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The optimal management of asymptomatic, presumed WHO grade I meningiomas remains controversial.To define the safety and efficacy of stereotactic radiosurgery (SRS) compared with active surveillance for the management of patients with asymptomatic parafalcine/parasagittal (PFPS) meningiomas.Data from SRS-treated patients from 14 centers and patients managed conservatively for an asymptomatic, PFPS meningioma were compared. Local tumor control rate and new neurological deficits development were evaluated in the active surveillance and the SRS-treated cohorts.There were 173 SRS-treated patients and 98 patients managed conservatively in the unmatched cohorts. After matching for patient age and tumor volume, there were 98 patients in each cohort. The median radiological follow-up period was 43 months for the SRS cohort and 36 months for the active surveillance cohort (P = .04). The median clinical follow-up for the SRS and active surveillance cohorts were 44 and 36 months, respectively. Meningioma control was noted in all SRS-treated patients and in 61.2% of patients managed with active surveillance (P.001). SRS-related neurological deficits occurred in 3.1% of the patients (n = 3), which were all transient. In the active surveillance cohort, 2% of patients (n = 2) developed neurological symptoms because of tumor progression (P = 1.0), resulting in death of 1 patient (1%).Up-front SRS affords superior radiological PFPS meningioma control as compared with active surveillance and may lower the risk of meningioma-related permanent neurological deficit and/or death.

Objective: the optimal management of asymptomatic, skull-based meningiomas is not well defined. The aim of this study is to compare the imaging and clinical outcomes of patients with asymptomatic, skull-based meningiomas managed either with upfront stereotactic radiosurgery (SRS) or active surveillance. Methods: this retrospective, multicenter study involved patients with asymptomatic, skull-based meningiomas. The study end-points included local tumor control and the development of new neurological deficits attributable to the tumor. Factors associated with tumor progression and neurological morbidity were also analyzed. Results: the combined unmatched cohort included 417 patients. Following propensity score matching for age, tumor volume, and follow-up 110 patients remained in each cohort. Tumor control was achieved in 98.2% and 61.8% of the SRS and active surveillance cohorts, respectively. SRS was associated with superior local tumor control (p < 0.001, HR = 0.01, 95% CI = 0.002-0.13) compared to active surveillance. Three patients (2.7%) in the SRS cohort and six (5.5%) in the active surveillance cohort exhibited neurological deterioration. One (0.9%) patient in the SRS-treated and 11 (10%) patients in the active surveillance cohort required surgical management of their meningioma during follow-up. Conclusions: SRS is associated with superior local control of asymptomatic, skull-based meningiomas as compared to active surveillance and does so with low morbidity rates. SRS should be offered as an alternative to active surveillance as the initial management of asymptomatic skull base meningiomas. Active surveillance policies do not currently specify the optimal time to intervention when meningioma growth is noted. Our results indicate that if active surveillance is the initial management of choice, SRS should be recommended when radiologic tumor progression is noted and prior to clinical progression., NA

Determining the appropriate surgical indications for obtunded octogenarians with traumatic acute subdural hematoma (aSDH) has been challenging. We sought to determine which easily available data would be useful adjuncts to assist in early and quick decision-making.We performed a single-center, retrospective review of patients aged ≥80 years with confirmed traumatic aSDH who had undergone emergent surgery. The clinical measurements included the Karnofsky performance scale score, Charlson comorbidity index, Glasgow coma scale (GCS), and abbreviated injury score. The radiographic measurements included the Rotterdam computed tomography score, aSDH thickness, midline shift, and optic nerve sheath diameter (ONSD). The neurologic outcomes were defined using the extended Glasgow outcome scale-extended (GOS-E) at hospital discharge and 3-month follow-up. The Pearson correlation coefficient was used to compare the ONSD with all clinical, radiographic, and outcome variables. Multivariate logistic regression was used to assess the relationship between the discharge and 3-month GOS-E scores between all clinical and radiographic variables.A total of 17 patients met the inclusion criteria. The mean age was 82.5 ± 1.6 years (range, 80-85 years), and the mean GCS score was 11.2 ± 4.1 (range, 4-15). The mean discharge and 3-month GOS-E scores were 3.4 ± 2.6 (range, 1-8) and 2.3 ± 2.1 (range, 1-7), respectively. We found significant negative correlations between the ONSD and the GCS score (r = -0.62; P0.01) and the ONSD and discharge GOS-E score (r = -0.49; P = 0.05). Multivariate analysis revealed a significant association between the abbreviated injury score and the discharge GOS-E score (P = 0.05).Octogenarians sustaining aSDH and requiring emergent surgery have poor outcomes. More data are needed to determine whether the ONSD can be a useful adjunct tool to predict the efficacy of emergent surgery.

Background The optimal management of patients with incidental meningiomas remains unclear. The aim of this study was to characterize the radiologic and neurological outcomes of expectant and stereotactic radiosurgery (SRS) management of asymptomatic meningioma patients. Methods Using data from 14 centers across 10 countries, the study compares SRS outcomes to active surveillance of asymptomatic meningiomas. Local tumor control of asymptomatic meningiomas and development of new neurological deficits attributable to the tumor were evaluated in the SRS and conservatively managed groups. Results In the unmatched cohorts, 727 meningioma patients underwent SRS and were followed for a mean of 57.2 months. In the conservatively managed cohort, 388 patients were followed for a mean of 43.5 months. Tumor control was 99.0% of SRS and 64.2% of conservatively managed patients (P < .001; OR 56.860 [95% CI 26.253-123.150]). New neurological deficits were 2.5% in the SRS and 2.8% of conservatively managed patients (P = .764; OR 0.890 [95% CI 0.416-1.904]). After 1:1 propensity matching for patient age, tumor volume, location, and imaging follow-up, tumor control in the SRS and conservatively managed cohorts was 99.4% and 62.1%, respectively (P < .001; OR 94.461 [95% CI 23.082-386.568]). In matched cohorts, new neurological deficits were noted in 2.3% of SRS-treated and 3.2% of conservatively managed patients (P = .475; OR 0.700 [95% CI 0.263-1.863]). Conclusions SRS affords superior radiologic tumor control compared to active surveillance without increasing the risk of neurological deficits in asymptomatic meningioma patients. While SRS and active surveillance are reasonable options, SRS appears to alter the natural history of asymptomatic meningiomas including tumor progression in the majority of patients treated.

Gamma knife radiosurgery (GKRS) is often performed to treat brain metastases (BrMs). Widely referenced guidelines have suggested post-treatment imaging studies at 3-month intervals. However, clinicians frequently obtain magnetic resonance imaging (MRI) studies at3 months after GKRS.We performed a retrospective medical record review study to assess the utility of early (3 months) MRI after GKRS in patients with BrMs.A total of 415 GKRS procedures were performed. For 325 patients, early MRI studies were obtained. A total of 31 patients had new or worsened neurological symptoms. The early MRI studies showed adverse findings in 25 patients (78%), which in 23 (72%) had resulted in a change in treatment. For 294 patients, no new or worsened neurological symptoms were found on early MRI studies. Of these 294 patients, 86 (29%) had ≥1 adverse finding on MRI, and 60 (20%) had a change in management as a result. However, no rapidly growing tumors or other emergent adverse findings were seen.Early MRI (within 3 months) after post GKRS will frequently show adverse findings even in asymptomatic patients, more often in patients aged65 years and patients with multiple treated BrMs. However, according to the nature of the adverse findings observed in our retrospective study, it is unlikely that the clinical outcomes would have been affected if the post-GKRS MRI studies had been deferred to 3 months after treatment. Our data support deferring post-GKRS MRI to 3 months after treatment in the absence of new neurological signs or symptoms.

Meningioma, a type of brain tumor, is a common incidental finding on brain imaging. The best management approach for patients with an incidental meningioma remains unclear. This retrospective multi-center study investigated the outcomes of patients with an incidental meningioma in a frontobasal location, who were managed with active surveillance (n = 28) compared to stereotactic radiosurgery (SRS) (n = 84). Within 5 years of follow-up, SRS improved the radiological control of incidental frontobasal meningiomas (0% vs. 52%), but no symptoms occurred in either group. In the active surveillance cohort, 12% underwent an intervention for tumor growth. The findings of this study provide information to enable shared decision making between clinicians and patients with incidental frontobasal meningiomas. Meningioma is a common incidental finding, and clinical course varies based on anatomical location. The aim of this sub-analysis of the IMPASSE study was to compare the outcomes of patients with an incidental frontobasal meningioma who underwent active surveillance to those who underwent upfront stereotactic radiosurgery (SRS). Data were retrospectively collected from 14 centres. The active surveillance (n = 28) and SRS (n = 84) cohorts were compared unmatched and matched for age, sex, and duration of follow-up (n = 25 each). The study endpoints included tumor progression, new symptom development, and need for further intervention. Tumor progression occurred in 52.0% and 0% of the matched active surveillance and SRS cohorts, respectively (p < 0.001). Five patients (6.0%) treated with SRS developed treatment related symptoms compared to none in the active monitoring cohort (p = 0.329). No patients in the matched cohorts developed symptoms attributable to treatment. Three patients managed with active surveillance (10.7%, unmatched; 12.0%, matched) underwent an intervention for tumor growth with no persistent side effects after treatment. No patients subject to SRS underwent further treatment. Active monitoring and SRS confer a similarly low risk of symptom development. Upfront treatment with SRS improves imaging-defined tumor control. Active surveillance and SRS are acceptable treatment options for incidental frontobasal meningioma., NA

BACKGROUND Primary decompressive craniectomy (DC) is commonly performed for patients with traumatic brain injury (TBI). Some, but not all patients, will benefit from invasive monitoring of intracranial pressure (ICP) after surgery. We intended to identify risk factors for elevated ICP after primary DC to treat TBI. METHODS A retrospective chart review study identified all patients at our institution who underwent primary DC for TBI during the study period and who had ICP monitors placed at the time of surgery. Various preoperative and intraoperative variables were assessed for correlation with the presence of postoperative elevated ICP. RESULTS Postoperative elevated ICP occurred in 36% of patients after DC. In univariate analysis, Glasgow Coma Scale

The optimal management of asymptomatic, petroclival meningiomas remains incompletely defined. The purpose of this study was to evaluate the safety and efficacy of upfront stereotactic radiosurgery (SRS) for patients with asymptomatic, petroclival region meningiomas. This retrospective, international, multicenter study involved patients treated with SRS for an asymptomatic, petroclival region meningioma. Study endpoints included local tumor control rate, procedural complications, and the emergence of new neurological deficits. There were 72 patients (22 males, mean age 59.53 years (SD ± 11.9)) with an asymptomatic meningioma located in the petroclival region who were treated with upfront SRS. Mean margin dose and maximum dose were 13.26 (SD ± 2.72) Gy and 26.14 (SD ± 6.75) Gy respectively. Median radiological and clinical follow-up periods post-SRS were 52.5 (IQR 61.75) and 47.5 months (IQR 69.75) respectively. At last follow-up, tumor control was achieved in all patients. SRS-related complications occurred in 6 (8.33%) patients, with 3 of them (4.17%) exhibiting new neurological deficits. Upfront SRS for asymptomatic, petroclival region meningiomas affords excellent local tumor control and does so with a relatively low risk of SRS-related complications. SRS can be considered at diagnosis of an asymptomatic petroclival region meningioma. If active surveillance is initially chosen, SRS should be recommended when growth is noted during radiological follow-up.

Neurologic symptoms from leukemic infiltration of the central nervous system are an oncologic emergency, and expeditious treatment is required to preserve function. We report the case of a 44-year-old patient with relapsed acute myeloid leukemia (AML) who developed sub-acute cranial neuropathies refractory to treatment with intrathecal (IT) chemotherapy. The patient was therefore treated with an emergent course of whole-brain radiotherapy, resulting in immediate improvement and subsequent resolution of cranial neuropathies. This case illustrates that while central nervous system involvement by AML is rare, radiotherapy remains an effective modality to avoid long-term morbidity in patients failing to respond to systemic or IT chemotherapy.

Purpose/Objective(s) Although patients with brain metastasis treated with stereotactic radiosurgery (SRS) in the definitive or post-operative setting have high rates of local control, surveillance imaging is necessary to assess for central nervous system (CNS) recurrence. Guidelines recommend magnetic resonance imaging (MRI) of the brain every three months for surveillance in asymptomatic patients post-SRS. However, optimal frequency and duration of surveillance imaging in long-term survivors is unknown. Our objective is to define the yield and cost of surveillance MRIs in long-term (> 1 year) survivors following SRS. Materials/Methods We identified a cohort of patients with brain metastases treated with SRS in the definitive or postoperative setting at a single institution from 8/2014 to 9/2019. Eligible patients had at least one-year of follow-up with absence of CNS disease failure up to and including the first MRI of the brain after 12 months from SRS. Each post-treatment MRI of the brain was assessed for disease progression or new lesions. CNS disease-free survival was time from SRS to last follow-up, death or CNS failure. Delay to diagnosis and cost per patient were estimated using hypothetical MRI schedules of 2, 3, 4 and 6 months from 1-year post-treatment while CNS disease-free. Delay to diagnosis was calculated as time from actual CNS progression to hypothetical imaging date. Medicare reimbursement median cost of $498 per MRI brain with and without contrast was used for this analysis. Results A total of 373 patients treated with SRS for brain metastasis were identified at our institution. 61 patients met eligibility criteria for inclusion in this study (median follow-up 2.50 years, median age at treatment 60 years). The median CNS disease-free survival in this population was 2.37 years from date of SRS. 15 patients (24.6%) had CNS progression at median time of 2.26 years. Of the 15 patients, 3 patients were symptomatic at recurrence. Median frequency of MRI after one year post SRS was 5.9 months. Per patient, $1156 was spent annually on MRIs of the brain after 12 months with average annual yield of 17.0%. The cost per diagnosis of CNS progression was $6806. A 2-month, 3-month, 4-month and 6-month MRI schedule had a respective estimated delay to diagnosis of 0.69 months, 1.13 months, 1.44 months and 3.19 months. The respective mean total cost of each MRI schedule per patient from one-year post-treatment while CNS disease-free was $4662, $3053, $2229 and $1380. Conclusion Patients with metastatic disease to the brain treated definitively or postoperatively with SRS without evidence of CNS recurrence at one year have a low rate of CNS failure and relatively good prognosis. Based strictly on limiting delay of diagnosis, a 2-month MRI Brain schedule is optimal in this population, albeit with a relatively small increase in financial cost over the patient's lifespan. We propose a multi-institutional study of long-term survivors with brain metastasis to strengthen these findings. Author Disclosure B.J. Rich: None. D. Kwon: None. Y.S. Soni: None. D.L. John: None. J.B. Bell: None. G. Azzam: None. E.A. Mellon: None. R. Yechieli: Support and guide school in strategic and management related matters; Toras Chaim Toras Emes, Miami FL.C. Benjamin: None. R. Benveniste: None. R.J. Komotar: None. M. Ivan: None. J. Morcos: None. T. Diwanji: None.

Background Delayed subdural fluid collections can occur after Ommaya reservoir placement and can cause neurological symptoms and interfere with treatment. We performed a retrospective chart review in order to study risk factors for delayed subdural fluid collections and clinical outcomes. Methods Retrospective chart review was performed for patients undergoing ommaya reservoir placement between 2010-2019 at our institution. Results Out of 53 patients who had Ommaya reservoir placement during the study period, 11 developed delayed subdural fluid collections (21%). HIV infection was the only statistically significant risk factor (p=0.001, Fisher exact test). Thrombocytopenia, ventricle size, use of the reservoir, and suboptimal catheter placement were not associated with development of delayed subdural fluid collections. 2 patients, both HIV positive, required surgical evacuation. Conclusions Delayed subdural fluid collections occur in a significant minority of patients after Ommaya reservoir placement, and some patients require surgical intervention. HIV infection is associated with a higher risk of development of delayed subdural fluid collections. This patient subpopulation may benefit from closer monitoring or adjustment of management protocols.

Patients who present with traumatic brain injury (TBI) combined with blunt cerebrovascular injuries (BCVI) are difficult to manage, in part because treatment for each entity may exacerbate the other. It is necessary to develop a treatment paradigm that ensures maximum benefit while mitigating the opposing risks. A cohort of 150 patients from 2015 to present, with either internal carotid artery (ICA) and/or vertebral artery (VA) dissections or pseudoaneurysms, was cross-referenced with those who had sustained TBI. Of the 38 patients identified with both TBI and BCVI, 25 suffered ICA injuries, 10 had VA injuries and 3 had combined ICA/VA injuries. Unilateral BCVI occurred in 30 patients, while 8 had bilateral BCVI. Two patients required surgical intervention for TBI, and 5 patients required endovascular intervention for BCVI. Positive emboli detection studies (EDS) on transcranial dopplers (TCD) were demonstrated in 19 patients, with 9 patients having radiographic evidence of stroke. Anti-platelet therapy was initiated in 32 patients, and anti-coagulation in 10 patients, without new or worsening intracranial hemorrhages (ICH). Overall, 76% of patients were able to be discharged home or to rehabilitation, with good recovery demonstrated in 73% of the patients who had appropriate follow-up. In the setting of concurrent TBI and BCVI, use of anti-platelet/coagulation to prevent stroke can be safe if monitored closely. Here we describe a treatment paradigm which weighs the risk and benefits of therapies based on severity of ICH and stroke prevention, which tended to result in good disposition and recovery.

Normal pressure hydrocephalus (NPH) is generally treated with ventriculoperitoneal shunts (VPS), with improved symptoms in the majority of patients. We performed a retrospective chart review study in order to describe patterns of, and risk factors for, delayed symptom progression after initially successful VPS placement. 69 consecutive patients underwent VPS placement for NPH, and were followed for a minimum of 12 months postoperatively. 55 patients (80%) had objective improvement in their NPH symptoms after surgery. Of these, 27 patients (49%) developed delayed deterioration of at least one of their NPH symptoms, at a mean of 28.3 months postoperatively (range, 3–77). 1 of the 27 patients was found to have shunt malfunction; 19 had specific clinical or imaging evidence of shunt function. 6/19 patients had transient improvement in their symptoms (lasting 30 days or more) after adjustment of their programmable shunt valves (32%), although symptoms in all of these patients later worsened. During a mean follow up period of 44.4 months (range, 15–87), 12 patients (44%) received other neurological diagnoses felt to at least partially explain their symptoms. Increased patient age was associated with likelihood of delayed symptom progression. We conclude that delayed symptom progression is common after VPS placement for NPH, including after initial symptom improvement; that symptom progression can often be temporarily palliated by shunt valve pressure adjustment; and that older patients are more likely to experience delayed symptom progression. We suggest that patients and their families be counselled accordingly before surgery.

Background Because less-invasive techniques can obviate the need for brain biopsy in the diagnosis of primary central nervous system lymphoma (PCNSL), it is common practice to wait for a thorough initial work-up, which may delay treatment. We conducted a systematic review and reviewed our own series of patients to define the role of LP and early brain biopsy in the diagnosis of PCNSL. Methods Our study was divided into 2 main sections: 1) systematic review assessing the sensitivity of cerebrospinal fluid (CSF) analysis on the diagnosis of PCNSL, and 2) a retrospective, single-center patient series assessing the diagnostic accuracy and safety of early biopsy in immunocompetent PCNSL patients treated at our institution from 2012 to 2018. Results Our systematic review identified 1481 patients with PCNSL. A preoperative LP obviated surgery in 7.4% of cases. Brain biopsy was the preferred method of diagnosis in 95% of patients followed by CSF (3.1%). In our institutional series, brain biopsy was diagnostic in 92.3% of cases (24/26) with 2 cases that required a second procedure for diagnosis. Perioperative morbidity was noted in 7.6% of cases (n = 2) due to hemorrhages after stereotactic brain biopsy that improved at follow-up. Conclusions The diagnostic yield of CSF analyses for PCNSL in immunocompetent patients remains exceedingly low. Our institutional series demonstrates that early biopsy for PCNSL is safe and accurate, and may avert protracted work-ups. We conclude that performing an early brain biopsy in a suspected case of PCNSL is a valid, safe option to minimize diagnostic delay.

Background Our understanding of radiation induced meningiomas (RIM) is limited. It has been suggested that RIM harbor more aggressive cellular pathology and must be observed vigilantly. However, the actual recurrence rates of RIM compared to the sporadic meningiomas has yet to be defined. Objective We employ a single center case-control study to retrospectively assess recurrence rates between RIM (n = 12) and sporadic meningiomas (n = 118). Methods The criteria for the RIM group included the following: 1) History of intracranial clinical-dose radiation 2) Initial pathology other than meningioma, 3) Radiation administered greater than 5 years prior to meningioma onset. Recurrence rates, extent of resection and outcomes were analyzed. Results There was a significant difference in recurrence rates between the RIM group and sporadic meningioma: 50% vs. 5% respectively, p = 0.004. There was no significant difference in race, preoperative tumor volume, extent of resection, Ki67, or age between the two groups. Multivariate analysis demonstrated that size (OR 0.95 95%CI (0.92–0.99)), extent of resection (OR 1.08 95%CI (1.01–1.14)), WHO grade (OR 160.24 95% CI (6.32–74509)) and history of previous radiation (OR 1.28 95%CI (1.01–1.62)) were independent risk factors for recurrence. RIM patients had significantly higher proportion of atypical or malignant histology compared to sporadic patients (p Conclusion RIM patients may have a higher predisposition for tumor recurrence than patients with sporadic RIM. The use of Ki67 indices may help identify patients with a higher risk of tumor recurrence. Prospective studies focusing on newly diagnosed patients with RIM may help identify an optimal surveillance and treatment plan.

Objective We sought to determine whether a set of simple criteria can identify patients in the neuroscience intensive care unit (NICU) at high risk of poor outcome and delivery of nonbeneficial care early in the course of their illness. Secondarily, factors affecting limitation of care protocols were assessed. Methods We prospectively identified patients who were admitted to the NICU with partial loss of brainstem reflexes persisting for >24 hours due to an intrinsic lesion of the brain (trauma, stroke, hemorrhage, etc.). Results The study included 102 patients. Seventy-two of them died after a mean of 16 days (median: 8 days), and 23 remained comatose, locked-in, or in a vegetative state. Four were conscious and following commands, while 3 were minimally conscious, episodically obeying simple commands. Three out of 4 conscious patients were young males with traumatic brain injuries. Patients who remained full code spent a mean of 22.2 days in the NICU, compared with 10.4 for those who had withdrawal of care (P = 0.022) and 11.9 for patients who received a do-not-resuscitate order (P = 0.045). Time to death did not differ significantly between the groups. Overall, institution of various limitations of care protocols correlated positively with older age (odds ratio [OR] = 1.07, P = 0.0008), being treated on the neurology service (OR = 4.4, P = 0.043), and having health insurance (OR = 5.4, P = 0.03). Conclusions We identified simple criteria that can be used to identify patients in the NICU setting for whom continued aggressive care is likely nonbeneficial. Our analysis revealed demographic, social, and economic factors correlating with proxies' willingness to consider limitation of care.

Objective Diagnosing tumor progression and pseudoprogression remains challenging for many clinicians. Accurate recognition of these findings remains paramount given necessity of prompt treatment. However, no consensus has been reached on the optimal technique to discriminate tumor progression. We sought to investigate the role of magnetic resonance perfusion (MRP) to evaluate tumor progression in glioma patients. Methods An institutional retrospective review of glioma patients undergoing MRP with concurrent clinical follow up visit was performed. MRP was evaluated in its ability to predict tumor progression, defined clinically or radiographically, at concurrent clinical visit and at follow up visit. The data was then analyzed based on glioma grade and subtype. Resusts A total of 337 scans and associated clinical visits were reviewed from 64 patients. Sensitivity, specificity, positive and negative predictive value were reported for each tumor subtype and grade. The sensitivity and specificity for high-grade glioma were 60.8% and 87.8% respectively, compared to low-grade glioma which were 85.7% and 89.0% respectively. The value of MRP to assess future tumor progression within 90 days was 46.9% (sensitivity) and 85.0% (specificity). Conclusion Based on our retrospective review, we concluded that adjunct imaging modalities such as MRP are necessary to help diagnose clinical disease progression. However, there is no clear role for stand-alone surveillance MRP imaging in glioma patients especially to predict future tumor progression. It is best used as an adjunctive measure in patients in whom progression is suspected either clinically or radiographically.

A 66-year-old female developed progressive multifocal leukoencephalopathy (PML) 17 months after treatment with bendamustine and rituximab chemoimmunotherapy. During her evaluation for PML, she was found to have a CD4 count of 176 cells/μL (reference range 492-1740). The patient demonstrated spontaneous recovery of symptoms that occurred in parallel with recovery of the CD4 counts. While PML is associated with rituximab therapy, the timing and patients' clinical course are atypical, raising the possibility of a previously unreported association with bendamustine therapy.

Lymphoma involving the pituitary gland is very rare and usually results from metastatic spread of systemic lymphoma. We present a case of primary central nervous system (CNS) large B cell lymphoma that manifested as pituitary apoplexy. A 45-year-old woman presented with headache, and then rapidly developed a third nerve palsy and bitemporal hemianopsia. Imaging suggested a pituitary macroadenoma, with spontaneous necrosis, extending into the suprasellar region, compressing the optic chiasm and invading the right cavernous sinus. The patient underwent transsphenoidal resection which revealed a vascular, firm tumor. An aggressive decompression of the optic chiasm was performed with complete resolution of both visual fields and third nerve palsy. Final pathology showed B cell lymphoma. Systemic work-up including bone marrow aspiration and CSF studies showed no other foci of lymphoma, and the patient was HIV-negative. Chemotherapy with methotrexate, vincristine, procarbazine, and dexamethasone was administered for primary CNS lymphoma. This is an uncommon diagnosis of which the clinician should be aware in order to tailor surgical intervention and provide early institution of proper therapy.

Little is known regarding the neurocognitive impact of temporal lobe tumor resection. To clarify subacute surgery-related changes in neurocognitive functioning (NCF) in patients with left (LTL) and right (RTL) temporal lobe glioma. Patients with glioma in the LTL (n = 45) or RTL (n = 19) completed comprehensive pre- and postsurgical neuropsychological assessments. NCF was analyzed with 2-way mixed design repeated-measures analysis of variance, with hemisphere (LTL or RTL) as an independent between-subjects factor and pre- and postoperative NCF as a within-subjects factor. About 60% of patients with LTL glioma and 40% with RTL lesions exhibited significant worsening on at least 1 NCF test. Domains most commonly impacted included verbal memory and executive functioning. Patients with LTL tumor showed greater decline than patients with RTL tumor on verbal memory and confrontation naming tests. Nonetheless, over one-third of patients with RTL lesions also showed verbal memory decline. In patients with temporal lobe glioma, NCF decline in the subacute postoperative period is common. As expected, patients with LTL tumor show more frequent and severe decline than patients with RTL tumor, particularly on verbally mediated measures. However, a considerable proportion of patients with RTL tumor also exhibit decline across various domains, even those typically associated with left hemisphere structures, such as verbal memory. While patients with RTL lesions may show even greater decline in visuospatial memory, this domain was not assessed. Nonetheless, neuropsychological assessment can identify acquired deficits and help facilitate early intervention in patients with temporal lobe glioma. ANOVA, analyses of varianceCOWA, Controlled Oral Word AssociationCTB Comp, Clinical Trial Battery CompositeFLAIR, fluid-attenuated inversion recoveryHVLT-R, Hopkins Verbal Learning Test-RevisedHVLT-R DR, HVLT-R delayed recallHVLT-R Rec, HVLT-R delayed recognitionHVLT-R TR, HVLT-R total recallLTL, left temporal lobeNCF, neurocognitive functioningRTL, right temporal lobeSD, standard deviationTMTA, Trail Making Test Part ATMTB, Trail Making Test Part B.

Object Embryonic stem (ES) cell–derived astrocytes have several theoretical and practical advantages as gene therapy vectors in the treatment of malignant gliomas. The aim of this study was to test the proapoptotic effects of ES cell–derived astrocytes expressing transgenic tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in human malignant glioma cells. Methods Mouse ES cells containing a doxycycline-inducible transgene were engineered with human TRAIL (hTRAIL) and then directed to differentiate into astrocytes. The ES cell-derived–TRAIL-expressing astrocytes were cocultured with human malignant glioma cells. Reverse transcriptase polymerase chain reaction, immunocytochemistry, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling, and flow cytometry were used to quantify results. In vitro coculture of ES cell–derived astrocytes expressing hTRAIL with A172 human malignant glioma cells after doxycycline induction caused a significant decrease in cell viability from 85 ± 2% at baseline to 8 ± 2% posttreatment (p < 0.001). Labeling with apoptotic markers showed that cell death occurred by means of apoptosis. A significant increase in apoptotic rate (88 ± 3%) from baseline (4 ± 2%) was found in A172 cells after doxycycline induction (p < 0.005). This effect was superior to the apoptotic rate seen after treatment with recombinant TRAIL (57 ± 2%). A decrease in cell viability and an increase in the apoptotic rate were not found in TRAIL-expressing–ES cell-derived astrocytes after induction with doxycycline or in A172 cells exposed to doxycycline alone. Conclusions Engineering of transgenic hTRAIL by using ES cell–derived astrocytes induced apoptosis in human malignant glioma cells while sparing nontumor astrocytes. The apoptotic effects of transgenic hTRAIL are greater than those of recombinant hTRAIL. Analysis of these results suggests that hTRAIL-expressing–ES cell-derived astrocytes should be considered in the development of new in vivo strategies to treat malignant human gliomas.

Pituicytomas are rare tumors. Previously reported pituicytomas all presented with signs and symptoms relating to mass effect or endocrinological dysfunction. We report a 47 year old man who presented with sudden, severe headache and was found to have a hemorrhagic suprasellar mass with hemorrhage into the third ventricle. A mass arising from the pituitary stalk was found at surgery, and thorough pathological analysis revealed a pituicytoma. Pituicytoma should be considered in the differential diagnosis of a hemorrhagic suprasellar mass.

Object. In this paper the authors describe the indications for and the results and complications of repeated transsphenoidal surgery (RTSS) to treat recurrent or residual pituitary adenoma. Methods. A retrospective review was conducted of 96 consecutive patients who underwent RTSS to treat recurrent or residual pituitary adenoma. Ninety-six patients underwent RTSS: 42 to treat a recurrent or residual pituitary mass and 54 to treat a recurrent or persistent hormone hypersecretion. There was no case of perioperative death and there was a 1% incidence of major complications. Postoperative endocrinological deficiencies were uncommon unless planned total hypophysectomy was performed to treat Cushing disease. Clinical remission occurred in 93% of patients undergoing RTSS to treat a tumor mass, and 15% of patients initially experienced remission only to face a relapse after a mean of 32 months. Endocrinological remission occurred in 57% of patients undergoing RTSS to treat hormone hypersecretion; most of these patients had Cushing disease. Thirty-five percent of patients with an initial endocrinological remission experienced a relapse of their symptoms after a mean of 31 months (thus, 37% of patients achieved sustained endocrinological remission). We failed to identify factors that accurately predicted initial symptom remission or delayed relapse following RTSS. Ten patients in our series eventually underwent a third transsphenoidal surgery without major complications. Conclusions. Repeated transsphenoidal surgery is a more effective treatment for recurrent or residual mass than it is for hormone hypersecretion and has acceptable rates of morbidity and mortality. If hypophysectomy is not performed, endocrinological deficiencies are unlikely following RTSS.

Object. The aim of this study was to identify the optimal surgical goals and techniques for managing symptomatic Rathke cleft cysts (RCCs). Methods. The authors conducted a retrospective study of 62 consecutive patients who had undergone surgery for RCCs. Postoperative follow up was a mean of 28 months. Fifty-six patients underwent transsphenoidal cyst decompression and biopsy procedures, and six underwent cyst wall resection. Postoperatively, symptoms improved in 91% of patients with headaches and 92% of patients with visual deficits. Decompression and biopsy were associated with a 10% incidence of new anterior pituitary hormone deficiencies and a 6% incidence of new permanent diabetes insipidus; the incidence of new hormone deficiencies was significantly higher in the few patients who had undergone cyst wall resection. The incidence of relapse, defined as cyst regrowth with either recurrent symptoms or chiasmal compression, was 16%. Resection of the cyst wall was associated with a trend toward a decreased risk of relapse. Sellar packing, sellar floor reconstruction, and irrigation with absolute ethanol did not affect the likelihood of relapse. Squamous metaplasia and inflammation increased the risk of relapse. Residual cyst demonstrated on postoperative magnetic resonance imaging was associated with an increased risk of subsequent asymptomatic cyst regrowth. Seven patients (11%) underwent repeated operation with symptomatic improvement and minimal morbidity; only one patient relapsed following a second surgery. Conclusions. Decompression and biopsy procedures in the treatment of RCCs lead to improvement in signs and symptoms, with low morbidity rates. Repeated operations will be required in as many as 16% of patients but are also associated with symptomatic improvement, low morbidity, and durable remission. Decompression and biopsy may represent the optimal surgical management of RCC.

Neurosurgeons are often involved in the care of patients with cerebral venous sinus thrombosis (CVST). Medical management of CVST includes appropriate diagnostic imaging studies, evaluation for potentially treatable causes of thrombosis, and control of increased intracranial pressure with m

Object Frameless image-guided stereotaxy is often used in the resection of high-grade gliomas. The authors of several studies, however, have suggested that brain shift may occur intraoperatively and result in inaccurate resection. To determine the usefulness of frameless stereotactic image-guided surgery of high-grade gliomas, the authors correlated factors predictive of brain shift, such as tumor size, periventricular location, and patient age (as an indicator of brain atrophy) with the extent of resection. Methods Inclusion criteria included the following: 1) stereotactic volumetric craniotomy for resection of tumor; 2) histologically proven high-grade glioma; 3) preoperative magnetic resonance (MR) imaging demonstration of an enhancing portion of tumor; 4) postoperative MR imaging within 48 hours to assess the extent of resection; and 5) preoperative intention to perform gross-total resection of the enhancing tumor. Fifty-four patients met these criteria between September 1997 and November 2002. Accurate resection was considered to be indicated by a lack of nodular enhancement on postoperative Gd-enhanced MR images obtained within 48 hours of surgery. Frameless stereotactic image-guided surgery resulted in the successful resection of 46 (85%) of 54 high-grade gliomas. Accurate resection was significantly more likely with tumors less than 30 ml in volume than with those greater than 30 ml (93 and 58%, respectively [p < 0.05]). In addition, small periventricular tumors were associated with significant less successful resection compared with nonperiventricular tumor (77 and 96%, respectively [p = 0.5]). Patient age did not affect the likelihood of successful resection. Conclusions Frameless image-guided stereotactic techniques can be reliably used for accurate resection of high-grade gliomas when the tumor is less than 30 ml in volume and not adjacent to the ventricular system. In cases involving tumors larger in volume or located near the ventricles, intraoperative ultrasonography or MR imaging updates should be considered.

e23165 Background: We have previously shown that Procollagen alpha 1 type 1 (Col1A1) is found more in low and intermediate grade glioma and less often in glioblastoma(GBM) (Cancer Invest. 23:577, 2005). We now investigate their role in cellular function. Methods: 4 glioma cell lines: Glioma 1 and U118 express high amount of Col1A1 ( Col1A1+) ; A172 and SW1783 express insignificant amount of Col1A1 ( Col1A1 - ) as the model . All four cell lines express SPARC. Scratch, transwell, and metrigel assay were used to study migration and invasion. Cell cycles were analyzed by flowcytometry. Results: U118 has the highest amount of SPARC followed by A172, SW1783 and Glioma 1. Thus it does not appear to have any relationship between these two proteins which are known as binding partner. Glioma 1 showed the least invasion and migration followed by U118, SW1783 and A172. Thus, Col1A1 expression appear to correlate with invasiveness. To further confirm this, we have silence Col1A1 in Glioma 1 and U118 using both siRNA and shRNA. All clones exhibit more migration and invasion. However, it does not affect both intracellular and extracellular levels of SPARC. Silencing Col1A1 results in increasing G2M arrest; 11% in U118 and 6% in Glioma 1. However it does not affect cellular proliferation. To further verify this, we have overexpressed Col1A1 in A172 and SW1783 using plasmid containing Col1A1 and DDK tag. These Col1A1 (+) A172 and SW1783 transfectants exhibit less migration and invasion. However, there is no effect on SPARC levels. These Col1A1 positive cells exhibit 12% increase in Go/G1 arrest and decrease in proliferation. A limited protein array also showed that silencing Col1A1 increase in STAT3, 5 and 6 and AKT levels. Interestingly, a difference in sensitivity to STAT3/5 inhibitors also noted in parental and their Col1A1 knock down transfectants. Conclusions: our results support the role of Col1A1 in glioma cell invasiveness, and hence confirm our previous data which showed that Col1A1 is found more in low grade and intermediate grade glioma. Thus, Col1A1 could be an additional useful marker to assess the aggressiveness of GBM beside histopathological grading. Col1A1 may also play a role in cellular signaling pathway.

The FMRFamide (dFMRFa) neuropeptide gene is expressed in about 17 diverse cell types in the Drosophila central nervous system. This expression pattern is generated by transcriptional control elements that are distributed over 8 kilobases of dFMRFa DNA. Previous studies identified one enhancer within the dFMRFa 5' region that is both necessary and sufficient to drive reporter transgene expression in one of the 17 dFMRFa cell types, the OL2 neurons. We now report the presence of two additional, non-overlapping enhancers within the gene: One drives expression by the six Tv neuroendocrine cells, and another in the four X and X2 interneurons. We also show that the Tv neuron-specific enhancer itself has complex organization, with several positively and negatively acting cis elements. Together, these results describe the organization of what is likely to be a prototypic neuronal gene promoter: an assemblage of multiple, independent, cell type-specific enhancers, each consisting of multiple quantitative elements.

Magnetic resonance imaging (MRI) or computerized tomography (CT) is routinely performed after resection of brain metastases (BrM), regardless of whether there are specific clinical concerns about residual tumor or potential complications. Routine imaging studies contribute a significant amount to the cost of medical care, and their yield and utility are unknown. An IRB-approved retrospective chart review study was performed to analyze all craniotomies for BrM performed at our institution from 2005 to 2012. Descriptive statistics were used to quantify the yield of postoperative imaging. 218 consecutive patients underwent 226 craniotomies for BrM. In 21 cases, new or worsened neurologic deficits occurred after surgery (9.0 %), and 19 of the 21 underwent postoperative imaging. 9 of the 19 patients (47 %) had significant findings on postoperative imaging, and 2 patients required reoperation. 201 patients had no new neurologic deficits (91 %), and 23 of these patients had no postoperative imaging. Of the 178 remaining patients, 160 underwent postoperative MRI and 18 underwent postoperative CT. 9 patients (5.1 %) had unexpected adverse imaging findings; 6 had small stroke, 1 had a subdural hemorrhage and 2 had possible or definite venous sinus occlusion. None of the imaging findings led to changes in management. 182 patients underwent imaging appropriate to detect residual tumor (177 gadolinium enhanced MRI and 5 contrast enhanced CT). Of these patients, 16 were known to have small residual tumors based on intraoperative findings. Of the remaining 166 patients felt to have had gross total tumor resection, 9 (5.4 %) were found to have a small amount of residual tumor on postoperative imaging; no patient had a change in treatment plan as a result. Routine postoperative imaging in patients undergoing craniotomy for BrM has a very low yield and may not be appropriate in the absence of new neurologic deficits, or specific clinical concerns about large amounts of residual tumor or intraoperative complications.

We have previously shown that Procollagen alpha 1 type 1 (Col1A1) is found in low and intermediate grade glioma and in less aggressive glioblastoma multiforme (GBM) (Cancer Invest. 23:577, 2005). However, these tumor cells are more prone to ER stress -inducing agents such as Befeldine (BFA) which block the transport of Procollagen to the cell surface. We also found that GBM cells which possess Col1A1 also express DDR2. The role of Col1A1/ DDR2 signaling in glioma is not known. We have used three GBM cell lines: Glioma1 established in our laboratory from a patient who progressed from grade 3 to grade 4, U-118, A-172 and U-373 to study this signaling pathway. Both Glioma1 and U-118 express Col1A1 and DDR1 and 2. A-172 and U-373 do not express Col1A1 but express both DDR2. U-373 does not express HSP47 which is an essential protein to fold collagen. In order to define the function of DDR2/ Col1A1 in GBM, we have used knock down COL1A1 and DDR2. Silencing Col1A1 leads to a significant increase in invasiveness by Matrigel assay which indicated that Col1A1 is important in preventing invasion in GBM and hence is found more in low and intermediate grade glioma. However, it has minimal effect on cell cycle or cell proliferation. Next, we have silenced DDR2 in all 4 cell lines and studied the biochemical changes. We found that silencing DDR2 does not affect cell proliferation, cell death or cell cycle. However, it does affect the sensitivity to BFA. In cell lines which possess Col1A1, the cell viability increased by 20 -30% (p Citation Format: Shumei Chen, Chunjing Wu, Ying-Ying Li, Medhi Wangpaichitr, Ronald J. Benveniste, James Turkson, Niramol Savaraj, Lynn G. Feun. The relationship of Procollagen alpha 1 type 1 (Col1A1) / DDR2 signaling in malignant glioma and sensitivity to STAT 3/5 inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3712.

Objectives Our practice has transitioned from using fat autograft to acellular dermal matrix (AlloDerm, LifeCell Corp, Woodlands, Texas, USA). We present the largest series to our knowledge of AlloDerm for sellar floor repair after transsphenoidal approach to pituitary adenoma and compare rates of postoperative cerebrospinal fluid (CSF) leak with an earlier cohort of patients whose CSF leaks were repaired with fat autograft. Design This is a retrospective cohort study comparing sellar repair with fat autograft versus inlay Alloderm between the years 2003 and 2012. The primary end point was postoperative CSF leak. Results A total of 429 patients (368 primary; 83 revision operations) without intraoperative lumbar drainage were included. A total of 18 postoperative CSF leaks were observed (3.9%). Intraoperative CSF leak occurred in 160 cases (35.5%). Among this subset of patients with intraoperative CSF leak, 95 underwent repair with AlloDerm and 46 underwent repair with fat autograft, with postoperative CSF leak rates of 8.4% and 15.2%, respectively (p = 0.34, chi-square test); 19 patients underwent repair with other techniques or no repair at all, with postoperative leak rate of 0%. Conclusions AlloDerm is an effective alternative to fat autograft in cases of low-flow CSF leak following transsphenoidal resection of pituitary adenoma.

3,4-Methylenedioxymethamphetamine (MDMA, or "Ecstasy" in tablet form) is a powerful sympathomimetic drug that is commonly perceived as safer than other stimulants such as methamphetamine or cocaine. "Molly" is a purified form of MDMA that is perceived by users as being even safer, as it is free of adulterants such as methamphetamine. Previously, all reports of intracranial hemorrhages in MDMA abusers were associated with coingestion of other sympathomimetic drugs, or with pre-existing cerebrovascular lesions. We describe a series of three young, otherwise healthy patients with various types of intracranial hemorrhages associated with "Molly" ingestion. All three patients underwent extensive workup including catheter angiography that did not demonstrate aneurysm, arteriovenous malformation, or vasculitis. We suggest that even the purified form of MDMA can cause serious intracranial hemorrhagic complications and should not be thought of as a safe recreational drug.

Experimental data indicate that antagonists of growth hormone-releasing hormone (GHRH) could be used clinically in disorders characterized by excessive GHRH/growth hormone (GH) secretion, but direct evidence for the effectiveness of GHRH antagonists on human pituitary tissue is still lacking. In this study, we investigated the inhibitory effect of our GHRH antagonists MZ-4-71 and JV-1-36 and the somatostatin (SST) analog RC-160 on superfused pituitary cells obtained from a human GH-secreting adenoma. Using Western blot analysis and immunohistochemistry, we demonstrated profuse expression of the GHRH receptor and its major splice variant SV1 and an increase in the expression of Gsa protein in the adenoma tissue. Exposure of the tumor cells to exogenous pulses of GHRH induced definite GH responses, causing a 3- to 5-fold elevation of the basal GH level. The antagonists MZ-4-71 and JV-1-36 did not alter basal GH secretion, indicating that the adenoma cells did not secrete GHRH in an autocrine manner. However, both antagonists prevented the stimulatory effect of exogenous GHRH. Similarly to the GHRH antagonists, neither SST-14 nor the SST analog RC-160 had an effect on the basal GH secretion of the tumor cells, but both peptides inhibited the stimulatory effect of exogenous GHRH, with RC-160 being more potent than SST. Our study provides direct evidence for the effectiveness of potent GHRH antagonists such as MZ-4-71 and JV-1-36 on human pituitary GH-secreting adenoma tissue and strongly suggests that these drugs could be used for therapy of GHRH-associated forms of acromegaly, particularly for those patients in whom surgery fails or is not an option.

Background/Aims: A significant minority of stereotactic biopsies (SBs) of brain lesions is nondiagnostic, yet there are no optimal strategies for preventing nondiagnostic SB (NDSB) and for managing patients after NDSB. We performed this study in order to identify risk factors for NDSB, to determine how diagnoses are eventually reached in these patients, and to ascertain whether NDSB affects clinical outcomes. Methods: Retrospective chart review of patients at our institution who underwent SB of brain lesions. Results: Twenty-four out of 100 SBs were nondiagnostic. NDSB was less likely in contrast-enhancing brain lesions in immunocompetent patients, with larger lesions and in the setting of diagnostic findings on intraoperative frozen section analysis. Of 16 patients with adequate postoperative follow-up, a diagnosis was eventually reached in 11, via further review of the pathology, retrieval of additional tissue specimens or additional noninvasive testing. Survival times for patients with NDSB and eventual tumor diagnoses were within expected ranges for patients with similar tumors. Three of the 5 patients who never received a final diagnosis enjoyed prolonged survival without progressive symptoms. Conclusions: Surgeons should consider taking additional specimens in the case of nondiagnostic intraoperative frozen section during SB. If a tumor is suspected and final pathology is nondiagnostic, outside review of the slides may be helpful, and sampling further tissue should be considered. For diseases other than tumors, the diagnosis will generally be made without a repeat biopsy. The delays in diagnosis resulting from NDSB do not appear to affect survival, at least in patients eventually found to have brain tumors.

We report a 65 year old man who presented with left hemiparesis, and was found to have multiple, discrete, peripherally enhancing, hemorrhagic intra-axial masses in the right hemisphere of the brain. Workup for malignancy elsewhere in the body was negative, and biopsy confirmed glioblastoma multiforme. The patient responded clinically to treatment with radiation therapy and temozolomide. We discuss the unusual aspects of this case and stress the importance of tissue diagnosis in managing suspected intracranial malignancies.

The occurrence of pheochromocytoma in multiple endocrine neoplasia type 2A (MEN 2A) carriers varies greatly. This study aims to determine PC expression for specific MEN 2A RET mutations.Charts of MEN 2A patients enrolled in our multiple endocrine neoplasia program from 1990 to 2001 were reviewed retrospectively. Statistical analysis was performed using SAS software (SAS Institute, Inc, Cary, NC).RET mutation data and pheochromocytoma data were compiled for 323 patients. Overall, penetrance of pheochromocytoma occurred in 102 of 323 patients (32%). Bilateral pheochromocytomas were observed in 67 patients (66%). The following codon-specific expression of pheochromocytoma was observed: 1 of 24 patients expressed codon 609 (4%), 0 of 5 patients expressed codon 611 (0%), 23 of 105 patients expressed codon 618 (22%), 4 of 45 patients expressed codon 620 (9%), and 74 of 149 patients expressed codon 634 (50%) (P.001). An association between pheochromocytoma expression and amino acid substitutions at codon 618 was observed as follows: 0 of 7 patients with C618F, 5 of 21 patients with C618G (24%), 11 of 27 patients with C618R (41%), 7 of 41 patients with C618S (17%), and 0 of 9 patients with C618Y (P = .04.) In our cohort, no deaths were attributable to PC with a median follow-up of 9 years.The penetrance of PC varies between MEN 2A RET codon mutations. Furthermore, we observed variable expression with different amino acid substitutions at the same codon. These results may help guide screening and therapy for MEN 2A patients.

We have previously shown that Col1A1 expression is found more frequently in low to intermediate grade glioma than high grade glioma(Cancer invest. 23:577,2005). On the other hand, its receptor DDR1 is found in high grade glioma and often signifies poor prognosis. We hypothesize that DDR2 which also binds to Col1A1 may play a role in mediating this complex relationship. We have investigated this relationship using 3 cell lines (2 cell lines, Glioma 1 and U-118, both express both Col1A1 and DDR1&2, A-172 which does not express Col1A1 but does express both DDR1&2). All cell lines were maintained in EMEM with 10% FCS. Treatment with Befeldin A (BFA), which blocks Col1a1 to the cell surface, results in ER stress with increase in GRP78 and growth inhibition in all three cell lines. U-118 was the most sensitive (ID50 of 9 ng/ml for U- 118, Glioma 1 (13ng/ml), and A-172 (24ng/ml)). Silencing Col1A1 resulted in decreased DDR1 & 2 in Glioma 1 and U-118 and decreased sensitivity to BFA by 20% for Glioma 1 and 10% in U-118. Silencing Col1 A1 resulted in G2M arrest and decrease in ERK1/2, JNK, and c-Jun, but increase in PDGF, CREB and P70 by protein array analysis and confirmed by Western blot. We further investigated the biological effect of silencing either DDR1 (primary DDR1a which is the major isoform found in Glioma 1 and DDR2). We found that silencing DDR 1 had no effect on DDR2 expression and vice versa. Interestingly, in contrast to silencing Col1A1, silencing either DDR1 or 2 had no effect on Col1A1 expression in Glioma 1 and U-118 and also no effect on cell cycle or cellular proliferation. In addition, silencing DDR1 or 2 led to decreased sensitivity to BFA for both Glioma and U-118 with increase in ID50 by 35-50% respectively. Furthermore, we have also found an increase in p-AKT, p-38, JNK and p-Jun after 48-hr post silencing of DDR2 while silencing DDR1 had minor effect. However, these proteins decreased after BFA treatment. In contrast, silencing DDR1 or DDR2 led to increased sensitivity to BFA in A-172 cells with reduction of ID50 by 20%. In addition, a decrease in p-AKT, p-38 and ERK were also seen. Silencing DDR1 or DDR2 also showed significant reduction in invasion in A-172 cell line, while minimal changes were seen in Glioma 1 and U-118. Since DDR1 has multiple subfamilies, while DDR1a is the most common one in brain tumor, it is possible that silencing one subfamily may upregulate the other subfamily. However, DDR2 has only one family and may explain the more profound effect in silencing DDR2. Taken together, our data suggest that the function of DDR2 is different among cell lines, and may be dictated by the presence of Col1A1 which is present in certain malignant glioma. We are currently investigating the possible mechanism(s) involved. Future targeted therapy in malignant glioma will need to take into consideration the different functions of DDR2. (Supported by Wanfang Hospital-Taipei medical university fellowship award and VA research grant) Citation Format: Shumei Chen, Chunjing Wu, Ying Ying Li, Medhi Wangpaichitr, Lynn G. Feun, Ronald Benveniste, Vy Dinh, Niramol Savaraj. The role of discoidin domain receptor 2 (DDR2) and its relationship with procollagen alpha 1 type 1(Col1A1) in malignant glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 43. doi:10.1158/1538-7445.AM2015-43

Object For gene therapy strategies currently in clinical trials, viral vectors are used to deliver transgenes directly to normal and tumor cells within the central nervous system (CNS). The use of viral vectors is limited by several factors. The aim of this study was to assess whether embryonic stem cell (ESC)–derived astrocytes expressing a doxycycline-inducible transgene can be used as a vector for gene therapy. Methods The authors generated a pure population of ESC-derived astrocytes carrying a transgene, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), inserted in the chromosome under the control of a highly regulated doxycycline-inducible expression system. Fully differentiated ESC-derived astrocytes were stereotactically transplanted in the mouse brain, and then cell migration and transgene expression were studied. Results The ESC-derived astrocytes started to migrate from the transplant site 48 hours after the procedure. They were found to have migrated throughout the brain tissue by 6 weeks. Transplanted ESC-derived astrocytes expressed the TRAIL transgene after doxycycline induction throughout the duration of the experiment. Teratoma formation was not observed in long-term experiments (12 weeks). Conclusions These data show that ESC-derived astrocytes can be used as delivery vectors for CNS tumors. This technique might have a major impact on the treatment of patients with malignant gliomas and a wide spectrum of other neurological diseases.

Object. Embryonic stem cell (ESC)‐derived astrocytes have many theoretical and practical advantages as vectors for delivery of gene therapy to the central nervous system (CNS). The aim of this study was to generate highly pure populations of ESC-derived astrocytes expressing drug-inducible transgenes, while minimizing contamination by undifferentiated ESCs Methods. Embryonic stem cells carrying a doxycycline-inducible green fluorescent protein (GFP) transgene were induced to differentiate into astrocytes by using feeder cell‐free conditions that are completely defined. More than 95% of these cells expressed the astrocyte markers glial fibrillary acidic protein and GLT-1 glutamate transporter, and the morphological characteristics of these cells were typical of astrocytes. The expression of additional astrocyte markers was detected using reverse transcription‐polymerase chain reaction. Undifferentiated ESCs comprised fewer than 0.1% of the cells after 10 days in this culture. Positive and negative selection techniques based on fluorescence-activated cell sorting were successfully used to decrease further the numbers of undifferentiated ESCs. Fully differentiated astrocytes expressed a GFP transgene under the tight control of a doxycycline-responsive promoter, and maintained their astrocytic phenotype 24 hours after transplantation into the mouse brain. Conclusions. This study shows that transgenic ESCs can be induced to differentiate into highly pure populations of astrocytes. The astrocytes continue to express the transgene under the tight control of a drug-inducible promoter and are suitable for transplantation into the mouse brain. The number of potentially hazardous ESCs can be minimized using cell-sorting techniques. This strategy may be used to generate cellular vectors for delivering gene therapy to the CNS.

Background Despite near complete penetrance and frequent early evaluation of medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia 2 (MEN 2) variants, a significant minority of patients are evaluated later in life. Methods With the aim of characterizing the expression of hereditary MTC in an older cohort, MEN 2 patients from our institutional database who were evaluated after age 50 years were identified, and clinical data were reviewed. Results Thirty-nine patients (36 MEN 2A, 3 FMTC, and no MEN 2B) who were evaluated after age 50 years were identified; they represented 9% of all MEN 2 patients who were enrolled in our program. Most of the patients (79%) had abnormal screening examinations, and the AJCC staging was significantly higher in this cohort compared with younger patients. Overall, 43% of the patients had normal calcitonin levels after operation. There were 3 observed MTC-related deaths, all from distant metastases; the overall survival rate was 86% at 5 years and 74% at 10 years. The distribution of RET mutations in this cohort was similar to younger patients. Conclusions These results suggest the presence of modifiers of MTC expression. Despite the tendency of older patients with hereditary MTC to have advanced stage disease at evaluation, they have high rates of biochemical cure, and the overall survival is excellent.

We have previously shown that certain gliomas expressed procollagen type1 alpha1(1α1). Procollagen is synthesized in the endoplasmic reticulum, modified and packaged in the Golgi body and transported out of the cells. Once exited, the N-and C-terminal are cleaved by peptidase and fibril is formed. The collagen can interact with integrin, Endo180, or discoindin domain receptor(DDR). DDR is a class of receptor tyrosine kinase. The binding to collagen triggers autophosphorylation of DDR and initiation of other signaling cascades which are poorly understood, but have been implicated for cellular proliferation and invasion. DDR is comprised of 2 members(DDR1 and DDR2). Thus far, the clinical relevance of this pathway is not known. However, DDR1 has been reported in glioblastoma multiforme, both in cell lines and tissue and correlates with poor prognosis. In this report, we investigated the expression of procollagen1α1, DDR1 and DDR2 in 6 glioma cell lines. Silencing procollagen1α1, DDR1 or DDR2 resulted in impairment of cell migration. Silencing procollagen1α1 resulted in cell cycle arrest at G2/M. This effect is less when silencing DDR1 or DDR2. However, silencing DDR1 or DDR2 resulted in attenuation of pERK and pAKT. Since there is no inhibitor of collagen or DDRs, we have used Brefeldin A, which can block procollagen secretion out of the cell. Treatment with Brefeldin A resulted in retention of procollagen in the ER. Thus, less procollagen was secreted and hence there was less ligand to bind DDRs. As a result, less DDRs were activated. Our data suggest that there is a definite relationship between collagen and DDRs in gliomas which can affect cellular proliferation and migration. The downstream of this signaling is not yet understood but it can be explored for future treatment of glioma which possess both the ligand and receptor.

AIDS is an increasingly common diagnosis seen by neurologists and neurosurgeons alike. Although the more common brain lesions associated with AIDS are due to central nervous system lymphomas, toxoplasma encephalitis or progressive multifocal leukoencephalopathy, relatively recent clinical evidence has shown that AIDS-independent cerebral tumours can arise as well, albeit less commonly. Previous incidents have been reported with HIV and AIDS patients presenting with cerebral astrocytomas. To our knowledge, there has never been a report in the literature of a brainstem anaplastic glioma occurring in an AIDS or HIV patient. We report a 55-year-old patient with HIV and brainstem anaplastic glioma. Its presentation, diagnostic difficulty, scans, histology and subsequent treatment are discussed. We also review the relevant literature on gliomas in HIV/AIDS patients.

SUMMARY Respiratory changes following transurethral resection of the prostate were studied in 26 men. Right-to-left pulmonary shunt determinations were made in ten patients, and total lung volume and weight determinations were made in the remainder. Nine of ten showed postoperative decrease in pulmonary shunt. The tenth showed no change. Total lung volume, functional residual capacity, inspiratory capacity, and body weight measurements showed no consistent change after transurethral resection. The significance of a large right-to-left shunt preoperatively, and its apparent decrease after surgery are discussed.