talaporfin and Brain-Neoplasms

What is the current status of photodynamic therapy (PDT) with regard to treating malignant brain tumors? Despite several decades of effort, PDT has yet to achieve standard of care.. The questions we wish to answer are: where are we clinically with PDT, why is it not standard of care, and what is being done in clinical trials to get us there.. Rather than a meta-analysis or comprehensive review, our review focuses on who the major research groups are, what their approaches to the problem are, and how their results compare to standard of care. Secondary questions include what the effective depth of light penetration is, and how deep can we expect to kill tumor cells.. A measurable degree of necrosis is seen to a depth of about 5mm. Cavitary PDT with hematoporphyrin derivative (HpD) results are encouraging, but need an adequate Phase III trial. Talaporfin with cavitary light application appears promising, although only a small case series has been reported. Foscan for fluorescence guided resection (FGR) plus intraoperative cavitary PDT results were improved over controls, but are poor compared to other groups. 5-Aminolevulinic acid-FGR plus postop cavitary HpD PDT show improvement over controls, but the comparison to standard of care is still poor.. Continued research in PDT will determine whether the advances shown will mitigate morbidity and mortality, but certainly the potential for this modality to revolutionize the treatment of brain tumors remains. The various uses for PDT in clinical practice should be pursued.

Topics: Aminolevulinic Acid; Brain Neoplasms; Cell Death; Clinical Trials as Topic; Fluorescence; Hematoporphyrin Derivative; Humans; Infratentorial Neoplasms; Mesoporphyrins; Nitric Oxide; Photochemotherapy; Photosensitizing Agents; Porphyrins; Signal Transduction; Surgery, Computer-Assisted

The objective of the present study was to perform a prospective evaluation of the potential efficacy and safety of intraoperative photodynamic therapy (PDT) using talaporfin sodium and irradiation using a 664-nm semiconductor laser in patients with primary malignant parenchymal brain tumors.. In 27 patients with suspected newly diagnosed or recurrent primary malignant parenchymal brain tumors, a single intravenous injection of talaporfin sodium (40 mg/m(2)) was administered 1 day before resection of the neoplasm. The next day after completion of the tumor removal, the residual lesion and/or resection cavity were irradiated using a 664-nm semiconductor laser with a radiation power density of 150 mW/cm(2) and a radiation energy density of 27 J/cm(2). The procedure was performed 22-27 hours after drug administration. The study cohort included 22 patients with a histopathologically confirmed diagnosis of primary malignant parenchymal brain tumor. Thirteen of these neoplasms (59.1%) were newly diagnosed glioblastomas multiforme (GBM).. Among all 22 patients included in the study cohort, the 12-month overall survival (OS), 6-month progression-free survival (PFS), and 6-month local PFS rates after surgery and PDT were 95.5%, 91%, and 91%, respectively. Among patients with newly diagnosed GBMs, all these parameters were 100%. Side effects on the skin, which could be attributable to the administration of talaporfin sodium, were noted in 7.4% of patients and included rash (2 cases), blister (1 case), and erythema (1 case). Skin photosensitivity test results were relatively mild and fully disappeared within 15 days after administration of photosensitizer in all patients.. Intraoperative PDT using talaporfin sodium and a semiconductor laser may be considered as a potentially effective and sufficiently safe option for adjuvant management of primary malignant parenchymal brain tumors. The inclusion of intraoperative PDT in a combined treatment strategy may have a positive impact on OS and local tumor control, particularly in patients with newly diagnosed GBMs. Clinical trial registration no.: JMA-IIA00026 (https://dbcentre3.jmacct.med.or.jp/jmactr/App/JMACTRS06/JMACTRS06.aspx?seqno=862).

Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Female; Glioma; Humans; Laser Therapy; Lasers, Semiconductor; Male; Middle Aged; Photochemotherapy; Photosensitizing Agents; Porphyrins; Treatment Outcome

To investigate the safety and efficacy of photodynamic therapy (PDT) using talaporfin sodium in patients with surgically, completely unresectable malignant gliomas with invasion into the eloquent areas of the brain associated with language and motor functions.. Subjects consisted of consecutive 14 adult patients with malignant gliomas that were shown on preoperative diagnostic imaging to have invaded the eloquent areas of the brain. Of these, 6 patients had newly diagnosed tumors and 8 patients had recurrent tumors. In 15 craniotomy and tumor resection procedures, PDT was used as additional intraoperative treatment 24 h after 40 mg/m(2) of talaporfin sodium had been injected intravenously. After the tumor bulk had been resected as extensively as possible either 1 or 2 sites of probable tumor invasion in the bottom of resection cavity were irradiated superficially with a 664-nm diode laser for 180 s (27 J/cm(2)) at a power density of 150 mW/cm(2).. PDT achieved a response rate of 80% at the treated sites in the 6 patients with newly diagnosed malignant gliomas. In these patients, the median progression-free survival time was 23 months. The median survival time in 3 patients who died was 26 months, and the remaining 3 patients survived for more than 3 years with a good Karnofsky Performance Scale (KPS). In the 8 patients with recurrent tumors who received PDT, their response rate was low (25.0%), their gliomas recurred 3 months after PDT, and their survival time was only 9 months following PDT. No adverse events directly attributable to PDT occurred in any patients. Protection against light was only required for approximately 3 days after PDT.. We examined the safety and efficacy of PDT using talaporfin sodium as an additional intraoperative treatment for malignant glioma. PDT in addition to surgical resection achieved better therapeutic results than conventional protocols, especially in patients with newly diagnosed malignant gliomas. However, the current methodology has some limitations with respect to patients with recurrent tumors. Larger-scale studies are required to confirm the clinical feasibility of PDT plus surgery.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Brain Neoplasms; Female; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Photochemotherapy; Photosensitizing Agents; Pilot Projects; Porphyrins; Treatment Outcome

Pleomorphic xanthoastrocytoma (PXA) is categorized as grade II, other astrocytic tumors per the 2016 World Health Organization classification. Despite being a relatively benign type of tumor, PXA often has an aggressive clinical course. The more malignant form of PXA is now known as anaplastic pleomorphic xanthoastrocytoma (A-PXA) and is categorized as a grade III tumor. Clinical and genetic factors associated with malignant transformation remain unclear. In particular, typical genetic expression patterns in PXA and A-PXA remain unidentified.. We present a case of recurrent PXA in which malignant transformation followed a promoter mutation in TERT. In this case, genetic chronologic changes accompanying malignant transformation of PXA were thoroughly examined. The promoter mutation was detected in the second operative specimen after stereotactic radiosurgery (SRS) at the first tumor recurrence. Subsequently, a malignant transformation to the A-PXA occurred at the time of the second recurrence, and the tumor repeatedly recurred afterward.. TERT promotor mutations may contribute to the malignant transformation of PXA; the mechanism of this mutation is unknown, but it may have been caused by SRS. Therefore, improvident use of radiation should be avoided to prevent the malignant transformation of PXA.

Topics: Adult; Antineoplastic Agents, Alkylating; Astrocytoma; Brain Neoplasms; Cell Transformation, Neoplastic; Combined Modality Therapy; Cyclin-Dependent Kinase Inhibitor p15; Cytoreduction Surgical Procedures; DNA Mutational Analysis; DNA, Neoplasm; Female; Gene Deletion; Genes, p16; Humans; Mutation; Neoplasm Proteins; Neoplasm Recurrence, Local; Nimustine; Photochemotherapy; Porphyrins; Promoter Regions, Genetic; Proto-Oncogene Proteins B-raf; Radiosurgery; Reoperation; Telomerase; Temporal Lobe

Photodynamic therapy (PDT) induces selective cell death of neoplastic tissue and connecting vasculature by combining photosensitizers with light. We have previously reported that PDT induces apoptotic cell death in glioma cells when the photosensitizer talaporfin sodium (NPe6) is used. Here, we investigated the combined effect of NPe6-PDT with temozolomide, a DNA-alkylating drug used in glioma therapy.. Human glioblastoma T98G cells and human glioma U251 cells were used as glioma cells. Cell viability was evaluated by WST-8 assay. Apoptosis was evaluated by measurement of caspase-3 activity and DNA-fragmentation. Intracellular reactive oxygen species were evaluated by dihydrorhodamine assay.. While the degree of NPe6-PDT induced cell death unchanged in T98G and U251 cells when temozolomide treatment was adjuvant, it was dose-dependently increased by concomitant treatment with temozolomide. Further, concomitantly administered temozolomide dose-dependently increased caspase-3 activity and DNA-fragmentation, while adjuvant-temozolomide did not. These results are suggesting that concomitantly administered temozolomide potentiates the effect of NPe6-PDT to facilitate apoptotic cell death. Additionally, concomitantly administered temozolomide increased intracellular NPe6-fluorescence and reactive oxygen species, suggesting that the augmentation effect of combined treatment may be due to increased intracellular accumulation of NPe6.. These results suggest that concomitant treatment with NPe6-PDT and temozolomide is a potentially useful therapy for glioma.

Topics: Antineoplastic Agents, Alkylating; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Dacarbazine; Drug Therapy, Combination; Glioma; Humans; Photochemotherapy; Photosensitizing Agents; Porphyrins; Temozolomide; Treatment Outcome

Photodynamic therapy (PDT) induces selective cell death of neoplastic tissue and connecting vasculature by combining photosensitizers with light. Here we clarified the types of cell death induced by PDT in combination with the photosensitizer talaporfin sodium (mono-L-aspartyl chlorine e6, NPe6) in order to evaluate the potential of this therapy as a treatment for glioma. PDT with NPe6 (NPe6-PDT) induces dose-dependent cell death in human glioblastoma T98G cells. Specifically, cell death modalities were observed in NPe6-PDT treated T98G cells, including signs of apoptosis (activation of caspase-3, expression of phosphatidylserine, and DNA fragmentation) and necrosis (stainability of propidium iodide). In addition, high doses of NPe6-PDT decreased the proportion of apoptotic cell death, while increasing necrosis. Closer examination of apoptotic characteristics revealed release of cytochrome-c from mitochondria as well as activation of both caspse-9 and caspase-3 in cells treated with low doses of NPe6-PDT. Benziloxycarbonyl-Leu-Gln(OMe)-His-Asp(OMe)-fluoromethyl-ketone (Z-LEHD-fmk), a caspase-9 specific inhibitor, and benziloxycarbonyl-Asp(OMe)-Gln-Met-Asp(OMe)-fluoromethyl-ketone (Z-DQMD-fmk), a caspase-3 specific inhibitor, showed dose-dependent prevention of cell death in NPe6-PDT treated cells, indicating that mitochondrial apoptotic pathway was a factor in the observed cell death. Further, the cell morphology was observed after PDT. Time- and NPe6-dose dependent necrotic features were increased in NPe6-PDT treated cells. These results suggest that NPe6-PDT could be an effective treatment for glioma if used in mild doses to avoid the increased necrosis that may induce undesirable obstacles.

Topics: Antineoplastic Agents; Brain Neoplasms; Caspase 3; Cell Death; Cell Line, Tumor; Cytochromes c; DNA Fragmentation; Glioma; Humans; Mitochondria; Necrosis; Photochemotherapy; Photosensitizing Agents; Porphyrins

We aimed to clarify the optimal timing for the fluorescence imaging of brain tumor tissue differentiated from brain edema after the administration of photosensitizers.. We have performed an in vivo study of the kinetics of 5-aminolevulinic acid (5-ALA) in comparison with talaporfin sodium using the rat brain tumor model and rat vasogenic edema model produced by cold injury. The in vivo kinetics of 5-ALA and talaporfin sodium in brain tumor model and the vasogenic edema model was determined by a fluorescence macroscope and a microplate reader.. The in vivo kinetic study of 5-ALA showed mild fluorescence intensity of protoporphyrin IX (PpIX) in brain tumor differentiated from vasogenic edema. The mean lesion-to-normal-brain ratio (L/N ratio) in the group of brain tumor model 2h after the administration of 5-ALA was 7.78+/-4.61, which was significantly higher (P<0.01) than that of the vasogenic edema 2h after the administration of 5-ALA (2.75+/-1.12). In vivo kinetic study of talaporfin sodium showed high fluorescence intensity and retention in brain tumor differentiated from vasogenic edema. The mean L/N ratio of the fluorescence intensity in the group of brain tumor model 12h after the administration of talaporfin sodium was 23.1+/-11.9, which was significantly higher (P<0.01) than that of the vasogenic edema 12h after the administration (8.93+/-8.03).. The optimization of fluorescence imaging of brain tumors differentiated from brain edema is possible in the case of 5-ALA within 6h, and also possible in the case of talaporfin sodium beyond 12h.

Topics: Aminolevulinic Acid; Animals; Brain; Brain Edema; Brain Neoplasms; Diagnosis, Differential; Image Enhancement; Kinetics; Metabolic Clearance Rate; Microscopy, Fluorescence; Photosensitizing Agents; Porphyrins; Rats; Rats, Wistar

The objective of the study was to investigate the potential of mono-L-aspartyl chlorine e6 (NPe6), a water-soluble photosensitizer derived from chlorophyll, for use in photodynamic diagnosis (PDD) of malignant brain tumor. A C6 glioma cell line was transplanted in the SD rat brain to create a brain tumor model. Five days after transplantation, NPe6 was administrated via the tail vein at concentrations ranging from 1.25 to 10 mg/kg; then the skull was opened in the rat brain, the site of tumor transplant was irradiated with a diode laser beam at 664 nm, and the time-course intensity and distribution of emerging fluorescence were observed. Furthermore, the correlation between fluorescence distribution and histopathological findings was investigated in the removed brain. Fluorescence was observed in the site of brain tumor transplant from 5 min after injection, and stable fluorescence was recognized at the site until 4 h after administration. No differences were noted in fluorescence intensity at NPe6 doses of 2.5 mg/kg or more; therefore, it was possible to estimate the optimal dose range. Fluorescence distribution had a clear correlation with tumor cell density, and it was possible to capture the margin of tumor cell invasion with fluorescence. The photosensitizer NPe6 is capable of assessing tumor cell density in malignant glioma tissue in terms of differences in fluorescence intensity. The usefulness of PDD using 5-aminoleveulinic acid during surgery for malignant glioma has been recognized in recent years. The results of the present study suggested the potential of NPe6 as a promising photosensitizer for use in PDD for accurate grasp of the extent of removal during the course of malignant glioma surgery.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Glioma; Lasers; Male; Neoplasm Transplantation; Photosensitizing Agents; Porphyrins; Rats; Rats, Sprague-Dawley