ORCID Profile
0000-0002-5080-5910
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Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.23999756
Abstract: TOLD MRI of patient receiving 0.17 mL/kg DDFPe pretreatment ( b A /b ) and posttreatment ( b B /b ) shows reversal of tumor hypoxia. T1 of tumor (mean ± SD) was 1,454 ± 75 ms preadministration of DDFPe and decreased to 1,281 ± 77 ms after treatment. NMR relaxation measurements before and after infusion of DDFPe ( b C /b ). NMR T1 measurements represent mean ± SD for the 4 patients encompassing tumor or contralateral normal brain imaged at 1.5 T. Baseline measurements (blue) were performed before administration of DDFPe, and postmeasurements (red) were made following intravenous administration of DDFPe, while patients breathed oxygen or carbogen following irradiation. Normal brain tissue showed no significant response ( i P /i = 0.70), while tumor showed significant change following administration of DDFPe and irradiation ( i P /i = 0.0059). Considering all measurements, tumor tissues had significantly longer T1 relaxation times than normal brain ( i P /i 0.0001). At baseline brain T1 was significantly shorter than tumor ( i P /i 0.0001) and this remained so after administering DDFPe ( i P /i = 0.0045).
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.CRC-22-0433
Abstract: Glioblastoma multiforme (GBM) is a hypoxic tumor resistant to radiotherapy. The purpose of this study was to assess the safety and efficacy of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM. In this multicenter phase Ib/II dose-escalation study, patients were administered DDFPe via intravenous infusion (0.05, 0.10, or 0.17 mL/kg) while breathing supplemental oxygen prior to each 2 Gy fraction of radiotherapy (30 fractions over 6 weeks). Patients also received standard-of-care chemotherapy [temozolomide (TMZ)]. Serial MRI scans were taken to monitor disease response. Adverse events were recorded and graded. TOLD (tissue oxygenation level–dependent) contrast MRI was obtained to validate modulation of tumor hypoxia. Eleven patients were enrolled. DDFPe combined with radiotherapy and TMZ was well tolerated in most patients. Two patients developed delayed grade 3 radiation necrosis during dose escalation, one each at 0.1 and 0.17 mL/kg of DDFPe. Subsequent patients were treated at the 0.1 mL/kg dose level. Kaplan–Meier analysis showed a median overall survival of 19.4 months and a median progression-free survival of 9.6 months, which compares favorably to historical controls. Among 6 patients evaluable for TOLD MRI, a statistically significant reduction in tumor T1 was observed after DDFPe treatment. This trial, although small, showed that the use of DDFPe as a radiosensitizer in patients with GBM was generally safe and may provide a survival benefit. This is also the first time than TOLD MRI has shown reversal of tumor hypoxia in a clinical trial in patients. The recommended dose for phase II evaluation is 0.1 mL/kg DDFPe. Trial Registration: NCT02189109 This study shows that DDFPe can be safely administered to patients, and it is the first-in-human study to show reversal of hypoxia in GBM as measured by TOLD MRI. This strategy is being used in a larger phase II/III trial which will hopefully show a survival benefit by adding DDFPe during the course of fractionated radiation and concurrent chemotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.23999759
Abstract: Swimmer plot for patients with GBM treated with DDFPe, radiotherapy, and TMZ, showing PD and survival in relation to tumor MGMT promoter methylation status (methylated indicated by dark gray bars and unmethylated by light gray bars) and IDH1 mutation status. WT, wild type IDH1 Mut, R132H IDH1 mutation present PD, progressive disease.
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.JOCN.2007.05.020
Abstract: The objective of this paper is to examine the efficacy and safety of hypofractionated stereotactic radiotherapy (SRT) in the treatment of skull base meningiomas. Thirty-eight patients were treated with a median prescribed dose of 37.5 Gy in 15 fractions to the 80% isodose. Median follow-up was 47 months. Ten males and 28 females of median age 55.5 years were followed. SRT was the primary treatment in 15 patients, adjuvant in 10 and given for recurrence in 14 patients. On clinical follow-up 27 patients are unchanged and in six their symptoms have resolved. One patient had symptomatic deterioration and four patients have developed new symptoms. No patients have radiological evidence of progression. Our data suggest that conventional hypofractionated radiotherapy schemes for benign CNS disease may be useful in conjunction with stereotactic techniques. Such schemes are attractive in terms of resource allocation and where tumour size or cranial nerve tolerance is of concern.
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.23999756.V1
Abstract: TOLD MRI of patient receiving 0.17 mL/kg DDFPe pretreatment ( b A /b ) and posttreatment ( b B /b ) shows reversal of tumor hypoxia. T1 of tumor (mean ± SD) was 1,454 ± 75 ms preadministration of DDFPe and decreased to 1,281 ± 77 ms after treatment. NMR relaxation measurements before and after infusion of DDFPe ( b C /b ). NMR T1 measurements represent mean ± SD for the 4 patients encompassing tumor or contralateral normal brain imaged at 1.5 T. Baseline measurements (blue) were performed before administration of DDFPe, and postmeasurements (red) were made following intravenous administration of DDFPe, while patients breathed oxygen or carbogen following irradiation. Normal brain tissue showed no significant response ( i P /i = 0.70), while tumor showed significant change following administration of DDFPe and irradiation ( i P /i = 0.0059). Considering all measurements, tumor tissues had significantly longer T1 relaxation times than normal brain ( i P /i 0.0001). At baseline brain T1 was significantly shorter than tumor ( i P /i 0.0001) and this remained so after administering DDFPe ( i P /i = 0.0045).
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.23999750.V1
Abstract: All-cause AEs of grade 2 or greater severity
Publisher: Wiley
Date: 27-11-2013
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.23999753.V1
Abstract: Baseline patient characteristics
Publisher: Elsevier BV
Date: 06-2012
Publisher: Elsevier BV
Date: 02-2014
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.23999750
Abstract: All-cause AEs of grade 2 or greater severity
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.23999762
Abstract: Kaplan–Meier analysis of PFS (left) and OS (right) for all 11 patients and for the 9 patients with IDHwt.
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.23999753
Abstract: Baseline patient characteristics
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.C.6760500.V1
Abstract: Purpose: Glioblastoma multiforme (GBM) is a hypoxic tumor resistant to radiotherapy. The purpose of this study was to assess the safety and efficacy of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM. Experimental Design: In this multicenter phase Ib/II dose-escalation study, patients were administered DDFPe via intravenous infusion (0.05, 0.10, or 0.17 mL/kg) while breathing supplemental oxygen prior to each 2 Gy fraction of radiotherapy (30 fractions over 6 weeks). Patients also received standard-of-care chemotherapy [temozolomide (TMZ)]. Serial MRI scans were taken to monitor disease response. Adverse events were recorded and graded. TOLD (tissue oxygenation level–dependent) contrast MRI was obtained to validate modulation of tumor hypoxia. Results: Eleven patients were enrolled. DDFPe combined with radiotherapy and TMZ was well tolerated in most patients. Two patients developed delayed grade 3 radiation necrosis during dose escalation, one each at 0.1 and 0.17 mL/kg of DDFPe. Subsequent patients were treated at the 0.1 mL/kg dose level. Kaplan–Meier analysis showed a median overall survival of 19.4 months and a median progression-free survival of 9.6 months, which compares favorably to historical controls. Among 6 patients evaluable for TOLD MRI, a statistically significant reduction in tumor T sub /sub was observed after DDFPe treatment. Conclusions: This trial, although small, showed that the use of DDFPe as a radiosensitizer in patients with GBM was generally safe and may provide a survival benefit. This is also the first time than TOLD MRI has shown reversal of tumor hypoxia in a clinical trial in patients. The recommended dose for phase II evaluation is 0.1 mL/kg DDFPe. Trial Registration: NCT02189109 Significance: This study shows that DDFPe can be safely administered to patients, and it is the first-in-human study to show reversal of hypoxia in GBM as measured by TOLD MRI. This strategy is being used in a larger phase II/III trial which will hopefully show a survival benefit by adding DDFPe during the course of fractionated radiation and concurrent chemotherapy. /
Publisher: IOP Publishing
Date: 24-03-2014
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.IJROBP.2005.12.002
Abstract: To investigate radiation necrosis in patients treated for glioma in terms of incidence, outcomes, predictive and prognostic factors. Records were reviewed for 426 patients followed up until death or for at least 3 years. Logistic regression analysis was performed to identify predictive and prognostic factors. Multivariate survival analysis was conducted using Cox proportional hazards regression. Separate analyses were performed for the subset of 352 patients who received a biologically effective dose (BED) > or =85.5 Gy2 (> or =45 Gy/25 fractions) who were at highest risk for radionecrosis. Twenty-one patients developed radionecrosis (4.9%). Actuarial incidence plateaued at 13.3% after 3 years. In the high-risk subset, radiation parameters confirmed as risk factors included total dose (p < 0.001), BED (p < 0.005), neuret (p < 0.001), fraction size (p = 0.028), and the product of total dose and fraction size (p = 0.001). No patient receiving a BED <96 Gy2 developed radionecrosis. Subsequent chemotherapy significantly increased the risk of cerebral necrosis (p = 0.001) even when adjusted for BED (odds ratio [OR], 5.8 95% confidence interval [CI], 1.6-20.3) or length of follow-up (OR, 5.4 95% CI, 1.5-19.3). Concurrent use of valproate appeared to delay the onset of necrosis (p = 0.013). The development of radionecrosis did not affect survival (p = 0.09). Cerebral necrosis is unlikely at doses below 50 Gy in 25 fractions. The risk increases significantly with increasing radiation dose, fraction size, and the subsequent administration of chemotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.C.6760500
Abstract: Purpose: Glioblastoma multiforme (GBM) is a hypoxic tumor resistant to radiotherapy. The purpose of this study was to assess the safety and efficacy of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM. Experimental Design: In this multicenter phase Ib/II dose-escalation study, patients were administered DDFPe via intravenous infusion (0.05, 0.10, or 0.17 mL/kg) while breathing supplemental oxygen prior to each 2 Gy fraction of radiotherapy (30 fractions over 6 weeks). Patients also received standard-of-care chemotherapy [temozolomide (TMZ)]. Serial MRI scans were taken to monitor disease response. Adverse events were recorded and graded. TOLD (tissue oxygenation level–dependent) contrast MRI was obtained to validate modulation of tumor hypoxia. Results: Eleven patients were enrolled. DDFPe combined with radiotherapy and TMZ was well tolerated in most patients. Two patients developed delayed grade 3 radiation necrosis during dose escalation, one each at 0.1 and 0.17 mL/kg of DDFPe. Subsequent patients were treated at the 0.1 mL/kg dose level. Kaplan–Meier analysis showed a median overall survival of 19.4 months and a median progression-free survival of 9.6 months, which compares favorably to historical controls. Among 6 patients evaluable for TOLD MRI, a statistically significant reduction in tumor T sub /sub was observed after DDFPe treatment. Conclusions: This trial, although small, showed that the use of DDFPe as a radiosensitizer in patients with GBM was generally safe and may provide a survival benefit. This is also the first time than TOLD MRI has shown reversal of tumor hypoxia in a clinical trial in patients. The recommended dose for phase II evaluation is 0.1 mL/kg DDFPe. Trial Registration: NCT02189109 Significance: This study shows that DDFPe can be safely administered to patients, and it is the first-in-human study to show reversal of hypoxia in GBM as measured by TOLD MRI. This strategy is being used in a larger phase II/III trial which will hopefully show a survival benefit by adding DDFPe during the course of fractionated radiation and concurrent chemotherapy. /
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.IJROBP.2007.08.046
Abstract: To compare intensity-modulated radiotherapy (IMRT) with three-dimensional conformal radiotherapy (3D-CRT) in terms of carcinogenic risk for actual clinical scenarios. Clinically equivalent IMRT plans were generated for prostate, breast, and head-and-neck cases treated with 3D-CRT. Two possible dose-response models for radiocarcinogenesis were generated based on A-bomb survivor data corrected for fractionation. Dose-volume histogram analysis was used to determine dose and its distribution to nontargeted tissues within the planning CT scan volume and thermoluminescent dosimetry for the rest of the body. Carcinogenic estimates were calculated with and without a correction factor accounting for cancer patients' advanced age and reduced longevity. For the model assuming a plateau in risk above 2-Gy single-fraction-equivalent (SFE), IMRT and 3D-CRT produced risks of 1.7% and 2.1%, respectively, for prostate 1.9% and 1.8%, respectively, for nasopharynx 1% each for tonsil and 1.4-2.2% and 1.5-1.6%, respectively, depending on technique, for breast. Assuming a reduction in risk above 2-Gy SFE, risks for IMRT and 3D-CRT were 1.1% and 1.5%, respectively, for prostate 1.4% and 1.2%, respectively, for nasopharynx 1% each for tonsil and 1.3-1.8% vs. 1.3-1.6%, respectively, for breast. Applying a correction factor of 0.5 for cancer patients halved these risks and their relative differences. Carcinogenic risks were comparable in absolute terms between modalities. Risks are dependant on technique used. Risks with IMRT are influenced by monitor unit demand and are therefore software/hardware dependant. The dose-response model accounting for cell killing at higher doses fitted best with actual observed risks.
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.23999762.V1
Abstract: Kaplan–Meier analysis of PFS (left) and OS (right) for all 11 patients and for the 9 patients with IDHwt.
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/2767-9764.23999759.V1
Abstract: Swimmer plot for patients with GBM treated with DDFPe, radiotherapy, and TMZ, showing PD and survival in relation to tumor MGMT promoter methylation status (methylated indicated by dark gray bars and unmethylated by light gray bars) and IDH1 mutation status. WT, wild type IDH1 Mut, R132H IDH1 mutation present PD, progressive disease.
Publisher: Elsevier BV
Date: 06-2009
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1016/J.IJROBP.2010.08.008
Abstract: To investigate differences in scatter and leakage between 6-MV intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3DCRT) to describe the relative contributions of internal patient scatter, collimator scatter, and head leakage and to discuss implications for second cancer induction. Dose was measured at increasing distances from the field edge in a water bath with a sloping wall (1) under full scatter conditions, (2) with the field edge abutting but outside the bath to prevent internal (water) scatter, and (3) with the beam aperture plugged to reflect leakage only. Internal patient scatter from IMRT is 11% lower than 3DCRT, but collimator scatter and head leakage are five and three times higher, respectively. Ultimately, total scattered dose is 80% higher with IMRT however this difference is small in absolute terms, being 0.14% of prescribed dose. Secondary dose from 3DCRT is mostly due to internal patient scatter, which contributes 70% of the total and predominates until 25 cm from the field edge. For IMRT, however, machine scatter/leakage is the dominant source, contributing 65% of the secondary dose. Internal scatter predominates for just the first 10 cm from field edge, collimator scatter for the next 10 cm, and head leakage thereafter. Out-of-field dose is 80% higher with IMRT, but differences are tiny in absolute terms. Reductions in internal patient scatter with IMRT are outweighed by increased machine scatter and leakage, at least for small fields. Reductions from IMRT in dose to tissues within the portals and in internal scatter, which predominates close to the field edge, means that calculations based solely on dose to distant tissues may overestimate carcinogenic risks.
Location: Australia
No related grants have been discovered for Jeremy Ruben.