Rac1 as a potential therapeutic target for chemo-radioresistant head and neck squamous cell carcinomas (HNSCC).

BACKGROUND: In order to improve therapy for HNSCC patients, novel methods to predict and combat local and/or distant tumour relapses are urgently needed. This study has been dedicated to the hypothesis that Rac1, a Rho GTPase, is implicated in HNSCC insensitivity to chemo-radiotherapy resulting in tumour recurrence development. METHODS: Parental and radiation-resistant (IRR) HNSCC cells were used to support this hypothesis. All cells were investigated for their sensitivity to ionising radiation and cisplatin, Rac1 activity, its intracellular expression and subcellular localisation. Additionally, tumour tissues obtained from 60 HNSCC patients showing different therapy response were evaluated for intratumoral Rac1 expression. RESULTS: Radiation-resistant IRR cells also revealed resistance to cisplatin accompanied by increased expression, activity and trend towards nuclear translocation of Rac1 protein. Chemical inhibition of Rac1 expression and activity resulted in significant improvement of HNSCC sensitivity to ionising radiation and cisplatin. Preclinical results were confirmed in clinical samples. Although Rac1 was poorly presented in normal mucosa, tumour tissues revealed increased Rac1 expression. The most pronounced Rac1 presence was observed in HNSCC patients with poor early or late responses to chemo-radiotherapy. Tissues taken at recurrence were characterised not only by enhanced Rac1 expression but also increased nuclear Rac1 content. CONCLUSIONS: Increased expression, activity and subcellular localisation of Rac1 could be associated with lower early response rate and higher risk of tumour recurrences in HNSCC patients and warrants further validation in larger independent studies. Inhibition of Rac1 activity can be useful in overcoming treatment resistance and could be proposed for HNSCC patients with primary or secondary chemo-radioresistance.

Heat distribution and heat transport in bone during radiofrequency catheter ablation.

BACKGROUND: To assess the feasibility of percutaneous radiofrequency ablation in large bone tumours, the heat distribution in cortical bone and marrow around inserted electrodes was measured. METHODS: Fresh bovine cadaver tibial bones were locally heated through drill holes for a maximum of half an hour using water-cooled single radiofrequency electrodes (Radionics Instruments Inc) by pulsed energy. Temperatures were measured in the marrow canal as well as in cortical bone by thermocouples at various distances from the inserted probes. RESULTS: Perpendicular to the probe, hyperthermia of more than 50 degrees C could be created in bone marrow in a sphere of approximately 3 cm, and of approximately 1 cm in cortical bone. CONCLUSION: As irreversible cellular damage can be expected when increasing the temperature to 50 degrees C for a duration of 6 min, this method may be effective for the minimal invasive ablation of neoplasms within human bone in cigar-shaped regions of approximately 3-cm diameter.

Head and neck tumors: fractionated frameless stereotactic interstitial brachytherapy-initial experience.

The authors used a frameless stereotactic navigation system, the Vogele-Bale-Hohner head holder, and a targeting device to reproducibly position brachytherapy needles for fractionated interstitial brachytherapy in 12 patients with inoperable cancers of the head and neck. In all cases, deviations of the needle relative to the planned position were within 1-15 mm depending on the location of the tumor.

[First experiences with computer-assisted frameless stereotactic interstitial brachytherapy (CASIB)]. / Erste Erfahrungen mit computerunterstützter stereotaktischer interstitieller Brachytherapie.

PURPOSE: To reach an optimal treatment result and to avoid damage to critical structures a homogeneous dose distribution in the tumor volume with a rapid decreasing dose to the surrounding structures is necessary. Fractionated interstitial brachytherapy of tumors in the ENT region employing needles depends on exact localization of the target volume during all fractions. Therefore reproducibility of positioning of the needle(s) plays an important role. MATERIAL AND METHODS: We used the ISG Viewing Wand system in combination with the Vogele-Bale-Hohner (VBH) head holder and a new targeting device. Point of entrance, pathway, and target point of the needle were planned and insertion of the needle simulated in advance. To date we have treated 7 patients with inoperable tumors in the ENT region. The actual position of the needle in the control CT was compared to the planned position. RESULTS: The accuracy of positioning of the needle depended on the location of the tumor. In a patient with a recurrent retroorbital adenocarcinoma the mean accuracy was 1 mm. Due to soft tissue displacement in the neck region and the resulting necessity to readjust the targeting device the needle was placed with a mean deviation of 15 mm between the planned and the actual position. CONCLUSIONS: Computer-assisted frameless stereotactic interstitial brachytherapy allows for precise, reproducible and preplanned insertion of hollow needles into target structures closely adherent to the surrounding tissue, thus avoiding damage of neighbouring structures. This technique is of great advantage in treating deeply seated tumors which are fixed to bony structures, especially at the skull base. Inaccuracy in the neck region caused by soft tissue shift requires improvement of the immobilization in this region.

[3D navigation for interstitial stereotaxic brachytherapy]. / 3D-Navigation in der interstitiellen stereotaktischen Brachytherapie.

AIM: The aim of this paper is to describe the adaption of 3D-navigation for interstitial brachytherapy. The new method leads to prospective and therefore improved planning of the therapy (position of the needle and dose distribution) and to the possibility of a virtual simulation (control if vessels or nerves are on the pathway of the needle). MATERIAL AND METHODS: The EasyGuide Neuro navigation system (Philips) was adapted in the way, that needles for interstitial brachytherapy were made connectable to the pointer and correctly displayed on the screen. To determine the positioning accuracy, several attempts were performed to hit defined targets on phantoms. Two methods were used: "free navigation", where the needle was under control of the navigation system, and the "guided navigation" where an aligned template was used additionally to lead the needle to the target. In addition a mask system was tested, whether it met the requirements of stable and reproducible positioning. The potential of applying this method in clinical practice was tested with an anatomical specimen. RESULTS: About 91% of all attempts lied within 5 mm. There were even better results on the more rigid table (94% < 4 mm). No difference could be seen between both application methods ("free navigation" and "navigation with template"), they showed the same accuracy. CONCLUSIONS: The accuracy of the phantom experiments and the confirmation by the experiment with the anatomical specimen showed that excellent results can be expected in clinical practice using rigid tables and patient supporting systems.

VBH head holder to improve frameless stereotactic brachytherapy of cranial tumors.

Precise target localization is essential for brachytherapy. We have adapted the VBH (Vogele-Bale-Hohner) head holder (Wellhoefer Dosimetry, Schwarzenbruck, Germany), originally developed at the University of Innsbruck, for frameless stereotactic surgery, for use in brachytherapy of cranial tumors. The VBH head holder allows for rigid, noninvasive head fixation by means of an individualized upper dental cast. Registration rods, rigidly attached to the dental cast, provide stable external points of reference. The dental cast is sucked against the upper palate by vacuum, and then the fixated patient is scanned. During simulation, the targeting device can be positioned with respect to the virtual patient using the ISG Viewing Wand. Following simulation, the real patient is repositioned under vacuum control, the targeting device repositioned as well, and the actual brachytherapy initiated. The VBH head holder is well tolerated by patients and simple to use, and various studies have confirmed submillimeter accuracy. The modified head holder in combination with a new targeting device allows for precise and well-planned insertion of hollow needles into a tumor using frameless stereotactic systems as well as being compatible for uses in other fields.