Peter Hunold

Radiolabeled Cetuximab plus Whole-Brain Irradiation (WBI) for the Treatment of Brain Metastases from Non-Small Cell Lung Cancer (NSCLC)

Background and Purpose:The addition of systemic drugs to whole-brain irradiation has not improved the survival of patients with multiple brain metastases, most likely because the agents did not readily cross the blood-brain barrier (BBB). Radiolabeling of cetuximab was performed to investigate whether this antibody crosses the BBB.Case Report:A patient with multiple brain lesions from non-small cell lung cancer was investigated. The largest metastasis (40 × 33 × 27 mm) was selected the reference lesion. On day 1, 200 mg/m2 cetuximab (0.25% hot and 99.75% cold antibody) were given. On day 3, 200 mg/m2 cetuximab (cold antibody) were given. Weekly doses of 250 mg/m2 cetuximab were administered for 3 months.Results:The reference lesion showed enhancement of radiolabeled cetuximab (123I-Erbi) on scintigraphy; 123I-Erbi crossed the BBB and accumulated in the lesion. The reference lesion measured 31 × 22 × 21 mm at 4 months. Enhancement of contrast medium was less pronounced.Conclusion:This is the first demonstration of cetuximab crossing the BBB and accumulating in brain metastasis.ZusammenfassungHintergrund und Ziel:Durch die systemische Gabe von Medikamenten zusätzlich zur Ganzhirnbestrahlung wurde bislang keine Verbesserung des Überlebens von Patienten mit multiplen Hirnmetastasen erreicht, höchstwahrscheinlich, weil die Substanzen die Blut-Hirn-Schranke (BBB) nicht adäquat überwinden. Cetuximab wurde radioaktiv markiert, um zu untersuchen, ob dieser Antikörper die BBB passieren kann.Fallbericht:Ein Patient mit multiplen Hirnmetastasen eines nichtkleinzelligen Bronchialkarzinoms wurde untersucht. Die größte Metastase (40 × 33 × 27 mm, Abbildung 1) wurde als Referenzmetastase definiert. An Tag 1 wurden 200 mg/m2 Cetuximab (0,25% heißer und 99,75% kalter Antikörper) appliziert, an Tag 3 erneut 200 mg/m2 Cetuximab (kalter Antikörper). Anschließend wurden wöchentlich 250 mg/m2 Cetuximab für 3 Monate verabreicht.Ergebnisse:In der Szintigraphie zeigte die Referenzmetastase eine Anreicherung des radioaktiv markierten Cetuximabs (123I-Erbi, Abbildung 2). 123I-Erbi passierte die BBB und akkumulierte in der Metastase. Nach 4 Monaten maß die Referenzmetastase noch 31 × 22 × 21 mm (Abbildung 3). Die Kontrastmittelanreicherung war geringer ausgeprägt.Schlussfolgerung:Erstmals wird gezeigt, dass Cetuximab die BBB passiert und sich in einer Hirnmetastase anreichert.

Dose-Escalation Study for Cardiac Radiosurgery in a Porcine Model

PURPOSE To perform a proof-of-principle dose-escalation study to radiosurgically induce scarring in cardiac muscle tissue to block veno-atrial electrical connections at the pulmonary vein antrum, similar to catheter ablation. METHODS AND MATERIALS Nine mini-pigs underwent pretreatment magnetic resonance imaging (MRI) evaluation of heart function and electrophysiology assessment by catheter measurements in the right superior pulmonary vein (RSPV). Immediately after examination, radiosurgery with randomized single-fraction doses of 0 and 17.5-35 Gy in 2.5-Gy steps were delivered to the RSPV antrum (target volume 5-8 cm(3)). MRI and electrophysiology were repeated 6 months after therapy, followed by histopathologic examination. RESULTS Transmural scarring of cardiac muscle tissue was noted with doses ≥32.5 Gy. However, complete circumferential scarring of the RSPV was not achieved. Logistic regressions showed that extent and intensity of fibrosis significantly increased with dose. The 50% effective dose for intense fibrosis was 31.3 Gy (odds ratio 2.47/Gy, P<.01). Heart function was not affected, as verified by MRI and electrocardiogram evaluation. Adjacent critical structures were not damaged, as verified by pathology, demonstrating the short-term safety of small-volume cardiac radiosurgery with doses up to 35 Gy. CONCLUSIONS Radiosurgery with doses >32.5 Gy in the healthy pig heart can induce circumscribed scars at the RSPV antrum noninvasively, mimicking the effect of catheter ablation. In our study we established a significant dose-response relationship for cardiac radiosurgery. The long-term effects and toxicity of such high radiation doses need further investigation in the pursuit of cardiac radiosurgery for noninvasive treatment of atrial fibrillation.

Pulmonary vein isolation by radiosurgery: implications for non-invasive treatment of atrial fibrillation

AIMS Electrical isolation of the pulmonary veins (PVs) has been established in clinical routine as a curative treatment for atrial fibrillation (AF). While catheter ablation carries procedural risks, radiosurgery might be able to non-invasively induce lesions at the PV ostia to block veno-atrial electrical conduction. This porcine feasibility and dose escalation study determined the effect of radiosurgery on electrophysiologic properties of the left atrial-PV junction. METHODS AND RESULTS Eight adult Goettingen mini-pigs underwent electrophysiological voltage mapping in the left atrium and the upper right PV. Radiation was delivered with a conventional linear accelerator. A single homogeneous dose ranging from 22.5 to 40 Gy was applied circumferentially to the target vein antrum. Six months after radiosurgery, electrophysiological mapping was repeated and a histological examination performed. Voltage mapping consistently showed electrical potentials in the upper right PV at baseline. Pacing the target vein prompted atrial excitation, thus proving veno-atrial electrical conduction. After 6 months, radiation had reduced PV electrogram amplitudes. This was dose dependent with a mean interaction effect of -5.8%/Gy. Complete block of atrio-venous electrical conduction occurred after 40 Gy dose application. Histology revealed transmural scarring of the targeted PV musculature with doses >30 Gy. After 40 Gy, it spanned the entire circumference in accordance with pulmonary vein isolation. CONCLUSION Pulmonary vein isolation to treat AF can be achieved by radiosurgery with a conventional linear accelerator. Yet, it requires a high radiation dose which might limit clinical applicability.

L1 cell adhesion molecule as a potential therapeutic target in murine models of endometriosis using a monoclonal antibody approach.

Background/Aims The neural cell adhesion molecule L1CAM is a transmembrane glycoprotein abnormally expressed in tumors and previously associated with cell proliferation, adhesion and invasion, as well as neurite outgrowth in endometriosis. Being an attractive target molecule for antibody-based therapy, the present study assessed the ability of the monoclonal anti-L1 antibody (anti-L1 mAb) to impair the development of endometriotic lesions in vivo and endometriosis-associated nerve fiber growth. Methods and Results Endometriosis was experimentally induced in sexually mature B6C3F1 (n=34) and CD-1 nude (n=21) mice by autologous and heterologous transplantation, respectively, of endometrial fragments into the peritoneal cavity. Transplantation was confirmed four weeks post-surgery by in vivo magnetic resonance imaging and laparotomy, respectively. Mice were then intraperitoneally injected with anti-L1 mAb or an IgG isotype control antibody twice weekly, over a period of four weeks. Upon treatment completion, mice were sacrificed and endometrial implants were excised, measured and fixed. Endometriosis was histologically confirmed and L1CAM was detected by immunohistochemistry. Endometriotic lesion size was significantly reduced in anti-L1-treated B6C3F1 and CD-1 nude mice compared to mice treated with control antibody (P<0.05). Accordingly, a decreased number of PCNA positive epithelial and stromal cells was detected in autologously and heterologously induced endometriotic lesions exposed to anti-L1 mAb treatment. Anti-L1-treated mice also presented a diminished number of intraperitoneal adhesions at implantation sites compared with controls. Furthermore, a double-blind counting of anti-neurofilament L stained nerves revealed significantly reduced nerve density within peritoneal lesions in anti-L1 treated B6C3F1 mice (P=0.0039). Conclusions Local anti-L1 mAb treatment suppressed endometriosis growth in B6C3F1 and CD-1 nude mice and exerted a potent anti-neurogenic effect on induced endometriotic lesions in vivo. The findings of this preliminary study in mice provide a strong basis for further testing in in vivo models.

Treatment Planning Considerations for Robotic Guided Cardiac Radiosurgery for Atrial Fibrillation

Purpose Robotic guided stereotactic radiosurgery has recently been investigated for the treatment of atrial fibrillation (AF). Before moving into human treatments, multiple implications for treatment planning given a potential target tracking approach have to be considered. Materials & Methods Theoretical AF radiosurgery treatment plans for twenty-four patients were generated for baseline comparison. Eighteen patients were investigated under ideal tracking conditions, twelve patients under regional dose rate (RDR = applied dose over a certain time window) optimized conditions (beam delivery sequence sorting according to regional beam targeting), four patients under ultrasound tracking conditions (beam block of the ultrasound probe) and four patients with temporary single fiducial tracking conditions (differential surrogate-to-target respiratory and cardiac motion). Results With currently known guidelines on dose limitations of critical structures, treatment planning for AF radiosurgery with 25 Gy under ideal tracking conditions with a 3 mm safety margin may only be feasible in less than 40% of the patients due to the unfavorable esophagus and bronchial tree location relative to the left atrial antrum (target area). Beam delivery sequence sorting showed a large increase in RDR coverage (% of voxels having a larger dose rate for a given time window) of 10.8-92.4% (median, 38.0%) for a 40-50 min time window, which may be significant for non-malignant targets. For ultrasound tracking, blocking beams through the ultrasound probe was found to have no visible impact on plan quality given previous optimal ultrasound window estimation for the planning CT. For fiducial tracking in the right atrial septum, the differential motion may reduce target coverage by up to -24.9% which could be reduced to a median of -0.8% (maximum, -12.0%) by using 4D dose optimization. The cardiac motion was also found to have an impact on the dose distribution, at the anterior left atrial wall; however, the results need to be verified. Conclusion Robotic AF radiosurgery with 25 Gy may be feasible in a subgroup of patients under ideal tracking conditions. Ultrasound tracking was found to have the lowest impact on treatment planning and given its real-time imaging capability should be considered for AF robotic radiosurgery. Nevertheless, advanced treatment planning using RDR or 4D respiratory and cardiac dose optimization may be still advised despite using ideal tracking methods.

Laryngeal Chondrosarcoma with Unusual Dissemination to the Humerus

We report the case of an 81-year-old woman admitted to our clinic with a 16-month history of hoarseness due to unilateral vocal cord immobilization, slowly progressive dysphagia and an episode of painless swelling of the right arm. Radiological and histological workup revealed a medium-grade conventional chondrosarcoma of the cricoid cartilage with paratracheal spread and dissemination to the lung and the humeral bone. To our knowledge, this is the first humeral bone metastasis of laryngeal chondrosarcoma reported in the literature. The course of the presented case underlines the need for an early and detailed clinical and radiological workup of vocal cord immobilization.

Disrupting Y-Box-Binding Protein 1 Function Using OSU-03012 Prevents Endometriosis Progression in In Vitro and In Vivo Models

The objective of the present study was to test the ability of OSU-03012 (2-amino-N-[4-[5-phenanthren-2-yl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]acetamide), a novel and potent celecoxib-derivative, to impair endometriosis progression in in vitro and in vivo models based on its ability to indirectly block Y-box-binding protein 1 (YB-1) function. 12Z human endometriotic epithelial cells and sexually mature female C57BL/6J mice were treated with OSU-03012. Cellular proliferation was quantified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid assay. Expression of YB-1 and phosphorylated YB-1 in 12Z cells and endometriotic lesions was evaluated by Western blotting and immunohistochemistry (IHC). The IHC for proliferating cell nuclear antigen was performed. OSU-03012 treatment resulted in decreased YB-1 and its phosphorylated form in both in vitro and in vivo models. Endometriotic lesion size was significantly reduced in OSU-03012-treated mice (27.6 ± 4.0 mm3) compared to those from the control group (50.5 ± 6.9 mm3, P < .0001). A significant reduction in endometriotic epithelial cell proliferation was observed in endometriotic lesions exposed to OSU-03012 treatment (P = .0346). In conclusion, targeting YB-1 via OSU-03012 showed a potent antiproliferative effect on endometriotic epithelial cells in vitro and in a mouse model of disease.

Sudden hypertension in a kidney transplant recipient after a skiing accident

Introduction Complications after renal transplants are frequent. A well-known but less frequent complication is arteriovenous fistula formation, which can remain asymptomatic or present with hematuria, hypertension, or renal insufficiency. Presentation of case We present the case of a young, male kidney transplant recipient with newly developed hypertension due to the formation of an arteriovenous fistula a long period after the last renal biopsy. Discussion In our case, the sonographic evaluation showed the aliasing phenomenon, which was useful in the detection of the AVF. Superselective transcatheter embolization is considered to be the treatment of choice in such cases and has been proven to be safe and effective, even in long-term evaluations. Conclusion Our findings in this case highlight a rarely reported clinical presentation which physicians should be aware of when evaluating patients who have received a renal transplant.