Annie W. Chan

TORC1 Is Essential for NF1-Associated Malignancies

Inactivating mutations in NF1 underlie the prevalent familial cancer syndrome neurofibromatosis type 1 [1]. The NF1-encoded protein is a Ras GTPase-activating protein (RasGAP) [2]. Accordingly, Ras is aberrantly activated in NF1-deficient tumors; however, it is unknown which effector pathways critically function in tumor development. Here we provide in vivo evidence that TORC1/mTOR activity is essential for tumorigenesis. Specifically, we show that the mTOR inhibitor rapamycin potently suppresses the growth of aggressive NF1-associated malignancies in a genetically engineered murine model. However, in these tumors rapamycin does not function via mechanisms generally assumed to mediate tumor suppression, including inhibition of HIF-1alpha and indirect suppression of AKT, but does suppress the mTOR target Cyclin D1 [3]. These results demonstrate that mTOR inhibitors may be an effective targeted therapy for this commonly untreatable malignancy. Moreover, they indicate that mTOR inhibitors do not suppress all tumor types via the same mechanism, suggesting that current biomarkers that rely on HIF-1alpha suppression may not be informative for all cancers. Finally, our results reveal important differences between the effects of mTOR inhibition on the microvasculature in genetically engineered versus xenograft models and indicate that the former may be required for effective preclinical screening with this class of inhibitors.

Adult medulloblastoma: prognostic factors and patterns of relapse.

OBJECTIVETo determine the patterns of relapse and the prognostic factors for adult medulloblastomas treated in the magnetic resonance imaging era. METHODSBetween 1986 and 1996, 32 adult patients (age, ≥16 yr) with medulloblastomas confined to the craniospinal axis were treated in our institutions. Twenty cases involved classic histological features and 12 involved the desmoplastic variant. The Chang staging distribution was as follows: T1, 2; T2, 17; T3, 10; T4, 3; M0, 24; M1, 1; M2, 4; M3, 3. Brainstem invasion was present in nine patients. Lesions were midline in 13 cases and lateral in 19. Resection was complete in 17 cases, subtotal in 6, and partial in 5, with biopsy only in 4 cases. All patients received postoperative radiotherapy, with median doses of 36 Gy to the entire craniospinal axis and 55 Gy to the posterior fossa. Twenty-four patients received chemotherapy (20 before radiotherapy, 3 after radiotherapy, and 1 before and after radiotherapy). RESULTSWith a median follow-up period of 5.4 years, 17 patients experienced recurrences. At 5 and 8 years, overall survival rates were 83 and 45% and disease-free survival rates were 57 and 40%, respectively. The 5- and 8-year posterior fossa control rates were 67 and 59%, respectively. Twenty-nine percent of all relapses occurred more than 5 years after treatment. The posterior fossa was the most common site of relapses. In univariate analyses, factors adversely affecting posterior fossa control were less than complete resection (P < 0.001), the presence of brainstem invasion (P = 0.02), and the use of chemotherapy (P = 0.03). The overall radiotherapy duration was marginally significant in predicting posterior fossa control, with 5-year posterior fossa control rates of 81 and 49% for durations of less than 48 days and 48 days or more, respectively (P = 0.06). In a multivariate analysis, complete resection was predictive of improved posterior fossa control (P = 0.02) and disease-free survival (P = 0.02) rates. Of the eight low-risk patients who received radiotherapy alone, three experienced recurrences in the bone as the only site of relapse. CONCLUSIONLate relapse is common among adult patients with medulloblastomas, and long-term follow-up monitoring is important. Because of the high risk of systemic failure among the low-risk patients treated with radiotherapy alone, the role of chemotherapy for this group of patients needs to be further investigated. Complete resection, the absence of brainstem invasion, and an overall radiotherapy duration of less than 48 days are important prognostic factors.

The effect of viewpoint on body representation in the extrastriate body area

Functional neuroimaging has revealed several brain regions that are selective for the visual appearance of others, in particular the face. More recent evidence points to a lateral temporal region that responds to the visual appearance of the human body (extrastriate body area or EBA). We tested whether this region distinguishes between egocentric and allocentric views of the self and other people. EBA activity increased significantly for allocentric relative to egocentric views in the right hemisphere, but was not influenced by identity. Whole-brain analyses revealed several regions that were influenced by viewpoint or identity. Modulation of EBA activity by viewpoint was modest relative to modulation by stimulus class. We propose that the EBA plays a relatively early role in social vision.

Stereotactic Radiotherapy for Vestibular Schwannomas: Favorable Outcome with Minimal Toxicity

OBJECTIVE:To determine the outcome and toxicity in patients with vestibular schwannomas treated with conventionally fractionated stereotactic radiotherapy (SRT) and to identify prognostic factors that are predictive of outcome. METHODS:Between 1992 and 2001, 70 patients with vestibular schwannomas were treated with linear accelerator-based SRT in our institutions. Eleven patients had neurofibromatosis Type II (NF2). The median age was 53 years (range, 17–82 yrs). The median tumor volume was 2.4 cm3 (range, 0.05–21.1 cm3). The indications for SRT were distributed as follows: 47% newly diagnosed, 31% progressive tumors after watchful waiting, 3% adjuvant postoperative radiation, and 19% recurrent tumors after surgical resection. The median dose was 54 Gy in 1.8 Gy per fraction, prescribed to 95% of the isodose line. Relocatable stereotactic frames were used for daily treatments. The median follow-up was 45.3 months. RESULTS:Tumor recurrence was defined as progressive enlargement of tumor on follow-up magnetic resonance imaging studies. One patient had a tumor recurrence at 38 months after SRT. The actuarial tumor control rates were 100 and 98% at 3 and 5 years, respectively. Three patients with a median tumor volume of 16.2 cm3 required surgical resection for persistent or increasing symptoms at a median of 37 months. The actuarial freedom from resection rates were 98 and 92% at 3 and 5 years, respectively. In multivariate analysis, tumor volume at time of treatment was predictive for neurosurgical intervention (surgical resection or shunt placement) after SRT (P = 0.001). The 3- and 5-year actuarial rates of freedom from any neurosurgical intervention were 100 and 97% for patients with tumor volume less than 8 cm3 and 74 and 47% respectively for patients with tumor of at least 8 cm3 (P < 0.0001). The 3-year actuarial rates of facial and trigeminal nerve preservation were 99 and 96%, respectively. Surgery before SRT was predictive of posttreatment trigeminal neuropathy. The 3-year actuarial rates of freedom from trigeminal neuropathy were 86 and 98% for patients with and without previous resection, respectively (P = 0.04). There was no difference in tumor control and cranial nerve function preservation rates seen in NF2 patients compared with non-NF2 patients. No second primary cancer or malignant transformation was observed. CONCLUSION:SRT in the conventionally fractionated approach results in a very favorable outcome with minimal toxicity, with results comparable to those of the best of the radiosurgery series. Patients with large tumors are more likely to undergo neurosurgical interventions after SRT. Patients who have undergone previous surgery are at increased risk of developing trigeminal neuropathy.

Proton beam radiosurgery for vestibular schwannoma: tumor control and cranial nerve toxicity.

OBJECTIVEWe sought to determine the tumor control rate and cranial nerve function outcomes in patients with vestibular schwannomas who were treated with proton beam stereotactic radiosurgery. METHODSBetween November 1992 and August 2000, 88 patients with vestibular schwannomas were treated at the Harvard Cyclotron Laboratory with proton beam stereotactic radiosurgery in which two to four convergent fixed beams of 160-MeV protons were applied. The median transverse diameter was 16 mm (range, 2.5–35 mm), and the median tumor volume was 1.4 cm3 (range, 0.1–15.9 cm3). Surgical resection had been performed previously in 15 patients (17%). Facial nerve function (House-Brackmann Grade 1) and trigeminal nerve function were normal in 79 patients (89.8%). Eight patients (9%) had good or excellent hearing (Gardner-Robertson [GR] Grade 1), and 13 patients (15%) had serviceable hearing (GR Grade 2). A median dose of 12 cobalt Gray equivalents (range, 10–18 cobalt Gray equivalents) was prescribed to the 70 to 108% isodose lines (median, 70%). The median follow-up period was 38.7 months (range, 12–102.6 mo). RESULTSThe actuarial 2- and 5-year tumor control rates were 95.3% (95% confidence interval [CI], 90.9–99.9%) and 93.6% (95% CI, 88.3–99.3%). Salvage radiosurgery was performed in one patient 32.5 months after treatment, and a craniotomy was required 19.1 months after treatment in another patient with hemorrhage in the vicinity of a stable tumor. Three patients (3.4%) underwent shunting for hydrocephalus, and a subsequent partial resection was performed in one of these patients. The actuarial 5-year cumulative radiological reduction rate was 94.7% (95% CI, 81.2–98.3%). Of the 21 patients (24%) with functional hearing (GR Grade 1 or 2), 7 (33.3%) retained serviceable hearing ability (GR Grade 2). Actuarial 5-year normal facial and trigeminal nerve function preservation rates were 91.1% (95% CI, 85–97.6%) and 89.4% (95% CI, 82–96.7%). Univariate analysis revealed that prescribed dose (P = 0.005), maximum dose (P = 0.006), and the inhomogeneity coefficient (P = 0.03) were associated with a significant risk of long-term facial neuropathy. No other cranial nerve deficits or cancer relapses were observed. CONCLUSIONProton beam stereotactic radiosurgery has been shown to be an effective means of tumor control. A high radiological response rate was observed. Excellent facial and trigeminal nerve function preservation rates were achieved. A reduced prescribed dose is associated with a significant decrease in facial neuropathy.

Localization to the Cortical Cytoskeleton Is Necessary for Nf2/Merlin-Dependent Epidermal Growth Factor Receptor Silencing

ABSTRACT Merlin, the product of the NF2 tumor suppressor gene, is closely related to the ERM (ezrin, radixin, moesin) proteins, which provide anchorage between membrane proteins and the underlying cortical cytoskeleton; all four proteins are members of the band 4.1 superfamily. Despite their similarity, the subcellular distributions and functional properties of merlin and the ERM proteins are largely distinct. Upon cell-cell contact merlin prevents internalization of and signaling from the epidermal growth factor receptor (EGFR) by sequestering it into an insoluble membrane compartment. Here we show that the extreme amino (N) terminus directs merlin biochemically to an insoluble membrane compartment and physically to the cortical actin network, with a marked concentration along cell-cell boundaries. This insoluble-membrane distribution is required for the growth-suppressing function of merlin and for the functional association of merlin with EGFR and other membrane receptors. Our data support a model whereby locally activated merlin sequesters membrane receptors such as EGFR at the cortical network, contributing to the long-held observation that the cortical actin cytoskeleton can control the lateral mobility of and signaling from certain membrane receptors.

Anti-vascular endothelial growth factor therapies as a novel therapeutic approach to treating neurofibromatosis-related tumors.

Patients with bilateral vestibular schwannomas associated with neurofibromatosis type 2 (NF2) experience significant morbidity such as complete hearing loss. We have recently shown that treatment with bevacizumab provided tumor stabilization and hearing recovery in a subset of NF2 patients with progressive disease. In the current study, we used two animal models to identify the mechanism of action of anti-vascular endothelial growth factor (VEGF) therapy in schwannomas. The human HEI193 and murine Nf2(-/-) cell lines were implanted between the pia and arachnoid meninges as well as in the sciatic nerve to mimic central and peripheral schwannomas. Mice were treated with bevacizumab (10 mg/kg/wk i.v.) or vandetanib (50 mg/kg/d orally) to block the VEGF pathway. Using intravital and confocal microscopy, together with whole-body imaging, we measured tumor growth delay, survival rate, as well as blood vessel structure and function at regular intervals. In both models, tumor vessel diameter, length/surface area density, and permeability were significantly reduced after treatment. After 2 weeks of treatment, necrosis in HEI193 tumors and apoptosis in Nf2(-/-) tumors were significantly increased, and the tumor growth rate decreased by an average of 50%. The survival of mice bearing intracranial schwannomas was extended by at least 50%. This study shows that anti-VEGF therapy normalizes the vasculature of schwannoma xenografts in nude mice and successfully controls the tumor growth, probably by reestablishing a natural balance between VEGF and semaphorin 3 signaling.

Cortical representations of bodies and faces are strongest in commonly experienced configurations

Faces and bodies are perhaps the most salient and evolutionarily important visual stimuli. Using human functional imaging, we found that the strength of face and body representations depends on long-term experience. Representations were strongest for stimuli in their typical combinations of visual field and side (for example, left field, right body), although all conditions were simply reflections and translations of one another. Thus, high-level representations reflect the statistics with which stimuli occur.

Wnt signaling promotes Müller cell proliferation and survival after injury.

PURPOSE Müller glia respond to retinal injury by a reactive gliosis, but only rarely do mammalian glial cells re-enter the cell cycle and generate new neurons. In the nonmammalian retina, however, Müller glia act as stem/progenitor cells. Here, we tested the function of Wnt signaling in the postinjury retina, focusing on its ability to influence mammalian Müller cell dedifferentiation, proliferation, and neurogenesis. METHODS A 532 nm frequency doubled neodymium-doped yttrium aluminum garnet (ND:YAG) laser was used to create light burns on the retina of Axin2(LacZ/+) Wnt reporter mice. At various time points after injury, retinas were analyzed for evidence of Wnt signaling as well as glial cell response, proliferation, and apoptosis. Laser injuries also were created in Axin2(LacZ/LacZ) mice, and the effect of potentiated Wnt signaling on retinal repair was assessed. RESULTS A subpopulation of mammalian Müller cells are Wnt responsive and, when Wnt signaling is increased, these cells showed enhanced proliferation in response to injury. In an environment of heightened Wnt signaling, caused by the loss of the Wnt negative regulator Axin2, Müller cells proliferated after injury and adopted the expression patterns of retinal progenitor cells (RPCs). The Wnt-responsive Müller cells also exhibited long-term survival and, in some cases, expressed the rod photoreceptor marker, rhodopsin. CONCLUSIONS The Wnt pathway is activated by retinal injury, and prolonging the endogenous Wnt signal causes a subset of Müller cells to proliferate and dedifferentiate into RPCs. These data raised the possibility that transient amplification of Wnt signaling after retinal damage may unlock the latent regenerative capacity long speculated to reside in mammalian neural tissues.

Extent of surgery in the management of locally advanced sinonasal malignancies.

The relative importance of surgery within multimodality regimens commonly used to treat advanced sinonasal malignancies remains unknown.