Histologic findings associated with laser interstitial thermotherapy for glioblastoma multiforme.

BACKGROUND: Laser-interstitial thermal therapy (LITT) has been supported by some authors as an ablative treatment of glioblastoma multiforme (GBM). Although the effects of LITT have been modeled in vivo, the histologic effects in a clinical circumstance have not been described. We analyzed tissue from a patient who underwent LITT as primary treatment for GBM. CASE PRESENTATION: A 62-year-old male was diagnosed with a left temporal GBM and underwent LITT at an outside institution. Despite corticosteroid therapy, the patient was referred with increasing headache and acalculia associated with progressive peritumoral edema two weeks after LITT procedure. En bloc resection of the enhancing lesion and adjacent temporal lobe was performed with steroid-independent symptom resolution (follow-up, > 2 years). Histologic analysis revealed three distinct histologic zones concentrically radiating from the center of the treatment site. An acellular central region of necrosis (Zone 1) was surrounded by a rim of granulation tissue with macrophages (CD68) (Zone 2; mean thickness, 1.3 ± 0.3 mm [±S.D.]). Viable tumor cells (identified by Ki-67, p53 and Olig2 immunohistochemistry) were found (Zone 3) immediately adjacent to granulation tissue. The histologic volume of thermal tissue ablation/granulation was consistent with preoperative (pre-resection) magnetic resonance (MR)-imaging. CONCLUSION: These findings are the first in vivo in humans to reveal that LITT causes a defined pattern of tissue necrosis, concentric destruction of tumor and tissue with viable tumor cells just beyond the zones of central necrosis and granulation. Furthermore, MR-imaging appears to be an accurate surrogate of tissue/tumor ablation in the early period (2 weeks) post-LITT treatment. Surgery is an effective strategy for patients with post-LITT swelling which does not respond to steroids.

Comparison of pulsed versus continuous convective flow for central nervous system tissue perfusion: laboratory investigation.

OBJECT: Although pulsatile and continuous infusion paradigms have been described for convective delivery of drugs, the effectiveness and properties of each flow paradigm are unknown. To determine the effectiveness and properties of pulsatile and continuous convective infusion paradigms, the authors compared these convective flow methods in the gray and white matter of primates. METHODS: Six primates (Macaca mulatta) underwent convective infusion of Gd-DPTA (5 mM) into the cerebral gray matter (thalamus) or white matter (frontal lobe) using pulsed (intermittent pulses of 15 µl/min) or continuous (1 µl/min) convective flow. Results were assessed by clinical MRI and histological analyses. RESULTS: Distribution of Gd-DTPA infusate in gray and white matter by pulsed and continuous flow was clearly identified using MRI, which revealed that both convective flow methods demonstrated an increase in the volume of distribution (Vd) with increasing volume of infusion (Vi) in the surrounding gray and white matter. Although the mean (± SD) gray matter Vd:Vi ratio for the pulsed infusions (4.2 ± 0.5) was significantly lower than the mean Vd:Vi ratio for continuous infusions (5.4 ± 0.5; a 22% difference [p = 0.0006]), the difference between pulsed (3.8 ± 0.4) and continuous (4.3 ± 1.2) infusions in white matter was not significantly different (p = 0.3). Pulsed infusions were associated with more leakback (12.3% ± 6.4% of Vi) than continuous infusions (3.9% ± 7.8%), although this difference was not significant (p = 0.2). All animals tolerated the infusions and there was no histological evidence of tissue injury at the infusion sites. CONCLUSIONS: Although pulsed and continuous infusion flow paradigms can be safely and effectively used for convective delivery into both gray and white matter, continuous infusion is associated with a higher Vd:Vi ratio than pulsatile infusion in gray matter. High rates of infusion (15 µl/min) can be used to deliver infusate without any significant leakback and without any clinical or histological evidence of injury.

Convection-enhanced delivery of M13 bacteriophage to the brain.

OBJECT: Recent studies indicate that M13 bacteriophage, a very large nanoparticle, binds to ß-amyloid and α-synuclein proteins, leading to plaque disaggregation in models of Alzheimer and Parkinson disease. To determine the feasibility, safety, and characteristics of convection-enhanced delivery (CED) of M13 bacteriophage to the brain, the authors perfused primate brains with bacteriophage. METHODS: Four nonhuman primates underwent CED of M13 bacteriophage (900 nm) to thalamic gray matter (4 infusions) and frontal white matter (3 infusions). Bacteriophage was coinfused with Gd-DTPA (1 mM), and serial MRI studies were performed during infusion. Animals were monitored for neurological deficits and were killed 3 days after infusion. Tissues were analyzed for bacteriophage distribution. RESULTS: Real-time T1-weighted MRI studies of coinfused Gd-DTPA during infusion demonstrated a discrete region of perfusion in both thalamic gray and frontal white matter. An MRI-volumetric analysis revealed that the mean volume of distribution (Vd) to volume of infusion (Vi) ratio of M13 bacteriophage was 2.3 ± 0.2 in gray matter and 1.9 ± 0.3 in white matter. The mean values are expressed ± SD. Immunohistochemical analysis demonstrated mean Vd:Vi ratios of 2.9 ± 0.2 in gray matter and 2.1 ± 0.3 in white matter. The Gd-DTPA accurately tracked M13 bacteriophage distribution (the mean difference between imaging and actual bacteriophage Vd was insignificant [p > 0.05], and was -2.2% ± 9.9% in thalamic gray matter and 9.1% ± 9.5% in frontal white matter). Immunohistochemical analysis revealed evidence of additional spread from the initial delivery site in white matter (mean Vd:Vi, 16.1 ± 9.1). All animals remained neurologically intact after infusion during the observation period, and histological studies revealed no evidence of toxicity. CONCLUSIONS: The CED method can be used successfully and safely to distribute M13 bacteriophage in the brain. Furthermore, additional white matter spread after infusion cessation enhances distribution of this large nanoparticle. Real-time MRI studies of coinfused Gd-DTPA (1 mM) can be used for accurate tracking of distribution during infusion of M13 bacteriophage.

Selective ablation of nociceptive neurons for elimination of hyperalgesia and neurogenic inflammation.

OBJECT: Neuropathic pain is mediated by nociceptive neurons that selectively express the vanilloid receptor 1 (VR1). Resiniferatoxin (RTX) is an excitotoxic VR1 agonist that causes destruction of VR1-positive neurons. To determine whether RTX can be used to ablate VR1-positive neurons selectively and to eliminate hyperalgesia and neurogenic inflammation without affecting tactile sensation and motor function, the authors infused it unilaterally into the trigeminal ganglia in Rhesus monkeys. METHODS: Either RTX (three animals) or vehicle (one animal) was directly infused (20 microl) into the right trigeminal ganglion in Rhesus monkeys. Animals were tested postoperatively at 1, 4, and 7 weeks thereafter for touch and pain perception in the trigeminal distribution (application of saline and capsaicin to the cornea). The number of eye blinks, eye wipes, and duration of squinting were recorded. Neurogenic inflammation was tested using capsaicin cream. Animals were killed 4 (one monkey) and 12 (three monkeys) weeks postinfusion. Histological and immunohistochemical analyses were performed. Throughout the duration of the study, response to high-intensity pain stimulation (capsaicin) was selectively and significantly reduced (p < 0.001, RTX-treated compared with vehicle-treated eye [mean +/- standard deviation]): blinks, 25.7 +/- 4.4 compared with 106.6 +/- 20.8; eye wipes, 1.4 +/- 0.8 compared with 19.3 +/- 2.5; and squinting, 1.4 +/- 0.6 seconds compared with 11.4 +/- 1.6 seconds. Normal response to sensation was maintained. Animals showed no neurological deficit or sign of toxicity. Neurogenic inflammation was blocked on the RTX-treated side. Immunohistochemical analysis of the RTX-treated ganglia showed selective elimination of VR1-positive neurons. CONCLUSIONS: Nociceptive neurons can be selectively ablated by intraganglionic RTX infusion, resulting in the elimination of high-intensity pain perception and neurogenic inflammation while maintaining normal sensation and motor function. Analysis of these findings indicated that intraganglionic RTX infusion may provide a new treatment for pain syndromes such as trigeminal neuralgia as well as others.