Coronary artery disease evaluation during transcatheter aortic valve replacement work-up using photon-counting CT and artificial intelligence.

PURPOSE: The purpose of this study was to evaluate the capabilities of photon-counting (PC) CT combined with artificial intelligence-derived coronary computed tomography angiography (PC-CCTA) stenosis quantification and fractional flow reserve prediction (FFRai) for the assessment of coronary artery disease (CAD) in transcatheter aortic valve replacement (TAVR) work-up. MATERIALS AND METHODS: Consecutive patients with severe symptomatic aortic valve stenosis referred for pre-TAVR work-up between October 2021 and June 2023 were included in this retrospective tertiary single-center study. All patients underwent both PC-CCTA and ICA within three months for reference standard diagnosis. PC-CCTA stenosis quantification (at 50% level) and FFRai (at 0.8 level) were predicted using two deep learning models (CorEx, Spimed-AI). Diagnostic performance for global CAD evaluation (at least one significant stenosis ≥ 50% or FFRai ≤ 0.8) was assessed. RESULTS: A total of 260 patients (138 men, 122 women) with a mean age of 78.7 ± 8.1 (standard deviation) years (age range: 51-93 years) were evaluated. Significant CAD on ICA was present in 126/260 patients (48.5%). Per-patient sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 96.0% (95% confidence interval [CI]: 91.0-98.7), 68.7% (95% CI: 60.1-76.4), 74.3 % (95% CI: 69.1-78.8), 94.8% (95% CI: 88.5-97.8), and 81.9% (95% CI: 76.7-86.4) for PC-CCTA, and 96.8% (95% CI: 92.1-99.1), 87.3% (95% CI: 80.5-92.4), 87.8% (95% CI: 82.2-91.8), 96.7% (95% CI: 91.7-98.7), and 91.9% (95% CI: 87.9-94.9) for FFRai. Area under the curve of FFRai was 0.92 (95% CI: 0.88-0.95) compared to 0.82 for PC-CCTA (95% CI: 0.77-0.87) (P < 0.001). FFRai-guidance could have prevented the need for ICA in 121 out of 260 patients (46.5%) vs. 97 out of 260 (37.3%) using PC-CCTA alone (P < 0.001). CONCLUSION: Deep learning-based photon-counting FFRai evaluation improves the accuracy of PC-CCTA ≥ 50% stenosis detection, reduces the need for ICA, and may be incorporated into the clinical TAVR work-up for the assessment of CAD.

Magnetic Resonance-guided Procedures: Consensus on Rationale, Techniques, and Outcomes.

Magnetic resonance (MR) image guidance has demonstrated significant potential in the field of interventional radiology in several applications. This article covers the main points of MR-guided hepatic tumor ablation as a representative of MR-guided procedures. Patient selection and appropriate equipment utilization are essential for successful MR-guided tumor ablation. Intra-procedural planning imaging enables the visualization of the tumor and surrounding anatomical structures in most cases without the application of a contrast agent, ensuring optimal planning of the applicator tract. MRI enables real-time, multiplanar imaging, thus simultaneous observation of the applicator and target tumor is possible during targeting with adaptable slice angulations in case of challenging tumor positions. Typical ablation zone appearance during therapy monitoring with MRI enables safe assessment of the therapy result, resulting in a high primary efficacy rate. Recent advancements in ablation probes have shortened treatment times, while technical strategies address applicator visibility issues. MR-imaging immediately after the procedure is used to rule out complications and to assess technical success. Especially in smaller neoplasms, MRI-guided liver ablation demonstrates positive outcomes in terms of technical success rates, as well as promising survival and recurrence rates. Additionally, percutaneous biopsy under MR guidance offers an alternative to classic guidance modalities, providing high soft tissue contrast and thereby increasing the reliability of lesion detection, particularly in cases involving smaller lesions. Despite these advantages, the use of MR guidance in clinical routine is still limited to few indications and centers, due to by high costs, extended duration, and the need for specialized expertise. In conclusion, MRI-guided interventions could benefit from ongoing advancements in hardware, software, and devices. Such progress has the potential to expand diagnostic and treatment options in the field of interventional radiology.

Dark-Blood Late Gadolinium Enhancement MRI Is Noninferior to Bright-Blood LGE in Non-Ischemic Cardiomyopathies.

(1) Background and Objectives: Dark-blood late gadolinium enhancement has been shown to be a reliable cardiac magnetic resonance (CMR) method for assessing viability and depicting myocardial scarring in ischemic cardiomyopathy. The aim of this study was to evaluate dark-blood LGE imaging compared with conventional bright-blood LGE for the detection of myocardial scarring in non-ischemic cardiomyopathies. (2) Materials and Methods: Patients with suspected non-ischemic cardiomyopathy were prospectively enrolled in this single-centre study from January 2020 to March 2023. All patients underwent 1.5 T CMR with both dark-blood and conventional bright-blood LGE imaging. Corresponding short-axis stacks of both techniques were analysed for the presence, distribution, pattern, and localisation of LGE, as well as the quantitative scar size (%). (3) Results: 343 patients (age 44 ± 17 years; 124 women) with suspected non-ischemic cardiomyopathy were examined. LGE was detected in 123 of 343 cases (36%) with excellent inter-reader agreement (κ 0.97-0.99) for both LGE techniques. Dark-blood LGE showed a sensitivity of 99% (CI 98-100), specificity of 99% (CI 98-100), and an accuracy of 99% (CI 99-100) for the detection of non-ischemic scarring. No significant difference in total scar size (%) was observed. Dark-blood imaging with mean 5.35 ± 4.32% enhanced volume of total myocardial volume, bright-blood with 5.24 ± 4.28%, p = 0.84. (4) Conclusions: Dark-blood LGE imaging is non-inferior to conventional bright-blood LGE imaging in detecting non-ischemic scarring. Therefore, dark-blood LGE imaging may become an equivalent method for the detection of both ischemic and non-ischemic scars.

T1 Mapping MOLLI 5(3)3 Acquisition Scheme Yields High Accuracy in 1.5 T Cardiac Magnetic Resonance.

Objectives: To systematically compare two modified Look-Locker inversion recovery (MOLLI) T1 mapping sequences and their impact on (1) myocardial T1 values native, (2) post-contrast and (3) extracellular volume (ECV). Methods: 200 patients were prospectively included for 1.5 T CMR for work-up of ischemic or non-ischemic cardiomyopathies. To determine native and post-contrast T1 for ECV calculation, two different T1 mapping MOLLI acquisition schemes, 5(3)3 (designed for native scans with long T1) and 4(1)3(1)2 (designed for post-contrast scans with short T1), were acquired in identical mid-ventricular short-axis slices. Both schemes were acquired in native and post-contrast scans. Results: Datasets from 163 patients were evaluated (age 55 ± 17 years; 38% female). Myocardial T1 native for 5(3)3 was 1017 ± 42 ms vs. 956 ± 40 ms for 4(1)3(1)2, with mean intraindividual difference −61 ms (p < 0.0001). Post-contrast myocardial T1 in patients was similar for both acquisition schemes, with 494 ± 48 ms for 5(3)3 and 490 ± 45 ms for 4(1)3(1)2 and mean intraindividual difference −4 ms. Myocardial ECV for 5(3)3 was 27.6 ± 4% vs. 27 ± 4% for 4(1)3(1)2, with mean difference −0.6 percentage points (p < 0.0001). Conclusions: The T1 MOLLI 5(3)3 acquisition scheme provides a reliable estimation of myocardial T1 for the clinically relevant range of long and short T1 values native and post-contrast. In contrast, the T1 MOLLI 4(1)3(1)2 acquisition scheme may only be used for post-contrast scans according to its designed purpose.

TRoponin of Unknown origin in STroke evaluated by multi-component cardiac Magnetic resonance Imaging - The TRUST-MI study.

Aims: Increased high-sensitive cardiac troponin I (hs-cTnI) levels are common in patients with acute ischemic stroke. However, only a minority demonstrates culprit lesions on coronary angiography, suggesting other mechanisms, e.g., inflammation, as underlying cause of myocardial damage. Late Gadolinium Enhancement (LGE)-cardiac magnetic resonance (CMR) with mapping techniques [T1, T2, extracellular volume (ECV)] allow the detection of both focal and diffuse myocardial abnormalities. We investigated the prevalence of culprit lesions by coronary angiography and myocardial tissue abnormalities by a comprehensive CMR protocol in troponin-positive stroke patients. Methods and results: Patients with troponin-positive acute ischemic stroke and no history of coronary artery disease were prospectively enrolled. Coronary angiography and CMR (LGE, T1 + T2 mapping, ECV) were performed within the first days of the acute stroke. Twenty-five troponin-positive patients (mean age 62 years, 44% females) were included. 2 patients (8%) had culprit lesions on coronary angiography and underwent percutaneous coronary intervention. 13 patients (52%) demonstrated LGE: (i) n = 4 ischemic, (ii) n = 4 non-ischemic, and (iii) n = 5 ischemic AND non-ischemic. In the 12 LGE-negative patients, mapping revealed diffuse myocardial damage in additional 9 (75%) patients, with a high prevalence of increased T2 values. Conclusions: Our data show a low prevalence of culprit lesions in troponin-positive stroke patients. However, > 50% of the patients demonstrated myocardial scars (ischemic + non-ischemic) by LGE-CMR. Mapping revealed additional myocardial abnormalities (mostly inflammatory) in the majority of LGE-negative patients. Therefore, a comprehensive CMR protocol gives important insights in the etiology of troponin which might have implications for the further work-up of troponin-positive stroke patients.

Using Multiparametric Cardiac Magnetic Resonance to Phenotype and Differentiate Biopsy-Proven Chronic from Healed Myocarditis and Dilated Cardiomyopathy.

(1) Objectives: To discriminate biopsy-proven myocarditis (chronic vs. healed myocarditis) and to differentiate from dilated cardiomyopathy (DCM) using cardiac magnetic resonance (CMR). (2) Methods: A total of 259 consecutive patients (age 51 ± 15 years; 28% female) who underwent both endomyocardial biopsy (EMB) and CMR in the years 2008−2021 were evaluated. According to right-ventricular EMB results, patients were divided into either chronic (n = 130, 50%) or healed lymphocytic myocarditis (n = 60, 23%) or DCM (n = 69, 27%). The CMR protocol included functional, strain, and late gadolinium enhancement (LGE) imaging, T2w imaging, and T2 mapping. (3) Results: Left-ventricular ejection fraction (LV-EF) was higher, and the indexed end-diastolic volume (EDV) was lower in myocarditis patients (chronic: 42%, median 96 mL/m²; healed: 49%, 86 mL/m²) compared to the DCM patients (31%, 120 mL/m²), p < 0.0001. Strain analysis demonstrated lower contractility in DCM patients vs. myocarditis patients, p < 0.0001. Myocarditis patients demonstrated a higher LGE prevalence (68% chronic; 59% healed) than the DCM patients (45%), p = 0.01. Chronic myocarditis patients showed a higher myocardial edema prevalence and ratio (59%, median 1.3) than healed myocarditis (23%, 1.3) and DCM patients (13%, 1.0), p < 0.0001. T2 mapping revealed elevated values more frequently in chronic (90%) than in healed (21%) myocarditis and DCM (23%), p < 0.0001. T2 mapping yielded an AUC of 0.89 (sensitivity 90%, specificity 76%) in the discrimination of chronic from healed myocarditis and an AUC of 0.92 (sensitivity 86%, specificity 91%) in the discrimination of chronic myocarditis from DCM, both p < 0.0001. (4) Conclusions: Multiparametric CMR imaging, including functional parameters, LGE and T2 mapping, may allow differentiation of chronic from healed myocarditis and DCM and therefore help to optimize patient management in this clinical setting.

Comprehensive Cardiac Magnetic Resonance to Detect Subacute Myocarditis.

(1) Background: Compared to acute myocarditis in the initial phase, detection of subacute myocarditis with cardiac magnetic resonance (CMR) parameters can be challenging due to a lower degree of myocardial inflammation compared to the acute phase. (2) Objectives: To systematically evaluate non-invasive CMR imaging parameters in acute and subacute myocarditis. (3) Methods: 48 patients (age 37 (IQR 28−55) years; 52% female) with clinically suspected myocarditis were consecutively included. Patients with onset of symptoms ≤2 weeks prior to 1.5T CMR were assigned to the acute group (n = 25, 52%), patients with symptom duration >2 to 6 weeks were assigned to the subacute group (n = 23, 48%). CMR protocol comprised morphology, function, 3D-strain, late gadolinium enhancement (LGE) imaging and mapping (T1, ECV, T2). (4) Results: Highest diagnostic performance in the detection of subacute myocarditis was achieved by ECV evaluation either as single parameter or in combination with T1 mapping (applying a segmental or global increase of native T1 > 1015 ms and ECV > 28%), sensitivity 96% and accuracy 91%. Compared to subacute myocarditis, acute myocarditis demonstrated higher prevalence and extent of LGE (AUC 0.76) and increased T2 (AUC 0.66). (5) Conclusions: A comprehensive CMR approach allows reliable diagnosis of clinically suspected subacute myocarditis. Thereby, ECV alone or in combination with native T1 mapping indicated the best performance for diagnosing subacute myocarditis. Acute vs. subacute myocarditis is difficult to discriminate by CMR alone, due to chronological connection and overlap of pathologic findings.

Fluid-based augmentation of magnetic resonance visualization of interventional devices.

PURPOSE: To evaluate the transient artifact augmentation of microtubes in magnetic resonance imaging by fluid injection. METHODS: Twenty-one fluorinated ethylene propylene catheters (inner diameter 760 µm) were filled with three different contrast media at various concentrations (Ferucarbotran, Resovist®, Bayer Schering Pharma; Manganese dichloride, MnCl2, Sigma-Aldrich; Gadobutrol, Gadovist®, Bayer Schering Pharma). Artifact appearance was determined in an ex vivo phantom at 1.5 T using three different sequences: T1-weighted three-dimensional volume interpolated breath-hold examination, T2-weighted turbo spin echo, and T1-weighted fast low angle shot. Catheter angulation to the main magnetic field (B0) was varied. Influence of parameters on artifact diameters was assessed with a multiple linear regression similar to an analysis of variance. RESULTS: Artifact diameter was significantly influenced by the contrast agent (p < 0.001), concentration of the contrast agent (p < 0.001), angulation of the phantom to B0 with the largest artifact at 90° (p < 0.001), and encoding direction with a larger diameter in phase encoding direction (PED, p < 0.001). Mean artifact diameters at 90° angulation to B0 in PED were 18.5 ± 5.4 mm in 0.5 mmol/ml Ferucarbotran, 8.7 ± 2.5 mm in 1 mmol/ml Gadobutrol, and 11.6 ± 4.6 mm in 5 mmol/ml MnCl2 . CONCLUSIONS: Fluid-based contrast agents might be applied to interventional devices and thus temporarily augment the artifact ensuring both visibility and safe navigation.

MR-Guided High-Power Microwave Ablation in Hepatic Malignancies: Initial Results in Clinical Routine.

PURPOSE: Evaluation of technique effectiveness, patient safety and ablation parameters of MR-guided microwave ablation in hepatic malignancies using an MR-conditional high-power microwave ablation system. MATERIALS AND METHODS: Institutional review board approval and informed patient consent were obtained. Patients who underwent MR-guided microwave ablation of hepatic malignancies in a 1.5T wide-bore scanner using a perfusion-cooled high-power microwave ablation system with a maximum generator power of 150 W were included. Ablation parameters comprising procedure durations, net ablation duration, applicator positions and ablation zone dimensions were recorded. Adverse events were classified according to the CIRSE classification system. Technique effectiveness was assessed after 1 month. Follow-up was conducted with contrast-enhanced MRI and ranged from 1 to 20 months (mean: 6.1 ± 5.4 months). RESULTS: Twenty-one consecutive patients (age: 63.4 ± 10.5 years; 5 female) underwent 22 procedures for 28 tumours (9 hepatocellular carcinomas, 19 metastases) with a mean tumour diameter of 14.6 ± 5.4 mm (range: 6-24 mm). Technique effectiveness was achieved in all lesions. Tumours were treated using 1.7 ± 0.7 applicator positions (range: 1-3). Mean energy and ablation duration per tumour were 75.3 ± 35.4 kJ and 13.3 ± 6.2 min, respectively. Coagulation zone short- and long-axis diameters were 29.1 ± 6.4 mm and 39.9 ± 7.4 mm, respectively. Average procedure duration was 146.4 ± 26.2 min (range: 98-187 min). One minor complication was reported. Five patients developed new tumour manifestations in the untreated liver. Local tumour progression was not observed during initial follow-up. CONCLUSION: MR-guided high-power microwave ablation provides safe and effective treatment of hepatic malignancies with short ablation times and within acceptable procedure durations.

MRI-guided percutaneous thermoablation in combination with hepatic resection as parenchyma-sparing approach in patients with primary and secondary hepatic malignancies: single center long-term experience.

BACKGROUND: Combination therapy using hepatic resection (HR) and intra-operative thermal ablation is a treatment approach for patients with technically unresectable liver malignancies. The aim of this study was to investigate safety, survival and local recurrence rates for patients with technically unresectable liver tumors undergoing HR and separate percutaneous MR-guided thermoablation procedure as an alternative approach. METHODS: Data from all patients with primary or secondary hepatic malignancies treated at a single institution between 2004 and 2018 with combined HR and MR-guided percutaneous thermoablation was collected and retrospectively analyzed. Complications, procedure related information and patient characteristics were collected from institutional records. Overall survival and disease-free survival were estimated using the Kaplan-Meier method. RESULTS: A total of 31 patients (age: 62.8 ± 9.1 years; 10 female) with hepatocellular carcinoma (HCC; n = 7) or hepatic metastases (n = 24) were treated for 98 hepatic tumors. Fifty-six tumors (mean diameter 28.7 ± 23.0 mm) were resected. Forty-two tumors (15.1 ± 7.6 mm) were treated with MR-guided percutaneous ablation with a technical success rate of 100%. Local recurrence at the ablation site occurred in 7 cases (22.6%); none of these was an isolated local recurrence. Six of 17 patients (35.3%) treated for colorectal liver metastases developed local recurrence. Five patients developed recurrence at the resection site (16.1%). Non-local hepatic recurrence was observed in 18 cases (58.1%) and extrahepatic recurrence in 11 cases (35.5%) during follow-up (43.1 ± 26.4 months). Ten patients (32.3%) developed complications after HR requiring pharmacological or interventional treatment. No complication requiring therapy was observed after ablation. Median survival time was 44.0 ± 7.5 months with 1-,3-, 5-year overall survival rates of 93.5, 68.7 and 31.9%, respectively. The 1-, 3- and 5-year disease-free survival rates were 38.7, 19.4 and 9.7%, respectively. CONCLUSION: The combination of HR and MR-guided thermoablation is a safe and effective approach in the treatment of technically unresectable hepatic tumors and can achieve long-term survival.

MR-guided microwave ablation in hepatic malignancies: clinical experiences from 50 procedures.

Purpose: To investigate technical success, technique efficacy, safety and outcome of MR-guided microwave ablation (MWA) in hepatic malignancies.Material and methods: In this prospective IRB-approved study, patients scheduled for percutaneous treatment of hepatic malignancies underwent MR-guided MWA in a closed-bore 1.5 T MR system. Technical success was assessed on post-procedural MR control imaging. Technique efficacy was evaluated 4 weeks after the procedure on multi-parametric MRI. Assessment of safety followed the Society of Interventional Radiology grading system. Kaplan-Meier survival estimates were calculated to evaluate overall survival (OS), time to local tumor progression (TLTP), and time to non-target progression (TNTP).Results: Between 2015 and 2019, 47 patients (60.5 ± 12.2 years; 39 male) underwent 50 procedures for 58 hepatic tumors (21 hepatocellular carcinomas; 37 metastases). Mean target tumor size was 16 ± 7mm (range: 6-39 mm). Technical success and technique efficacy were 100% and 98%, respectively. Lesions were treated using 2.6 applicator positions (range: 1-6). Mean energy, ablation duration per tumor, and procedure duration were 43.2 ± 23.5 kJ, 26.7 ± 13.1 min and 211.2 ± 68.7 min, respectively. 10 minor (20%) and 3 major (6%) complications were observed. Median post-interventional hospital admission was 1 day (range: 1-19 days). Median OS was 41.6 (IQR: 26.4-) months. Local recurrence occurred after 4 procedures (8%) with TLTP ranging between 3.1 and 41.9 months. Non-target recurrence was observed in 64% of patients after a median TNTP of 13.8 (IQR 2.3-) months.Conclusion: MR-guided MWA allows for safe and successful treatment of hepatic malignancies with a high technique efficacy however with relatively long procedure durations.

Postoperative stereotactic radiosurgery and hypofractionated radiotherapy for brain metastases using Gamma Knife and CyberKnife: a dual-center analysis.

BACKGROUND: Postoperative stereotactic radiosurgery (SRS) and hypofractionated stereotactic radiotherapy (hFSRT) to tumor cavities is emerging as a new standard of care after resection of brain metastases. Both Gamma Knife (GK) and CyberKnife (CK) are modalities commonly used for stereotactic radiotherapy, but fractional schemes are not consistent. The objective of this study was to evaluate outcomes in patients receiving postoperative stereotactic radiotherapy of resected brain metastases (BM) using different fractionation schedules and modalities in two large centers. METHODS: Patients with newly diagnosed BM who underwent postoperative SRS or hFSRT with either GK or CK at two large cancer centers were retrospectively evaluated. We analyzed local control (LC), regional control (RC) and overall survival (OS). RESULTS: From 04/14 to 05/18 79 patients with 81 resection cavities were treated. Forty-seven patients (59.5%) received GK and 32 patients (40.5%) received CK treatment. Fifty-four cavities (66.7%) were treated with hFSRT and 27 (33.3%) with SRS. The most common hFSRT and SRS scheme was 3x10 Gy and 1x16 Gy, respectively. Median OS was 11.7 months with survival rates of 44.7% at 1 year and 18.5% at 2 years. LC was 83.3% after 1 year. Median time to regional progression was 12.0 months with RC rates of 61.1% at 6 months and 41.0% at 12 months. There was no difference in OS, LC or RC between GK and CK treatments or SRS and hFSRT. CONCLUSIONS: Both SRS and hFSRT provide high local control rates in resected BM regardless of the applied modality.

Intraoperative radiotherapy as an immediate adjuvant treatment of rectal cancer due to limited access to external-beam radiotherapy.

BACKGROUND: Neoadjuvant external-beam radiotherapy (EBRT) with concomitant chemotherapy is the current standard-of-care for locally-advanced rectal cancer. Intraoperative radiotherapy (IORT) is to date only recommended for pelvic recurrences or incompletely resectable tumors. We here report on patients with stage II/III rectal cancer that were treated with IORT in a regional Russian university center due to limited access to EBRT. METHODS: We retrospectively analyzed data from patients that were diagnosed with locally-advanced rectal cancer and underwent surgery from December 2012 to October 2016 at a regional oncological center in Russia (Krasnodar). During this period, access to EBRT was limited due to a temporary lack of a sufficient number of EBRT facilities. Patients unable to travel to a distant radiotherapy site received IORT alone, those that could travel received neoadjuvant external beam (chemo-) radiotherapy. Factors of interest were tumor stage, tumor differentiation, resection status, surgery type and neoadjuvant or adjuvant chemotherapy. We assessed local progression-free survival (L-PFS), PFS and overall survival (OS). RESULTS: A total of 172 patients were included in this analysis. Of those, 92 (53.5%) were treated with IORT alone (median dose: 15 Gy [8.4-17 Gy]) and 80 (46.5%) received both neoadjuvant EBRT (median dose: 50.4 Gy [40-50.4 Gy]) and IORT (median dose: 15 Gy [15-17 Gy]). The median age was 65 years [33-82]. The median follow-up was 23 months [0-63 months]. The incidence of toxicity was low in both groups with an overall complication rate of 5.4%. Local PFS at 4 years was comparable with 59.4% in the IORT group and 65.4% in the IORT/EBRT group (p = 0.70). Similarly, there was no difference in OS or PFS (p = 0.66, p = 0.51, respectively). CONCLUSIONS: IORT is a valuable option for patients with locally-advanced rectal cancer in the absence of access to EBRT.

The HIV-derived protein Vpr52-96 has anti-glioma activity in vitro and in vivo.

Patients with actively replicating human immunodeficiency virus (HIV) exhibit adverse reactions even to low irradiation doses. High levels of the virus-encoded viral protein R (Vpr) are believed to be one of the major underlying causes for increased radiosensitivity. As Vpr efficiently crosses the blood-brain barrier and accumulates in astrocytes, we examined its efficacy as a drug for treatment of glioblastoma multiforme (GBM).In vitro, four glioblastoma-derived cell lines with and without methylguanine-DNA methyltransferase (MGMT) overexpression (U251, U87, U251-MGMT, U87-MGMT) were exposed to Vpr, temozolomide (TMZ), conventional photon irradiation (2 to 6 Gy) or to combinations thereof. Vpr showed high rates of acute toxicities with median effective doses of 4.0±1.1 µM and 15.7±7.5 µM for U251 and U87 cells, respectively. Caspase assays revealed Vpr-induced apoptosis in U251, but not in U87 cells. Vpr also efficiently inhibited clonogenic survival in both U251 and U87 cells and acted additively with irradiation. In contrast to TMZ, Vpr acted independently of MGMT expression.Dose escalation in mice (n=12) was feasible and resulted in no evident renal or liver toxicity. Both, irradiation with 3x5 Gy (n=8) and treatment with Vpr (n=5) delayed intracerebral tumor growth and prolonged overall survival compared to untreated animals (n=5; p3x5 Gy<0.001 and pVpr=0.04; log-rank test).Our data show that the HIV-encoded peptide Vpr exhibits all properties of an effective chemotherapeutic drug and may be a useful agent in the treatment of GBM.

Impact of flattening-filter-free radiation on the clonogenic survival of astrocytic cell lines.

BACKGROUND AND PURPOSE: Flattening-filter-free (FFF) beams are increasingly used in radiotherapy as delivery times can be substantially reduced. However, the relative biologic effectiveness (RBE) of FFF may be increased relative to conventional flattened (FLAT) beams due to differences in energy spectra. Therefore, we investigated the effects of FFF and FLAT beams on the clonogenic survival of astrocytoma cells. MATERIAL AND METHODS: Three cell lines (U251, U251-MGMT, and U87) were irradiated with 6-MV and 10-MV X-rays from a linear accelerator in FFF- or FLAT-beam modes at dose rates in the range of 0.5-24 Gy/min. The surviving fraction (SF) as function of dose (2-12 Gy) was determined by the colony formation assay and fitted by the linear-quadratic model. For both beams (FFF or FLAT), the cells were pelleted in conical 15-ml centrifuge tubes and irradiated at 2-cm depth in a 1 × 1-cm(2) area on the central axis of a 30 × 30-cm(2) field. Dosimetry was performed with a 0.3-cm(3) rigid ionization chamber. RBE was determined for FFF versus FLAT irradiation. RESULTS: The RBE of FFF at 7.3-11.3 Gy was 1.027 ± 0.013 and 1.063 ± 0.018 relative to FLAT beams for 6- and 10-MV beams, respectively, and was only significantly higher than 1 for 10 MV. Significantly increased survival rates were seen for lower dose rates (0.5 Gy/min FLAT vs. 5 Gy/min FLAT) at higher doses (11.9 Gy), while no differences were seen at dose rates ≥ 1.4 Gy/min (1.4 Gy/min FFF vs. 14 Gy/min FFF and 2.4 Gy/min FFF vs. 24 Gy/min FFF). CONCLUSIONS: FFF beams showed only a slightly increased RBE relative to FLAT beams in this experimental set-up, which is unlikely to result in clinically relevant differences in outcome.