Bio

Clinical Focus


  • Spinal Cancer - Surgery
  • Pituitary Adenomas - Neurosurgery
  • Brain / Central Nervous System Tumors - Neurosurgery
  • Cancer > Neuro Oncology
  • Germ Cell Tumors - Neurosurgery
  • Brain / Central Nervous System Tumors
  • Multiple Endocrine Neoplasias
  • Neuroendocrine
  • Spinal Cancer
  • Acoustic Neuroma
  • Leptommeningeal Disease - Neurosurgery
  • Spinal Cancer - Neurosurgery
  • Skull Base Tumors - Neurosurgery
  • Neurosurgery
  • Acoustic Neuroma - Head and Neck Surgery
  • Brain / Central Nervous System Tumors - Neuro Oncology
  • Skull Base Tumors
  • Germ Cell Tumors
  • Neurological Surgery
  • Skull Base Tumors - Head and Neck Surgery
  • Neuroendocrine - Surgery
  • Pituitary Adenomas
  • Multiple Endocrine Neoplasias - Neurosurgery
  • Leptommeningeal Disease

Academic Appointments


Administrative Appointments


  • Assocoate Dean, Post-graduate Medical Edcation, Stanford University School of Medicine (2012 - Present)
  • Director, Stanford Brain Tumor Center (2010 - Present)
  • Program Director, Stanford Neurosurgery Resident Training Program (2004 - Present)
  • Surgical Director, Stanford Pituitary Center (2004 - Present)
  • Director, Stanford Surgical Neuro-oncology (1998 - Present)

Honors & Awards


  • Excellence in Resident Teaching, Stanford Neurosurgery (2000)
  • Outstanding Teacher Award, MGH Neurosurgery (1994)
  • Golden Amygdala Teaching Award, UCSF Neurosurgery (1990)
  • Rhodes Scholarship, Rhodes Trust (1975-1978)

Professional Education


  • Internship:UCSF Medical Center (1981) CA
  • Residency:UCSF Medical Center (1986) CA
  • Fellowship:University of Pittsburgh School of Medicine (1990) PA
  • Board Certification: Neurological Surgery, American Board of Neurological Surgery (1989)
  • Medical Education:Harvard Medical School (1980) MA
  • MBA, Boston University, Business Administration (1990)
  • MD, Harvard Medical School, Medicine (1980)
  • MA, Oxford University, Neuroscience (1978)

Research & Scholarship

Current Research and Scholarly Interests


Microsurgical treatment of tumors of the brain, spinal cord, pituitary gland and skull base;
Radiosurgery of tumors;
Molecular biology of brain tumors.

Clinical Trials


  • Verubulin, Radiation Therapy, and Temozolomide to Treat Patients With Newly Diagnosed Glioblastoma Multiforme Not Recruiting

    This, international, multi-center, Phase 2 study of verubulin will be conducted in patients with newly diagnosed Glioblastoma Multiforme (GBM). The study will be conducted in two parts. Part A is an open-label dose finding study that will determine the safety and tolerability of verubulin in combination with standard treatment. Part B is a randomized open-label study that will investigate progression-free survival and overall survival of patients receiving verubulin, at the dose determined in Part A, in combination with standard treatment versus standard treatment alone.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cathy Recht, (650) 725 - 8630.

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  • PI/II of Temozolomide & Hypofractionated Radiotherapy in Tx of Supratentorial Glioblastoma Multiform Recruiting

    The purpose of this study is to investigate the safety and effectiveness of a combination treatment for glioblastoma multiforme utilizing radiotherapy with the FDA approved chemotherapy drug temozolomide

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  • Phase I Vorinostat Concurrent With Stereotactic Radiosurgery (SRS) in Brain Metastases From Non-Small Cell Lung Cancer Recruiting

    The purpose of this study is to determine the maximum tolerated dose (MTD) of vorinostat given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLCA) brain metastases in patient with 1-4 lesions.

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  • XERECEPT® (hCRF) for Patients Requiring Dexamethasone to Treat Edema Associated With Brain Tumors Not Recruiting

    The purpose of this study is to compare the safety and efficacy of XERECEPT® to dexamethasone (Decadron) a common treatment for symptoms of brain swelling (edema). This study is specifically aimed at patients who require chronic high doses of dexamethasone to manage symptoms.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lynn Adler, (650) 725 - 8630.

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  • Phase I Trial of Arsenic Trioxide and Stereotactic Radiotherapy for Recurrent Malignant Glioma Not Recruiting

    To investigate the safety of delivering arsenic trioxide (ATO) in combination with stereotactic radiotherapy in recurrent malignant glioma by performing an open label, Phase I dose escalation trial. Results from this study will provide a basis for further study of ATO combined with radiation therapy as a radiosensitizer for malignant brain tumors in future Phase II studies.

    Stanford is currently not accepting patients for this trial. For more information, please contact Laurie Tupper, (650) 498 - 4143.

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  • Phase I/II Study of Fractionated Stereotactic Radiosurgery to Treat Large Brain Metastases Recruiting

    To determine the optimal treatment dose for large brain metastases. Brain metastases are conventionally treated with radiation to the whole brain and/or focal radiation with stereotactic radiosurgery. With conventional radiation, control rates (i.e., the ability to completely eradicate the tumor) of large brain metastases of size greater 4 cm3 are poor. By treating these tumors over 3 treatment sessions, we hope to improve the control rate and decrease side effects for patients.

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  • XERECEPT® (hCRF) for Primary Glioma Patients Requiring Dexamethasone to Treat Peritumoral Brain Edema Not Recruiting

    The purpose of this study is to examine the safety and efficacy of XERECEPT (human Corticotropin-Releasing Factor, or hCRF) compared to dexamethasone in patients with primary malignant glioma who require increased dexamethasone doses to control symptom of peritumoral brain edema.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cathy Recht, (650) 725 - 8630.

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  • An Open-Labeled, Extended-Use of XERECEPT (hCRF) for Patients in Studies NTI 0302, 0303, or Other Designated Studies Not Recruiting

    The purpose of this study is to examine the long-term safety and tolerability of human corticotropin-releasing factor (hCRF), XERECEPT®, in patients requiring dexamethasone (Decadron) to treat peritumoral brain edema. This open-label, extended-use study is open to all patients who participate in either of the blinded studies, NTI 0302, NTI 0303, or other designated studies, including patients who may have discontinued blinded study medication early but completed the protocol-stipulated follow-up periods.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lynn Adler, (650) 725 - 8630.

    View full details

Teaching

2013-14 Courses


Graduate and Fellowship Programs


Publications

Journal Articles


  • Risk of Leptomeningeal Disease in Patients Treated With Stereotactic Radiosurgery Targeting the Postoperative Resection Cavity for Brain Metastases INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Atalar, B., Modlin, L. A., Choi, C. Y., Adler, J. R., Gibbs, I. C., Chang, S. D., Harsh, G. R., Li, G., Nagpal, S., Hanlon, A., Soltys, S. G. 2013; 87 (4): 713-718

    Abstract

    We sought to determine the risk of leptomeningeal disease (LMD) in patients treated with stereotactic radiosurgery (SRS) targeting the postsurgical resection cavity of a brain metastasis, deferring whole-brain radiation therapy (WBRT) in all patients.We retrospectively reviewed 175 brain metastasis resection cavities in 165 patients treated from 1998 to 2011 with postoperative SRS. The cumulative incidence rates, with death as a competing risk, of LMD, local failure (LF), and distant brain parenchymal failure (DF) were estimated. Variables associated with LMD were evaluated, including LF, DF, posterior fossa location, resection type (en-bloc vs piecemeal or unknown), and histology (lung, colon, breast, melanoma, gynecologic, other).With a median follow-up of 12 months (range, 1-157 months), median overall survival was 17 months. Twenty-one of 165 patients (13%) developed LMD at a median of 5 months (range, 2-33 months) following SRS. The 1-year cumulative incidence rates, with death as a competing risk, were 10% (95% confidence interval [CI], 6%-15%) for developing LF, 54% (95% CI, 46%-61%) for DF, and 11% (95% CI, 7%-17%) for LMD. On univariate analysis, only breast cancer histology (hazard ratio, 2.96) was associated with an increased risk of LMD. The 1-year cumulative incidence of LMD was 24% (95% CI, 9%-41%) for breast cancer compared to 9% (95% CI, 5%-14%) for non-breast histology (P=.004).In patients treated with SRS targeting the postoperative cavity following resection, those with breast cancer histology were at higher risk of LMD. It is unknown whether the inclusion of whole-brain irradiation or novel strategies such as preresection SRS would improve this risk or if the rate of LMD is inherently higher with breast histology.

    View details for DOI 10.1016/j.ijrobp.2013.07.034

    View details for Web of Science ID 000325763300022

    View details for PubMedID 24054875

  • A perspective on craniopharyngioma. World neurosurgery Lober, R. M., Harsh, G. R. ; 79 (5-6): 645-6

    View details for PubMedID 23111221

  • Multi-institutional validation of a preoperative scoring system which predicts survival for patients with glioblastoma. Journal of clinical neuroscience Chaichana, K. L., Pendleton, C., Chambless, L., Camara-Quintana, J., Nathan, J. K., Hassam-Malani, L., Li, G., Harsh, G. R., Thompson, R. C., Lim, M., Quinones-Hinojosa, A. 2013; 20 (10): 1422-1426

    Abstract

    Glioblastoma is the most common and aggressive type of primary brain tumor in adults. Average survival is approximately 1 year, but individual survival is heterogeneous. Using a single institutional experience, we have previously identified preoperative factors associated with survival and devised a prognostic scoring system based on these factors. The aims of the present study are to validate these preoperative factors and verify the efficacy of this scoring system using a multi-institutional cohort. Of the 334 patients in this study from three different institutions, the preoperative factors found to be negatively associated with survival in a Cox analysis were age >60 years (p<0.0001), Karnofsky Performance Scale score ≤80 (p=0.03), motor deficit (p=0.02), language deficit (p=0.04), and periventricular tumor location (p=0.04). Patients possessing 0-1, 2, 3, and 4-5 of these variables were assigned a preoperative grade of 1, 2, 3, and 4, respectively. Patients with a preoperative grade of 1, 2, 3, and 4 had a median survival of 17.9, 12.3, 10, and 7.5 months, respectively. Survival of each of these grades was statistically significant (p<0.05) in log-rank analysis. This grading system, based only on preoperative variables, may provide patients and physicians with prognostic information that may guide medical and surgical therapy before any intervention is pursued.

    View details for DOI 10.1016/j.jocn.2013.02.007

    View details for PubMedID 23928040

  • CyberKnife radiosurgery for the management of skull base and spinal chondrosarcomas. Journal of neuro-oncology Jiang, B., Veeravagu, A., Feroze, A. H., Lee, M., Harsh, G. R., Soltys, S. G., Gibbs, I. C., Adler, J. R., Chang, S. D. 2013; 114 (2): 209-218

    Abstract

    The use of CyberKnife (CK) stereotactic radiosurgery (SRS) for the management of central nervous system chondrosarcomas has not been previously reported. To evaluate outcomes of primary, recurrent, and metastatic chondrosarcomas of the skull base and spine treated with CK SRS, a retrospective observational study of 16 patients treated between 1996 and 2011 with CK SRS was performed using an IRB-approved database at Stanford University Medical Center. Twenty lesions (12 cranial, 8 spinal) across six males and ten females were analyzed. The median age at SRS was 51 years and median follow-up was 33 months. Median tumor volume was 11.0 cm(3) and median marginal dosages were 22, 24, 26, 27, and 30 Gy for one to five fractionations, respectively. Overall Kaplan-Meier survival rates were 88, 88, 80, and 66 % at 1, 3, 5, and 10 years after initial presentation. Survival rates at 1, 3, and 5 years after CK were 81, 67, and 55 %, respectively. Actuarial tumor control was 41 ± 13 % at 60 months. At 36 months follow-up, tumor control was 80 % in primary lesions, 50 % in recurrent lesions, and 0.0 % in metastatic disease (p = 0.07). Tumor control was 58 % in cranial lesions and 38 % in spinal lesions. Radiation injury was reported in one patient. CK SRS appears to be a safe adjuvant therapy and offers moderate control for primary cranial chondrosarcoma lesions. There appears to be a clinically, albeit not statistically, significant trend towards poorer outcomes in similarly treated metastatic, recurrent, and spinal chondrosarcomas (p = 0.07). Lesions not candidates for single fraction SRS may be treated with hypofractionated SRS without increased risk for radiation necrosis.

    View details for DOI 10.1007/s11060-013-1172-9

    View details for PubMedID 23748573

  • Cochlea radiation dose correlates with hearing loss after stereotactic radiosurgery of vestibular schwannoma. World neurosurgery Hayden Gephart, M. G., Hansasuta, A., Balise, R. R., Choi, C., Sakamoto, G. T., Venteicher, A. S., Soltys, S. G., Gibbs, I. C., Harsh, G. R., Adler, J. R., Chang, S. D. 2013; 80 (3-4): 359-363

    Abstract

    OBJECTIVE: For multisession radiosurgery, no published data relate the volume and dose of cochlear irradiation to quantified risk of hearing loss. We conducted a retrospective, dosimetric study to evaluate the relationship between hearing loss after stereotactic radiosurgery (SRS) and the dose-volume of irradiated cochlea. METHODS: Cochlear dose data were retrospectively collected on consecutive patients who underwent SRS (18 Gy in 3 sessions) for vestibular schwanoma between 1999 and 2005 at Stanford University Hospital. Inclusion criteria included Gardner-Robertson (GR) grade I or II hearing prior to radiosurgical treatment, complete audiograms, and magnetic resonance imaging (MRI) follow-up. A cochlea dose-volume histogram was generated for each of the 94 patients who qualified for this study. RESULTS: GR grade I-II hearing posttreatment was maintained in 74% of patients (70/94). Median time to last follow-up audiogram was 2.4 years (range 0.4-8.9) and to last MRI was 3.6 years (range 0.5-9.4). Each higher level of cochlear irradiation was associated with increased risk of hearing loss. Larger cochlear volume was associated with lower risk of hearing loss. Controlling for differences in cochlear volume among subjects, each additional mm(3) of cochlea receiving 10 to 16 Gy (single session equivalent doses of 6.6-10.1 Gy3) significantly increased the odds of hearing loss by approximately 5%. CONCLUSIONS: Larger cochlear volume is associated with lower risk of hearing loss following trisession SRS for vestibular schwannoma. Controlling for this phenomenon, higher radiation dose and larger irradiated cochlear volume are significantly associated with higher risk of hearing loss. This study confirms and quantifies the risk of hearing loss following trisession SRS for vestibular schwannoma.

    View details for DOI 10.1016/j.wneu.2012.04.001

    View details for PubMedID 22484770

  • Diffusion-Weighted MRI: Distinction of Skull Base Chordoma from Chondrosarcoma. AJNR. American journal of neuroradiology Yeom, K. W., Lober, R. M., Mobley, B. C., Harsh, G., Vogel, H., Allagio, R., Pearson, M., Edwards, M. S., Fischbein, N. J. 2013; 34 (5): 1056-1061

    Abstract

    Chordoma and chondrosarcoma of the skull base are rare tumors with overlapping presentations and anatomic imaging features but different prognoses. We hypothesized that these tumors might be distinguished by using diffusion-weighted MR imaging.We retrospectively reviewed 19 patients with pathologically confirmed chordoma or chondrosarcoma who underwent both conventional and diffusion-weighted MR imaging. Differences in distributions of ADC were assessed by the Kruskal-Wallis test. Associations between histopathologic diagnosis and conventional MR imaging features (T2 signal intensity, contrast enhancement, and tumor location) were assessed with the Fisher exact test.Chondrosarcoma was associated with the highest mean ADC value (2051 ± 261 × 10(-6) mm(2)/s) and was significantly different from classic chordoma (1474 ± 117 × 10(-6) mm(2)/s) and poorly differentiated chordoma (875 ± 100 × 10(-6) mm(2)/s) (P < .001). Poorly differentiated chordoma was characterized by low T2 signal intensity (P = .001), but other conventional MR imaging features of enhancement and/or lesion location did not reliably distinguish these tumor types.Diffusion-weighted MR imaging may be useful in assessing clival tumors, particularly in differentiating chordoma from chondrosarcoma. A prospective study of a larger cohort will be required to determine the value of ADC in predicting histopathologic diagnosis.

    View details for DOI 10.3174/ajnr.A3333

    View details for PubMedID 23124635

  • Cavity Volume Dynamics After Resection of Brain Metastases and Timing of Postresection Cavity Stereotactic Radiosurgery NEUROSURGERY Atalar, B., Choi, C. Y., Harsh, G. R., Chang, S. D., Gibbs, I. C., Adler, J. R., Soltys, S. G. 2013; 72 (2): 180-185

    Abstract

    An alternative treatment option to whole-brain irradiation after surgical resection of brain metastases is resection cavity stereotactic radiosurgery (SRS).To review the dynamics of cavity volume change after surgical resection with the goal of determining the optimal timing for cavity SRS.Preresection tumor, postresection/pre-SRS cavity, and post-SRS cavity volumes were measured for 68 cavities in 63 patients treated with surgery and postresection cavity SRS. Percent differences between volumes were calculated and correlation analyses were performed to assess volume changes before and after SRS.For the majority of tumors, the postresection cavity volume was smaller than the preresection tumor volume by a median percent volume change of -29% (range, -82% to 1258%), with larger preresection tumors resulting in greater cavity shrinkage (P < .001). To determine the optimal timing for cavity SRS, we examined cavity volume dynamics by comparing the early postresection (postoperative days 0-3) and treatment planning magnetic resonance imaging scans (median time to magnetic resonance imaging, 20 days; range, 9-33 days) and found no association between the postresection day number and volume change (P = .75). The volume decrease resulting from tumor resection was offset by the addition of a 2-mm clinical target volume margin, which is our current technique.The greatest volume change occurs immediately after surgery (postoperative days 0-3) with no statistically significant volume change occurring up to 33 days after surgery for most patients. Therefore, there is no benefit of cavity shrinkage in waiting longer than the first 1 to 2 weeks to perform cavity SRS.

    View details for DOI 10.1227/NEU.0b013e31827b99f3

    View details for Web of Science ID 000313734400028

    View details for PubMedID 23149969

  • Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage JOURNAL OF BIOLOGICAL CHEMISTRY Yamaguchi, Y., Shao, Z., Sharif, S., Du, X., Myles, T., Merchant, M., Harsh, G., Glantz, M., Recht, L., Morser, J., Leung, L. L. 2013; 288 (5): 3097-3111

    Abstract

    Osteopontin (OPN), which is highly expressed in malignant glioblastoma (GBM), possesses inflammatory activity modulated by proteolytic cleavage by thrombin and plasma carboxypeptidase B2 (CPB2) at a highly conserved cleavage site. Full-length OPN (OPN-FL) was elevated in cerebrospinal fluid (CSF) samples from all cancer patients compared with noncancer patients. However, thrombin-cleaved OPN (OPN-R) and thrombin/CPB2-double-cleaved OPN (OPN-L) levels were markedly increased in GBM and non-GBM gliomas compared with systemic cancer and noncancer patients. Cleaved OPN constituted ?23 and ?31% of the total OPN in the GBM and non-GBM CSF samples, respectively. OPN-R was also elevated in GBM tissues. Thrombin-antithrombin levels were highly correlated with cleaved OPN, but not OPN-FL, suggesting that the cleaved OPN fragments resulted from increased thrombin and CPB2 in this extracellular compartment. Levels of VEGF and CCL4 were increased in CSF of GBM and correlated with the levels of cleaved OPN. GBM cell lines were more adherent to OPN-R and OPN-L than OPN-FL. Adhesion to OPN altered gene expression, in particular genes involved with cellular processes, cell cycle regulation, death, and inflammation. OPN and its cleaved forms promoted motility of U-87 MG cells and conferred resistance to apoptosis. Although functional mutation of the RGD motif in OPN largely abolished these functions, OPN(RAA)-R regained significant cell binding and signaling function, suggesting that the SVVYGLR motif in OPN-R may substitute for the RGD motif if the latter becomes inaccessible. OPN cleavage contributes to GBM development by allowing more cells to bind in niches where they acquire anti-apoptotic properties.

    View details for DOI 10.1074/jbc.M112.362954

    View details for Web of Science ID 000314397900019

    View details for PubMedID 23204518

  • What Is the Optimal Treatment of Large Brain Metastases? An Argument for a Multidisciplinary Approach INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Choi, C. Y., Chang, S. D., Gibbs, I. C., Adler, J. R., Harsh, G. R., Atalar, B., Lieberson, R. E., Soltys, S. G. 2012; 84 (3): 688-693

    Abstract

    Single-modality treatment of large brain metastases (>2 cm) with whole-brain irradiation, stereotactic radiosurgery (SRS) alone, or surgery alone is not effective, with local failure (LF) rates of 50% to 90%. Our goal was to improve local control (LC) by using multimodality therapy of surgery and adjuvant SRS targeting the resection cavity.We retrospectively evaluated 97 patients with brain metastases >2 cm in diameter treated with surgery and cavity SRS. Local and distant brain failure (DF) rates were analyzed with competing risk analysis, with death as a competing risk. The overall survival rate was calculated by the Kaplain-Meier product-limit method.The median imaging follow-up duration for all patients was 10 months (range, 1-80 months). The 12-month cumulative incidence rates of LF, with death as a competing risk, were 9.3% (95% confidence interval [CI], 4.5%-16.1%), and the median time to LF was 6 months (range, 3-17 months). The 12-month cumulative incidence rate of DF, with death as a competing risk, was 53% (95% CI, 43%-63%). The median survival time for all patients was 15.6 months. The median survival times for recursive partitioning analysis classes 1, 2, and 3 were 33.8, 13.7, and 9.0 months, respectively (p = 0.022). On multivariate analysis, Karnofsky Performance Status (?80 vs. <80; hazard ratio 0.54; 95% CI 0.31-0.94; p = 0.029) and maximum preoperative tumor diameter (hazard ratio 1.41; 95% CI 1.08-1.85; p = 0.013) were associated with survival. Five patients (5%) required intervention for Common Terminology Criteria for Adverse Events v4.02 grade 2 and 3 toxicity.Surgery and adjuvant resection cavity SRS yields excellent LC of large brain metastases. Compared with other multimodality treatment options, this approach allows patients to avoid or delay whole-brain irradiation without compromising LC.

    View details for DOI 10.1016/j.ijrobp.2012.01.028

    View details for Web of Science ID 000309560600051

    View details for PubMedID 22445007

  • Stereotactic Radiosurgery of the Postoperative Resection Cavity for Brain Metastases: Prospective Evaluation of Target Margin on Tumor Control INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Choi, C. Y., Chang, S. D., Gibbs, I. C., Adler, J. R., Harsh, G. R., Lieberson, R. E., Soltys, S. G. 2012; 84 (2): 336-342

    Abstract

    Given the neurocognitive toxicity associated with whole-brain irradiation (WBRT), approaches to defer or avoid WBRT after surgical resection of brain metastases are desirable. Our initial experience with stereotactic radiosurgery (SRS) targeting the resection cavity showed promising results. We examined the outcomes of postoperative resection cavity SRS to determine the effect of adding a 2-mm margin around the resection cavity on local failure (LF) and toxicity.We retrospectively evaluated 120 cavities in 112 patients treated from 1998-2009. Factors associated with LF and distant brain failure (DF) were analyzed using competing risks analysis, with death as a competing risk. The overall survival (OS) rate was calculated by the Kaplan-Meier product-limit method; variables associated with OS were evaluated using the Cox proportional hazards and log rank tests.The 12-month cumulative incidence rates of LF and DF, with death as a competing risk, were 9.5% and 54%, respectively. On univariate analysis, expansion of the cavity with a 2-mm margin was associated with decreased LF; the 12-month cumulative incidence rates of LF with and without margin were 3% and 16%, respectively (P=.042). The 12-month toxicity rates with and without margin were 3% and 8%, respectively (P=.27). On multivariate analysis, melanoma histology (P=.038) and number of brain metastases (P=.0097) were associated with higher DF. The median OS time was 17 months (range, 2-114 months), with a 12-month OS rate of 62%. Overall, WBRT was avoided in 72% of the patients.Adjuvant SRS targeting the resection cavity of brain metastases results in excellent local control and allows WBRT to be avoided in a majority of patients. A 2-mm margin around the resection cavity improved local control without increasing toxicity compared with our prior technique with no margin.

    View details for DOI 10.1016/j.ijrobp.2011.12.009

    View details for Web of Science ID 000308062700035

    View details for PubMedID 22652105

  • Mucocele formation under pedicled nasoseptal flap AMERICAN JOURNAL OF OTOLARYNGOLOGY Vaezeafshar, R., Hwang, P. H., Harsh, G., Turner, J. H. 2012; 33 (5): 634-636

    Abstract

    The pedicled nasoseptal flap has become an indispensible tool for the reconstruction of skull base defects. This flap is easily harvested, provides a large surface area of vascularized tissue, and has few reported complications. We describe the case of a 60-year-old man who underwent endoscopic, endonasal transsphenoidal surgery with septal flap reconstruction who developed a sphenoid sinus mucocele postoperatively. We also have reviewed the literature for similar findings and discuss this complication in the setting of pituitary surgery and endoscopic skull base repair. Although likely a rare occurrence, mucocele formation after septal flap reconstruction should be recognized and monitored with postoperative nasal endoscopy and radiologic imaging. Reoperation or mucocele drainage may be necessary if symptomatic or in cases of rapid enlargement.

    View details for DOI 10.1016/j.amjoto.2012.05.003

    View details for Web of Science ID 000308833800028

    View details for PubMedID 22771247

  • Management of intracranial and extracranial chordomas with CyberKnife stereotactic radiosurgery JOURNAL OF CLINICAL NEUROSCIENCE Jiang, B., Veeravagu, A., Lee, M., Harsh, G. R., Lieberson, R. E., Bhatti, I., Soltys, S. G., Gibbs, I. C., Adler, J. R., Chang, S. D. 2012; 19 (8): 1101-1106

    Abstract

    Chordomas are rare, malignant bone tumors of the axial skeleton, occurring particularly at the cranial base or in the sacro-coccygeal region. Although slow growing, chordomas are locally aggressive and challenging to treat. We evaluate the outcomes of skull base and spinal chordomas in 20 patients treated with CyberKnife (CK) stereotactic radiosurgery (SRS) (Accuray, Sunnyvale, CA, USA) between 1994 and 2010 at Stanford Hospital. There were 12 males and eight females (10-78 years; median age: 51.5 years). Eleven patients received CK as primary adjuvant therapy and nine patients received CK for multiple recurrences. The average tumor volume treated was 16.1cm(3) (2.4-45.9 cm(3)), with a mean marginal dose of 32.5 Gy (18-50 Gy). Median follow-up was 34 months (2-131 months). Overall, tumor control was achieved in 11 patients (55%), with eight patients showing tumor size reduction. However, nine patients showed progression and eventually succumbed to the disease (mean time from CK to death was 26.3 months). Of the patients treated with CK as the primary adjuvant therapy, 81.8% had stable or improved outcomes. Only 28.6% of those treated with CK for recurrences had stable or improved outcomes. The overall Kaplan-Meyer survival at five years from the first CK treatment was 52.5%. Moderate tumor control rates can be achieved with few complications with CK SRS. Poor control is associated with complex multiple surgical resections, long delay between initial resection and CK therapy, and recurrently aggressive disease uncontrolled by prior radiation.

    View details for DOI 10.1016/j.jocn.2012.01.005

    View details for Web of Science ID 000306500400009

    View details for PubMedID 22727205

  • The predictive value of serum myeloperoxidase for vasospasm in patients with aneurysmal subarachnoid hemorrhage NEUROSURGICAL REVIEW Lim, M., Bower, R. S., Wang, Y., Sims, L., Bower, M. R., Camara-Quintana, J., Li, G., Cheshier, S., Harsh, G. R., Steinberg, G. K., Guccione, S. 2012; 35 (3): 413-419

    Abstract

    Vasospasm is a major contributor to morbidity and mortality in aneurysmal subarachnoid hemorrhage (SAH), with inflammation playing a key role in its pathophysiology. Myeloperoxidase (MPO), an inflammatory marker, was examined as a potential marker of vasospasm in patients with SAH. Daily serum samples from patients with aneurysmal SAH were assayed for MPO, and transcranial Doppler (TCDs) and neurological exams were assessed to determine vasospasm. Suspected vasospasm was confirmed by angiography. Peak MPO levels were then compared with timing of onset of vasospasm, based on clinical exams, TCDs and cerebral angiography. Patients with vasospasm had a mean MPO level of 115.5 ng/ml, compared to 59.4 ng/ml in those without vasospasm, 42.0 ng/ml in those with unruptured aneurysms, and 4.3 ng/ml in normal controls. In patients who experienced vasospasm, MPO was elevated above the threshold on the day of, or at any point prior to, vasospasm in 10 of 15 events (66.7%), and on the day of, or within 2 days prior to, vasospasm in 8 of 15 events (53.3%). Elevated serum MPO correlates with clinically evident vasospasm following aneurysmal SAH. The potential utility of MPO as a marker of vasospasm is discussed.

    View details for DOI 10.1007/s10143-012-0375-4

    View details for Web of Science ID 000305230000023

    View details for PubMedID 22370810

  • The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Willingham, S. B., Volkmer, J., Gentles, A. J., Sahoo, D., Dalerba, P., Mitra, S. S., Wang, J., Contreras-Trujillo, H., Martin, R., Cohen, J. D., Lovelace, P., Scheeren, F. A., Chao, M. P., Weiskopf, K., Tang, C., Volkmer, A. K., Naik, T. J., Storm, T. A., Mosley, A. R., Edris, B., Schmid, S. M., Sun, C. K., Chua, M., Murillo, O., Rajendran, P., Cha, A. C., Chin, R. K., Kim, D., Adorno, M., Raveh, T., Tseng, D., Jaiswal, S., Enger, P. O., Steinberg, G. K., Li, G., So, S. K., Majeti, R., Harsh, G. R., van de Rijn, M., Teng, N. N., Sunwoo, J. B., Alizadeh, A. A., Clarke, M. F., Weissman, I. L. 2012; 109 (17): 6662-6667

    Abstract

    CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRP?, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.

    View details for DOI 10.1073/pnas.1121623109

    View details for Web of Science ID 000303249100065

    View details for PubMedID 22451913

  • Extravascular Papillary Endothelial Hyperplasia Mimicking Neoplasm After Radiosurgery: Case Report NEUROSURGERY Karamchandani, J., Vogel, H., Fischbein, N., Gibbs, I., Edwards, M. S., Harsh, G. 2012; 70 (4): E1043-E1048

    Abstract

    Papillary endothelial hyperplasia (PEH) is a rare form of exuberant reactive endothelial proliferation that can mimic neoplasm. We report the largest series of patients with histologically confirmed intracranial extravascular PEH developing in the field of previous treatment with stereotactic radiosurgery.We collected the clinical, radiological, surgical, and pathological findings from 4 patients in whom intracranial extravascular PEH developed after treatment with stereotactic radiosurgery. In all patients, the development of an enlarging hemorrhagic mass lesion at the site of previous radiotherapy on magnetic resonance imaging was radiographically suspicious for neoplasm and prompted biopsy or resection. All 4 patients elected to undergo biopsy or surgical resection. Histological examination of the biopsy and resection specimens in all patients demonstrated the classic features of PEH.The interval to the development of PEH ranged from 5 months to 6 years, 10 months. Clinical follow-up was available for 3 of the 4 patients. None of these 3 patients have demonstrated evidence of recurrence during a mean follow-up period of 22 months (range, 15-30 months). These patients share common radiological features, potentially allowing preoperative diagnosis and improved guidance of clinical management. These cases suggest a link between radiosurgery and the development of PEH. These findings also suggest that PEH should be considered in the differential diagnosis for patients treated with radiosurgery in whom a hemorrhagic mass lesion subsequently develops at or near the site of previous treatment. We think that complete surgical excision is the best treatment for intracranial PEH.

    View details for DOI 10.1227/NEU.0b013e31822e81f9

    View details for Web of Science ID 000301934000010

    View details for PubMedID 22426048

  • The dynamics of post-operative plasma ACTH values following transsphenoidal surgery for Cushing's disease PITUITARY Srinivasan, L., Laws, E. R., Dodd, R. L., Monita, M. M., Tannenbaum, C. E., Kirkeby, K. M., Chu, O. S., Harsh, G. R., Katznelson, L. 2011; 14 (4): 312-317

    Abstract

    Rapid assessment of adrenal function is critical following transsphenoidal surgery (TSS) for Cushing's disease (CD) in order to determine surgical efficacy. We hypothesize that there may be a role for ACTH measurement as a rapid indicator of adrenal function. Following surgery for CD, glucocorticoids were withheld and paired plasma ACTH and serum cortisol levels were measured every 6 h. Post-operative hypocortisolemia was defined as serum cortisol <2 mcg/dl or a serum cortisol <5 mcg/dl with the onset of symptoms of adrenal insufficiency within 72 h. We studied 12 subjects, all female, mean age 44.6 years (range 25-55), including 13 surgeries: nine subjects attained hypocortisolemia. Plasma ACTH levels decreased more in subjects with hypocortisolemia (0.9 pg/ml/hr, P = 0.0028) versus those with persistent disease (0 0.2 pg/ml/hr, P = 0.26) within the first 48 h after surgery. In contrast to subjects with persistent disease, all subjects with hypocortisolemia achieved a plasma ACTH <20 pg/ml by 19 h (range 1-19 h). Four of the nine subjects with hypocortisolemia achieved plasma ACTH <20 pg/ml by 13 h and the remaining five subjects by 19 h. Hypocortisolemia occurred between 3-36 h following achievement of a plasma ACTH <20 pg/ml. In CD, a reduction in postoperative plasma ACTH levels differentiates subjects with surgical remission versus subjects with persistent disease. The utility of plasma ACTH measurements in the postoperative management of CD remains to be determined.

    View details for DOI 10.1007/s11102-011-0295-2

    View details for Web of Science ID 000300349800003

    View details for PubMedID 21298507

  • Multisession Stereotactic Radiosurgery for Vestibular Schwannomas: Single-Institution Experience With 383 Cases NEUROSURGERY Hansasuta, A., Choi, C. Y., Gibbs, I. C., Soltys, S. G., Tse, V. C., Lieberson, R. E., Hayden, M. G., Sakamoto, G. T., Harsh, G. R., Adler, J. R., Chang, S. D. 2011; 69 (6): 1200-1209

    Abstract

    Single-session stereotactic radiosurgery (SRS) treatment of vestibular schwannomas results in excellent tumor control. It is not known whether functional outcomes can be improved by fractionating the treatment over multiple sessions.To examine tumor control and complication rates after multisession SRS.Three hundred eighty-three patients treated with SRS from 1999 to 2007 at Stanford University Medical Center were retrospectively reviewed. Ninety percent were treated with 18 Gy in 3 sessions, targeting a median tumor volume of 1.1 cm3 (range, 0.02-19.8 cm3).During a median follow-up duration of 3.6 years (range, 1-10 years), 10 tumors required additional treatment, resulting in 3- and 5-year Kaplan-Meier tumor control rates of 99% and 96%, respectively. Five-year tumor control rate was 98% for tumors < 3.4 cm3. Neurofibromatosis type 2-associated tumors were associated with worse tumor control (P = .02). Of the 200 evaluable patients with pre-SRS serviceable hearing (Gardner-Robertson grade 1 and 2), the crude rate of serviceable hearing preservation was 76%. Smaller tumor volume was associated with hearing preservation (P = .001). There was no case of post-SRS facial weakness. Eight patients (2%) developed trigeminal dysfunction, half of which was transient.Multisession SRS treatment of vestibular schwannomas results in an excellent rate of tumor control. The hearing, trigeminal nerve, and facial nerve function preservation rates reported here are promising.

    View details for DOI 10.1227/NEU.0b013e318222e451

    View details for Web of Science ID 000296794500024

    View details for PubMedID 21558974

  • Gene-protein correlation in single cells NEURO-ONCOLOGY Renfrow, J. J., Scheck, A. C., Dhawan, N. S., Lukac, P. J., Vogel, H., Chandler, J. P., Raizer, J. J., Harsh, G. R., Chakravarti, A., Bredel, M. 2011; 13 (8): 880-885

    Abstract

    We present a novel methodology combining traditional fluorescent in situ hybridization with an in situ protein detection technology called proximity ligation assay. This method has potential to perform a detailed analysis of the relationship between gene status and corresponding protein expression in cells and tissues. We demonstrate that the fluorescent in situ gene protein assay methodology is capable of resolving gene and protein patterns simultaneously on a cell-by-cell basis.

    View details for DOI 10.1093/neuonc/nor071

    View details for Web of Science ID 000293820900008

    View details for PubMedID 21798849

  • Stereotactic Radiosurgery of Cranial Nonvestibular Schwannomas: Results of Single- and Multisession Radiosurgery NEUROSURGERY Choi, C. Y., Soltys, S. G., Gibbs, I. C., Harsh, G. R., Sakamoto, G. T., Patel, D. A., Lieberson, R. E., Chang, S. D., Adler, J. R. 2011; 68 (5): 1200-1208

    Abstract

    Surgical resection of nonvestibular cranial schwannomas carries a considerable risk of postoperative complications. Stereotactic radiosurgery (SRS) offers a non-invasive treatment alternative. The efficacy and safety of multi-session SRS of nonvestibular cranial schwannomas has not been well studied.To analyze the results of single- and multi-session SRS of nonvestibular cranial schwannomas.From 2001 to 2007, 42 lesions in 40 patients were treated with SRS at Stanford University Medical Center, targeting schwannomas of cranial nerves IV (n = 1), V (n = 18), VII (n = 6), X (n = 5), XII (n = 2), jugular foramen (n = 8), and cavernous sinus (n = 2). SRS was delivered to a median marginal dose of 18 Gy (range, 15-33 Gy) in 1 to 3 sessions, targeting a median tumor volume of 3.2 cm (range, 0.1-23.7 cm). The median doses for treatments in 1 (n = 18), 2 (n = 9), and 3 (n = 15) sessions were 17.5, 20, and 18 Gy, respectively.With a median follow-up of 29 months (range, 6-84 months), tumor control was achieved in 41 of the 42 lesions. Eighteen of 42 lesions (43%) decreased in size; 23 tumors (55%) remained stable. There were 2 cases of new or worsening cranial nerve deficits in patients treated in single session; no patient treated with multi-session SRS experienced any cranial nerve toxicity (P = 0.18).SRS of nonvestibular cranial schwannomas provides excellent tumor control with minimal risk of complications. There was a trend towards decreased complications with multi-session SRS.

    View details for DOI 10.1227/NEU.0b013e31820c0474

    View details for Web of Science ID 000289230300033

    View details for PubMedID 21273918

  • NFKBIA Deletion in Glioblastomas. NEW ENGLAND JOURNAL OF MEDICINE Bredel, M., Scholtens, D. M., Yadav, A. K., Alvarez, A. A., Renfrow, J. J., Chandler, J. P., Yu, I. L., Carro, M. S., Dai, F., Tagge, M. J., Ferrarese, R., Bredel, C., Phillips, H. S., Lukac, P. J., Robe, P. A., Weyerbrock, A., Vogel, H., Dubner, S., Mobley, B., He, X., Scheck, A. C., Sikic, B. I., Aldape, K. D., Chakravarti, A., Harsh, G. R. 2011; 364 (7): 627-637

    Abstract

    Amplification and activating mutations of the epidermal growth factor receptor (EGFR) oncogene are molecular hallmarks of glioblastomas. We hypothesized that deletion of NFKBIA (encoding nuclear factor of ?-light polypeptide gene enhancer in B-cells inhibitor-?), an inhibitor of the EGFR-signaling pathway, promotes tumorigenesis in glioblastomas that do not have alterations of EGFR.We analyzed 790 human glioblastomas for deletions, mutations, or expression of NFKBIA and EGFR. We studied the tumor-suppressor activity of NFKBIA in tumor-cell culture. We compared the molecular results with the outcome of glioblastoma in 570 affected persons.NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. Restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy of cells cultured from tumors with NFKBIA deletion; it also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated with unfavorable outcomes. Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification. These outcomes were poor as compared with the outcomes in patients with tumors that had normal gene dosages of NFKBIA and EGFR. A two-gene model that was based on expression of NFKBIA and O(6)-methylguanine DNA methyltransferase was strongly associated with the clinical course of the disease.Deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival.

    View details for DOI 10.1056/NEJMoa1006312

    View details for Web of Science ID 000287406000008

    View details for PubMedID 21175304

  • Bevacizumab improves quality of life in patients with recurrent glioblastoma. Chemotherapy research and practice Nagpal, S., Harsh, G., Recht, L. 2011; 2011: 602812-?

    Abstract

    Objective. To quantify the benefits in survival and quality of life in patients receiving bevacizumab (BEV) for recurrent glioblastoma (GBM). Methods. This is a retrospective study of 40 adult patients with recurrent GBM treated between 2005 and 2009 at a single institution. All patients had initial treatment with surgery, radiation, and concurrent temozolomide, then monthly temozolomide. Over 250 charts were screened. Sufficient data was available for 20 patients treated with BEV and 20 patients who did not receive BEV at the time of recurrence. The independent living score (ILS), designed to reward long-term independent survival, was calculated for each patient. Results. The mean ILS was nearly double in the BEV group compared to the No-BEV group (15.0 versus 8.2, P = 0.002, t-test). Two months after initiation of therapy, the median steroid dose dropped by over 90% in patients treated with BEV, but doubled in the NoBEV group. Median survival from the time of recurrence was significantly affected: 10.6 months in the BEV group versus 4.2 months (P < 0.001, log rank survival) in the NoBEV group. Conclusions. BEV increases independent living and lengthens overall survival after GBM recurrence. Reduction in steroid dose may contribute to prolonged independence.

    View details for DOI 10.1155/2011/602812

    View details for PubMedID 22312554

  • Extravascular Papillary Endothelial Hyperplasia Mimicking Neoplasm Following Radiosurgery. Neurosurgery Karamchandani, J., Vogel, H., Fischbein, N., Gibbs, I., Edwards, M. S., Harsh, G. 2011

    Abstract

    BACKGROUND AND IMPORTANCE:: Papillary endothelial hyperplasia (PEH) is a rare form of exuberant reactive endothelial proliferation that can mimic neoplasm. We report the largest series of patients with histologically confirmed intracranial extravascular PEH developing in the field of prior treatment with stereotactic radiosurgery. CLINICAL PRESENTATION:: We collected the clinical, radiological, surgical, and pathologic findings in four cases of patients who developed intracranial extravascular PEH following treatment with stereotactic radiosurgery. In all cases the development of an enlarging hemorrhagic mass lesion in the site of prior radiotherapy on MRI was radiographically suspicious for neoplasm and prompted biopsy or resection. In all four cases the patients elected to undergo biopsy or surgical resection. Histologic examination of the biopsy and resection specimens in all cases demonstrated the classic features of PEH. CONCLUSION:: The interval to the development of PEH ranged from five months to six years and ten months. Clinical follow up was available for three of the four patients. None of these three patients has demonstrated evidence of recurrence during a mean follow-up period of 22 months (15-30 months). These cases share common radiological features, potentially allowing for pre-operative diagnosis and improved guidance of clinical management. These cases suggest a link between radiosurgery and the development of PEH. These findings also suggest that PEH should be considered in the differential diagnosis for patients treated with radiosurgery who subsequently develop a hemorrhagic mass lesion at or near the site of prior treatment. We think that complete surgical excision is the best treatment for intracranial PEH.

    View details for PubMedID 21937944

  • Cyberknife Stereotactic Radiosurgery for Treatment of Atypical (Who Grade II) Cranial Meningiomas NEUROSURGERY Choi, C. Y., Soltys, S. G., Gibbs, I. C., Harsh, G. R., Jackson, P. S., Lieberson, R. E., Chang, S. D., Adler, J. R. 2010; 67 (5): 1180-1188

    Abstract

    The optimal management of subtotally resected atypical meningiomas is unknown.To perform a retrospective review of patients with residual or recurrent atypical meningiomas treated with stereotactic radiosurgery (SRS).Twenty-five patients were treated, either immediately after surgery (n = 15) or at the time of radiographic progression or treatment failure (n = 10). SRS was delivered to with a median marginal dose of 22 Gy (range, 16-30) in 1 to 4 fractions (median, 1), targeting a median tumor volume of 5.3 cm³ (range, 0.3-26.0).With a median follow-up time of 28 months (range, 3-67), the 12-, 24-, and 36-month actuarial local and regional control rates for all patients were 94%, 94%, 74%, and 90%, 90%, 62%, respectively. There were 2 cases of radiation toxicity. On univariate analysis, the number of recurrences before SRS (P = .046), late SRS (ie, waiting until tumor progression to initiate treatment) (P = .03), and age at treatment ? 60 years (P = .01) were significant predictors of recurrence. Of the 20 radiation-naïve patients, 2 patients failed with the targeted lesion and 3 elsewhere in the resection bed, resulting in 12-, 24- and 36-month actuarial local and regional control rates of 100%, 100%, 73% and 93%, 93%, 75%, respectively. The overall locoregional control rates at 12, 24, and 36 months were 93%, 93%, and 54%, respectively.Irradiation of the entire postoperative tumor bed may not be necessary for the majority of patients with subtotally resected atypical meningiomas. Patients in this series achieved outcomes comparable to that of historical control rates for larger volume, conventionally fractionated radiotherapy.

    View details for DOI 10.1227/NEU.0b013e3181f2f427

    View details for Web of Science ID 000283479500003

    View details for PubMedID 20871435

  • Retrosellar intracranial extracerebral glioneuronal heterotopion: case report CLINICAL NEUROPATHOLOGY Karamchandani, J., Fischbein, N., Harsh, G., Katznelson, L., Vogel, H. 2010; 29 (5): 297-300

    Abstract

    We report the case of an 18-year-old woman with an intradural retroclival retrosellar glioneuronal heterotopion. At the time of surgery, a well circumscribed pale-tan mass was identified posterior to and distinct from the posterior pituitary. Pathologic examination showed disorganized, non-neoplastic glial tissue characteristic of glioneuronal heterotopia. To our knowledge, this is the first report of such a lesion in this location.

    View details for Web of Science ID 000281967000004

    View details for PubMedID 20860892

  • Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice JOURNAL OF CLINICAL INVESTIGATION Kioi, M., Vogel, H., Schultz, G., Hoffman, R. M., Harsh, G. R., Brown, J. M. 2010; 120 (3): 694-705

    Abstract

    Despite the high doses of radiation delivered in the treatment of patients with glioblastoma multiforme (GBM), the tumors invariably recur within the irradiation field, resulting in a low cure rate. Understanding the mechanism of such recurrence is therefore important. Here we have shown in an intracranial GBM xenograft model that irradiation induces recruitment of bone marrow-derived cells (BMDCs) into the tumors, restoring the radiation-damaged vasculature by vasculogenesis and thereby allowing the growth of surviving tumor cells. BMDC influx was initiated by induction of HIF-1 in the irradiated tumors, and blocking this influx prevented tumor recurrence. Previous studies have indicated that BMDCs are recruited to tumors in part through the interaction between the HIF-1-dependent stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4. Pharmacologic inhibition of HIF-1 or of the SDF-1/CXCR4 interaction prevented the influx of BMDCs, primarily CD11b+ myelomonocytes, and the postirradiation development of functional tumor vasculature, resulting in abrogation of tumor regrowth. Similar results were found using neutralizing antibodies against CXCR4. Our data therefore suggest a novel approach for the treatment of GBM: in addition to radiotherapy, the vasculogenesis pathway needs to be blocked, and this can be accomplished using the clinically approved drug AMD3100, a small molecule inhibitor of SDF-1/CXCR4 interactions.

    View details for DOI 10.1172/JCI40283

    View details for Web of Science ID 000275272700008

    View details for PubMedID 20179352

  • An RNAi Screen Identifies TRRAP as a Regulator of Brain Tumor-Initiating Cell Differentiation CELL STEM CELL Wurdak, H., Zhu, S., Romero, A., Lorger, M., Watson, J., Chiang, C., Zhang, J., Natu, V. S., Lairson, L. L., Walker, J. R., Trussell, C. M., Harsh, G. R., Vogels, H., Feld-Habermann, B., Orth, A. P., Miraglia, L. J., Rines, D. R., Skirboll, S. L., Schultz, P. G. 2010; 6 (1): 37-47

    Abstract

    Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer associated with a very poor prognosis. Recently, the initiation and growth of GBM has been linked to brain tumor-initiating cells (BTICs), which are poorly differentiated and share features with neural stem cells (NSCs). Here we describe a kinome-wide RNA interference screen to identify factors that control the tumorigenicity of BTICs. We identified several genes whose silencing induces differentiation of BTICs derived from multiple GBM patients. In particular, knockdown of the adaptor protein TRRAP significantly increased differentiation of cultured BTICs, sensitized the cells to apoptotic stimuli, and negatively affected cell cycle progression. TRRAP knockdown also significantly suppressed tumor formation upon intracranial BTIC implantation into mice. Together, these findings support a critical role for TRRAP in maintaining a tumorigenic, stem cell-like state.

    View details for DOI 10.1016/j.stem.2009.11.002

    View details for Web of Science ID 000274029700010

    View details for PubMedID 20085741

  • Passive Antibody-Mediated Immunotherapy for the Treatment of Malignant Gliomas NEUROSURGERY CLINICS OF NORTH AMERICA Mitra, S., Li, G., Harsh, G. R. 2010; 21 (1): 67-?

    Abstract

    Despite advances in understanding the molecular mechanisms of brain cancer, the outcome of patients with malignant gliomas treated according to the current standard of care remains poor. Novel therapies are needed, and immunotherapy has emerged with great promise. The diffuse infiltration of malignant gliomas is a major challenge to effective treatment; immunotherapy has the advantage of accessing the entire brain with specificity for tumor cells. Therapeutic immune approaches include cytokine therapy, passive immunotherapy, and active immunotherapy. Cytokine therapy involves the administration of immunomodulatory cytokines to activate the immune system. Active immunotherapy is the generation or augmentation of an immune response, typically by vaccination against tumor antigens. Passive immunotherapy connotes either adoptive therapy, in which tumor-specific immune cells are expanded ex vivo and reintroduced into the patient, or passive antibody-mediated therapy. In this article, the authors discuss the preclinical and clinical studies that have used passive antibody-mediated immunotherapy, otherwise known as serotherapy, for the treatment of malignant gliomas.

    View details for DOI 10.1016/j.nec.2009.08.010

    View details for Web of Science ID 000278059500007

    View details for PubMedID 19944967

  • Lanreotide promotes apoptosis and is not radioprotective in GH3 cells ENDOCRINE-RELATED CANCER Ning, S., Knox, S. J., Harsh, G. R., Culler, M. D., Katznelson, L. 2009; 16 (3): 1045-1055

    Abstract

    Somatostatin analogs are a mainstay of medical therapy in patients with GH producing human pituitary tumors, and it has been suggested that somatostatin analogs may be radioprotective. We utilized GH secreting rat GH3 cells to investigate whether a somatostatin analog may limit the effects of radiation on proliferation and apoptosis in vitro and on tumor growth in vivo. Treatment with lanreotide alone at doses of either 100 or 1000 nM for 48 h reduced clonogenic survival by 5-10%. Radiation alone produced a dose-dependent survival curve with a SF2 of 48-55%, and lanreotide had no effect on this curve. The addition of lanreotide resulted in a 23% increase in the proportion of apoptotic sub-G1 cells following irradiation (P<0.01). In a mouse GH3 tumor xenograft model, lanreotide 10 mg/kg moderately inhibited the growth of GH3 tumors, with a 4x tumor growth delay (TGD) time that ranged from 4.5 to 8.3 days. Fractionated local tumor radiation alone significantly inhibited tumor growth and produced a TGD of 35.1+/-5.7 days for 250 cGy fractions. The combination of lanreotide, either antecedent to or concurrent, with radiation of 250, 200 or 150 cGy/fraction for 5 days inhibited tumor growth and produced the TGD times that were similar to radiation alone (P>0.05). Pretreatment with lanreotide had the most significant radiosensitizing effect. These studies demonstrate that the somatostatin analog lanreotide is not radioprotective in GH3 cells, and further studies are necessary to determine the impact of lanreotide on apoptosis.

    View details for DOI 10.1677/ERC-09-0003

    View details for Web of Science ID 000272670300027

    View details for PubMedID 19528243

  • Papillary Tumor of the Spinal Cord Report of 2 Cases AMERICAN JOURNAL OF SURGICAL PATHOLOGY Mobley, B., Kalani, M. S., Harsh, G. R., Edwards, M. S., Vogel, H. 2009; 33 (8): 1191-1197

    Abstract

    Intramedullary spinal cord tumors constitute a small fraction of central nervous system tumors in the pediatric population; of these, the majority are ependymomas or astrocytomas. We report 2 pediatric spinal cord tumor cases with unique morphologic and immunohistochemical features. The first patient presented at age 7 with an intramedullary tumor of the thoracic spine. She suffered lumbar, cerebellar, and temporal lobe recurrences despite surgical resection and radiation. The second patient presented at age 17 with an intramedullary tumor of the cervical spine. The tumor recurred locally and in the cerebellum. Magnetic resonance imaging studies demonstrated gadolinium enhancement in each case. Microscopy showed papillary and solid cytoarchitecture with monomorphous epithelioid cells arranged around vascular papillae. Immunohistochemistry in each case revealed diffuse epithelial membrane antigen, cytokeratin, and E-cadherin reactivity. Glial fibrillary acidic protein staining was focal in case 1 and completely negative in case 2. Neural cell adhesion molecule showed patchy membranous reactivity and synaptophysin was negative. Electron microscopy showed ependymal differentiation. The clinical features, including propensity for recurrence and remote subarachnoid spread, and the pathologic features of these tumors are reminiscent of papillary tumor of the pineal region, ependymoma, and choroid plexus papilloma. The cases presented may constitute a new neoplastic entity within the recently described spectrum of central nervous system tumors with ependymal features.

    View details for Web of Science ID 000268850300010

    View details for PubMedID 19417584

  • Monosomy of Chromosome 10 Associated With Dysregulation of Epidermal Growth Factor Signaling in Glioblastomas JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Yadav, A. K., Renfrow, J. J., Scholtens, D. M., Xie, H., Duran, G. E., Bredel, C., Vogel, H., Chandler, J. P., Chakravarti, A., Robe, P. A., Das, S., Scheck, A. C., Kessler, J. A., Soares, M. B., Sikic, B. I., Harsh, G. R., Bredel, M. 2009; 302 (3): 276-289

    Abstract

    Glioblastomas--uniformly fatal brain tumors--often have both monosomy of chromosome 10 and gains of the epidermal growth factor receptor (EGFR) gene locus on chromosome 7, an association for which the mechanism is poorly understood.To assess whether coselection of EGFR gains on 7p12 and monosomy 10 in glioblastomas promotes tumorigenic epidermal growth factor (EGF) signaling through loss of the annexin A7 (ANXA7) gene on 10q21.1-q21.2 and whether ANXA7 acts as a tumor suppressor gene by regulating EGFR in glioblastomas.Multidimensional analysis of gene, coding sequence, promoter methylation, messenger RNA (mRNA) transcript, protein data for ANXA7 (and EGFR), and clinical patient data profiles of 543 high-grade gliomas from US medical centers and The Cancer Genome Atlas pilot project (made public 2006-2008; and unpublished, tumors collected 2001-2008). Functional analyses using LN229 and U87 glioblastoma cells.Associations among ANXA7 gene dosage, coding sequence, promoter methylation, mRNA transcript, and protein expression. Effect of ANXA7 haploinsufficiency on EGFR signaling and patient survival. Joint effects of loss of ANXA7 and gain of EGFR expression on tumorigenesis.Heterozygous ANXA7 gene deletion is associated with significant loss of ANXA7 mRNA transcript expression (P = 1 x 10(-15); linear regression) and a reduction (mean [SEM]) of 91.5% (2.3%) of ANXA7 protein expression compared with ANXA7 wild-type glioblastomas (P = .004; unpaired t test). ANXA7 loss of function stabilizes the EGFR protein (72%-744% increase in EGFR protein abundance) and augments EGFR transforming signaling in glioblastoma cells. ANXA7 haploinsufficiency doubles tumorigenic potential of glioblastoma cells, and combined ANXA7 knockdown and EGFR overexpression promotes tumorigenicity synergistically. The heterozygous loss of ANXA7 in approximately 75% of glioblastomas in the The Cancer Genome Atlas plus infrequency of ANXA7 mutation (approximately 6% of tumors) indicates its role as a haploinsufficiency gene. ANXA7 mRNA transcript expression, dichotomized at the median, associates with patient survival in 191 glioblastomas (log-rank P = .008; hazard ratio [HR], 0.667; 95% confidence interval [CI], 0.493-0.902; 46.9 vs 74.8 deaths/100 person-years for high vs low ANXA7 mRNA expression) and with a separate group of 180 high-grade gliomas (log-rank P = .00003; HR, 0.476; 95% CI, 0.333-0.680; 21.8 vs 50.0 deaths/100 person-years for high vs low ANXA7 mRNA expression). Deletion of the ANXA7 gene associates with poor patient survival in 189 glioblastomas (log-rank P = .042; HR, 0.686; 95% CI, 0.476-0.989; 54.0 vs 80.1 deaths/100 person-years for wild-type ANXA7 vs ANXA7 deletion).Haploinsufficiency of the tumor suppressor ANXA7 due to monosomy of chromosome 10 provides a clinically relevant mechanism to augment EGFR signaling in glioblastomas beyond that resulting from amplification of the EGFR gene.

    View details for Web of Science ID 000267948100021

    View details for PubMedID 19602687

  • A Network Model of a Cooperative Genetic Landscape in Brain Tumors JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Bredel, M., Scholtens, D. M., Harsh, G. R., Bredel, C., Chandler, J. P., Renfrow, J. J., Yadav, A. K., Vogel, H., Scheck, A. C., Tibshirani, R., Sikic, B. I. 2009; 302 (3): 261-275

    Abstract

    Gliomas, particularly glioblastomas, are among the deadliest of human tumors. Gliomas emerge through the accumulation of recurrent chromosomal alterations, some of which target yet-to-be-discovered cancer genes. A persistent question concerns the biological basis for the coselection of these alterations during gliomagenesis.To describe a network model of a cooperative genetic landscape in gliomas and to evaluate its clinical relevance.Multidimensional genomic profiles and clinical profiles of 501 patients with gliomas (45 tumors in an initial discovery set collected between 2001 and 2004 and 456 tumors in validation sets made public between 2006 and 2008) from multiple academic centers in the United States and The Cancer Genome Atlas Pilot Project (TCGA).Identification of genes with coincident genetic alterations, correlated gene dosage and gene expression, and multiple functional interactions; association between those genes and patient survival.Gliomas select for a nonrandom genetic landscape-a consistent pattern of chromosomal alterations-that involves altered regions ("territories") on chromosomes 1p, 7, 8q, 9p, 10, 12q, 13q, 19q, 20, and 22q (false-discovery rate-corrected P<.05). A network model shows that these territories harbor genes with putative synergistic, tumor-promoting relationships. The coalteration of the most interactive of these genes in glioblastoma is associated with unfavorable patient survival. A multigene risk scoring model based on 7 landscape genes (POLD2, CYCS, MYC, AKR1C3, YME1L1, ANXA7, and PDCD4) is associated with the duration of overall survival in 189 glioblastoma samples from TCGA (global log-rank P = .02 comparing 3 survival curves for patients with 0-2, 3-4, and 5-7 dosage-altered genes). Groups of patients with 0 to 2 (low-risk group) and 5 to 7 (high-risk group) dosage-altered genes experienced 49.24 and 79.56 deaths per 100 person-years (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.10-2.40; Cox regression model P = .02), respectively. These associations with survival are validated using gene expression data in 3 independent glioma studies, comprising 76 (global log-rank P = .003; 47.89 vs 15.13 deaths per 100 person-years for high risk vs low risk; Cox model HR, 3.04; 95% CI, 1.49-6.20; P = .002) and 70 (global log-rank P = .008; 83.43 vs 16.14 deaths per 100 person-years for high risk vs low risk; HR, 3.86; 95% CI, 1.59-9.35; P = .003) high-grade gliomas and 191 glioblastomas (global log-rank P = .002; 83.23 vs 34.16 deaths per 100 person-years for high risk vs low risk; HR, 2.27; 95% CI, 1.44-3.58; P<.001).The alteration of multiple networking genes by recurrent chromosomal aberrations in gliomas deregulates critical signaling pathways through multiple, cooperative mechanisms. These mutations, which are likely due to nonrandom selection of a distinct genetic landscape during gliomagenesis, are associated with patient prognosis.

    View details for Web of Science ID 000267948100020

    View details for PubMedID 19602686

  • Predictors of peritumoral edema after stereotactic radiosurgery of supratentorial meningiomas NEUROSURGERY Patil, C. G., Hoang, S., Borchers, D. J., Sakamoto, G., Soltys, S. G., Gibbs, I. C., Harsh, G. R., Chang, S. D., Adler, J. R. 2008; 63 (3): 435-440

    Abstract

    Anecdotal evidence suggests that radiosurgical ablation of parasagittal meningiomas may be associated with increased risk of subsequent edema. Potential predictors of postradiosurgical peritumoral edema, including parasagittal tumor location, tumor size, and treatment dose, were evaluated.We retrospectively reviewed records of 102 patients with 111 supratentorial meningiomas treated with CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiosurgery (SRS). A median marginal dose of 18.0 Gy (range, 11.3-25.0 Gy) was delivered in 1 to 5 sessions (fractions). Potential predictors of posttreatment symptomatic edema were evaluated using Fisher's exact test.Of the 102 patients followed for a mean of 20.9 months (range, 6-77 mo), 15 (14.7%) developed symptomatic edema after SRS. Nine of 31 with parasagittal meningiomas (29.0%) and 6 of 80 with nonparasagittal supratentorial meningiomas (7.5%) developed symptomatic edema (P = 0.0053). Compared with patients with meningiomas in nonmidline supratentorial locations, patients with parasagittal meningiomas were more than 4 times as likely to develop symptomatic edema after SRS (odds ratio, 4.1; 95% confidence interval, 1.5-11.5). The 6-, 12-, and 18-month actuarial rates of symptomatic edema development were significantly greater for patients with parasagittal meningiomas than for patients with nonparasagittal meningiomas (17.8 versus 1.3%, 25.4 versus 5.8%, and 35.2 versus 7.8%, respectively).Patients with parasagittal meningiomas are at greater risk of developing peritumoral symptomatic edema after SRS. Close follow-up after SRS may be particularly important in such patients. These results highlight the need to pursue strategies that could decrease the incidence of postradiosurgical edema in patients with parasagittal meningioma.

    View details for Web of Science ID 000259625600010

    View details for PubMedID 18812954

  • National trends, complications, and outcomes following transsphenoidal surgery for Cushing's disease from 1993 to 2002. Neurosurgical focus Patil, C. G., Lad, S. P., Harsh, G. R., Laws, E. R., Boakye, M. 2007; 23 (3): E7-?

    Abstract

    Information about complications, patient outcomes, and mortality rate after transsphenoidal surgery (TSS) for Cushing's disease has been derived largely from single-institution series. In this study the authors report on inpatient death, morbidity, and outcomes following TSS for Cushing's disease on a national level.All patients in the Nationwide Inpatient Sample (NIS) database who had undergone transsphenoidal resection of a pituitary tumor for Cushing's disease between 1993 and 2002 were included in the study. The number of cases per year, length of stay (LOS), and rates of inpatient complications, death, and adverse outcomes (death or discharge to institution other than home) were abstracted. Univariate and multivariate analyses were performed to determine the effects of patient and hospital characteristics on outcome measures.According to the NIS, there were an estimated 3525 cases of TSS for Cushing's disease in the US between 1993 and 2002. During this period, there was a trend toward a small increase in the number of TSSs for Cushing's disease. The in-hospital mortality rate was 0.7%, and the complication rate was 42.1%. Diabetes insipidus (15%), fluid and electrolyte abnormalities (12.5%), and neurological deficits (5.6%) were the most common complications reported. Multivariate analysis showed that complications were more likely in patients with pre-operative comorbidities. Patients older than 64 years were much more likely to have an adverse outcome (odds ratio [OR] 20.8) and a prolonged hospital stay (OR 2.2). Women were less likely than men to have an adverse outcome (OR 0.3). A single postoperative complication increased the mean LOS by 3 days, more than tripled the odds of an adverse outcome, and increased the hospital charges by more than US $7000.The authors provided a national perspective on trends, inpatient complications, and outcomes after TSS for Cushing's disease in the US. Postoperative complications had a significantly negative effect on LOS, adverse outcome, and resource utilization. Advanced age and multiple preoperative comorbidities were identified as important risk factors, and their effects on patient outcomes were quantified.

    View details for PubMedID 17961019

  • Efficacy and safety of CyberKnife radiosurgery for acromegaly. Pituitary Roberts, B. K., Ouyang, D. L., Lad, S. P., Chang, S. D., Harsh, G. R., Adler, J. R., Soltys, S. G., Gibbs, I. C., Remedios, L., Katznelson, L. 2007; 10 (1): 19-25

    Abstract

    Acromegaly is a disease characterized by GH hypersecretion, and is typically caused by a pituitary somatotroph adenoma. The primary mode of therapy is surgery, and radiotherapy is utilized as an adjuvant strategy to treat persistent disease. The aim of this study was to determine the efficacy and tolerability of CyberKnife stereotactic radiosurgery in acromegaly.A retrospective review of biochemical and imaging data for subjects with acromegaly treated with CyberKnife stereotactic radiosurgery between 1998 and 2005 at Stanford University Hospital.Nine patients with active acromegaly were treated with radiosurgery using the CyberKnife (CK).Biochemical response based on serum insulin-like growth factor-1 (IGF-1), anterior pituitary hormone function, and tumor size with MRI scans were analyzed.After a mean follow up of 25.4 months (range, 6-53 months), CK radiosurgery resulted in complete biochemical remission in 4 (44.4%) subjects, and in biochemical control with the concomitant use of a somatostatin analog in an additional subject. Smaller tumor size was predictive of treatment success: baseline tumor volume was 1.28 cc (+/- 0.81, SD) vs. 3.93 cc (+/- 1.54) in subjects with a normal IGF-1 vs. those with persistent, active disease, respectively (P = 0.02). The mean biologically effective dose (BED) was higher in subjects who achieved a normal IGF-1 vs. those with persistent, active disease, 172 Gy(3) (+/-28) vs. 94 Gy(3) (+/-17), respectively (P < 0.01). At least one new anterior pituitary hormone deficiency was observed after CK in 3 (33%) patients: two developed hypogonadism, and one developed panhypopituitarism.CK radiosurgery may be a valuable adjuvant therapy for the management of acromegaly.

    View details for PubMedID 17273921

  • Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappa B-mediated resistance to O-6-alkylating agents in human glioblastomas JOURNAL OF CLINICAL ONCOLOGY Bredel, M., Bredel, C., Juric, D., Duran, G. E., Yu, R. X., Harsh, G. R., Vogel, H., Recht, L. D., Scheck, A. C., Sikic, B. I. 2006; 24 (2): 274-287

    Abstract

    Pre-existing and acquired drug resistance are major obstacles to the successful treatment of glioblastomas.We used an integrated resistance model and genomics tools to globally explore molecular factors and cellular pathways mediating resistance to O6-alkylating agents in glioblastoma cells.We identified a transcriptomic signature that predicts a common in vitro and in vivo resistance phenotype to these agents, a proportion of which is imprinted recurrently by gene dosage changes in the resistant glioblastoma genome. This signature was highly enriched for genes with functions in cell death, compromise, and survival. Modularity was a predominant organizational principle of the signature, with functions being carried out by groups of interacting molecules in overlapping networks. A highly significant network was built around nuclear factor-kappaB (NF-kappaB), which included the persistent alterations of various NF-kappaB pathway elements. Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) was identified as a new regulatory component of a putative cytoplasmic signaling cascade that mediates NF-kappaB activation in response to DNA damage caused by O6-alkylating agents. Expression of the corresponding zinc finger protein A20 closely mirrored the expression of the TNFAIP3 transcript, and was inversely related to NF-kappaB activation status in the resistant cells. A prediction model based on the resistance signature enabled the subclassification of an independent, validation cohort of 31 glioblastomas into two outcome groups (P = .037) and revealed TNFAIP3 as part of an optimized four-gene predictor associated significantly with patient survival (P = .022).Our results offer strong evidence for TNFAIP3 as a key regulator of the cytoplasmic signaling to activate NF-kappaB en route to O6-alkylating agent resistance in glioblastoma cells. This pathway may be an attractive target for therapeutic modulation of glioblastomas.

    View details for DOI 10.1200/JCO.2005.02.9405

    View details for Web of Science ID 000234741700008

    View details for PubMedID 16365179

  • Concomitant ectatic posterior communicating artery and tentorial meningioma as a source of oculomotor palsy: case report. Neurosurgery Babbitz, J. D., Harsh, G. R. 2005; 57 (6): E1316-?

    Abstract

    Although non-aneurysmal vascular compression of the oculomotor nerve is rare, it should be considered in the evaluation of unilateral oculomotor palsy.A 36-year-old non-diabetic man presented with two months of intermittent retro-orbital headache and third nerve paresis caused by compression of the oculomotor nerve between an ectatic, atherosclerotic posterior communicating artery (PComA) and a small tentorial meningioma. At operation, the subarachnoid portion of the nerve, prevented from migrating posteriorly and laterally by the meningioma, was grooved by the apex of the artery's loop.Microvascular decompression (MVD) of the artery loop from the nerve and resection of the meningioma were performed. Postoperatively, the patient's retro-orbital headache and oculomotor paresis, with the exception of mild anisocoria, resolved. Tumor infiltrating the posterior tentorium and lateral cavernous sinus was treated by Cyberknife radiosurgery five months later. One year after surgery, the patient had improvement in his headaches, full extra-ocular movements, and minimal residual anisocoria.Only one other report describes MVD of the third nerve from PComA compression. A review is presented of MVD carried out for similar cases of non-aneurysmal vascular compression of the oculomotor nerve. By analogy from cases in which an aneurysm is the compressing vascular structure, prompt surgical treatment is advocated. Complete evaluation of an isolated third nerve palsy should include MRI sequences designed to detect vascular compression of cranial nerves.

    View details for PubMedID 16331147

  • Identification of phenotypic neural stem cells in a pediatric astroblastoma JOURNAL OF NEUROSURGERY Huhn, S. L., Yung, Y., Cheshier, S., Harsh, G., Ailles, L., Weissman, I., Vogel, H., Tse, V. 2005; 103 (5): 446-450

    Abstract

    The goal of this study was to illustrate the findings of a significant subpopulation of cells within a pediatric astroblastoma that have the specific cell surface phenotype found on known human neural stem cells.Cells with a cell surface marker profile characteristic of human neural stem cells were isolated using fluorescence-activated cell sorting from a mostly nonmitotic astroblastoma removed from the brain of an 11-year-old girl. An unusually high proportion (24%) of the cells were CD133 positive and CD24, CD34, and CD45 negative (CD133(+)CD24(-)CD34(-)CD45(-) cells), the phenotypic antigenic pattern associated with neural stem cells; very few CD133-positive cells were not also CD24, CD34, and CD45 negative. Some cells (12%) were CD34 positive, indicating the presence within the tumor of hematopoietic stem cells. Cells formed cytospheres that resembled neurospheres when seeded into stem cell media and coexpressed beta-tubulin and glial fibrillary acidic protein (GFAP) but did not express the oligodendrocyte marker O4. Cell proliferation was demonstrated by incorporation of bromodeoxyuridine. The cells lost their capacity for self-renewal in vitro after four to six passages, although they continued to coexpress beta-tubulin and GFAP. The cells did not differentiate into neurons or astrocytes when placed in differentiation medium.Although this astroblastoma contained a high proportion of phenotypic neural stemlike cells, the cells had limited proliferative capacity and multipotency. Their role in astroblastoma formation and growth is unknown.

    View details for Web of Science ID 000233081900012

    View details for PubMedID 16302618

  • Functional network analysis reveals extended gliomagenesis pathway maps and three novel MYC-interacting genes in human gliomas CANCER RESEARCH Bredel, M., Bredel, C., Juric, D., Harsh, G. R., Vogel, H., Recht, L. D., Sikic, B. I. 2005; 65 (19): 8679-8689

    Abstract

    Gene expression profiling has proven useful in subclassification and outcome prognostication for human glial brain tumors. The analysis of biological significance of the hundreds or thousands of alterations in gene expression found in genomic profiling remains a major challenge. Moreover, it is increasingly evident that genes do not act as individual units but collaborate in overlapping networks, the deregulation of which is a hallmark of cancer. Thus, we have here applied refined network knowledge to the analysis of key functions and pathways associated with gliomagenesis in a set of 50 human gliomas of various histogenesis, using cDNA microarrays, inferential and descriptive statistics, and dynamic mapping of gene expression data into a functional annotation database. Highest-significance networks were assembled around the myc oncogene in gliomagenesis and around the integrin signaling pathway in the glioblastoma subtype, which is paradigmatic for its strong migratory and invasive behavior. Three novel MYC-interacting genes (UBE2C, EMP1, and FBXW7) with cancer-related functions were identified as network constituents differentially expressed in gliomas, as was CD151 as a new component of a network that mediates glioblastoma cell invasion. Complementary, unsupervised relevance network analysis showed a conserved self-organization of modules of interconnected genes with functions in cell cycle regulation in human gliomas. This approach has extended existing knowledge about the organizational pattern of gene expression in human gliomas and identified potential novel targets for future therapeutic development.

    View details for DOI 10.1158/0008-5472

    View details for Web of Science ID 000232199400018

    View details for PubMedID 16204036

  • alpha(v)beta(3) integrin in central nervous system tumors HUMAN PATHOLOGY Lim, M., Guccione, S., Haddix, T., Sims, L., Cheshier, S., Chu, P., Vogel, H., Harsh, G. 2005; 36 (6): 665-669

    Abstract

    alpha(v)beta(3) Is an integrin specifically expressed in endothelial cells of newly forming blood vessels. Integrin-mediated angiogenesis is hypothesized to play a central role in the development and the progression of central nervous system neoplasms. Accordingly, it is considered a potential target for antiangiogenic therapy. In the current study, we compare the expression of alpha(v)beta(3) in ependymomas, oligodendrogliomas, pilocytic astrocytomas, medulloblastomas, and vestibular schwannomas (acoustic neuromas). Samples of 5 tumors of each of the 5 tumor types were harvested surgically and frozen. After the pathological diagnosis was confirmed, immunohistochemistry was performed using an anti- alpha(v)beta(3) monoclonal antibody (LM609). The expression of alpha(v)beta(3) was assessed using a 4-tiered (0-3) grading scheme reflecting the percentage of positively staining vessels. All vestibular schwannomas demonstrated strong (grade 3) alpha(v)beta(3) expression. The expression was uniformly prominent in Antoni B regions of the tumors. Of 5 ependymomas, 4 demonstrated uniformly strong alpha(v)beta(3). Oligodendrogliomas, medulloblastomas, and pilocytic astrocytomas demonstrated more variable alpha(v)beta(3). alpha(v)beta(3) may contribute significantly to angiogenesis in vestibular schwannomas and ependymomas. Despite the high vascular density of oligodendrogliomas, pilocytic astrocytomas, and medulloblastomas, these tumors had variable moderate alpha(v)beta(3) expression. This discrepancy suggests temporal and/or regional variability in the angiogenesis in these types of tumor. This study provides the first demonstration of alpha(v)beta(3) expression in vestibular schwannomas, medulloblastomas, and pilocytic astrocytomas.

    View details for DOI 10.1016/j.humpath.2005.03.014

    View details for Web of Science ID 000230633500010

    View details for PubMedID 16021573

  • High-resolution genome-wide mapping of genetic alterations in human glial brain tumors CANCER RESEARCH Bredel, M., Bredel, C., Juric, D., Harsh, G. R., Vogel, H., Recht, L. D., Sikic, B. I. 2005; 65 (10): 4088-4096

    Abstract

    High-resolution genome-wide mapping of exact boundaries of chromosomal alterations should facilitate the localization and identification of genes involved in gliomagenesis and may characterize genetic subgroups of glial brain tumors. We have done such mapping using cDNA microarray-based comparative genomic hybridization technology to profile copy number alterations across 42,000 mapped human cDNA clones, in a series of 54 gliomas of varying histogenesis and tumor grade. This gene-by-gene approach permitted the precise sizing of critical amplicons and deletions and the detection of multiple new genetic aberrations. It has also revealed recurrent patterns of occurrence of distinct chromosomal aberrations as well as their interrelationships and showed that gliomas can be clustered into distinct genetic subgroups. A subset of detected alterations was shown predominantly associated with either astrocytic or oligodendrocytic tumor phenotype. Finally, five novel minimally deleted regions were identified in a subset of tumors, containing putative candidate tumor suppressor genes (TOPORS, FANCG, RAD51, TP53BP1, and BIK) that could have a role in gliomagenesis.

    View details for Web of Science ID 000229062000015

    View details for PubMedID 15899798

  • Amplification of whole tumor genomes and geneby-gene mapping of genomic aberrations from limited sources of fresh-frozen and paraffin-embedded DNA JOURNAL OF MOLECULAR DIAGNOSTICS Bredel, M., Bredel, C., Juric, D., Kim, Y., Vogel, H., Harsh, G. R., Recht, L. D., Pollack, J. R., Sikic, B. I. 2005; 7 (2): 171-182

    Abstract

    Sufficient quantity of genomic DNA can be a bottleneck in genome-wide analysis of clinical tissue samples. DNA polymerase Phi29 can be used for the random-primed amplification of whole genomes, although the amplification may introduce bias in gene dosage. We have performed a detailed investigation of this technique in archival fresh-frozen and formalin-fixed/paraffin-embedded tumor DNA by using cDNA microarray-based comparative genomic hybridization. Phi29 amplified DNA from matched pairs of fresh-frozen and formalin-fixed/paraffin-embedded tumor samples with similar efficiency. The distortion in gene dosage representation in the amplified DNA was nonrandom and reproducibly involved distinct genomic loci. Regional amplification efficiency was significantly linked to regional GC content of the template genome. The biased gene representation in amplified tumor DNA could be effectively normalized by using amplified reference DNA. Our data suggest that genome-wide gene dosage alterations in clinical tumor samples can be reliably assessed from a few hundred tumor cells. Therefore, this amplification method should lend itself to high-throughput genetic analyses of limited sources of tumor, such as fine-needle biopsies, laser-microdissected tissue, and small paraffin-embedded specimens.

    View details for Web of Science ID 000228736900004

    View details for PubMedID 15858140

  • Anterior skull base surgery OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA Kaplan, M. J., Fischbein, N. J., Harsh, G. R. 2005; 38 (1): 107-?

    Abstract

    This article focuses on selected key anatomic considerations in anterior skull base surgery, briefly reviews common pathologies of the paranasal sinuses, and provides an overview of surgical approaches, complications, and results.

    View details for DOI 10.1016/j.otc.2004.09.010

    View details for Web of Science ID 000226736500011

    View details for PubMedID 15649503

  • Characterization of the integrin alpha v beta 3 in arteriovenous malformations and cavernous malformations CEREBROVASCULAR DISEASES Lim, M., Haddix, T., Harsh, G. R., Vogel, H., Steinberg, G. K., Guccione, S. 2005; 20 (1): 23-27

    Abstract

    Alpha V beta 3 (alphavbeta3) is an integrin specifically expressed on the endothelial cells of central nervous system (CNS) neoplasms. However, no data exist on the expression of alphavbeta3 in vascular malformations of the CNS. In this study, we investigate the expression of alphavbeta3 in arteriovenous malformations (AVMs) and cavernous malformations (CMs).Frozen samples of AVMs from 12 patients and CMs from 5 patients were obtained intraoperatively. Once the final pathology had been confirmed, immunohistochemistry was performed using an antibody to the integrin alphavbeta3. The alphavbeta3 expression pattern was graded according to the percentage of positively staining vessels.Ten of 12 AVMs demonstrated alphavbeta3 immunopositivity. Six of these 10 AVMs had moderate or strong staining. Most notably, 5 of the 6 moderate or strongly staining AVMs came from patients 22 years of age or younger. Four of these 6 AVMs had previously been embolized. None of the cavernous malformations demonstrated alphavbeta3 immunopositivity.alphavbeta3 may contribute to the formation of AVMs in younger patients. alphavbeta3 may also provide a potential therapeutic target. The lack of alphavbeta3 expression in cavernous malformations, despite their high vascular densities, suggests that the pathophysiology of their formation differs from that of AVMs.

    View details for DOI 10.1159/000086123

    View details for Web of Science ID 000230678700005

    View details for PubMedID 15925879

  • Glial tumor grading and outcome prediction using dynamic spin-echo MR susceptibility mapping compared with conventional contrast-enhanced MR: Confounding effect of elevated rCBV of oligodendroglimoas AMERICAN JOURNAL OF NEURORADIOLOGY Lev, M. H., Ozsunar, Y., Henson, J. W., Rasheed, A. A., Barest, G. D., Harsh, G. R., Fitzek, M. M., Chiocca, E. A., Rabinov, J. D., Csavoy, A. N., Rosen, B. R., Hochberg, F. H., Schaefer, P. W., Gonzalez, R. G. 2004; 25 (2): 214-221
  • Glial tumor grading and outcome prediction using dynamic spin-echo MR susceptibility mapping compared with conventional contrast-enhanced MR: confounding effect of elevated rCBV of oligodendrogliomas [corrected]. AJNR. American journal of neuroradiology Lev, M. H., Ozsunar, Y., Henson, J. W., Rasheed, A. A., Barest, G. D., Harsh, G. R., Fitzek, M. M., Chiocca, E. A., Rabinov, J. D., Csavoy, A. N., Rosen, B. R., Hochberg, F. H., Schaefer, P. W., Gonzalez, R. G. 2004; 25 (2): 214-221

    Abstract

    The MR imaging characteristics of oligodendrogliomas and astrocytomas on spin-echo (SE), echo-planar relative cerebral blood volume (rCBV) maps, to our knowledge, have not previously been emphasized. We compared the specificity of SE rCBV mapping with that of conventional, contrast material-enhanced MR imaging in differentiating high- from low-grade glial tumors and in predicting survival of patients with these lesions.Thirty consecutive adult patients with suspected gliomas underwent conventional and rCBV MR imaging. Representative maximal rCBV regions of interest were chosen from each lesion. Resultant values were normalized to those of corresponding, contralateral, uninvolved regions. These normalized CBV (nCBV) values were correlated with degree of contrast enhancement, histopathologic tumor grade, and survival.Twenty-two patients had astroctyomas and eight had oligodendrogliomas. With an nCBV cutoff ratio of 1.5, 13 of 13 high-grade astrocytomas were correctly categorized, three of which did not enhance. Seven of nine low-grade astrocytomas were correctly classified by their nCBV values, including one enhancing lesion. Of eight oligodendrogliomas, four of four high-grade and two of four low-grade tumors had elevated nCBV values; two low-grade oligodendrogliomas enhanced, one with nCBV greater than 1.5 and one with nCBV less than 1.5. In 19 patients with astrocytoma for whom survival data were available, correlation with survival was better for nCBV (mean survival 91 +/- 14 months for nCBV < 1.5 versus 24 +/- 27 months for nCBV > 1.5, P <.0001) than for enhancement (mean survival 61 +/- 35 months without enhancement versus 22 +/- 29 months with enhancement, P =.03).Elevated SE rCBV was a sensitive, but not specific, marker for high-grade histopathology: all high-grade tumors had nCBV foci values greater than 1.5. No tumor with nCBV region of interest less than 1.5 was high grade (100% predictive value for excluding high grade). Degree of nCBV elevation was a stronger predictor of both tumor grade and survival than was degree of enhancement. A significant proportion of low-grade glial neoplasms, most notably oligodendrogliomas, may display high rCBV foci not reflective of high-grade histopathology.

    View details for PubMedID 14970020

  • Effects of tumor suppressor gene (p53) on brain tumor angiogenesis and expression of angiogenic modulators ANTICANCER RESEARCH Tse, V., Yung, Y., Santarelli, J. G., Juan, D., Hsiao, M., Haas, M., Harsh, G., Silverberg, G. 2004; 24 (1): 1-10

    Abstract

    p53 retarded tumor growth by several known mechanisms, including suppression of cell proliferation and inhibition of tumor angiogenesis. Vascular endothelial growth factors (VEGF) and angiopoietins (Ang-1, Ang-2) are major angiogeneic modulators. The current study examined the effect of p53 on the expression of these factors in conjunction with tumor growth and vascular formation.Growth characteristics of rat glioma cells (RT-2) infected with retrovirus (MSCV) encoding a full-length human wild-type p53 gene were examined by clonogenic assay. Expression of the transgene in vitro was verified by RT-PCR and immunoprecipitation. Tumor morphology, vascular architecture and the expression of VEGF, Ang-1, Ang-2 and Tie-2 were examined by immunohistochemistry and semi-quantitative RT-PCR.p53-infected cells showed retardation in growth and colony formation. In vivo, expression of the transgene resulted in prolonged survival and reduction of tumor volume (62%) and reduced the expression of VEGF (57.8%) and Tie-2 (15.4%) but not Ang-1 and Ang-2. The tumor exhibited increased necrosis (38%), hemorrhage and abnormal vascular architecture.p53 causes tumor regression by suppressing tumor proliferation and indirectly induces involution of tumor vessels by fostering unopposed activity of Ang-2 in an environment of diminishing VEGF.

    View details for Web of Science ID 000189271900001

    View details for PubMedID 15015569

  • Quality assurance of magnetic resonance spectroscopic imaging-derived metabolic data INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Hunjan, S., Adalsteinsson, E., Kim, D. H., Harsh, G. R., Boyer, A. L., Spielman, D., Xing, L. 2003; 57 (4): 1159-1173

    Abstract

    Spatially resolved metabolite maps, as measured by magnetic resonance spectroscopic imaging (MRSI) methods, are being increasingly used to acquire metabolic information to guide therapy, with metabolite ratio maps perhaps providing the most diagnostic information. We present a quality assurance procedure for MRSI-derived metabolic data acquired ultimately for guiding conformal radiotherapy.An MRSI phantom filled with brain-mimicking solutions was custom-built with an insert holding eight vials containing calibration solutions of precisely varying metabolite concentrations that emulated increasing grade/density of brain tumor. Phantom metabolite ratios calculated from fully relaxed 1D, 2D, and 3D MRS data for each vial were compared with calibrated metabolite ratios acquired at 9.4 T. Additionally, 3D ratio maps were "discretized" to eight pseudoabnormality levels on a slice-by-slice basis and the accuracy of this procedure was verified.Regression analysis revealed expected linear relationships between experimental and calibration metabolite ratios with intercepts close to zero for the three acquisition modes. 1D MRS data agreed most with theoretical considerations (regression coefficient, b = 0.969; intercept 0.008). The 2D (b = 1.049; intercept -0.199) and 3D (correlation coefficient r(2) = 0.9978-0.7336 for five slices) MRSI indicated reduced MRS data quality in regions of degraded B(0) and B(1) homogeneity. Pseudoabnormality levels were found to be consistent with expectations within regions of adequate B(0) homogeneity.This simple phantom-based approach to generate baseline calibration curves for all MRS acquisition modes may be useful to identify temporal deviations from acceptable data quality in a routine clinical environment or for testing new MRS and MRSI acquisition software.

    View details for DOI 10.1016/S0630-3016(03)01564-5

    View details for Web of Science ID 000186293800031

    View details for PubMedID 14575849

  • Magnetic resonance image-guided proteomics of human glioblastoma multiforme JOURNAL OF MAGNETIC RESONANCE IMAGING Hobbs, S. K., Shi, G. Y., Homer, R., Harsh, G., Atlas, S. W., Bednarski, M. D. 2003; 18 (5): 530-536

    Abstract

    To investigate the correlation between gadolinium contrast-enhancement patterns on T1-weighted magnetic resonance (MR) images and spatial changes in protein expression profiles in human glioblastoma multiforme (GBM) and the use of imaging as a noninvasive technique to evaluate the heterogeneity of solid tumors prior to microarray analysis.Four patients with MR images and confirmed diagnosis of GBM were enrolled in the study. Intraoperative stereotaxy was used in conjunction with MR images to identify contrast-enhanced (CE) and nonenhanced (NE) regions of the tumor during surgical resection. Total protein was extracted from resected tumor samples using standard techniques and subjected to proteomic analysis using surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS).We found that protein profiles from CE and NE regions within a given tumor have qualitative and semiquantitative proteomic pattern differences, suggesting an altered gene expression profile that correlates with detectable tissue imaging parameters. We also found that CE regions within the same tumor exhibited distinct differences in protein expression profiles, despite similar histological features. In addition, there were marked similarities in the proteomic patterns among the NE regions across all patients, while the CE regions were distinct, suggesting that the CE regions have complex protein profiles unique to individuals.The results demonstrate that major differences in protein expression patterns within a tumor can be correlated to radiographic findings. Image-guided proteomics holds promise for characterizing tissue prior to microarray analysis designed to identify specific diagnostic markers and therapeutic targets within solid tumors.

    View details for DOI 10.1002/jmri.10395

    View details for Web of Science ID 000186295300002

    View details for PubMedID 14579395

  • The temporal-spatial expression of VEGF, angiopoietins-1 and 2, and Tie-2 during tumor angionenesis and their functional correlation with tumor neovascular architecture NEUROLOGICAL RESEARCH Tse, V., Xu, L., Yung, Y. C., Santarelli, J. G., Juan, D., Fabel, K., Silverberg, G., Harsh, G. 2003; 25 (7): 729-738

    Abstract

    Angiopoietins play a pivotal role in tumor angiogenesis by modulating vascular endothelial proliferation and survival. The expression of angiopoietins 1 and 2 (Ang-1 and Ang-2) and vascular endothelial growth factor (VEGF) has been documented in human malignant glioma. The expression of Ang-1, Ang-2, VEGF, and Tie-2, a member of the receptor tyrosine kinases and the natural receptor for both Ang-1 and Ang-2, follows a distinct transcriptional profile in vivo. Ang-2 and VEGF were expressed early in tumor formation and their levels increased throughout tumor growth. Their expression coincided with the expansion of the tumor mass and the formation of the vascular tree. There was no significant change in the expression of Tie-2 and Ang-1. The expression of Ang-1 and Tie-2 was more noticeable at the periphery of the tumor. The expression of Ang-2 was more robust at the periphery and within the tumor mass, and VEGF was more concentrated within the center of the tumor. This distinct expression profile may explain the morphology of the newly formed vessels at various times and regions of the tumor. The lack of concomitant expression of Ang-1 may underscore the unopposed endovascular induction by Ang-2 and VEGF resulting in the chaotic appearance and fragility of tumor vessels.

    View details for Web of Science ID 000186229300010

    View details for PubMedID 14579791

  • Synchronous subarachnoid drop metastases from a pituitary adenoma with multiple recurrences - Case report JOURNAL OF NEUROSURGERY Lehman, N. L., Horoupian, D. S., Harsh, G. R. 2003; 98 (5): 1120-1123

    Abstract

    The authors report the case of a 49-year-old man with synchronous drop metastases from a multiply recurrent somatotroph pituitary adenoma. The metastatic lesions were found in the subarachnoid space of the cauda equina and foramen magnum 18 years after the initial diagnosis of the disease. Five transsphenoidal resections had previously failed to cure the sellar tumor. Two of these, performed 4 and 5 years before the patient's current presentation, had been complicated by cerebrospinal fluid rhinorrhea that necessitated lumbar drainage. Resections of the two subarachnoid lesions, separated by 14 months, removed pathologically aggressive pituitary adenomas. There were no signs of local recurrence or subarachnoid dissemination of disease during the postoperative follow-up periods, which lasted 18 and 4 months, respectively. Previous cases of subarachnoid spread of a pituitary adenoma have been associated with multiple intracranial metastases, multiple intraspinal metastases, or widely disseminated disease. This case demonstrates that subarachnoid metastasis of a pituitary adenoma, particularly when it follows multiple operations, is not invariably widely disseminated or associated with a very poor prognosis.

    View details for Web of Science ID 000182619000032

    View details for PubMedID 12744376

  • Pituitary apoplexy after leuprolide injection for ovum donation JOURNAL OF ADOLESCENT HEALTH Engel, G., Huston, M., Oshima, S., Beck, C., Harsh, G., Rosenthal, M. H., Camargo, C. A. 2003; 32 (1): 89-93

    Abstract

    Patients with occult pituitary adenomas infrequently present with pituitary apoplexy. Precipitation of pituitary apoplexy by gonadotropin releasing hormone or gonadotropin releasing hormone agonists has been described. The pathophysiologic mechanism by which these agents induce apoplexy remains unclear. We describe a case of pituitary apoplexy in a young woman receiving leuprolide in preparation for ovum donation. Severe hyponatremia, cerebral vasospasm and infarction, and diabetes insipidus complicated this patient's prolonged hospital course. To our knowledge, pituitary apoplexy after gonadotropin releasing hormone agonist use for ovum donation has not been previously described. The use of leuprolide or other gonadotropin releasing hormone agonists for pituitary down-regulation in conjunction with ovarian stimulation can have serious consequences in women harboring unrecognized pituitary adenomas. Thorough endocrine screening should be performed prior to initiating therapy.

    View details for Web of Science ID 000180206800014

    View details for PubMedID 12507807

  • In vivo 3-T MR spectroscopy in the distinction of recurrent glioma versus radiation effects: Initial experience RADIOLOGY Rabinov, J. D., Lee, P. L., Barker, F. G., Louis, D. N., Harsh, G. R., Cosgrove, G. R., Chiocca, E. A., Thornton, A. F., Loeffler, J. S., Henson, J. W., Gonzalez, R. G. 2002; 225 (3): 871-879

    Abstract

    To determine if 3-T magnetic resonance (MR) spectroscopy allows accurate distinction of recurrent tumor from radiation effects in patients with gliomas of grade II or higher.This blinded prospective study included 14 patients who underwent in vivo 3-T MR spectroscopy prior to stereotactic biopsy. All patients received a previous diagnosis of glioma (grade II or higher) and high-dose radiation therapy (>54 Gy). Prior to MR spectroscopy, conventional MR imaging was performed at 1.5 T to identify a gadolinium-enhanced region within the irradiated volume. Diagnosis was assigned by means of histopathologic analysis of the biopsy samples.Sixteen of 17 biopsy locations could be classified as predominantly tumor or predominantly radiation effect on the basis of the ratio of choline at the biopsy site to normal creatine level by using a value greater than 1.3 as the criterion for tumor. The remaining case, classified as recurrent tumor on the basis of MR spectroscopy results, was diagnosed as predominantly radiation effect on the basis of histopathologic findings. Disease in this patient progressed to biopsy-proven recurrence within 3 months. Overall, the ratio of choline at the biopsy site to normal creatine level was significantly elevated (unpaired two-tailed Student t test, P <.002) in those biopsy samples composed predominantly of tumor (n = 9) compared with those containing predominantly radiation effects (n = 8). The ratio was not significantly different between the two histopathologic groups.In vivo 3-T MR spectroscopy has sufficient spatial resolution and chemical specificity to allow distinction of recurrent tumor from radiation effects in patients with treated gliomas.

    View details for DOI 10.1148/radiol.2253010997

    View details for Web of Science ID 000179420800035

    View details for PubMedID 12461273

  • Proton beam stereotactic radiosurgery of vestibular schwannomas INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Harsh, G. R., Thornton, A. F., Chapman, P. H., Bussiere, M. R., Rabinov, J. D., Loeffler, J. S. 2002; 54 (1): 35-44

    Abstract

    The proton beam's Bragg peak permits highly conformal radiation of skull base tumors. This study, prompted by reports of transient (30% each) and permanent (10% each) facial and trigeminal neuropathy after stereotactic radiosurgery of vestibular schwannomas with marginal doses of 16-20 Gy, assessed whether proton beam radiosurgery using a marginal dose of only 12 Gy could control vestibular schwannomas while causing less neuropathy.Sixty-eight patients (mean age 67 years) were treated between 1992 and 1998. The mean tumor volume was 2.49 cm(3). The dose to the tumor margin (70% isodose line) was 12 Gy. The prospectively specified follow-up consisted of neurologic evaluation and MRI at 6, 12, 24, and 36 months.After a mean clinical follow-up of 44 months and imaging follow-up of 34 months in 64 patients, 35 tumors (54.7%) were smaller and 25 (39.1%) were unchanged (tumor control rate 94%; actuarial control rate 94% at 2 years and 84% at 5 years). Three tumors enlarged: one shrank after repeated radiosurgery, one remained enlarged at the time of unrelated death, and one had not been imaged for 4 years in a patient who remained asymptomatic at last follow-up. Intratumoral hemorrhage into one stable tumor required craniotomy that proved successful. Thus, 97% of tumors required no additional treatment. Three patients (4.7%) underwent shunting for hydrocephalus evident as increased ataxia. Of 6 patients with functional hearing ipsilaterally, 1 improved, 1 was unchanged, and 4 progressively lost hearing. Cranial neuropathies were infrequent: persistent facial hypesthesia (2 new, 1 exacerbated; 4.7%); intermittent facial paresthesias (5 new, 1 exacerbated; 9.4%); persistent facial weakness (2 new, 1 exacerbated; 4.7%) requiring oculoplasty; transient partial facial weakness (5 new, 1 exacerbated; 9.4%), and synkinesis (5 new, 1 exacerbated; 9.4%).Proton beam stereotactic radiosurgery of vestibular schwannomas at the doses used in this study controls tumor growth with relatively few complications.

    View details for Web of Science ID 000177780900005

    View details for PubMedID 12182972

  • Dural marginal zone lymphoma with massive amyloid deposition: rare low-grade primary central nervous system B-cell lymphoma - Case report JOURNAL OF NEUROSURGERY Lehman, N. L., Horoupian, D. S., Warnke, R. A., Sundram, U. N., Peterson, K., Harsh, G. R. 2002; 96 (2): 368-372

    Abstract

    The authors report the case of a 63-year-old woman who presented with a primary dural extranodal marginal zone lymphoma (MZL) associated with massive kappa light chain amyloidosis of the meninges. Extranodal MZL is a low-grade B-cell lymphoma that may show variable degrees of plasmacytic differentiation. Like solitary plasmacytoma of soft tissue, which can also be associated with amyloid, extranodal MZL generally responds well to local therapy and has a good prognosis. It is important to distinguish these entities from high-grade primary central nervous system (CNS) B-cell lymphomas and more aggressive and/or widespread, potentially amyloidogenic conditions such as multiple myeloma, lympho-plasmacytoid lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma. To the authors' knowledge this is the first reported case of dural MZL associated with massive meningeal amyloid deposition. Extranodal MZL is a rare low-grade primary CNS B-cell lymphoma that may be associated with amyloidosis. It should be considered in the differential diagnosis of CNS lymphoproliferative lesions and CNS amyloidosis.

    View details for Web of Science ID 000173591900025

    View details for PubMedID 11838814

  • Pedicled rhinotomy for clival chordomas invaginating the brainstem. Neurosurgical focus Harsh, G., Ojemann, R., Varvares, M., Swearingen, B., Cheney, M., Joseph, M. 2001; 10 (3): E8-?

    Abstract

    Clival chordomas are frequently midline lesions whose posterior growth may breach the dura and invaginate the brainstem. This precludes safe delivery of potentially curative high-dose fractionated proton radiotherapy. To avoid this problem, the authors performed pedicled rhinotomy to resect chordomas in 10 patients.Pedicled rhinotomy is a midface transnasal route to the intercarotid sella and clivus from the tuberculum sellae to the mid-C-2 level. It involves a lateral rhinotomy incision, osteotomies of nasal bones and cartilage, lateral rotation of the nose, removal of the nasal septum and medial maxillary walls, opening of ethmoid and sphenoid sinuses, and dissection of nasopharynx and oropharynx to expose the clivus and craniovertebral junction. Tumors involving the sella, medial cavernous sinuses, middle and lower clivus, and C-1 arch and dens can be removed even if they traverse the dura. Closure involves dural repair, grafting of fat and split-thickness skin, rotation of a vascularized mucosal pedicle, and reattachment of nasal cartilage. Ten clival chordomas in adult patients were surgically removed via a pedicled rhinotomy approach. Seven patients had previously undergone a total of nine skull base procedures. In eight of the 10 patients, tumors compressing the brainstem were completely removed using this technique. One patient required an additional subtemporal resection of a suprasellar tumor before definitive radiotherapy could be undertaken. No patient sustained any new neurological deficit; in eight patients headache, diplopia, or hemiparesis improved. One patient developed postoperative cerebrospinal fluid leakage and meningitis that were successfully treated with antibiotic agents and shunt placement.Pedicled rhinotomy provides excellent shallow-field exposure of midline clival chordomas and permits relief of brainstem compression and the postoperative administration of potentially curative proton beam irradiation.

    View details for PubMedID 16734411

  • Daily low-dose carboplatin as a radiation sensitizer for newly diagnosed malignant glioma JOURNAL OF NEURO-ONCOLOGY Peterson, K., Harsh, G., Fisher, P. G., Adler, J., Le, Q. 2001; 53 (1): 27-32

    Abstract

    Surgical resection followed by local field radiotherapy is currently our most effective approach to treatment for most patients with malignant glioma. Carboplatin chemotherapy has direct cytotoxic effects on glioma cells and acts as a radiation sensitizer to enhance cell killing. Its demonstrated efficacy as a sensitizer in other solid tumors led to this clinical trial of carboplatin as a radiation sensitizer in the treatment of newly diagnosed glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). Fourteen patients (nine GBM and five AA) were treated with daily low-dose carboplatin 25 mg/m2 intravenously within 2 h of their fractionated radiotherapy to a total dose of 600 mg/m2. No significant toxicities attributable to this combined therapy were observed. All patients have progressed, with median time to progression of 16 weeks. Eleven patients have died, with median survival of 38 weeks for the entire cohort. Although this regimen appeared safe, there was no benefit in survival time compared to historical patients treated with radiotherapy. The limitations and future potential for the strategy of radiation sensitization are discussed.

    View details for Web of Science ID 000170979800004

    View details for PubMedID 11678427

  • Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene-marking and neuropathological study JOURNAL OF NEUROSURGERY Harsh, G. R., Deisboeck, T. S., Louis, D. N., Hilton, J., Colvin, M., Silver, J. S., Qureshi, N. H., Kracher, J., FINKELSTEIN, D., Chiocca, E. A., Hochberg, F. H. 2000; 92 (5): 804-811

    Abstract

    The gene therapy paradigm of intratumoral activation of ganciclovir (GCV) following transduction of tumor cells by retroviral vectors bearing the thymidine kinase (tk) gene has produced dramatic remissions of malignant gliomas in animal models. In human trials, although the technique has been deemed safe, little antitumor effect has been demonstrated. To evaluate the basis of this inefficacy in human gliomas, the authors conducted a gene-marking trial involving neuropathological and biochemical studies of treated tumor specimens.Five patients with malignant recurrent gliomas underwent stereotactic biopsy sampling and intratumoral implantation procedures with three aliquots of 10(6) vector-producing cells (VPCs) in columns. After 5 days, the tumor was resected and the tumor bed reimplanted with VPCs, and a course of GCV was given. Patients received clinical and radiological follow up for 6 months. Tumor specimens were analyzed neuropathologically and for tk gene expression by anti-TK immunohistochemistry and TK enzymatic activity. Four patients tolerated the treatment well but experienced tumor progression. The other developed an abscess after the second operation and died. Increased TK enzymatic activity was demonstrated in the one tumor specimen analyzed. Immunohistochemical evidence of tk gene expression was limited to VPCs. Transduction of tumor cells was not seen. Viable tumor cells were seen near VPCs containing TK. The lymphocytic immune response was mild.Except for the risk of infection inherent in reoperation, this tk-GCV paradigm was both feasible and safe. Pathological studies indicated that limited dissemination of VPCs and vector from the infusion site and failure to transduce tumor cells with the tk gene are major barriers to efficacy.

    View details for Web of Science ID 000086675600009

    View details for PubMedID 10794295

  • Simulated brain tumor growth dynamics using a three-dimensional cellular automaton JOURNAL OF THEORETICAL BIOLOGY Kansal, A. R., Torquato, S., Harsh, G. R., Chiocca, E. A., Deisboeck, T. S. 2000; 203 (4): 367-382

    Abstract

    We have developed a novel and versatile three-dimensional cellular automaton model of brain tumor growth. We show that macroscopic tumor behavior can be realistically modeled using microscopic parameters. Using only four parameters, this model simulates Gompertzian growth for a tumor growing over nearly three orders of magnitude in radius. It also predicts the composition and dynamics of the tumor at selected time points in agreement with medical literature. We also demonstrate the flexibility of the model by showing the emergence, and eventual dominance, of a second tumor clone with a different genotype. The model incorporates several important and novel features, both in the rules governing the model and in the underlying structure of the model. Among these are a new definition of how to model proliferative and non-proliferative cells, an isotropic lattice, and an adaptive grid lattice.

    View details for Web of Science ID 000086468100004

    View details for PubMedID 10736214

  • Cranial reconstruction for metastatic breast cancer PLASTIC AND RECONSTRUCTIVE SURGERY Sieveking, N. E., Turk, A. E., Beck, C. E., Harsh, G. 2000; 105 (5): 1737-1741

    Abstract

    All women with advanced breast cancer who are medically stable despite their disease are candidates for tumor extirpation and reconstruction. Advanced breast cancer today is incurable, and many prognostic factors can be used to try to predict a clinical course and response to therapy; however, no guidelines are available. Our case report most likely represents a metastasis to the calvarium with intracranial extension, reported to occur in about 3 percent of primary breast cancer patients. As demonstrated here, tumor ablation with immediate, one-stage reconstruction of large scalp defects is possible without the need for free tissue transfer or a delay in adjuvant therapy. Local tissue rearrangement has been employed for coverage of defects up to 50 percent of the cranium. The resulting donor defects can be closed with split-thickness skin grafts over pericranium. Serial tissue expansion and rearrangement can be used secondarily to replace skin grafts with hair-bearing scalp. Bony defects can be managed with either autogenous or alloplastic materials. Split-calvarial bone grafts can be harvested from the same operative field and cover small to medium-sized defects. Other sources of autogenous grafts include split ribs and iliac bone. Metals, calcium ceramics, and polymers such as methylmethacrylate can be used to cover intracranial contents and restore calvarial contour when defects are large or when autogenous material is not available. Palliation from tumor burden, prevention of pathologic fracture and oncologic emergencies, controlling pain, and enhancing quality of life are the goals of the oncologic and reconstructive surgeons in cases of advanced breast cancer. These goals are becoming even more important as new forms and combinations of chemotherapy, radiation, and gene therapy are extending the life expectancy of women with breast carcinoma.

    View details for Web of Science ID 000086208800020

    View details for PubMedID 10809105

  • Multicolumn infusion of gene therapy cells into human brain tumors: Technical report NEUROSURGERY Qureshi, N. H., Bankiewicz, K. S., Louis, D. N., Hochberg, F. H., Chiocca, E. A., Harsh, G. R. 2000; 46 (3): 663-668

    Abstract

    Effective gene therapy for brain tumors may require saturation of the tumors with tumoricidal doses of the therapeutic gene. Safe, precise, and efficient delivery of gene therapy vectors is required. Most reported cases of and published protocols for gene therapy for brain tumors involve freehand injection of retroviral vector-producing cells (VPCs) into the brain. Major disadvantages of this method include the inaccuracy of hand-guided needle placement and limited control of injection parameters. These factors can result in failure to deliver the viral vectors to specifically targeted sites within the brain, extensive tissue disruption resulting from excessively forceful injection, and reflux of the injectate along the needle tract.We describe a novel stereotactic strategy for saturating tumor volumes with tumoricidal doses of gene therapy vectors and a new, more precise method of infusing VPCs. With our new instrument, the multicolumn stereotactic infusion system, needle placement is stereotactically guided and both VPC infusion and needle withdrawal are mechanically controlled.This technique, which has been used effectively for six patients, permits precise deposition of columns of VPCs throughout the targeted tumor volume.This technique should facilitate saturation of tumors with tumoricidal doses of gene therapy vectors and should improve the results of gene therapy protocols that rely on intraparenchymal injection for delivery.

    View details for Web of Science ID 000085684200070

    View details for PubMedID 10719863

  • Cellular automaton of idealized brain tumor growth dynamics BIOSYSTEMS Kansal, A. R., Torquato, S., Harsh, G. R., Chiocca, E. A., Deisboeck, T. S. 2000; 55 (1-3): 119-127

    Abstract

    A novel cellular automaton model of proliferative brain tumor growth has been developed. This model is able to simulate Gompertzian tumor growth over nearly three orders of magnitude in radius using only four microscopic parameters. The predicted composition and growth rates are in agreement with a test case pooled from the available medical literature. The model incorporates several new features, improving previous models, and also allows ready extension to study other important properties of tumor growth, such as clonal competition.

    View details for Web of Science ID 000086628800014

    View details for PubMedID 10745115

Conference Proceedings


  • Risk of Leptomeningeal Disease in Patients Treated With Stereotactic Radiosurgery Targeting the Postoperative Resection Cavity for Brain Metastases Modlin, L. A., Atalar, B., Choi, C. Y., Gibbs, I. C., Chang, S. D., Harsh, G. R., Adler, J. R., Soltys, S. G. ELSEVIER SCIENCE INC. 2012: S116-S117
  • DEVELOPMENT AND VALIDATION OF A PRE-OPERATIVE PROGNOSTIC SCORING SYSTEM FOR PATIENTS WITH GLIOBLASTOMA Chaichana, K., Pendleton, C., Chambless, L., Nathan, J., Camara-Quintana, J., Li, G., Harsh, G., Thompson, R., Lim, M., Quinones-Hinojosa, A. OXFORD UNIV PRESS INC. 2011: 154-155
  • AN RNAI SCREEN IDENTIFIES TRRAP AS A REGULATOR OF BRAIN TUMOR-INITIATING CELL DIFFERENTIATION Skirboll, S. L., Wurdak, H., Zhu, S., Romero, A., Lorger, M., Watson, J., Chiang, C., Zhang, J., Natu, V. S., Lairson, L. L., Walker, J. R., Trussell, C. M., Harsh, G. R., Vogel, H., Felding-Habermann, B., Orth, A. P., Miraglia, L. J., Rines, D. R., Schultz, P. G. OXFORD UNIV PRESS INC. 2010: 122-122
  • Stereotactic Radiosurgery of the Post-operative Resection Cavity for Brain Metastases: Optimization of the Treatment Technique Soltys, S. G., Gibbs, I. C., Chang, S. D., Adler, J. R., Harsh, G. R., LIEBERSON, R. E., Choi, C. Y. ELSEVIER SCIENCE INC. 2010: S7-S7
  • Role of I kappa B alpha as a negative regulator of EGFR and a molecular determinant of prognosis in glioblastoma multiforme Bredel, M., Renfrow, J., Yadav, A., Alvarez, A., LIN, D., Scholtens, D., He, X., Chandler, J., Scheck, A., Harsh, G. AMER SOC CLINICAL ONCOLOGY. 2009
  • ISOLATION OF BRAIN CANCER STEM CELLS FROM GLIOBLASTOMA USING AN ANTIBODY LIBRARY Raveh, T., Luppen, C., Cox, D., Higgins, D., Cheshier, S., Ailles, L., Edwards, M. S., Harsh, G., Weissman, I. OXFORD UNIV PRESS INC. 2008: 904-904
  • Isolation of brain cancer stem cells using signaling pathway reporters Ailles, L., Cheshier, S., Raveh, T., Higgins, D., Harsh, G., Edwards, M., Weissman, I. OXFORD UNIV PRESS INC. 2007: 593-593
  • Osteopontin (OPN) expression correlates with glioma aggressiveness Guccione, S., Jang, T., Yang, Y., Cao, H., Haddix, T., Glantz, M., Le, Q., Recht, L., Harsh, G. OXFORD UNIV PRESS INC. 2007: 468-468
  • Elevated serum levels of VEGF, bFGF, MMP-2, and MMP-9 in patients with Moyamoya disease Lim, M., Wang, Y., Bower, R., Cheshier, S., Sims, L., Choi, S., Harsh, G., Steinberg, G., Guccione, S. LIPPINCOTT WILLIAMS & WILKINS. 2006: 701-701
  • Characterization of avb3 integrin in vascular malformations Lim, M., Harsh, G., Haddix, T., Vogel, H., Chu, P. L., Steinberg, G., Guccione, S. LIPPINCOTT WILLIAMS & WILKINS. 2005: 517-517
  • Identification of blood markers for GBMS with the aid of genomic array and MRI Lim, M., Harsh, G., Wang, Y. Y., Bednarski, M., Guccione, S. OXFORD UNIV PRESS INC. 2004: 338-339

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