Glioblastoma (GBM) has less than one-year survival rate due to local recurrence post treatment or growth of "left-over" residual disease post surgical resection. To personalize treatment strategies and reduce the rate of recurrence, it is important to develop imaging based therapeutic strategies and prediction markers to identify GBM recurrence. Given the role of the vasculature in tumor growth and survival, here we utilize multi-parametric ultrasound and photoacoustic imaging to validate if changes in vascular structure and function could be predictive of treatment response in patient- derived orthotopic Glioblastoma xenograft models. Patient-derived GBM cell lines were implanted in the brain of Swiss nu/nu mice. After the tumors reached 2-4 mm in diameter, the mice were divided into 4 groups namely – no treatment, surgical resection, therapy and surgical resection with therapy. Photodynamic therapy (PDT), a light based cytotoxic therapy, with photosensitizer Benzoporphyrin derivative (BPD) or FDA approved chemotherapy temozolomide were administered in the mice. Fujifilm VisualSonics LAZR system with a 20 MHz transducer was used to obtain power Doppler (%vascularity in tumors) and photoacoustic oxygen saturation (StO2) maps of the brain tumors at different time points pre and post treatment. The mice were either euthanized for immunofluorescence to validate the imaging markers or longitudinally monitored for tumor volume until moribund.The no-treatment group or the surgery only group did not have significant changes in vascular density or StO2. We observed a statistically significant decrease in StO2 immediately post BPD-PDT (primarily a vascular therapy) but not with temozolomide (a cellular therapy). Furthermore, we also observed that the sustenance of hypoxia or low StO2 in tumors for 24-72 hours can be a predictive biomarker for tumor recurrence. Overall, these results suggest the utility of ultrasound and photoacoustic imaging in monitoring treatment response and developing treatment prediction strategies for glioblastoma.
The purpose of this study is to describe a new technique for en bloc temporal bone resection using a diamond threadwire saw (T-saw) as an alternative to cutting the temporal bone with an osteotome. This technique has been performed in 10 patients with external auditory canal and middle ear cancers without any injury to the internal carotid artery or jugular vein. The authors conclude that the use of a diamond threadwire saw after transposing the internal carotid artery anteriorly is a safe, simple, and reliable technique for en bloc temporal bone resection.
Standard chemoradiation often enriches drug-resistant tumor cell populations that can lead to recurrent and treatment-refractory disease. Preclinical models of glioblastoma brain tumors, for instance, suggest that the cancer stem cell subpopulation becomes enriched and re-populates the tumor milieu following conventional therapies. Here, we show evidence that photodynamic therapy (PDT) is effective against several patient-derived glioblastoma stem cell cultures. Moreover, sub-lethal PDT results in re-sensitization of cancer stem cell phenotypes with induced drug-resistance to chemotherapy.
Abstract Glioblastoma stem cells (GSCs) are potent tumor initiators resistant to radiochemotherapy, and this subpopulation is hypothesized to re‐populate the tumor milieu due to selection following conventional therapies. Here, we show that 5‐aminolevulinic acid (ALA) treatment—a pro‐fluorophore used for fluorescence‐guided cancer surgery—leads to elevated levels of fluorophore conversion in patient‐derived GSC cultures, and subsequent red light‐activation induces apoptosis in both intrinsically temozolomide chemotherapy‐sensitive and ‐resistant GSC phenotypes. Red light irradiation of ALA‐treated cultures also exhibits the ability to target mesenchymal GSCs (Mes–GSCs) with induced temozolomide resistance. Furthermore, sub‐lethal light doses restore Mes–GSC sensitivity to temozolomide, abrogating GSC‐acquired chemoresistance. These results suggest that ALA is not only useful for fluorescence‐guided glioblastoma tumor resection, but that it also facilitates a GSC drug‐resistance agnostic, red light‐activated modality to mop up the surgical margins and prime subsequent chemotherapy.
Objective: Surgical eradication of malignant glioma cells is theoretically impossible. Therefore, reducing the number of remaining tumor cells around the brain-tumor interface (BTI) is crucial for achieving satisfactory clinical results. The usefulness of fluorescence-guided resection for the treatment of malignant glioma was recently reported, but the detection of infiltrating tumor cells in the BTI using a surgical microscope is not realistic. Therefore, we developed an intraoperative rapid fluorescence cytology system, and evaluated its clinical feasibility for the management of malignant glioma. Materials and methods: Twenty-five selected patients with malignant glioma (newly diagnosed: 17; recurrent: 8) underwent surgical resection under photodiagnosis using photosensitizer Talaporfin sodium and a semiconductor laser. Intraoperatively, a crush smear preparation was made from a tiny amount of tumor tissue, and the fluorescence emitted upon 620/660 nm excitation was evaluated rapidly using a compact fluorescence microscope in the operating theater. Results: Fluorescence intensities of tumor tissues measured using a surgical microscope correlated with the tumor cell densities of tissues evaluated by measuring the red fluorescence emitted from the cytoplasm of tumor cells using a fluorescence microscope. A “weak fluorescence” indicated a reduction in the tumor cell density, whereas “no fluorescence” did not indicate the complete eradication of the tumor cells, but indicated that few tumor cells were emitting fluorescence.Conclusion: The rapid intraoperative detection of fluorescence from glioma cells using a compact fluorescence microscope was a useful to evaluate the presence of tumor cells in the resection cavity walls, and provides surgical implications for the more complete resection of malignant gliomas.
