Kathleen R Lamborn

Mayo Foundation for Medical Education and Research, Scottsdale, AZ, United States

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Publications (268)1430.95 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients.Methods We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients.ResultsTwenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6(S235/236) but possible compensatory increase in phospho-Akt(S473). Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho-extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months.Conclusion Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.
    Neuro-Oncology 01/2014; · 6.18 Impact Factor
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    ABSTRACT: Therapeutic outcomes for patients with brain metastases need to improve. A critical review of trials specifically addressing brain metastases shows key issues that could prevent acceptance of results by regulatory agencies, including enrolment of heterogeneous groups of patients and varying definitions of clinical endpoints. Considerations specific to disease, modality, and treatment are not consistently addressed. Additionally, the schedule of CNS imaging and consequences of detection of new or progressive brain metastases in trials mainly exploring the extra-CNS activity of systemic drugs are highly variable. The Response Assessment in Neuro-Oncology (RANO) working group is an independent, international, collaborative effort to improve the design of trials in patients with brain tumours. In this two-part series, we review the state of clinical trials of brain metastases and suggest a consensus recommendation for the development of criteria for future clinical trials.
    The Lancet Oncology 09/2013; 14(10):396-406. · 25.12 Impact Factor
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    ABSTRACT: PURPOSE: Gamma knife radiosurgery (RS) may be an alternative to open surgery for mesial temporal lobe epilepsy (MTLE), but morbidities and the anticonvulsant mechanisms of RS are unclear. Examination of visual field defects (VFDs) after RS may provide evidence of the extent of a postoperative fixed lesion. VFDs occur in 52-100% of patients following open surgery for MTLE. METHODS: This multicenter prospective trial of RS enrolled patients with unilateral hippocampal sclerosis and concordant video-electroencephalography (EEG) findings. Patients were randomized to low (20 Gy) or high (24 Gy) doses delivered to the amygdala, hippocampal head, and parahippocampal gyrus. Postoperative perimetry were obtained at 24 months after RS. Visual field defect ratios (VFDRs) were calculated to quantify the degree of VFDs. Results were contrasted with age, RS dose and 50% isodose volume, peak volume of radiation-induced change at the surgical target, quality of life measurements, and seizure remission. KEY FINDINGS: No patients reported visual changes and no patients had abnormal bedside visual field examinations. Fifteen (62.5%) of 24 patients had postoperative VFDs, all homonymous superior quadrantanopsias. None of the VFDs were consistent with injury to the optic nerve or chiasm. Clinical diagnosis of VFDs correlated significantly with VFDRs (p = 0.0005). Patients with seizure remission had smaller (more severe) VFDRs (p = 0.04). No other variables had significant correlations. SIGNIFICANCE: VFDs appeared after RS in proportions similar to historical comparisons from open surgery for MTLE. The nature of VFDs was consistent with lesions of the optic radiations. The findings support the hypothesis that the mechanism of RS involves some degree of tissue damage and is not confined entirely to functional changes in neuromodulation.
    Epilepsia 05/2013; · 3.96 Impact Factor
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    ABSTRACT: Background The objective of this study was to examine the predictive value of parameters of 3D (1)H magnetic resonance spectroscopic imaging (MRSI) prior to treatment with radiation/chemotherapy (baseline) and at a postradiation 2-month follow-up (F2mo) in relationship to 6-month progression-free survival (PFS6) and overall survival (OS).Methods Sixty-four patients with newly diagnosed glioblastoma multiforme (GBM) being treated with radiation and concurrent chemotherapy were involved in this study. Evaluated were metabolite indices and metabolite ratios. Logistic linear regression and Cox proportional hazards models were utilized to evaluate PFS6 and OS, respectively. These analyses were adjusted by age and MR scanner field strength (1.5 T or 3 T). Stepwise regression was performed to determine a subset of the most relevant variables.ResultsAssociated with shorter PFS6 were a decrease in the ratio of N-acetyl aspartate to choline-containing compounds (NAA/Cho) in the region with a Cho-to-NAA index (CNI) >3 at baseline and an increase of the CNI within elevated CNI regions (>2) at F2mo. Patients with higher normalized lipid and lactate at either time point had significantly worse OS. Patients who had larger volumes with abnormal CNI at F2mo had worse PFS6 and OS.Conclusions Our study found more 3D MRSI parameters that predicted PFS6 and OS for patients with GBM than did anatomic, diffusion, or perfusion imaging, which were previously evaluated in the same population of patients.
    Neuro-Oncology 02/2013; · 6.18 Impact Factor
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    ABSTRACT: The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor-β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents.
    Neuro-Oncology 10/2012; · 6.18 Impact Factor
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    ABSTRACT: PURPOSE: A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG).EXPERIMENTAL DESIGN: This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days of the first cycle and 200 mg/m(2)/day for 5 days of the subsequent 28-day cycles.RESULTS: In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose-limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells.CONCLUSION: Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway. Clin Cancer Res; 1-8. ©2012 AACR.
    Clinical Cancer Research 08/2012; · 7.84 Impact Factor
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    ABSTRACT: Advances in the management of gliomas, including the approval of agents such as temozolomide and bevacizumab, have created an evolving therapeutic landscape in glioma treatment, thus affecting our ability to reliably use historical controls to comparatively assess the activity of new therapies. Furthermore, the increasing availability of novel, targeted agents--which are competing for a small patient population, in view of the low incidence of primary brain tumours--draws attention to the need to improve the efficiency of phase 2 clinical testing in neuro-oncology to expeditiously transition the most promising of these drugs or combinations to potentially practice-changing phase 3 trials. In this report from the Response Assessment in Neurooncology (RANO) group, we review phase 2 trial designs that can address these challenges and capitalise on scientific and clinical advances in brain tumour treatment in neuro-oncology to accelerate and optimise the selection of drugs deserving further testing in phase 3 trials. Although there is still a small role for single-arm and non-comparative phase 2 designs, emphasis is placed on the potential role that comparative randomised phase 2 designs--such as screening designs, selection designs, discontinuation designs, and adaptive designs, including seamless phase 2/3 designs--can have. The rational incorporation of these designs, as determined by the specific clinical setting and the trial's endpoints or goals, has the potential to substantially advance new drug development in neuro-oncology.
    The Lancet Oncology 05/2012; 13(5):e196-204. · 25.12 Impact Factor
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    ABSTRACT: Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types. SIGNIFICANCE: Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain.
    Cancer Discovery 05/2012; 2(5):458-71. · 10.14 Impact Factor
  • Neuro-Oncology 04/2012; 14(4):391. · 6.18 Impact Factor
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    ABSTRACT: The purpose of this study is to evaluate the roles of resection extent and adjuvant radiation in the treatment of craniopharyngiomas. We reviewed the records of 122 patients ages 11-52 years who received primary treatment for craniopharyngioma between 1980 and 2009 at the University of California, San Francisco (UCSF). Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were development of panhypopituitarism, diabetes insipidus (DI), and visual field defects. Of 122 patients, 30 (24%) were treated with gross total resection (GTR) without radiation therapy (RT), 3 (3%) with GTR + RT, 41 (33.6%) with subtotal resection (STR) without RT, and 48 (39.3%) with STR + RT. Median age at diagnosis was 30 years, with 46 patients 18 years or younger. Median follow-up for all patients was 56.4 months (interquartile range 18.9-144.2 months) and 47 months (interquartile range 12.3-121.8 months) for the 60 patients without progression. Fifty six patients progressed, 10 have died, 6 without progression. Median PFS was 61.1 months for all patients. PFS rate at 2 years was 61.5% (95% CI: 52.1-70.9). OS rate at 10 years was 91.1% (95% CI 84.3-97.9). There was no significant difference in PFS and OS between patients treated with GTR vs. STR + XRT (PFS; p = 0.544, OS; p = 0.735), but STR alone resulted in significantly shortened PFS compared to STR + RT or GTR (p < 0.001 for both). STR was associated with significantly shortened OS compared to STR + RT (p = 0.050) and trended to shorter OS compared to GTR (p = 0.066). GTR was associated with significantly greater risk of developing DI (56.3 vs. 13.3% with STR + XRT, p < 0.001) and panhypopituitarism (54.8 vs. 26.7% with STR + XRT, p = 0.014). In conclusion, for patients with craniopharyngioma, STR + RT may provide superior clinical outcome, achieving better disease control than STR and limiting side effects associated with aggressive surgical resection.
    Journal of Neuro-Oncology 02/2012; 108(1):133-9. · 3.12 Impact Factor
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    ABSTRACT: The spatial heterogeneity in magnetic resonance (MR) metabolic and diffusion parameters and their relationship were studied for patients with treatment-naive grade 3 gliomas. MR data were evaluated from 51 patients with newly diagnosed grade 3 gliomas. Anatomic, diffusion, and metabolic imaging data were considered. Variations in metabolite levels, apparent diffusion coefficient (ADC), and fractional anisotropy (FA) were evaluated in regions of gadolinium enhancement and T2 hyperintensity as well as regions with abnormal metabolic signatures. Contrast enhancement was present in only 21 of the 51 patients. When present, the enhancing component of the lesion had higher choline-to-N-acetylaspartate index (CNI), higher choline, lower N-acetylaspartate, similar creatine, similar ADC and FA, and higher lactate/lipid than the nonenhancing lesion. Regions with CNI ≥ 4 had higher choline, lower N-acetylaspartate, higher lactate/lipid, higher ADC, and lower FA than normal-appearing white matter and regions with intermediate CNI values. For lesions that exhibited gadolinium enhancement, the metabolite levels and diffusion parameters in the region of enhancement were consistent with it corresponding to the most abnormal portion of the tumor. For nonenhancing lesions, areas with CNI ≥ 4 were the most abnormal in metabolic and diffusion parameters. This suggests that the region with the highest CNI might provide a good target for biopsies for nonenhancing lesions to obtain a representative histologic diagnosis of its degree of malignancy. Metabolic and diffusion parameter levels may be of interest not only for directing tissue sampling but also for defining the targets for focal therapy and assessing response to therapy.
    Translational oncology 02/2012; 5(1):10-8. · 3.40 Impact Factor
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    ABSTRACT: To evaluate prognostic factors for survival after stereotactic radiosurgery (SRS) for new, progressive, or recurrent brain metastases (BM) after prior whole brain radiotherapy (WBRT). Patients treated between 1991 and 2007 with Gamma Knife SRS for BM after prior WBRT were retrospectively reviewed. Potential prognostic factors were analyzed overall and by primary site using univariate and stepwise multivariate analyses and recursive partitioning analysis, including age, Karnofsky performance status (KPS), primary tumor control, extracranial metastases, number of BM treated, total SRS target volume, and interval from WBRT to SRS. A total of 310 patients were analyzed, including 90 breast, 113 non-small-cell lung, 31 small-cell lung, 42 melanoma, and 34 miscellaneous patients. The median age was 56, KPS 80, number of BM treated 3, and interval from WBRT to SRS 8.1 months; 76% had controlled primary tumor and 60% had extracranial metastases. The median survival was 8.4 months overall and 12.0 vs. 7.9 months for single vs. multiple BM treated (p = 0.001). There was no relationship between number of BM and survival after excluding single-BM patients. On multivariate analysis, favorable prognostic factors included age <50, smaller total target volume, and longer interval from WBRT to SRS in breast cancer patients; smaller number of BM, KPS >60, and controlled primary in non-small-cell lung cancer patients; and smaller total target volume in melanoma patients. Among patients treated with salvage SRS for BM after prior WBRT, prognostic factors appeared to vary by primary site. Although survival time was significantly longer for patients with a single BM, the median survival time of 7.9 months for patients with multiple BM seems sufficiently long for salvage SRS to appear to be worthwhile, and no evidence was found to support the use of a cutoff for number of BM appropriate for salvage SRS.
    International journal of radiation oncology, biology, physics 11/2011; 83(1):303-9. · 4.59 Impact Factor
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    ABSTRACT: The disease outcome for patients with cancer is typically described in terms of estimated survival from diagnosis. Conditional probability offers more relevant information regarding survival for patients once they have survived for some time. We report conditional survival probabilities on the basis of 498 patients with glioblastoma multiforme receiving radiation and chemotherapy. For 1-year survivors, we evaluated variables that may inform subsequent survival. Motivated by the trend in data, we also evaluated the assumption of constant hazard. Patients enrolled onto seven phase II protocols between 1975 and 2007 were included. Conditional survival probabilities and 95% CIs were calculated. The Cox proportional hazards model was used to evaluate prognostic values of age, Karnofsky performance score (KPS), and prior progression 1-year post diagnosis. To assess the constant hazard assumption, we used a likelihood-ratio test to compare the Weibull and exponential distributions. The probabilities of surviving an additional year given survival to 1, 2, 3, and 4 years were 35%, 49%, 69%, and 93%, respectively. For patients who survived for 1 year, lower KPS and progression were significantly predictive of shorter survival (both P < .001), but age was not (hazard ratio, 1.22 for a 10-year increase; P = .25). The Weibull distribution fits the data significantly better than exponential (P = .02), suggesting nonconstant hazard. Conditional probabilities provide encouraging information regarding life expectancy to survivors of glioblastoma multiforme. Our data also showed that the constant hazard assumption may be violated in modern brain tumor trials. For single-arm trials, we advise using individual patient data from historical data sets for efficacy comparisons.
    Journal of Clinical Oncology 11/2011; 29(31):4175-80. · 18.04 Impact Factor
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    ABSTRACT: This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.
    Neuro-Oncology 09/2011; 13(12):1331-8. · 6.18 Impact Factor
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    ABSTRACT: The management and prognosis of glioblastoma patients after Stupp protocol treatment and progression during bevacizumab (BV) treatment remain undefined. We compared the morbidity and survival of patients whose glioblastomas progressed during BV treatment requiring craniotomy with those of patients not treated with BV. We retrospectively reviewed patients who underwent craniotomy for recurrent glioblastoma from 2005 to 2009. Patients operated on for progression during BV (preoperative BV) were compared with patients receiving no BV or receiving BV after surgery (postoperative BV). Patients receiving BV preoperatively were compared with those patients whose gliobastoma progressed on BV treatment but were not operated on (no surgery). There were 23 preoperative BV patients, 135 no BV patients, 16 postoperative BV patients, and 25 no surgery patients. Patients receiving BV preoperatively had a worse postoperative overall survival rate (hazard ratio, 3.1; P < .001) and worse postoperative progression-free survival rate (hazard ratio, 3.4, P < .001) than patients not receiving BV. Patients receiving BV preoperatively had a higher perioperative morbidity rate (44%) than patients not receiving preoperative BV (21%) (P = 0.02). Survival after diagnosis was comparable between groups (86-93 weeks, P = .9), consistent with glioblastomas developing BV evasion being not intrinsically more aggressive, but possibly BV evasion conferring a uniquely poor prognosis. No surgery patients had a shorter overall survival after progression during BV treatment compared with preoperative BV patients (hazard ratio, 3.6, P < .001). Patients whose glioblastomas progress while receiving BV leading to craniotomy exhibit shorter postoperative survival and more perioperative morbidity than patients not treated with BV. Although there may be benefits to surgical debulking, the decision to pursue repeat surgery in patients in whom BV treatment failed must be balanced against the increased risk of perioperative complications.
    Neurosurgery 08/2011; 70(2):361-70. · 2.53 Impact Factor
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    ABSTRACT: Historically, the North American Brain Tumor Consortium used 6-month progression-free survival (PFS6) as the primary outcome for recurrent glioma phase II clinical trials. In some trials, a subset of patients received the trial treatment before surgery to assess tumor uptake and biological activity. We compared PFS6 and overall survival (OS) for patients with glioblastoma undergoing surgery at progression to results for those without surgery to evaluate the impact of surgical intervention on these outcomes. Two data sets were analyzed. The first included 511 patients enrolled during the period 1998-2005, 105 of whom had surgery (excluding biopsies) during the study or ≤ 30 days prior to registration. Analysis was stratified on the basis of whether temozolomide was part of the protocol treatment regimen. The second data set included 247 patients enrolled during 2005-2008, 103 of whom underwent surgery during the clinical trial or immediately prior to study registration. A combined data set consisting of all patients who did not receive temozolomide was also compiled. No statistically significant difference in PFS6 or OS was found between the surgery and nonsurgery groups in either data set alone or in the combined data set (P > .45). We conclude that PFS6 and OS results for patients with and without surgical intervention at the time of progression are similar, allowing data from these patients to be combined in assessing the benefit of new treatments without the need for stratification or other statistical adjustment.
    Neuro-Oncology 08/2011; 13(10):1118-24. · 6.18 Impact Factor
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    ABSTRACT: Cilengitide is a cyclic pentapeptide that is a specific inhibitor of the αvβ3 and αvβ5 integrins. Preclinical studies demonstrate antiangiogenic activity and anti-invasive activity in a number of glioma models. This study was designed to evaluate the efficacy and tumor delivery of cilengitide in patients with recurrent glioblastoma. Patients with recurrent glioblastoma who require a surgical resection for optimal clinical care received 3 intravenous doses of cilengitide at either 500 or 2000 mg (day -8, -4, -1) prior to undergoing tumor resection with corresponding blood samples for plasma to tumor comparisons. After recovery from surgery, patients were treated with cilengitide (2000 mg i.v. twice weekly, maximum of 2 years of treatment). The study accrued 30 patients with recurrent glioblastoma, 26 were evaluable for efficacy. The 6-month progression free survival rate was 12%. Cilengitide was detected in all tumor specimens with higher levels in the group receiving 2000 mg dosing while corresponding plasma concentrations were low, often below the lower limit of detection. These results confirm drug delivery and possibly retention in tumor. This study provides evidence that with established dosing, cilengitide is adequately delivered to the tumor, although as a single agent, efficacy in recurrent glioblastoma is modest. However, these results demonstrating drug delivery to tumor do support continued investigation of this agent as preliminary results from recent studies combining cilengitide with cytotoxic therapies are promising.
    Journal of Neuro-Oncology 07/2011; 106(1):147-53. · 3.12 Impact Factor
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    ABSTRACT: The duration of visual symptoms associated with a nonfunctioning pituitary adenoma (NFA) is a predictive factor for chances of visual improvement. The authors investigated factors associated with increased duration of visual symptoms in patients with NFAs. The authors retrospectively reviewed NFAs resected at their institution between 2004 and 2010 for duration of visual symptoms, postoperative improvement, and associated factors. Seventy-five patients underwent NFA resection with a median visual symptom duration of 6.5 months (range 1 week-15 years). A multivariate logistic regression showed that duration of symptoms (p = 0.04), but not age at surgery (p = 0.2), predicted postoperative normalization of vision. Univariate nonparametric analyses investigating age at symptom onset, sex, race, insurance type, ophthalmological conditions, income, marital status, emergency department admission, language, and medical provider found that age was the only variable significantly prolonging symptom duration (p = 0.04), a finding confirmed by a multivariate regression analysis. Patients 20-39, 40-59, and 60-79 years old had median durations of symptoms of 4, 7, and 9 months, respectively. Seven older patients had symptoms attributed to preexisting ophthalmological conditions for a median of 18 months before NFA diagnosis. Among age and race subgroups, the largest difference in median symptom duration was between white patients in the 60-79-year age range (duration of 5 months) and nonwhite patients in the 60-79-year age range (duration of 24 months) (p = 0.04). The authors found that older age was associated with delayed NFA diagnosis in visually impaired patients. Contributing factors were the attributing of visual symptoms from NFAs to other ophthalmological conditions in these patients, and delayed presentation in elderly nonwhite patients. These findings highlight challenges associated with timely NFA diagnosis in visually impaired patients, a key factor for chances of improvement.
    Journal of Neurosurgery 07/2011; 116(2):283-9. · 3.15 Impact Factor
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    ABSTRACT: Rathke cleft cysts (RCCs), benign remnants of the Rathke pouch typically arising in the sella, sometimes have suprasellar extension. Purely suprasellar RCCs are rarely reported. To compare the presentations, surgical outcomes, and pathology of purely suprasellar RCCs and sellar-based RCCs. We retrospectively reviewed records, magnetic resonance images, laboratory results, and pathology of 151 RCC patients surgically managed at our institution from 1989 to 2009. The RCCs were classified as purely sellar (type I, n = 76), sellar with suprasellar extension (type II, n = 56), or purely suprasellar (type III, n = 19). The RCCs with a suprasellar component (types II and III) more commonly presented with visual dysfunction (P < .001). Complete cyst drainage occurred in 89%, 55%, and 38% of type I, II, and III RCCs, respectively (P < .001). Vision improved in 100%, 55%, and 33% and headache improved in 74%, 64%, and 29% of type I, II, and III patients, respectively (P = .02). Temporary or permanent postoperative diabetes insipidus occurred in 5%, 16%, and 21% of type I, II, and III patients, respectively. (P < .001). In a multivariate analysis, RCC type was the only factor predicting recurrence. Kaplan-Meier 3-year recurrence/progression rates were 0%, 16%, and 29% for type I, II, and III RCCs, respectively (P < .001, type I vs II, type I vs III; P = .5 type II vs III). The RCCs with a suprasellar component are neurosurgically challenging because of their proximity to the optic chiasm and infundibulum. Compared with sellar-based RCCs, RCCs with a suprasellar component more frequently present with visual dysfunction, are more difficult to completely eliminate, recur more frequently, and are associated with higher postoperative endocrine morbidity, and their preoperative visual dysfunction and headache less frequently improve with surgery. These factors must be considered during the treatment of RCCs with a suprasellar component.
    Neurosurgery 06/2011; 69(5):1058-68; discussion 1068-7. · 2.53 Impact Factor
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    ABSTRACT: Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma. Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse. Aflibercept 4 mg/kg was administered intravenously on day 1 of every 2-week cycle. The 6-month progression-free survival rate was 7.7% for the glioblastoma cohort and 25% for patients with anaplastic glioma. Overall radiographic response rate was 24% (18% for glioblastoma and 44% for anaplastic glioma). The median progression-free survival was 24 weeks for patients with anaplastic glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with glioblastoma (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. The main treatment-related National Cancer Institute Common Terminology Criteria grades 3 and 4 adverse events (38 total) included fatigue, hypertension, and lymphopenia. Two grade 4 CNS ischemias and one grade 4 systemic hemorrhage were reported. Aflibercept rapidly decreases permeability on dynamic contrast enhanced magnetic resonance imaging, and molecular analysis of baseline tumor tissue identified tumor-associated markers of response and resistance. Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma.
    Journal of Clinical Oncology 05/2011; 29(19):2689-95. · 18.04 Impact Factor

Publication Stats

10k Citations
1,430.95 Total Impact Points

Institutions

  • 2010–2012
    • Mayo Foundation for Medical Education and Research
      • Department of Oncology
      Scottsdale, AZ, United States
    • Northwestern University
      • Feinberg School of Medicine
      Evanston, IL, United States
  • 1992–2012
    • University of California, San Francisco
      • • Department of Radiology and Biomedical Imaging
      • • Department of Neurology
      • • Department of Neurological Surgery
      • • Diller Family Comprehensive Cancer Center
      • • Division of Hospital Medicine
      San Francisco, CA, United States
  • 2011
    • University of Texas MD Anderson Cancer Center
      • Department of Neuro Oncology
      Houston, TX, United States
    • University of Texas Southwestern Medical Center
      Dallas, Texas, United States
    • Duke University Medical Center
      Durham, North Carolina, United States
    • University of Virginia
      • Department of Neurology
      Charlottesville, VA, United States
    • National Cancer Institute (USA)
      Maryland, United States
    • Stanford Medicine
      Stanford, California, United States
  • 2009–2010
    • Partners HealthCare
      Boston, Massachusetts, United States
    • Harvard Medical School
      • Department of Radiation Oncology
      Boston, MA, United States
  • 2008
    • University of Texas Health Science Center at San Antonio
      • Pharmacotherapy Education and Research Center
      San Antonio, TX, United States
  • 2007
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 2006
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2005–2006
    • University of California, Los Angeles
      • Department of Pathology and Laboratory Medicine
      Los Angeles, California, United States
  • 1994–2006
    • University of California, Davis
      • • School of Medicine
      • • Department of Internal Medicine
      • • UC Davis Medical Center
      Davis, CA, United States
  • 1997–2005
    • CSU Mentor
      • Department of Medicine
      Long Beach, California, United States
  • 2003
    • California State University, Sacramento
      Sacramento, California, United States
  • 2001
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 1990
    • Stanford University
      • Department of Medicine
      Stanford, CA, United States