Jeffrey N. Bruce

Handheld cellular telephones and risk of acoustic neuroma

Abstract—The hypothesis that intracranial energy deposition from handheld cellular telephones causes acoustic neuroma was tested in an epidemiologic study of 90 patients and 86 control subjects. The relative risk was 0.9 (p = 0.07) and did not vary significantly by the frequency, duration, and lifetime hours of use. In patients who used cellular telephones, the tumor occurred more often on the contralateral than ipsilateral side of the head. Further efforts should focus on potentially longer induction periods.

Regression of Recurrent Malignant Gliomas with Convection-Enhanced Delivery of Topotecan.

BACKGROUND Convection-enhanced delivery of chemotherapeutics for the treatment of malignant glioma is a technique that delivers drugs directly into a tumor and the surrounding interstitium through continuous, low-grade positive-pressure infusion. This allows high local concentrations of drug while overcoming the limitations imposed by toxicity and the blood-brain barrier in systemic therapies that prevent the use of many potentially effective drugs. OBJECTIVE To examine the safety profile of a conventional chemotherapeutic agent, topotecan, via convection-enhanced delivery in the treatment of recurrent malignant gliomas and secondarily to assess radiographic response and survival. METHODS We performed a prospective, dose-escalation phase Ib study of the topoisomerase-I inhibitor topotecan given by convection-enhanced delivery in patients with recurrent malignant gliomas. RESULTS Significant antitumor activity as described by radiographic changes and prolonged overall survival with minimal drug-associated toxicity was demonstrated. A maximum tolerated dose was established for future phase II studies. CONCLUSION Topotecan by convection-enhanced delivery has significant antitumor activity at concentrations that are nontoxic to normal brain. The potential for use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent phase II and III trials.

A review of malignant meningiomas: diagnosis, characteristics, and treatment

Anaplastic or malignant meningiomas (WHO Grade III) represent the most rare but aggressive subtype, accounting for 1–3% of all intracranial meningiomas. Due in large part to their scarcity, malignant meningiomas have been understudied and therefore represent an area where significant clinical advances may be made. To this point, our understanding of the genetic and histologic attributes of these lesions has grown, though the management and treatment of these aggressive tumors is less well elucidated and thus has room for further study. In this review, we describe the current understanding of malignant meningiomas in terms of their genetic alterations and unique histologic markers. Using this as a foundation, we will then discuss the current therapeutic strategies for managing these lesions and the future direction that such interventions may take.

Rapid recurrence and malignant transformation of pilocytic astrocytoma in adult patients

Pilocytic astrocytoma is a slow-growing, circumscribed glioma that most frequently occurs within the pediatric population. In general, surgical resection for pilocytic astrocytoma is thought to be curative with tumor recurrence or malignant transformation being relatively rare. However, there have been very few studies specifically looking at the prognosis for adult patients diagnosed with pilocytic astrocytoma. To evaluate the frequency of recurrence and malignant transformation of pilocytic astrocytoma in adults, we performed a retrospective analysis of all adult patients who underwent surgical resection for this tumor at our institution over a period of 10xa0years. In our cohort of 20 patients, there were 6 (30%) recurrences with four patients requiring repeat surgery due to symptomatic progression. Relatively rapid recurrences were noted with the median time to recurrence being 16.5xa0months. All recurrences occurred within 4xa0years of initial surgery while patients requiring repeat surgery presented within 17xa0months of initial surgery. Based on this study estimated rates of freedom from recurrence (FFR) at 12 and 24xa0months after initial surgery are 94xa0±xa05% and 76xa0±xa010%, respectively. A high rate of malignant transformation was observed in the patients that underwent repeat surgery with 75% (3/4) progressing to anaplastic astrocytoma on pathological examination. This study provides further evidence that the clinical course of a subset of adult patients with pilocytic astrocytoma will not be benign. The potential for rapid tumor recurrence and malignant transformation necessitates careful post-operative follow-up for adult patients with this tumor.

Surgical management of craniopharyngiomas

Surgical treatment of craniopharyngiomas has been historically challenging and, despite advancements in microsurgical and skull base techniques, continues to pose a challenge to modern day surgeons. In particular, proponents of subtotal resection in conjunction with radiotherapy argue that this less aggressive approach can yield equivalent control rates with lower morbidity, while others argue that gross total resection is superior. Regardless of whether gross total or subtotal resection is the goal, surgical planning must include a thorough endocrine and neuro-ophthalmologic evaluation as well as imaging, and the approach, whether transsphenoidal or transcranial, must take into account the nature of the tumor and its location. In addition, optimal management of craniopharyngiomas must consist of an individualized and multidisciplinary approach not only including neurological surgery, but also including endocrinology, neuro-ophthalmology, neuropsychology, and, often, radiation-oncology.

Motor deficits correlate with resting state motor network connectivity in patients with brain tumours

While a tumour in or abutting primary motor cortex leads to motor weakness, how tumours elsewhere in the frontal or parietal lobes affect functional connectivity in a weak patient is less clear. We hypothesized that diminished functional connectivity in a distributed network of motor centres would correlate with motor weakness in subjects with brain masses. Furthermore, we hypothesized that interhemispheric connections would be most vulnerable to subtle disruptions in functional connectivity. We used task-free functional magnetic resonance imaging connectivity to probe motor networks in control subjects and patients with brain tumours (nu2009=u200922). Using a control dataset, we developed a method for automated detection of key nodes in the motor network, including the primary motor cortex, supplementary motor area, premotor area and superior parietal lobule, based on the anatomic location of the hand-motor knob in the primary motor cortex. We then calculated functional connectivity between motor network nodes in control subjects, as well as patients with and without brain masses. We used this information to construct weighted, undirected graphs, which were then compared to variables of interest, including performance on a motor task, the grooved pegboard. Strong connectivity was observed within the identified motor networks between all nodes bilaterally, and especially between the primary motor cortex and supplementary motor area. Reduced connectivity was observed in subjects with motor weakness versus subjects with normal strength (Pu2009<u20090.001). This difference was driven mostly by decreases in interhemispheric connectivity between the primary motor cortices (Pu2009<u20090.05) and between the left primary motor cortex and the right premotor area (Pu2009<u20090.05), as well as other premotor area connections. In the subjects without motor weakness, however, performance on the grooved pegboard did not relate to interhemispheric connectivity, but rather was inversely correlated with connectivity between the left premotor area and left supplementary motor area, for both the left and the right hands (Pu2009<u20090.01). Finally, two subjects who experienced severe weakness following surgery for their brain tumours were followed longitudinally, and the subject who recovered showed reconstitution of her motor network at follow-up. The subject who was persistently weak did not reconstitute his motor network. Motor weakness in subjects with brain tumours that do not involve primary motor structures is associated with decreased connectivity within motor functional networks, particularly interhemispheric connections. Motor networks become weaker as the subjects become weaker, and may become strong again during motor recovery.

Simultaneous above and below approach to giant pituitary adenomas: surgical strategies and long-term follow-up

Introduction Giant pituitary adenomas of excessive size, fibrous consistency or unfavorable geometric configuration may be unresectable through conventional operative approaches. We present our select case series for operative resection and long-term follow-up for these unusual tumors, employing both a staged procedure and a combined transsphenoidal-transcranial above and below approach. Method A retrospective chart review was performed on patients operated via the staged, and combined approaches by the senior author (J.N·B.). Preoperative characteristics and postoperative outcomes were reviewed. A detailed description of the operative technique and perioperative management is provided. Results Between 1993 and 1996, two patients harboring giant pituitary adenomas underwent an intentionally staged resection, and between 1997 and 2006, nine patients harboring giant pituitary adenomas underwent surgery via a single-stage above and below approach. Nine patients (82%) presented with non-secreting adenomas and two patients (18%) presented with prolactinomas refractory to medical management. Gross total resection was achieved in six patients (55%), near total resection in 1 (9%), and subtotal removal in 4 (36%). Seven patients (64%) experienced visual improvement postoperatively and no major complications occurred. Long-term follow-up averaged 51.6xa0months. Panhypopituitarism was observed in four patients, partial hypopituitarism in four, persistent DI in two, and persistent SIADH in one. Conclusions The addition of a transcranial component to the transsphenoidal approach offers additional visualization of critical neurovascular structures during giant pituitary adenoma resection. Complications rates are similar to other series in which complex pituitary adenomas are resected by other means. The above and below approach is both safe and effective and the immediate and long-term advantages of a single-stage approach justify its utility in this select group of patients.

Diversity and divergence of the glioma-infiltrating T-cell receptor repertoire

Significance High-throughput sequencing of T-cell receptor (TCR) repertoires provides a high-dimensional biomarker for monitoring the immune system. We applied this approach, measuring the extent to which the TCR repertoires of T-cell populations infiltrating malignant brain tumors diverge from their peripheral blood. Our analytical strategy separates the statistical properties of the repertoire derived from VJ cassette combination usage from the VJ-independent contribution that reflects the antigen-binding component of the receptor. We discovered a TCR signature strongly inversely correlated with the VJ-independent divergence between the peripheral and tissue-infiltrating repertoires of these patients. Importantly, this signature is detectable in peripheral blood and could serve as a means of noninvasively monitoring immune response in patients. Although immune signaling has emerged as a defining feature of the glioma microenvironment, how the underlying structure of the glioma-infiltrating T-cell population differs from that of the blood from which it originates has been difficult to measure directly in patients. High-throughput sequencing of T-cell receptor (TCR) repertoires (TCRseq) provides a population-wide statistical description of how T cells respond to disease. We have defined immunophenotypes of whole repertoires based on TCRseq of the α- and β-chains from glioma tissue, nonneoplastic brain tissue, and peripheral blood from patients. Using information theory, we partitioned the diversity of these TCR repertoires into that from the distribution of VJ cassette combinations and diversity due to VJ-independent factors, such as selection due to antigen binding. Tumor-infiltrating lymphocytes (TILs) possessed higher VJ-independent diversity than nonneoplastic tissue, stratifying patients according to tumor grade. We found that the VJ-independent components of tumor-associated repertoires diverge more from their corresponding peripheral repertoires than T-cell populations in nonneoplastic brain tissue, particularly for low-grade gliomas. Finally, we identified a “signature” set of TCRs whose use in peripheral blood is associated with patients exhibiting low TIL divergence and is depleted in patients with highly divergent TIL repertoires. This signature is detectable in peripheral blood, and therefore accessible noninvasively. We anticipate that these immunophenotypes will be foundational to monitoring and predicting response to antiglioma vaccines and immunotherapy.

Neurosurgical oncology: advances in operative technologies and adjuncts

AbstractnModern glioma surgery has evolved around the central tenet of safely maximizing resection. Recent surgical adjuncts have focused on increasing the maximum extent of resection while minimizing risk to functional brain. Technologies such as cortical and subcortical stimulation mapping, intraoperative magnetic resonance imaging, functional neuronavigation, navigable intraoperative ultrasound, neuroendoscopy, and fluorescence-guided resection have been developed to augment the identification of tumor while preserving brain anatomy and function. However, whether these technologies offer additional long-term benefits to glioma patients remains to be determined. Here we review advances over the past decade in operative technologies that have offered the most promising benefits for glioblastoma patients.n

A novel adenoviral vector labeled with superparamagnetic iron oxide nanoparticles for real-time tracking of viral delivery.

In vivo tracking of gene therapy vectors challenges the investigation and improvement of biodistribution of these agents in the brain, a key feature for their targeting of infiltrative malignant gliomas. The glioma-targeting Ad5/3-cRGD gene therapy vector was covalently bound to super-paramagnetic iron oxide (Fe(3)O(4)) nanoparticles (SPION) to monitor its distribution by MRI. Transduction of labeled and unlabeled vectors was assessed on the U87 glioma cell line and normal human astrocytes (NHA), and was higher in U87 compared to NHA, but was similar between labeled and unlabeled virus. An in vivo study was performed by intracranial subcortical injection of labeled-Ad5/3-cRGD particles into a pig brain. The labeled vector appeared in vivo as a T2-weighted hyperintensity and a T2-gradient echo signal at the injection site, persisting up to 72 hours post-injection. We describe a glioma-targeting vector that is labeled with SPION, thereby allowing for MRI detection with no change in transduction capability.