B K Kleinschmidt-DeMasters

Children's Hospital Colorado, Aurora, Colorado, United States

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Publications (180)870.93 Total impact

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    ABSTRACT: Growth hormone (GH) pituitary tumors are associated with significant morbidity and mortality. Current treatments, including surgery and medical therapy with somatostatin analogs (SSA), dopamine agonists and/or a GH receptor antagonist, result in disease remission in approximately half of patients. Predictors of GH tumor response to different therapies have been incompletely defined based on histologic subtype, particularly densely (DG) versus sparsely (SG) granulated adenomas. The aim of this study was to examine our own institutional experience with GH adenomas and correlate how subtype related to clinical parameters as well as response to surgery and medical therapies. A retrospective chart review of 101 acromegalic patients operated by a single neurosurgeon was performed. Clinical data were correlated with histologic subtype and disease control, as defined by IGF-1 levels, and random growth hormone levels in response to surgery and/or medical therapies. SG tumors, compared to DG, occurred in younger patients (p = 0.0010), were 3-fold larger (p = 0.0030) but showed no differences in tumor-invasion characteristics (p = 0.12). DG tumors had a higher rate of remission in response to surgery compared to SG, 65.7 vs. 14.3 % (p < 0.0001), as well as to medical therapy with SSAs (68.8 % for DG vs. 28.6 % for SG tumors; p = 0.028). SG tumors not controlled with SSAs consistently responded to a switch to, or addition of, a GH receptor antagonist. Histological GH tumor subtyping implicates a different clinical phenotype and biologic behavior, and provides prognostic significance for surgical success and response to medical therapies.
    Endocrine. 08/2014;
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    ABSTRACT: Metastatic leptomeningeal spread from spinal cord gangliogliomas (GGs) is exceedingly rare.
    American Journal of Clinical Pathology 08/2014; 142(2):254-60. · 2.88 Impact Factor
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    ABSTRACT: The clinical features, pathologic changes, and immune repertoire in a remarkable case of chronic varicella-zoster virus (VZV) ganglioneuritis without rash are described.
    Neurology 11/2013; · 8.25 Impact Factor
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    ABSTRACT: Brainstem gangliogliomas (GGs) often cannot be resected, have a much poorer prognosis than those located in more common supratentorial sites, and may benefit from novel therapeutic approaches. Therapeutically-targetable BRAF c.1799T>A (p.V600E) (BRAF(V600E) ) mutations are harbored in roughly 50% of collective GGs taken from all anatomical sites. Large numbers of pediatric brainstem GGs, however, have not been specifically assessed and anatomic- and age-restricted assessment of genetic and biological factors are becoming increasingly important. Pediatric brainstem GGs (n=13), non-brainstem GGs (n=11), and brainstem pilocytic astrocytomas (PAs) (n=8) were screened by standard Sanger DNA sequencing of BRAF exon 15. Five of 13 (38%) pediatric GG harbored a definitive BRAF(V600E) mutation, with 2 others exhibiting an equivocal result by this method. BRAF(V600E) was also seen in 5/11 (45%) non-brainstem GGs and 1/8 (13%) brainstem PAs. VE1 immunostaining for BRAF(V600E) showed concordance with sequencing in 9/9 brainstem GGs including the two cases equivocal by Sanger. The equivocal brainstem GGs were subsequently shown to harbor BRAF(V600E) using a novel, more sensitive, RNA-sequencing approach, yielding a final BRAF(V600E) mutation frequency of 54% (7/13) in brainstem GGs. BRAF(V600E) -targeted therapeutics should be a consideration for the high percentage of pediatric brainstem GGs refractory to conventional therapies.
    Brain Pathology 11/2013; · 4.74 Impact Factor
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    ABSTRACT: Astrocytic dysfunction is implicated in epilepsy through many proposed molecular mechanisms, but there is also a clinicopathologic entity of epilepsy featuring astrocytic inclusions.(1) At least 17 cases of early-onset epilepsy with eosinophilic, hyaline astrocytic inclusions have been reported since the early 1990s.(2-8) Most of these cases also involve developmental delay.(2-8) The diagnosis is made by neuropathologic analysis that demonstrates brightly eosinophilic, hyaline, refractile astrocytic inclusions seen under light microscopy with hematoxylin & eosin stain.(2-8) We review the clinicopathologic entity of pediatric epilepsy with hyaline astrocytic inclusions and report an illustrative case.
    Neurology 07/2013; 81(3):e14-e16. · 8.25 Impact Factor
  • Hilary S Serracino, B K Kleinschmidt-Demasters
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    ABSTRACT: Skull and dura serve as effective barriers to penetration by most tumors, often preventing masses originating intracranially from extending into the contiguous bone and soft tissues, or those arising in head and neck regions from extending into the dura and brain tissue. We review our 15-year experience with extracranial tumors that had sufficiently invaded adjacent skull, dura, or brain from the "outside-in" to require a neurosurgeon to participate in the surgical resection and discuss our 40 cases in context with the literature. Sinonasal-origin tumors (n = 17) and cutaneous tumors (n = 10) were the most frequent skull-invaders. Most of the cutaneous tumor types were squamous cell carcinomas (n = 9); diverse sinonasal-origin types included 4 squamous cell carcinomas, 4 adenoid cystic carcinomas, 2 sinonasal undifferentiated carcinomas, 2 sinonasal adenocarcinomas, and single examples each of sinonasal-origin hemangiopericytoma, solitary fibrous tumor, melanoma, mucocele, and teratocarcinoma. There were 9 olfactory neuroblastomas, and middle ear-origin basal cell carcinoma, recurrent glomus jugulare, and orbital malignant hidradenoma were also seen. Unique tumors included a cutaneous cylindroma invasive of skull convexity occurring in familial cylindromatosis and a ganglioneuroma of the middle ear with massive bilateral skull base extension. Convexity dural spread, a seldom-reported pattern of dissemination, was seen in 1 olfactory neuroblastoma and 1 adenoid cystic carcinoma. The ability to show skull/dural invasion did not correlate with specific histopathologic features; even benign tumor types can show skull/dural penetration.
    Journal of neuropathology and experimental neurology. 06/2013;
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    ABSTRACT: Background Tissue invasion is a hallmark of most human cancers and remains a major source of treatment failure in patients with glioblastoma (GBM). Although EGFR amplification has been previously associated with more invasive tumor behavior, existing experimental models have not supported quantitative evaluation of interpatient differences in tumor cell migration or testing of patient-specific responses to therapies targeting invasion. To explore these questions, we optimized an ex vivo organotypic slice culture system allowing for labeling and tracking of tumor cells in human GBM slice cultures.Methods With use of time-lapse confocal microscopy of retrovirally labeled tumor cells in slices, baseline differences in migration speed and efficiency were determined and correlated with EGFR amplification in a cohort of patients with GBM. Slices were treated with gefitinib to evaluate anti-invasive effects associated with targeting EGFR.ResultsMigration analysis identified significant patient-to-patient variation at baseline. EGFR amplification was correlated with increased migration speed and efficiency compared with nonamplified tumors. Critically, gefitinib resulted in a selective and significant reduction of tumor cell migration in EGFR-amplified tumors.Conclusions These data provide the first identification of patient-to-patient variation in tumor cell migration in living human tumor tissue. We found that EGFR-amplified GBM are inherently more efficient in their migration and can be effectively targeted by gefitinib treatment. These data suggest that stratified clinical trails are needed to evaluate gefitinib as an anti-invasive adjuvant for patients with EGFR-amplified GBM. In addition, these results provide proof of principle that primary slice cultures may be useful for patient-specific screening of agents designed to inhibit tumor invasion.
    Neuro-Oncology 06/2013; · 6.18 Impact Factor
  • B K Kleinschmidt-Demasters, M B S Lopes
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    ABSTRACT: This article reviews recent literature on sellar region masses that most closely mimic non-secretory pituitary adenomas: hypophysitis, pituicytoma, spindle cell oncocytoma, and granular cell tumor of neurohypophysis. Even today, these 4 entities often cannot be confidently distinguished from each other clinically or by preoperative neuroimaging features. Thus, they often come to biopsy/surgical resection and require tissue confirmation of diagnosis. Causes of secondary and primary hypophysitis will be discussed, including two newly-described types, IgG4 plasma cell hypophysitis and hypophysitis caused by anti-CTLA4 antibody therapy for cancer. For the neoplastic conditions, emphasis will be placed on literature that has emerged since these entities were first codified in the 2007 World Health Organization fascicle (38, 39, 119). The finding that immunohistochemical staining for thyroid transcription factor-1 (TTF-1) is shared by pituicytoma, spindle cell oncocytoma, and granular cell tumor of neurohypophysis suggests common lineage and explains why histological overlap can be encountered. We incorporate our own experiences over the last 30 years from two referral institutions with specialty practices in pituitary region masses.
    Brain Pathology 05/2013; · 4.74 Impact Factor
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    ABSTRACT: Orbital invasion by pituitary tumors is rare. To the best of the authors' knowledge, adrenocorticotrophin (ACTH)-secreting pituitary tumors with orbital invasion have not been described in MEDLINE indexed literature. The authors report 2 cases of ACTH-secreting tumors with orbital invasion. One patient had a history of endoscopic transsphenoidal subtotal resection of an ACTH-secreting tumor and presented with recurrence in the orbit. The second patient had a long history of visual loss considered to be secondary to glaucoma. Neuroimaging revealed a destructive mass involving the sella turcica with extension in the right orbit. Debulking of the mass was performed via a transsphenoidal approach, and histopathology revealed an ACTH-secreting adenoma. ACTH-secreting adenoma should be considered in the differential of tumors involving the sella turcica with orbital invasion.
    Ophthalmic plastic and reconstructive surgery 05/2013; · 0.69 Impact Factor
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    ABSTRACT: BACKGROUND: Rhabdoid tumors (RTs) are aggressive tumors of early childhood that occur most often in brain (AT/RTs) or kidney (KRTs). Regardless of location, they are characterized by loss of functional SMARCB1 protein, a component of the SWI/SNF chromatin remodeling complex. The aim of this study was to determine genes and biological process dysregulated in common to both AT/RTs and KRTs. PROCEDURE: Gene expression for AT/RTs was compared to that of other brain tumors and normal brain using microarray data from our lab. Similar analysis was performed for KRTs and other kidney tumors and normal kidney using data from GEO. Dysregulated genes common to both analyses were analyzed for functional significance. RESULTS: Unsupervised hierarchical clustering of RTs identified three major subsets: two comprised of AT/RTs, and one of KRTs. Compared to other tumors, 1,187, 663, and 539 genes were dysregulated in each subset, respectively. Only 14 dysregulated genes were common to all three subsets. Compared to normal tissue, 5,209, 4,275, and 2,841 genes were dysregulated in each subset, with an overlap of 610 dysregulated genes. Among these genes, processes associated with cell proliferation, MYC activation, and epigenetic dysregulation were common to all three RT subsets. CONCLUSIONS: The low overlap of dysregulated genes in AT/RTs and KRTs suggests that factors in addition to SMARCB1 loss play a role in determining subsequent gene expression. Drugs which target cell cycle or epigenetic genes may be useful in all RTs. Additionally, targeted therapies tailored to specific RT subset molecular profiles should be considered. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 02/2013; · 2.35 Impact Factor
  • Hilary Somerset, C Corbett Wilkinson, B K Kleinschmidt-Demasters
    Brain Pathology 01/2013; 23(1):113-6. · 4.74 Impact Factor
  • Marlin Dustin Richardson, Hilary Somerset, B K Kleinschmidt-Demasters, Allen Waziri
    Brain Pathology 11/2012; 22(6):861-4. · 4.74 Impact Factor
  • Yao Schmidt, B K Kleinschmidt-Demasters, Dara L Aisner, Kevin O Lillehei, Denise Damek
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    ABSTRACT: Pleomorphic xanthoastrocytomas with anaplastic features (PXA-As) are rare tumors about which little is known regarding clinicopathologic and molecular features. Several studies have identified BRAF V600E mutations in PXA-As, but the percentage with mutation may differ between adult and pediatric examples, and limited information exists about immunohistochemistry for isocitrate dehydrogenase 1 (IDH1). Ten cases of adult PXA-As seen at our institution since 2000 were assessed for BRAF V600E mutation by polymerase chain reaction testing (PCR) and IDH1 by immunohistochemistry. Patients ranged in age from 18-68 years; four PXA-As affected temporal lobe and two were cystic. Four patients underwent gross total resection and 9 of 10 patients received cranial irradiation and/or adjuvant chemotherapy. Five survived less than 5 years, although 2 of 5 patients died from non-tumor causes. Four long-term survivors are alive at 7.5, 9.8, 11.4, and 11.9 years post-diagnosis. Two of four long term survivors had BRAF V600E mutation: patients were ages 18 and 28 years. A 48-year-old male without BRAF mutation survives at 9.8 years, even with thalamic location; conversely a 68-year-old female with temporal lobe tumor and BRAF mutation survived 1.9 years after diagnosis. All tumors were IDH1 immunonegative. This case series details clinicopathologic features of a subset of rare PXA-As in adults. BRAF V600E mutation was identified in 50 % of these cases.
    Journal of Neuro-Oncology 10/2012; · 3.12 Impact Factor
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    ABSTRACT: Congenital glioblastoma (cGBM) is an uncommon tumor of infancy with a reported variable but often poor cure rate, even with intensive therapy. Five patients with cGBMs, arising de novo and not in familial tumor predisposition kindreds, were studied for histological and biological features, using Affymetrix microarray. Tumors were large, often associated with hemorrhage, extended into the thalamus, and often bulged into the ventricles. One patient died acutely from bleeding at the time of operation. The 4 surviving patients underwent surgery (1 gross total resection, 3 subtotal resections or biopsies) and moderate intensity chemotherapy without radiation, and remain progression-free at a median time of 36 months (range, 30-110 months). Affymetrix microarrays measured gene expression on the 3 cGBMs from which frozen tissue was available. Unsupervised hierarchical clustering of cGBMs versus 168 other central nervous system tumors demonstrated that cGBMs clustered most closely with other high-grade gliomas. Gene expression profiles of cGBMs were compared with non-congenital pediatric and adult GBMs. cGBMs demonstrated marked similarity to both pediatric and adult GBMs, with only 31 differentially expressed genes identified (false discovery rate, <0.05). Unique molecular features of cGBMs included over-expression of multiple genes involved in glucose metabolism and tissue hypoxia. cGBMs show histological and biological overlap with pediatric and adult GBMs but appear to have a more favorable outcome, with good response to moderate intensity chemotherapy with only subtotal resection or biopsy. Further study may determine whether identified gene expression differences contribute to the improved survival seen in these tumors.
    Neuro-Oncology 06/2012; 14(7):931-41. · 6.18 Impact Factor
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    ABSTRACT: Gangliogliomas (GGs) primary to brainstem are rare, with the overwhelming majority of GGs occurring in supratentorial, especially temporal lobe, locations. A less favorable prognosis exists for brainstem GGs, despite their usually identical WHO grade I status. Few large clinical series, and limited biological information, exists on these tumors, especially gene expression. Seven pediatric brainstem GGs, all with classic histological features, seen at our institution since 2000 were identified. Frozen section material was available for gene expression microarray profiling from five of seven brainstem GGs and compared with that from three non-brainstem pediatric GGs. Significant upregulation of a number of genes was identified, most of which were involved in pathways of neural signaling, embryonic development, and pattern specification in pediatric brainstem GGs compared to non-brainstem. The single largest upregulated gene was a 256-fold increase in the expression of the neuropeptide prepronociceptin (PNOC); the protein product of this gene has been implicated in neuronal growth. Overexpression was validated by Western blot and by immunohistochemistry (IHC). Strong IHC expression of PNOC was seen in neoplastic neurons of 7/7 brainstem GGs, but was significantly weaker in non-brainstem GGs, and completely negative in normal pediatric autopsy brainstem controls. PNOC IHC was often superior to IHC for NeuN, synaptophysin, or neurofilament for highlighting neoplastic neurons. Pediatr Blood Cancer 2012; 59: 1173-1179. © 2012 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 06/2012; 59(7):1173-9. · 2.35 Impact Factor
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    ABSTRACT: The use of natalizumab to treat multiple sclerosis (MS) has been associated with the development of progressive multifocal leukoencephalopathy (PML), with 242 PML cases reported as of May 3, 2012. Fortunately, rapid withdrawal of the drug and administration of plasma exchange has allowed survival in many of these patients, but a new problem, immune reconstitution inflammatory syndrome (IRIS), has emerged after drug withdrawal. This report provides an update on PML in natalizumab-treated patients and reviews what is currently known about PML-IRIS in this setting; autopsy findings from a well-studied patient are illustrated. This patient with relapsing-remitting MS had been treated for 4 years with natalizumab, with discontinuation of drug after diagnosis of PML by cerebrospinal fluid polymerase chain reaction testing. Disease was manifested by severe paraparesis and expressive aphasia, which progressed before and after the diagnosis of PML. Immune reconstitution inflammatory syndrome was diagnosed, comfort care was instituted, but demise did not occur until 9 months later. Autopsy showed ongoing severe PML-IRIS, with massive cavitary brain lesions containing abundant perivascular and parenchymal CD8-positive T-cell infiltrates. Bone marrow and spleen, but not brain, contained monoclonal T-cell populations by polymerase chain reaction-based gene rearrangement studies, indicating overstimulation of peripheral T cells; T-cell lymphoma was not identified by morphological or immunohistochemical criteria.
    Journal of Neuropathology and Experimental Neurology 06/2012; 71(7):604-17. · 4.35 Impact Factor
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    ABSTRACT: The co-occurrence of gliomas and multiple sclerosis (MS) in the same patient is uncommon, but a well-reported phenomenon. Most have been high grade astrocytic tumors that developed after the diagnosis of MS, leading authors to postulate that chronic gliosis in demyelinative plaques might be the underlying substrate for secondary induction of a glial neoplasm. Until recently, however, genetic tools have not been available to test the hypothesis that high grade gliomas might arise from longstanding chronic gliosis, with transformation to low grade glioma, and eventually GBM, i.e., be secondary GBMs. We searched our surgical neuropathology and MS Brain Bank databases over the past 25 years (1987-2011) and identified eight cases of co-occurring MS and glioma. After careful review to guarantee both diagnoses, cases were studied by fluorescence in situ hybridization for genetic markers appropriate to diagnosis, as well as by direct sequencing for IDH1/2 and P53. No unusual genetic features were detected in our cohort; further, the 4 GBMs we did identify did not have clinical features of secondary glioblastomas nor did any of the four manifest IDH-1 immunohistochemical expression or IDH1/2 mutations, as might be expected in secondary GBMs. Conversely, PTEN loss and EGFR expression, features often found in primary GBMs, but seldom identified in secondary GBMs, were found in 3 of 4 GBMs. We conclude that gliomas in MS patients have genetic features paralleling counterparts in non-MS patients. There is no strong genetic evidence for GBMs to be secondary GBMs.
    Journal of Neuro-Oncology 05/2012; 109(2):261-72. · 3.12 Impact Factor
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    ABSTRACT: Growth hormone (GH) pituitary tumors are almost always benign adenomas, yet are associated with significant morbidity and mortality. Surgical and medical responses of GH tumors are often incomplete, and therefore predictors of residual or recurrent disease are needed. Clinical features, including patient gender, age or size of adenoma, have proven to be unreliable predictors of recurrence. Differing clinical behavior between the two GH tumor subtypes, sparsely granulated (SG) versus densely granulated (DG), has been reported, but has not been used routinely in clinical management. SG tumors are more common in younger patients (<50 years), and are usually larger tumors. SG tumors have been reported to be less responsive to somatostatin analogs (SSA) than DG tumors. The mechanisms underlying these potential differences in tumor behavior, however, are poorly defined. Subsets (up to 50 %) of DG adenomas harbor a gsp mutation that can activate cAMP that provides a theoretical intracellular target for somatostatin therapy. In contrast, some SG tumors have reduced somatostatin receptor expression and mutations in the extracellular domain of the GH receptor that may contribute to SSA resistance. While DG versus SG growth hormone adenomas are readily distinguished by immunohistochemistry, other less common GH adenoma variants still require electron microscopy (EM) for confident subclassification. Whether these less common variants possess unique clinical features is unknown. Research is needed to identify clinically relevant biomarkers of GH pituitary tumors that predict risk of recurrence and response to medical therapy.
    Endocrine 03/2012; 42(1):18-28. · 1.42 Impact Factor
  • Jeffrey Schowinsky, John Corboy, Timothy Vollmer, B K Kleinschmidt-DeMasters
    Acta Neuropathologica 03/2012; 123(5):751-2. · 9.73 Impact Factor
  • Acta Neuropathologica 12/2011; 122(6):783-5. · 9.73 Impact Factor

Publication Stats

4k Citations
870.93 Total Impact Points

Institutions

  • 2013
    • Children's Hospital Colorado
      • Department of Pediatrics
      Aurora, Colorado, United States
  • 1989–2013
    • University of Colorado
      • • Department of Pathology
      • • Department of Medicine
      • • Department of Pediatrics
      • • Department of Neurosurgery
      • • Department of Neurology
      • • Department of Surgery
      Denver, CO, United States
  • 2005
    • University of Colorado Hospital
      • Department of Neurology
      Denver, Colorado, United States
  • 1997
    • Colorado State University
      • Veterinary Teaching Hospital
      Fort Collins, CO, United States
  • 1992
    • University of Texas Health Science Center at San Antonio
      • Division of Endocrinology
      San Antonio, TX, United States