Standardized intraoperative 5-ALA photodynamic therapy for newly diagnosed glioblastoma patients: a preliminary analysis of the INDYGO clinical trial.

PURPOSE: Glioblastoma (GBM) is the most aggressive malignant primary brain tumor. The unfavorable prognosis despite maximal therapy relates to high propensity for recurrence. Thus, overall survival (OS) is quite limited and local failure remains the fundamental problem. Here, we present a safety and feasibility trial after treating GBM intraoperatively by photodynamic therapy (PDT) after 5-aminolevulinic acid (5-ALA) administration and maximal resection. METHODS: Ten patients with newly diagnosed GBM were enrolled and treated between May 2017 and June 2018. The standardized therapeutic approach included maximal resection (near total or gross total tumor resection (GTR)) guided by 5-ALA fluorescence-guided surgery (FGS), followed by intraoperative PDT. Postoperatively, patients underwent adjuvant therapy (Stupp protocol). Follow-up included clinical examinations and brain MR imaging was performed every 3 months until tumor progression and/or death. RESULTS: There were no unacceptable or unexpected toxicities or serious adverse effects. At the time of the interim analysis, the actuarial 12-months progression-free survival (PFS) rate was 60% (median 17.1 months), and the actuarial 12-months OS rate was 80% (median 23.1 months). CONCLUSIONS: This trial assessed the feasibility and the safety of intraoperative 5-ALA PDT as a novel approach for treating GBM after maximal tumor resection. The current standard of care remains microsurgical resection whenever feasible, followed by adjuvant therapy (Stupp protocol). We postulate that PDT delivered immediately after resection as an add-on therapy of this primary brain cancer is safe and may help to decrease the recurrence risk by targeting residual tumor cells in the resection cavity. Trial registration NCT number: NCT03048240. EudraCT number: 2016-002706-39.

Protective STA-MCA bypass to prevent brain ischemia during high-flow bypass surgery: case series of 10 patients.

BACKGROUND: High-flow extracranial-intracranial bypass is associated with a significant risk of ischemic stroke. The goal of this study is to evaluate the effectiveness of STA-MCA bypass preceding a high-flow bypass as a means of protecting the brain from ischemia during the high-flow bypass anastomosis in patients with otherwise untreatable aneurysms. MATERIALS AND METHOD: This prospective study included 10 consecutive patients treated for complex/giant aneurysm using a previous combined STA-MCA bypass and high-flow EC-IC bypass between June 2016 and January 2018 when classical endovascular or microsurgical exclusion was estimated too risky. Early cranial Doppler, MRI, CT scan, and conventional angiography were performed in each patient to confirm patency of bypasses, measure flow in the anastomoses, detect any ischemic lesions, and evaluate exclusion of the aneurysm. RESULTS: The mean age at treatment was 55 years (range 34 to 67). The mean time of microsurgical procedure was 11 h (range 9 to 12). In all patients, the high-flow bypass was patent intraoperatively and complete occlusion of aneurysm was obtained. No ischemic lesions were noted on early MRI. One patient died from a large hemispheric infarction related to a common carotid artery dissection 10 days after the microsurgical procedure and immediate postoperative epidural hematoma was noted in one other patient. CONCLUSION: In this study, we described the use of a protective STA-MCA bypass, performed prior to the high-flow bypass, in order to reduce the risk of perioperative ischemic lesions without increasing the morbidity of the surgical procedure. This treatment paradigm was feasible in all ten patients without complications related to the STA-MCA anastomosis.

Photodynamic therapy for glioblastoma: A preliminary approach for practical application of light propagation models.

PURPOSE: Photodynamic therapy (PDT) is a promising treatment modality to be added in the management of glioblastoma multiforme (GBM). Light distribution modeling is required for planning and optimizing PDT. Several models have been developed to predict the light propagation inside biological tissues. In the present study, two analytical methods of light propagation emitted from a cylindrical fiber source were evaluated: a discrete and a continuous method. METHODS: The two analytical approaches were compared according to their fluence rate results. Several cylindrical diffuse lengths were evaluated, and the relative deviation in the fluence rates was estimated. Moreover, a sensitivity analysis was conducted to compute the variance of each analytical model. RESULTS: The discrete method provided fluence rate estimations closer to the Monte-Carlo simulations than the continuous method. The sensitivity study results did not reveal significant differences between the variance of the two analytical models. CONCLUSIONS: Although the discrete model provides relevant light distribution, the heterogeneity of GBM tissues was not considered. With the improvement in parallel computing that drastically decreased the computing time, replacing the analytical model by a Monte-Carlo GPU-accelerated code appeared relevant to the GBM case. Nonetheless, the analytical modeling may still function in the optimization algorithms, which might be used in the Photodynamic treatment planning system. Lasers Surg. Med. 50:523-534, 2018. © 2017 Wiley Periodicals, Inc.

MRI assessment of treatment delivery for interstitial photodynamic therapy of high-grade glioma in a preclinical model.

BACKGROUND: High-grade gliomas are primary brain tumors that have shown increasing incidence and unfavorable outcomes. Local control is crucial to the management of this pathology. Photodynamic therapy (PDT), based on the light-induced activation of a photosensitizer (PS), achieves local treatment by inducing selective lesions in tumor tissue. OBJECTIVES: Previous studies have reported the outcomes of PDT for glioblastoma via immunohistological data. Our study aimed to evaluate MRI findings, including diffusion, and perfusion sequences, compared with immunohistological data from the same population to address the efficiency of light fractionation. MATERIALS AND METHODS: Twenty-six "nude" rats grafted with human U87 cells into the right putamen underwent PDT. After PS precursor (5-ALA) intake, an optical fiber was introduced into the tumor. The rats were randomized into the following groups: those without illumination and those that received two or five fractions of light. Treatment effects were assessed with early high-field MRI to measure the volume of necrosis and edema using diffusion and perfusion sequences; the MRI results were compared with immunohistology results, including necrosis and apoptosis markers. RESULTS: Elevated diffusion values were observed on MRI in the centers of the tumors of the treated animals, especially in the 5-fraction group (P < 0.01). Perfusion was decreased around the treatment site, especially in the 5-fraction group (P = 0.024). The MRI findings were consistent with previously published histological data. The median volume of necrosis was significantly different between the sham group and treated groups, 0 mm3 versus 2.67 mm3 , P < 0.001. The same trend was previously observed in histology data when grading the absence or presence of necrosis and when the presence of necrosis was significantly more predominant for the treated group than for the untreated group (P < 001). Additionally, cell death represented by apoptosis marker data (TUNEL method) was significantly higher in the 5-fraction group than in the 2-fraction group (P = 0.01). CONCLUSION: Diffusion and perfusion MRI revealed histological lesions. Interstitial PDT (iPDT) induced specific lesions in the tumor tissue, which were observed with MRI and confirmed by histopathological analysis. Thus, MRI may provide a non-invasive and reliable tool to assess treatment outcomes after PDT. Lasers Surg. Med. 50:460-468, 2018. © 2017 Wiley Periodicals, Inc.

A novel device for intraoperative photodynamic therapy dedicated to glioblastoma treatment.

AIM: Photodynamic therapy (PDT) appears to be a valuable new treatment modality for cancer therapy. Studies have reported successful application of PDT for glioblastoma. Here, we introduce a new device dedicated to intraoperative PDT delivered early after fluoro-guided resection combined with a transfer function that determines the treatment time based on the size of the surgical resection cavity. MATERIALS & METHODS: First, we describe the device, which is composed of a trocar, a balloon filled with a diffusing solution, and a fiber guide in which a cylindrical light diffuser is inserted. Ex vivo experiments were performed to measure the fluence rate inside biological tissues. A calibration factor was defined to convert power measurements into fluence rate values. Calf brains were used to simulate light propagation in human brain tissue, and the photosensitizer administration effect on optical properties was discussed. The temperature elevation during illumination was evaluated. RESULTS: Light power was measured in tissues surrounding the device during ex vivo experiments. Using the previously characterized calibration factor, power measurements were converted to fluence rate values to obtain the transfer function. No thermal elevation was observed during a 2-h temperature test, and the impact of protoporphyrin IX on brain optical properties was considered negligible. CONCLUSION: A discussion of experimental precision is presented. The light duration determined by the abacus had a standard deviation of <1 min. This value is weak compared with the total illumination time necessary to treat one patient. The main advantage of our device lies in its straightforward implementation of intraoperative PDT for neurosurgery with acceptable dosimetry and easy treatment time.

Interstitial photodynamic therapy and glioblastoma: Light fractionation in a preclinical model.

BACKGROUND: Glioblastoma is a high-grade cerebral tumor with local recurrence and poor outcome. Photodynamic therapy (PDT) is a localized treatment based on the light activation of a photosensitizer (PS) in the presence of oxygen, which results in the formation of cytotoxic species. The delivery of fractionated light may enhance treatment efficacy by reoxygenating tissues. OBJECTIVE: To evaluate the efficiency of two light-fractionation schemes using immunohistological data. MATERIALS AND METHODS: Human U87 cells were grafted into the right putamen of 39 nude rats. After PS precursor intake (5-ALA), an optic fiber was introduced into the tumor. The rats were randomly divided into three groups: without light, with light split into 2 fractions and with light split into 5 fractions. Treatment effects were assessed using brain immunohistology. RESULTS: Fractionated treatments induced intratumoral necrosis (P < 0.001) and peritumoral edema (P = 0.009) associated with a macrophagic infiltration (P = 0.006). The ratio of apoptotic cells was higher in the 5-fraction group than in either the sham (P = 0.024) or 2-fraction group (P = 0.01). Peripheral vascularization increased after treatment (P = 0.017), and these likely new vessels were more frequently observed in the 5-fraction group (P = 0.028). CONCLUSION: Interstitial PDT with fractionated light resulted in specific tumoral lesions. The 5-fraction scheme induced more apoptosis but led to greater peripheral neovascularization. Lasers Surg. Med. 49:506-515, 2017. © 2016 Wiley Periodicals, Inc.

Fluorescence guided resection and glioblastoma in 2015: A review.

High-grade gliomas represent a widely heterogeneous group of tumors, the most frequent of which is glioblastoma multiforme. Its annual incidence has risen over the last decades, particularly amongst elderly people. The actual standards of care allow for a 15-month median survival rate for WHO grade IV gliomas. As recurrence occurs in more than 85% of patients at the surgical margins, the initial resection extent is a cornerstone of disease control. Fluorescence guided resection (FGR) aims at increasing complete resections and, thus, local control. This technique uses 5-aminolevulinic acid (5-ALA), a natural intermediate substance in the heme-porphyrin biosynthesis pathway, and a protoporphyrin IX (PpIX) precursor. PpIX is fluorescent under blue light exposure. Recent studies reported a significant increase in complete resections using FGR, which were associated with prolonged progression free survival, fewer reinterventions, and delayed neurological deterioration. Here, we depict the principles of this surgical technique, its actual outcomes, and future developments.

A Warp-Knitted Light-Emitting Fabric-Based Device for In Vitro Photodynamic Therapy: Description, Characterization, and Application on Human Cancer Cell Lines.

Photodynamic therapy (PDT) appears to be a promising strategy in biomedical applications. However, the complexity of its parameters prevents wide acceptance. This work presents and characterizes a novel optical device based on knitted light-emitting fabrics and dedicated to in vitro PDT involving low irradiance over a long illumination period. Technical characterization of this device, called CELL-LEF, is performed. A cytotoxic study of 5-ALA-mediated PDT on human cancer cell lines is provided as a proof of concept. The target of delivering an irradiance of 1 mW/cm2 over 750 cm2 is achieved (mean: 0.99 mW/cm2; standard deviation: 0.13 mW/cm2). The device can maintain a stable temperature with the mean thermal distribution of 35.1 °C (min: 30.7 °C; max: 38.4 °C). In vitro outcomes show that 5-ALA PDT using CELL-LEF consistently and effectively induced a decrease in tumor cell viability: Almost all the HepG2 cells died after 80 min of illumination, while less than 60% of U87 cell viability remained. CELL-LEF is suitable for in vitro PDT involving low irradiance over a long illumination period.

Pre-therapy 18F-FDG PET quantitative parameters help in predicting the response to radioimmunotherapy in non-Hodgkin lymphoma.

PURPOSE: Radioimmunotherapy (RIT) is a new treatment option for patients with non-Hodgkin lymphoma (NHL). Response to RIT currently remains difficult to predict using conventional prognostic factors and could be refined using functional imaging. The goal of this work is to evaluate the value of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in predicting response to Yttrium 90-labeled monoclonal antibodies for patients with NHL. METHODS: Thirty-five patients with NHL who had undergone (18)F-FDG PET prior to RIT with either (90)Y-ibritumomab tiuxetan (group A; n = 17) or (90)Y-epratuzumab tetraxetan (group B; n = 18) were included in this retrospective study. Four functional criteria were determined for each tumour lesion in a given patient: maximum and mean standard uptake values (SUVmax and SUVmean), functional lesion volume (LVol) and total lesion glycolysis (TLG, product of the volume and the SUVmean). For each patient, we determined highest SUVmax and SUVmean, cumulative TLG (TLGcum) and sum of all LVol (TVol) and compared their predictive value on response (complete or partial response according to IWC) to RIT with those of conventional prognostic factors in group A and B. RESULTS: A total of 154 lesions were analysed. Nineteen patients (54%) responded to RIT according to IWC. In group A, response rate was 54, 75 and 75% in patients with a SUV max <20 g/ml, a TVol <100 ml and a TLGcum <1060 g, respectively while no patient above these thresholds responded (p < 0.005). In group B, the response rate was 93% for with SUVmax <15 g/ml while no patient above this threshold responded. With TLGcum below 1,360 g, 100% of the patient responded, compared with 37% of patients whose TLGcum was above this threshold (p < 0.05). By contrast, conventional prognostic factors failed to predict response. CONCLUSIONS: Our preliminary results indicate that pre-therapy (18)F-FDG PET functional parameters such as SUVmax and TLG may help predicting more accurately response to single agent Y90 based RIT.

Biologically effective dose and prediction of obliteration of unruptured arteriovenous malformations treated by upfront Gamma Knife radiosurgery: a series of 149 consecutive cases.

OBJECTIVE: Arteriovenous malformations (AVMs) present no pathologic tissue, and radiation dose is confined in a clear targeted volume. The authors retrospectively evaluated the role of the biologically effective dose (BED) after Gamma Knife radiosurgery (GKRS) for brain AVMs. METHODS: A total of 149 consecutive cases of unruptured AVMs treated by upfront GKRS in Lille University Hospital, France, were included. The mean length of follow-up was 52.9 months (median 48, range 12-154 months). The primary outcome was obliteration, and the secondary outcome was complication appearance. The marginal dose was 24 Gy in a vast majority of cases (n = 115, 77.2%; range 18-25 Gy). The mean BED was 220.1 Gy2.47 (median 229.9, range 106.7-246.8 Gy2.47). The mean beam-on time was 32.3 minutes (median 30.8, range 9-138.7 minutes). In the present series, the mean radiation dose rate was 2.259 Gy/min (median 2.176, range 1.313-3.665 Gy/min). The Virginia score was 0 in 29 (19.5%), 1 in 61 (40.9%), 2 in 41 (27.5%), 3 in 18 (12.1%), and 4 in 0 (0%) patients, respectively. The mean Pollock-Flickinger score was 1.11 (median 1.52, range 0.4-2.9). Univariate (for obliteration and complication appearance) and multivariate (for obliteration only) analyses were performed. RESULTS: A total of 104 AVMs (69.8%) were obliterated at the last follow-up. The strongest predictor for obliteration was BED (p = 0.03). A radiosurgical obliteration score is proposed, derived from a fitted multivariable model: (0.018 × BED) + (1.58 × V12) + (-0.013689 × beam-on time) + (0.021 × age) - 4.38. The area under the receiver operating characteristic curve was 0.7438; after internal validation using bootstrap methods, it was 0.7088. No statistically significant relationship between radiation dose rate and obliteration was found (p = 0.29). Twenty-eight (18.8%) patients developed complications after GKRS; 20 (13.4%) of these patients had transient adverse radiological effects (perilesional edema developed). Predictors for complication appearance were higher prescription isodose volume (p = 0.005) and 12-Gy isodose line volume (V12; p = 0.001), higher Pollock-Flickinger (p = 0.02) and Virginia scores (p = 0.003), and lower beam-on time (p = 0.03). CONCLUSIONS: The BED was the strongest predictor of obliteration of unruptured AVMs after upfront GKRS. A radiosurgical score comprising the BED is proposed. The V12 appears as a predictor for both efficacy and toxicity. Beam-on time was illustrated as statistically significant for both obliteration and complication appearance. The radiation dose rate did not influence obliteration in the current analysis. The exact BED threshold remains to be established by further studies.

Evaluation and validation of the convolution algorithm for Leksell Gamma knife radiosurgery.

The new Leksell Gamma knife convolution algorithm requires evaluation prior to implementation in clinical practice. The superiority of this algorithm, which takes into account tissue electron densities, was evaluated using EBT3 GafChromicTM films within an anthropomorphic phantom. The CIRS anthropomorphic head phantom was chosen for its relevance to validate the convolution algorithm. Absolute dose and dose distributions were measured and compared with the outputs calculated from the Leksell Gamma Plan algorithms (TMR10 and the convolution algorithm). The measured absolute dose and the dose distributions in the homogeneous region of the anthropomorphic phantom were clearly in agreement with the dose distribution computed by the convolution algorithm. In a heterogeneous region where soft tissues contain a medium, such as aluminium, or an air gap, the measured dose profiles drastically changed, and only the convolution algorithm was able to correctly compute the dose to water in water. The convolution algorithm was able to take into account regions with high or very low electron densities such that the measured absolute dose was nearly equal to that computed by the convolution algorithm, with a common accepted dose measurement error of 2%.

Management of Patients with Renal Failure Undergoing Dialysis During 131I Therapy for Thyroid Cancer.

Radioactive iodine (131I) therapy may be used to treat thyroid cancer in end-stage renal disease patients who undergo hemodialysis. Because iodine uses predominantly renal clearance, treatment management in hemodialysis patients may be problematic, and no formal recommendations on hemodialysis currently exist. This work details our experience with treating thyroid cancer with iodine in chronic renal failure patients who require hemodialysis and details the dosimetry results obtained during treatment to ensure that the dose to the bone marrow (BM) was acceptable. Methods: We treated 6 patients in the metabolic radiotherapy unit after thyroid stimulation. Two hemodialysis sessions in the metabolic radiotherapy unit were performed at 42 and 90 h after radiopharmaceutical administration. BM toxicity was estimated with activity measurements from blood samples and with whole-body measurements that were regularly repeated during hospitalization and measured with a γ-counter. The patients underwent thyroid and hematologic monitoring to assess treatment efficacy and therapeutic toxicity in the short, medium, and long term. Results: Whole-body activity was reduced on average by 66.7% (range, 60.1%-71.5%) after the first dialysis session and by 53.3% (range, 30.4%-67.8%) after the second. The mean estimated total absorbed dose to the BM was 0.992 Gy for all patients (range, 0.431-2.323 Gy). We did not observe any significant hematologic toxicity, and the clinical, biologic, and ultrasound test results confirmed the success of ablative treatment for most patients. Conclusion: In hemodialysis patients with thyroid cancer, an 131I activity approximately 30% lower than the nominal dose appears to strike an appropriate balance between absence of BM toxicity and therapeutic efficacy. To avoid overirradiation, we recommend pretherapeutic dosimetry studies for metastatic patients to calculate the amount of activity to be administered. We also recommend dosimetry monitoring during the hemodialysis sessions performed after therapeutic dose administration and under the same conditions.

Parallelized Monte-Carlo dosimetry using graphics processing units to model cylindrical diffusers used in photodynamic therapy: From implementation to validation.

The Monte-Carlo method is the standard method for computing the dosimetry of both ionizing and non-ionizing radiation. Because this technique is highly time-consuming in conventional implementations, several improvements have recently been developed to speed-up simulations. Among the improvements, the use of graphics processing units (GPU) to parallelize algorithms provides a cost-efficient solution to accelerate the Monte-Carlo method. Parallel implementation of Monte-Carlo using GPU technology is described in the context of photodynamic therapy (PDT) dosimetry. This algorithm has been optimized to compute light emitted from optical fibers with cylindrical diffusers that are used in interstitial PDT applications. A comparison of the experimental measurements used to assess the results of the Monte-Carlo method is detailed. Illumination profiles of several commercially available diffusers are measured using an optical phantom that mimics the optical properties of the brain. Additionally, this Monte-Carlo method is compared to ex-vivo measurements made by a device dedicated to intraoperative PDT treatment of brain tumors. The results of the GPU Monte-Carlo validation are in accordance with the recommendations of the American Association of Physicists in Medicine. The acceleration obtained with the GPU implementation is in accordance with the literature and is sufficiently fast to be integrated in a treatment planning system dedicated to planning routine clinical interstitial PDT treatments.

INtraoperative photoDYnamic Therapy for GliOblastomas (INDYGO): Study Protocol for a Phase I Clinical Trial.

BACKGROUND: Glioblastoma (GBM) is characterized by marked proliferation, major infiltration, and poor prognosis. Despite current treatments, including surgery, radiation oncology, and chemotherapy, the overall median survival is 15 mo and the progression-free survival is 7 to 8 mo. Because of systematic relapse of the tumor, the improvement of local control remains an issue. In this context, photodynamic therapy (PDT) may offer a new treatment modality for GBM. OBJECTIVE: To assess the feasibility of intraoperative PDT early after surgical resection of GBM without unacceptable and unexpected toxicities. METHODS: The INDYGO clinical trial (INtraoperative photoDYnamic Therapy for GliOblastomas) treatment will be carried out in addition to the current standard of care (SOC) of glioblastoma: maximum resection surgery followed by concomitant radio-chemotherapy and adjuvant chemotherapy. PDT treatment will be delivered during surgery early, after the fluorescence-guided resection. Immunological responses and biomarkers will also be investigated during the follow-up. A total of 10 patients will be recruited during this study. EXPECTED OUTCOMES: Clinical follow-up after the SOC with PDT is expected to be similar (no significant difference) to the SOC alone. DISCUSSION: This INDYGO trial assesses the feasibility of intraoperative 5-aminolevulinic acid PDT, a novel seamless approach to treat GBM. The technology is easily embeddable within the reference treatment at a low-incremental cost. The safety of this new treatment modality is a preliminary requirement before a multicenter randomized clinical trial can be further conducted to assess local control improvement by treating infiltrating and nonresected GBM cells.

Comparison of different treatment schemes in 5-ALA interstitial photodynamic therapy for high-grade glioma in a preclinical model: An MRI study.

BACKGROUND: There is currently no therapy that prevents high-grade glioma recurrence. Thus, these primary brain tumors have unfavorable outcomes. Recently, 5-ALA photodynamic therapy (PDT) has been proposed to delay relapse and is highly expected to have potential synergistic effects with the current standard of care. However, PDT treatment delivery needs to be optimized by evaluating the impact of both the number of fractions and the light power used. OBJECTIVES: Previous studies have reported MRI examination-based outcomes for PDT in glioblastoma. Our study aimed to compare MRI markers across different treatment schemes that use interstitial PDT in high-grade glioma in a preclinical model. MATERIALS AND METHODS: Forty-eight "nude" rats were grafted with human U87 cells into the right putamen and subsequently submitted to interstitial PDT. The rats were randomized into six groups, including two different sham groups and four different treated groups (5 fractions at 5 mW or 30 mW and 2 fractions at 5 mW or 30 mW). After photosensitizer (PS) precursor (5-ALA) intake, an optical fiber was introduced into the tumor. Treatment effects were assessed with early high-field MRI to acquire T1 and T2 diffusion and perfusion images. RESULTS: There was no difference in the variation of the diffusion coefficient among the six groups (p = 0.0549, Kruskal-Wallis test). However, a significant difference was identified among the six groups in terms of variation in perfusion (p = 0.048, Kruskal-Wallis test), supporting a lesional effect in the treated groups. Additionally, the sham groups had significantly smaller edema volumes than were observed in the treated groups. Moreover, the 5-fraction group treated with 30 mW was associated with edema volumes that were significantly greater than those in the 5-fraction group treated with 5 mW (p = 0.019). CONCLUSION: Based on observations of MRI data and considering treatment effects, the 5-fraction group treated at 5 mW was not significantly different from the other treated groups in terms of cell deaths, characterized by diffusion imaging, or necrosis level. However, the significantly lower level of edema observed in this group indicated that this treatment scheme had limited toxicity.

Glossopharyngeal neuralgia treated by Gamma Knife radiosurgery: safety and efficacy through long-term follow-up.

OBJECTIVE Glossopharyngeal neuralgia (GPN) is a rare and disabling condition. Just as for trigeminal neuralgia, Gamma Knife radiosurgery (GKRS) is increasingly proposed as a therapeutic option for GPN. The purpose of this study was to assess long-term safety and efficacy of GKRS for this indication. METHODS From 2007 to 2015, 9 patients (4 male and 5 female) underwent a total of 10 GKRS procedures. All of the patients presented with GPN that was refractory to all medical treatment, and all had a long history of pain. One patient had previously undergone surgical microvascular decompression. In 5 cases, a neurovascular conflict had been identified on MRI. For the GKRS procedure, the glossopharyngeal nerve was localized on MRI and CT under stereotactic conditions. The target was located at the glossopharyngeal meatus of the jugular foramen. The dose administered to the nerve was 80 Gy in 3 procedures and 90 Gy in the others. Follow-up was planned for 3, 6, and 12 months after the procedure and annually thereafter. RESULTS Eight patients experienced an improvement in their pain. The median length of time from GKRS to symptom improvement in this group was 7 weeks (range 2-12 months). At the first follow-up, 6 patients were pain-free (pain intensity scores of I-III, based on an adaptation of the Barrow Neurological Institute scoring system for trigeminal neuralgia), including 4 patients who were also medication-free (I). One patient had partial improvement (IV) and 2 patients had no change. The mean duration of follow-up was 46 months (range 10-90 months). At the last follow-up 6 patients remained pain-free (pain scores of I-III), including 4 patients who were pain free with no medication (I). No side effect was observed. CONCLUSIONS Because of its safety and efficacy, GKRS appears to be a useful tool for treatment of GPN, including first-line treatment.

Automatic segmentation of pelvic structures from magnetic resonance images for prostate cancer radiotherapy.

PURPOSE: Target-volume and organ-at-risk delineation is a time-consuming task in radiotherapy planning. The development of automated segmentation tools remains problematic, because of pelvic organ shape variability. We evaluate a three-dimensional (3D), deformable-model approach and a seeded region-growing algorithm for automatic delineation of the prostate and organs-at-risk on magnetic resonance images. METHODS AND MATERIALS: Manual and automatic delineation were compared in 24 patients using a sagittal T2-weighted (T2-w) turbo spin echo (TSE) sequence and an axial T1-weighted (T1-w) 3D fast-field echo (FFE) or TSE sequence. For automatic prostate delineation, an organ model-based method was used. Prostates without seminal vesicles were delineated as the clinical target volume (CTV). For automatic bladder and rectum delineation, a seeded region-growing method was used. Manual contouring was considered the reference method. The following parameters were measured: volume ratio (Vr) (automatic/manual), volume overlap (Vo) (ratio of the volume of intersection to the volume of union; optimal value = 1), and correctly delineated volume (Vc) (percent ratio of the volume of intersection to the manually defined volume; optimal value = 100). RESULTS: For the CTV, the Vr, Vo, and Vc were 1.13 (+/-0.1 SD), 0.78 (+/-0.05 SD), and 94.75 (+/-3.3 SD), respectively. For the rectum, the Vr, Vo, and Vc were 0.97 (+/-0.1 SD), 0.78 (+/-0.06 SD), and 86.52 (+/-5 SD), respectively. For the bladder, the Vr, Vo, and Vc were 0.95 (+/-0.03 SD), 0.88 (+/-0.03 SD), and 91.29 (+/-3.1 SD), respectively. CONCLUSIONS: Our results show that the organ-model method is robust, and results in reproducible prostate segmentation with minor interactive corrections. For automatic bladder and rectum delineation, magnetic resonance imaging soft-tissue contrast enables the use of region-growing methods.

Intrinsic 2D/3D registration based on a hybrid approach: use in the radiosurgical imaging process.

During the latest years, numerous methods of multimodal image matching have been developed. Associated with medical imaging, these developments make it possible to match images using intrinsic data, as anatomical data, instead of external referential, as stereotactic frames. Thus, the use of intrinsic registration considerably increases possibilities in medical image analysis. Unfortunately, these techniques mostly remain in the research field and are rarely used in clinical daily practice. In this paper, we present a method for matching projective imaging (2D, radiography, angiography...) and tomographic imaging (3D, Magnetic Resonance Imaging, Computed Tomography). Furthermore, we propose a radiosurgical application for Arteriovenous Malformation (AVM). Radiosurgery planning for the treatment of AVM requires multiple image acquisitions in multimodality to define the irradiation target and to compute the dosimetry. All the planning images are acquired with a stereotactic frame. We describe in this paper the image registration technique that we propose to include diagnostic images in the planning process and the different steps required to validate our approach. In the current state, the results obtained do not enable us to replace the conventional technique due to the accuracy expected, but the analysis of the results shows that improvements of the protocol would make this application finally operational.

From MIP image to MRA segmentation using fuzzy set theory.

The aim of this paper is to describe a semi-automatic method of segmentation in magnetic resonance angiography (MRA). This method, based on fuzzy set theory, uses the information (gray levels) contained in the maximum intensity projection (MIP) image to segment the 3D vascular structure from slices. Tests have been carried out on vascular phantom and on clinical MRA images. This 3D segmentation method has proved to be satisfactory for the detection of vascular structures even for very complex shapes. Finally, this MIP-based approach is semi-automatic and produces a robust segmentation thanks to the contrast-to-noise ratio and to the slice profile which are taken into account to determine the membership of a voxel to the vascular structure.

Nuclear medicine for photodynamic therapy in cancer: Planning, monitoring and nuclear PDT.

Photodynamic therapy (PDT) is a modality with promising results for the treatment of various cancers. PDT is increasingly included in the standard of care for different pathologies. This therapy relies on the effects of light delivered to photosensitized cells. At different stages of delivery, PDT requires imaging to plan, evaluate and monitor treatment. The contribution of molecular imaging in this context is important and continues to increase. In this article, we review the contribution of nuclear medicine imaging in oncology to PDT for planning and therapeutic monitoring purposes. Several solutions have been proposed to plan PDT from nuclear medicine imaging. For instance, photosensitizer biodistribution has been evaluated with a radiolabeled photosensitizer or with conventional radiopharmaceuticals on positron emission tomography. The effects of PDT delivery have also been explored with specific SPECT or PET radiopharmaceuticals to evaluate the effects on cells (apoptosis, necrosis, proliferation, metabolism) or vascular damage. Finally, the synergy between photosensitizers and radiopharmaceuticals has been studied considering the Cerenkov effect to activate photosensitized cells.