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.

Intracerebral and intrathecal infusion of the TGF-beta 2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: toxicology and safety.

Here, we provide first evidence that long-term continuous infusion of highly purified antisense phosphorothioate oligodeoxynucleotides (S-ODN) into brain parenchyma is well tolerated and thus highly suitable for in vivo application. AP 12009 is an S-ODN for the therapy of malignant glioma. It is directed against human transforming growth factor-beta (TGF-beta2) mRNA. In the clinical setting, AP 12009 is administered intratumorally by continuous infusion directly into the brain tumor. In view of this clinical application, the focus of our data is on local toxicology studies in rabbits and monkeys to evaluate the safety of AP 12009. AP 12009 was administered either by intrathecal bolus injection into the subarachnoidal space of the lumbar region of both cynomolgus monkeys and rabbits or by continuous intraparenchymatous infusion directly into the brain tissue of rabbits. Intrathecal bolus administration of 0.1 ml of 500 microM AP 12009 showed neither clinical signs of toxicity nor macroscopically visible or histomorphologic changes. After a 7-day intraparenchymatous continuous infusion of 500 microM AP 12009 at 1 microl/h in rabbits, there was no evidence of toxicity except for local mild to moderate lymphocytic leptomeningoencephalitis. Additionally, AP 12009 showed good tolerability in safety pharmacology as well as in acute toxicity studies and 4-week subchronic toxicity studies in mice, rats, and monkeys. This favorable safety profile proves the suitability of AP 12009 for local administration in brain tumor patients from the point of view of toxicology.

Diagnostic and therapeutic value due to suspected diagnosis, long-term complications, and indication for sural nerve biopsy.

In order to elicit the usefulness of sural nerve biopsy we retrospectively evaluated the courses of disease of every patient, who underwent this procedure in our department between January 1995 and March 2000. Sixty seven patients with the suspected diagnosis of peripheral neuropathy could be included. From these chart reviews and patient questionings were done. Inflammatory-demyelinating neuropathies were suspected in 14 patients (20.9%), specific histological findings confirmed diagnosis in 50% of these patients and resulted in therapy. In cases of polyneuropathy of unknown etiology (46 patients, 68.6%) diagnosis was made in 11 patients (23.9%), and lead to therapy in 9 patients (19.6%), merely. In all, diagnostic consequences arouse in 32.8%, therapeutic consequences in 26.9%. The follow-up of 47 patients (mean 24.4 months) found chronic pain in the distribution of the sural nerve in 14 patients (29.8%), dysesthesia in 22 patients (46.8%), and persistent sensory loss in 34 patients (72.3%). Only 24 patients (51.1%) would submit to biopsy again. Because of high complication rates and poor results we conclude that sural nerve biopsy should be done only in carefully selected cases after thorough clinical work-up, and should be limited to cases of suspected inflammatory neuropathies, collagenoses and immunologic neuropathies, and hereditary neuropathies.

Vertigo and hearing disturbance as the first sign of a glioblastoma (World Health Organization grade IV).

OBJECTIVE: To describe vertigo and hearing disturbance as a first sign of glioblastoma. STUDY DESIGN: Case report. SETTING: Ear, Nose, and Throat Department of the University of Regensberg, Germany. Primary Care Center. PATIENTS: A patient with a left temporal glioblastoma. RESULTS: A 67-year-old man presented with a 2-month history of vertigo and hearing disturbance. Radiological imaging revealed a left temporal tumor with dural inflation and erosion of the petrous bone and superior semicircular duct. The surgery involved total resection of the tumor and resurfacing of the gap in the superior canal. The histopathological examination revealed World Health Trade Organization IV glioblastoma. Postoperatively, the debilitating symptoms were relieved and the patient received radiation therapy. Tumor progression indicated a recraniotomy and a mastoidectomy. The tumor was only partially resected, and required chemotherapy. It subsequently developed otoliquorrhea and required a remastoidectomy. Histopathology of a pathological fracture of the X thoracic vertebra revealed a metastasis of the known glioblastoma. The patient died from respiratory distress syndrome. CONCLUSION: To the best of our knowledge, we are presenting the first case with transdural infiltration of bony structures by a glioblastoma at the moment of diagnosis. The transdural spread could be via the sinus petrosus and along the nervous petrosus major in the petrosal bone. Superior canal dehiscence syndrome should be considered in the differential diagnosis of vertigo and hearing disturbance. Two different processes for the etiology of the superior canal dehiscence syndrome are discussed previously in the literature; however, we present a new entity with a tumor-cause dehiscence of the bone overlying the superior canal.

Intracerebral haemorrhage: surgical therapy vs. patient-adapted treatment concept.

In spontaneous intracerebral haemorrhage (SICH), the indication for surgery is still controversial. Therefore we developed clinical guidelines for therapy and compared the outcome of these patients to an exclusively surgically treated group. We retrospectively evaluated outcome in 70 patients with SICH, who were treated only surgically and compared this group with 58 prospectively collected patients, who were treated surgically (n=13) or medically (n=45). Initial level of consciousness, haematoma volume, and ventricular extension of blood were inversely correlated with mortality (p<0.0001, respectively). Use of clinical guidelines reduced the number of operations without affecting the outcome. We can formulate the following guidelines according to our data: comatose patients with and without brain herniation signs should be treated conservatively. Patients with a haematoma volume between 25 and 85 ml and a clinical deterioration are candidates for surgical therapy.