Contributing factors to quality of life after vertebral artery dissection: a prospective comparative study.

BACKGROUND: Vertebral artery dissection (VAD) may cause cerebral ischemia and impair quality of life (QOL) despite of good functional outcome. The aim of this study was the multimodal analysis of patient characteristics after VAD to identify contributing factors. METHODS: In an exploratory study, 34 consecutive patients with first-ever spontaneous VAD were prospectively examined in comparison to 38 patients with cerebral ischemia without dissection and 25 stroke mimics as control groups. Multimodal assessment was performed for clinical, neurological, cognitive, psychological and radiological data at baseline and for QOL, functional outcome, and stress symptoms by questionnaire at six months follow-up. Subgroup analysis stratified for QOL by Stroke Specific Quality of Life Scale (SS-QOL) were done for patients with good functional outcome (modified Ranking Scale (mRS) scoring 0-2). Predictors for QOL at follow-up were analyzed by regression model. RESULTS: 88.2% of patients with VAD suffered from acute cerebral ischemia. Thirteen of 32 VAD patients (40.6%) rated QOL at follow-up as bad (SS-QOL score ≤ 3.9) despite of good functional outcome (mRS score 0-2). Subgroup analysis yielded significantly higher scores for posttraumatic stress symptoms (p = 0.002) in this subgroup. Posttraumatic stress symptoms, severity of neurological disorders, and impaired neuropsychological baseline performance proved to be independent predictors for reduced QOL at follow-up according to regression analysis. CONCLUSION: VAD leads to impaired QOL at 6 months follow-up due to multiple factors. The data suggest that posttraumatic stress symptoms are of significant importance for the QOL after VAD. Clinical monitoring should address this topic to make timely treatment possible.

Perioperative intensity-modulated brachytherapy for refractory orbital rhabdomyosarcomas in children.

PURPOSE: To evaluate the feasibility and toxicity of perioperative intensity-modulated brachytherapy (IMBT) as well as functional outcome in children with therapy-refractory orbital rhabdomyosarcomas (RMS). PATIENTS AND METHODS: Since 1993, children with therapy-refractory orbital RMS have been treated by a multidisciplinary approach combining function-preserving, mostly R1 tumor resection and perioperative IMBT at the University Hospital of Schleswig-Holstein, Germany. All children with orbital RMS, who were enrolled in this multidisciplinary treatment protocol between 1993 and 2002, were prospectively assessed with respect to evaluation of side effects and functional outcome. RESULTS: Ten children (six boys, four girls) were included. Median age was 6.5 years (range, 1-19 years) at the beginning of our treatment and 6.0 years (range 1-17 years) at diagnosis. All children were in Intergroup Rhabdomyosarcoma Study Group (IRSG) group III and had embryonal subtype. Estimated 5-year survival was 62% +/- 18%. There was no radiation-related toxicity grade 3 or 4 observed. The eyes were primarily preserved in all cases. One child underwent secondary orbital exenteration 10 months after completion of IMBT. Visual acuity could be preserved apart from one child developing significant visual deterioration due to radiation cataract grade 2. The cosmetic results were good or very good in eight and moderate in two children. Four children died of their disease. CONCLUSION: This interdisciplinary, individually tailored and function-preserving treatment procedure has proven to be a well-tolerated therapeutic option in cases with refractory orbital RMS. It provides both improvement of local tumor control and quality of life.

Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies.

Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors.

Feasibility of combined operation and perioperative intensity-modulated brachytherapy of advanced/recurrent malignancies involving the skull base.

PURPOSE: To assess the technical feasibility and toxicity of combined operation and perioperative intensity-modulated fractionated interstitial brachytherapy (IMBT) in advanced-stage malignancies involving the skull base with the goal of preserving the patients' senses of sight. PATIENTS AND METHODS: This series consisted of 18 consecutive cases: ten patients with paranasal sinus carcinomas, five with sarcomas, two with primitive neuroectodermal tumors (PNETs), and one with parotid gland carcinoma. After, in most cases, subtotal surgical resection (R1-R2: carried out so that the patients' senses of sight were preserved), two to twelve (mean five) afterloading plastic tubes were placed into the tumor bed. IMBT was performed with an iridium-192 stepping source in pulsed-dose-rate/high-dose-rate (PDR/HDR) afterloading technique. The total IMBT dose, ranging from 10 to 30 Gy, was administered in a fractionated manner (3-5 Gy/day, 5 days/week). RESULTS: Perioperative fractionated IMBT was performed in 15 out of 18 patients and was well tolerated. Complications that partially prevented or delayed IMBT in some cases included cerebrospinal fluid leakage (twice), meningitis (twice), frontal brain syndrome (twice), afterloading tube displacement (twice), seizure (once), and general morbidity (once). No surgery- or radiation-induced injuries to the cranial nerves or eyes occurred. Median survival times were 33 months after diagnosis and 16 months after combined operation and IMBT. CONCLUSION: Perioperative fractionated IMBT after extensive but vision-preserving tumor resection seems to be a safe and well-tolerated treatment of advanced/recurrent malignancies involving the skull base. These preliminary data suggest that combined operation and perioperative fractionated IMBT is a palliative therapeutic option in the management of fatal malignancies involving the base of the skull, a strategy which leaves the patients' visual acuity intact.

Protein expression of Fas, Fas ligand, Bcl-2 and TGFbeta2 and correlation with survival in initial and recurrent human gliomas.

Several studies have recently demonstrated that human gliomas express Fas, Fas ligand (FasL), Bcl-2 and TGFbeta2 at some degree. These factors are considered to interact with apoptotic processes and to have immuno-reactive potential. Their role for tumor evasion from the immune surveillance is currently under examination. To date, there is only limited information about the definite expression patterns of these four factors in human gliomas, particularly in pilocytic astrocytoma (PA) and recurrent tumors. We analyzed 75 human gliomas for the immunohistochemical expression of Fas, FasL, Bcl-2, and TGFbeta2: (1) 25 PAs (WHO grade I), (2) 25 primary glioblastomas (WHO grade IV), and (3) 25 paired initial and recurrent glioblastomas (WHO grade IV), respectively. Co-expression of all four factors was present in the majority of specimens, i.e. in 72% (18/25) of PAs and 88% (47/50) of primary glioblastomas. Pilocytic astrocytomas showed significantly higher scores of TGFbeta2 expression (p < 0.05) and significantly lower Fas, Fas ligand and Bcl-2 scores (p < 0.05) than glioblastomas. There were no significant expression differences in initial versus recurrent glioblastoma specimens. Likewise, no significant correlation was observed between protein expression and clinical parameters, i.e. total survival time or progression free survival time, as documented by Kaplan-Meier method and log rank-test. In conclusion, Fas, FasL, Bcl-2 and TGFbeta2 are differently expressed in PAs versus glioblastomas. These factors, however, are not associated with patient prognosis. The broad co-expression of these factors may enable new therapeutic approaches in the future.

Cerebral edema leading to decompressive craniectomy: an assessment of the preceding clinical and neuromonitoring trends.

The aim of this study was to examine the pre-operative clinical and neuromonitoring courses in patients with a decompressive craniectomy to assess and to compare clinical and neuromonitoring signs indicating extensive cerebral edema. We conducted a retrospective analysis of the clinical signs and courses of simultaneous monitoring of intracranial pressure (ICP) and cerebral oxygenation (PtiO2) in 26 consecutive patients who were sedated and treated with a decompressive craniectomy due to extensive cerebral edema after aneurysmal subarachnoid hemorrhage (SAH) (n = 20) or severe head injury (SHI) (n = 6). Pathological monitoring trends always preceded clinical deterioration. In 18 of 26 patients extensive cerebral edema was indicated solely by increasing ICP > 20 mmHg or decreasing PtiO2 < 10 mmHg or both. Anisocoria occurred in only 8 of 26 patients. As opposed to SHI patients, 9 of 20 SAH patients showed decreasing PtiO2 as first warning sign clearly before neurological deterioration or ICP increase. This series shows the utility of combined ICP and PtiO2 monitoring in patients who develop extensive cerebral edema. Pathological monitoring trends indicate deterioration prior to clinical signs which offers a wider therapeutical window. PtiO2 monitoring appears to be particularly valuable after aneurysmal SAH as adjunct to ICP monitoring and CT imaging.