
Toxicology and applied pharmacology  2007;224(3):290-299.
Photodynamic therapy (PDT) is emerging as a promising non-invasive treatment for cancers. PDT involves either local or systemic administration of a photosensitizing drug, which preferentially localizes within the tumor, followed by illumination of the involved organ with light, usually from a laser source. Here, we provide a selective overview of our experience with PDT at Case Western Reserve University, specifically with the silicon phthalocyanine photosensitizer Pc 4. We first review our in-vitro studies evaluating the mechanism of cell killing by Pc 4-PDT. Then we briefly describe our clinical experience in a Phase I trial of Pc 4-PDT and our preliminary translational studies evaluating the mechanisms behind tumor responses. Preclinical work identified (a) cardiolipin and the anti-apoptotic proteins Bcl-2 and Bcl-xL as targets of Pc 4-PDT, (b) the intrinsic pathway of apoptosis, with the key participation of caspase-3, as a central response of many human cancer cells to Pc 4-PDT, (c) signaling pathways that could modify apoptosis, and (d) a formulation by which Pc 4 could be applied topically to human skin and penetrate at least through the basal layer of the epidermis. Clinical-translational studies enabled us to develop an immunohistochemical assay for caspase-3 activation, using biopsies from patients treated with topical Pc 4 in a Phase I PDT trial for cutaneous T-cell lymphoma. Results suggest that this assay may be used as an early biomarker of clinical response.
PMCID: PMC2128784  PMID: 17397888
Photodynamic Therapy; silicon phthalocyanine; Pc 4; cutaneous T-cell lymphoma; apoptosis
20.  Photodynamic therapy for esophageal cancer 
Photodynamic therapy (PDT) is a treatment that uses a photosensitizing drug that is administered to the patient, localized to a tumor, and then activated with a laser to induce a photochemical reaction to destroy the cell. PDT using porfimer sodium followed by excimer dye laser irradiation is approved as a curative treatment for superficial esophageal cancer in Japan. While endoscopic submucosal dissection (ESD) is currently more popular for esophageal cancer, there is evidence to support PDT as an alternative treatment and as a salvage treatment for local failure after chemoradiotherapy (CRT). A photosensitizing agent has also been developed that requires a shorter sun shade period after administration, and studies are currently underway to establish an esophageal cancer indication for this next-generation PDT in Japan.
PMCID: PMC4200616  PMID: 25333005
Esophageal cancer; photodynamic therapy (PDT); salvage therapy
21.  Targeting EGFR with photodynamic therapy in combination with Erbitux enhances in vivo bladder tumor response 
Molecular Cancer  2009;8:94.
Photodynamic therapy (PDT) is a promising cancer treatment modality that involves the interaction of the photosensitizer, molecular oxygen and light of specific wavelength to destroy tumor cells. Treatment induced hypoxia is one of the main side effects of PDT and efforts are underway to optimize PDT protocols for improved efficacy. The aim of this study was to investigate the anti-tumor effects of PDT plus Erbitux, an angiogenesis inhibitor that targets epidermal growth factor receptor (EGFR), on human bladder cancer model. Tumor-bearing nude mice were assigned to four groups that included control, PDT, Erbitux and PDT plus Erbitux and tumor volume was charted over 90-day period.
Our results demonstrate that combination of Erbitux with PDT strongly inhibits tumor growth in the bladder tumor xenograft model when compared to the other groups. Downregulation of EGFR was detected using immunohistochemistry, immunofluorescence and western blotting. Increased apoptosis was associated with tumor inhibition in the combination therapy group. In addition, we identified the dephosphorylation of ErbB4 at tyrosine 1284 site to play a major role in tumor inhibition. Also, at the RNA level downregulation of EGFR target genes cyclin D1 and c-myc was observed in tumors treated with PDT plus Erbitux.
The combination therapy of PDT and Erbitux effectively inhibits tumor growth and is a promising therapeutic approach in the treatment of bladder tumors.
PMCID: PMC2777152  PMID: 19878607
22.  Utility of Biomarkers in Prediction of Response to Ablative Therapy in Barrett’s Esophagus 
Gastroenterology  2008;135(2):370-379.
Background & Aims
Photodynamic therapy (PDT) has been shown to be effective in the treatment of high-grade dysplasia (HGD)/mucosal carcinoma in Barrett’s esophagus (BE). Substantial proportions of patients do not respond to PDT or progress to carcinoma despite PDT. The role of biomarkers in predicting response to PDT is unknown. We aimed to determine if biomarkers known to be associated with neoplasia in BE can predict loss of dysplasia in patients treated with ablative therapy for HGD/intramucosal cancer.
Patients with BE and HGD/intramucosal cancer were studied prospectively from 2002 to 2006. Biomarkers were assessed using fluorescence in situ hybridization performed on cytology specimens, for region-specific and centromeric probes. Patients were treated with PDT using cylindric diffusing fibers (wavelength, 630 nm; energy, 200 J/cm fiber). Univariate and multiple variable logistic regression was performed to determine predictors of response to PDT.
A total of 126 consecutive patients (71 who underwent PDT and 55 patients who did not undergo PDT and were under surveillance, to adjust for the natural history of HGD), were included in this study. Fifty (40%) patients were responders (no dysplasia or carcinoma) at 3 months after PDT. On multiple variable analysis, P16 allelic loss (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.10 – 0.96) predicted decreased response to PDT. BE segment length (OR, 0.71; 95% CI, 0.59 – 0.85), and performance of PDT (OR, 7.17; 95% CI, 2.50 –20.53) were other independent predictors of loss of dysplasia.
p16 loss detected by fluorescence in situ hybridization can help predict loss of dysplasia in patients with BE and HGD/mucosal cancer. Biomarkers may help in the selection of appropriate therapy for patients and improve treatment outcomes.
PMCID: PMC3896328  PMID: 18538141
23.  Parameter Determination for Singlet Oxygen Modeling of BPD-Mediated PDT 
Photodynamic therapy (PDT) offers a cancer treatment modality capable of providing minimally invasive localized tumor necrosis. To accurately predict PDT treatment outcome based on pre-treatment patient specific parameters, an explicit dosimetry model is used to calculate apparent reacted 1O2 concentration ([1O2]rx) at varied radial distances from the activating light source inserted into tumor tissue and apparent singlet oxygen threshold concentration for necrosis ([1O2]rx, sd) for type-II PDT photosensitizers. Inputs into the model include a number of photosensitizer independent parameters as well as photosensitizer specific photochemical parameters ξ, σ, and β. To determine the specific photochemical parameters of benzoporphyrin derivative monoacid A (BPD), mice were treated with BPD-PDT with varied light source strengths and treatment times. All photosensitizer independent inputs were assessed pre-treatment and average necrotic radius in treated tissue was determined post-treatment. Using the explicit dosimetry model, BPD specific ξ, σ, and β photochemical parameters were determined which estimated necrotic radii similar to those observed in initial BPD-PDT treated mice using an optimization algorithm that minimizes the difference between the model and that of the measurements. Photochemical parameters for BPD are compared with those of other known photosensitizers, such as Photofrin. The determination of these BPD specific photochemical parameters provides necessary data for predictive treatment outcome in clinical BPD-PDT using the explicit dosimetry model.
PMCID: PMC4437730  PMID: 25999644
Explicit Dosimetry; BPD; Photodynamic Therapy
24.  Cooperative Clinical Trial of Photodynamic Therapy for Early Gastric Cancer With Photofrin Injection® and YAG-OPO Laser 
Background and Objective: Photodynamic therapy (PDT) treats malignant tumors using photosensitizers and light. We employed a new pulse laser as the excitation light source for PDT, i.e. an optical parametric oscillator (OPO) system pumped by a Q-switched Nd:YAG laser, because it provides extremely high peak power.
Study Design/Materials and Methods: The effects of PDT using the photosensitizer Photofrin® and the new laser were evaluated in 12 patients with early gastric cancer.
Results: Complete responses (CR) were obtained in 75% of 12 assessable patients, CR was observed in all cases with mucosal carcinoma (response rate 100%).
Regarding toxicity, mild photosensitivity was seen in one case and it lasted several weeks. The other major side effect was decrease of total protein, which was observed in six patients (40%), lasting several months. There were no serious abnormalities in symptoms or laboratory tests.
Conclusion: We conclude that the YAG-OPO laser is suitable as an excitation light source for PDT.
PMCID: PMC2362606  PMID: 18493468
25.  Induction of Immune Mediators in Glioma and Prostate Cancer Cells by Non-Lethal Photodynamic Therapy 
PLoS ONE  2011;6(6):e21834.
Photodynamic therapy (PDT) uses the combination of photosensitizing drugs and harmless light to cause selective damage to tumor cells. PDT is therefore an option for focal therapy of localized disease or for otherwise unresectable tumors. In addition, there is increasing evidence that PDT can induce systemic anti-tumor immunity, supporting control of tumor cells, which were not eliminated by the primary treatment. However, the effect of non-lethal PDT on the behavior and malignant potential of tumor cells surviving PDT is molecularly not well defined.
Methodology/Principal Findings
Here we have evaluated changes in the transcriptome of human glioblastoma (U87, U373) and human (PC-3, DU145) and murine prostate cancer cells (TRAMP-C1, TRAMP-C2) after non-lethal PDT in vitro and in vivo using oligonucleotide microarray analyses. We found that the overall response was similar between the different cell lines and photosensitizers both in vitro and in vivo. The most prominently upregulated genes encoded proteins that belong to pathways activated by cellular stress or are involved in cell cycle arrest. This response was similar to the rescue response of tumor cells following high-dose PDT. In contrast, tumor cells dealing with non-lethal PDT were found to significantly upregulate a number of immune genes, which included the chemokine genes CXCL2, CXCL3 and IL8/CXCL8 as well as the genes for IL6 and its receptor IL6R, which can stimulate proinflammatory reactions, while IL6 and IL6R can also enhance tumor growth.
Our results indicate that PDT can support anti-tumor immune responses and is, therefore, a rational therapy even if tumor cells cannot be completely eliminated by primary phototoxic mechanisms alone. However, non-lethal PDT can also stimulate tumor growth-promoting autocrine loops, as seen by the upregulation of IL6 and its receptor. Thus the efficacy of PDT to treat tumors may be improved by controlling unwanted and potentially deleterious growth-stimulatory pathways.
PMCID: PMC3128096  PMID: 21738796

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