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S. Clifford Schold

Bio: S. Clifford Schold is an academic researcher from University of Pittsburgh. The author has contributed to research in topics: Glioma & Procarbazine. The author has an hindex of 32, co-authored 55 publications receiving 4308 citations. Previous affiliations of S. Clifford Schold include University of Texas at Dallas & Duke University.


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Journal ArticleDOI
TL;DR: This is the first multicenter trial demonstrating improved survival with the combination of chemotherapy plus RT compared with previous reports of RT alone, and high-dose methotrexate combined with cranial irradiation is an effective therapeutic approach to PCNSL, but neurotoxicity is a delayed risk of this approach.
Abstract: PURPOSE: Primary CNS lymphoma (PCNSL) is an aggressive primary brain tumor. Cranial irradiation alone rarely results in long-term disease control or prolonged survival. We prospectively studied the use of combination chemotherapy plus cranial irradiation in newly diagnosed patients with PCNSL. PATIENTS AND METHODS: We enrolled 102 newly diagnosed, immunocompetent patients with PCNSL; 98 were assessable. Patients first received five cycles of methotrexate 2.5 g/m2, vincristine, procarbazine, and intraventricular methotrexate (12 mg). Whole-brain radiotherapy (RT) was administered to a total dose of 45 Gy and all patients received high-dose cytarabine after RT. RESULTS: Fifty-eight percent of patients with measurable disease had a complete response to preirradiation chemotherapy and 36% had a partial (> 50%) response, for a 94% response rate. Median progression-free survival was 24.0 months and overall survival was 36.9 months. Age was an important prognostic factor; median survival was 50.4 months in patie...

639 citations

Journal ArticleDOI
01 Dec 1988-Cancer
TL;DR: The increased incidence of primary brain lymphoma in the US appears to be real: It antedates the AIDS epidemic and does not appear to be related to organ transplantation, another cause of increased risk of brain lymph cancer.
Abstract: There have been a number of clinical reports suggesting an increasing incidence of primary brain lymphoma unrelated to acquired immune deficiency syndrome (AIDS) and organ transplantation. To investigate this issue, the US incidence of this rare lymphoma was assessed using data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program (1973 through 1984). Never-married men, a relatively high risk group for AIDS, were excluded from the analyses. Brain lymphoma incidence increased from 2.7 in 1973 through 1975 to 7.5 cases per ten million population in 1982 through 1984 (chi-square trend, 15.25; P less than 0.001), and it increased among both men (chi-square trend, 6.74; P = 0.009) and women (chi-square trend, 10.48; P = 0.001). Increases in incidence also were observed among persons younger than 60 years of age (chi-square trend, 4.10; P = 0.04) and persons 60 years of age and older (chi-square trend, 9.16; P = 0.002). This increased incidence of brain lymphoma appears to be real: It antedates the AIDS epidemic and does not appear to be related to organ transplantation, another cause of increased risk of brain lymphoma. Although part of the increase may be an artifact of improvements in diagnostic technology and practice, most of the observed increase antedates the widespread use of such technologies. Finally, the increase in incidence of brain lymphoma does not appear to be related to overall trends in the incidence of brain tumors and non-Hodgkin's lymphoma, and it is not related to time trends in nosology.

391 citations

Journal ArticleDOI
TL;DR: The presence of anti‐Ri antibody identifies a subset of patients with paraneoplastic ataxia and eye movement disorders (opsoclonus) who usually suffer from breast or other gynecological cancer; the antibody when present is a useful marker for an underlying malignancy.
Abstract: The serum and cerebrospinal fluid (CSF) of 8 women with ataxia, 6 of whom also had eye movement abnormalities believed to be opsoclonus, were found to contain a highly specific antineuronal antibody we call anti-Ri. Seven of the 8 women also had or developed cancer: carcinoma of the breast in 5, adenocarcinoma in an axillary lymph node in 1, and carcinoma of the fallopian tube in 1. Four patients presented with the neurological disorder; the cancer was diagnosed first in the other 4. Immunohistochemical studies using serum or CSF from all 8 patients revealed a highly specific antibody interaction with central nervous system neuronal nuclei but not with glial or other cells; the titer ranged from 1:5,000 to 1:320,000 in serum and from 1:2,000 to 1:16,000 in CSF. Biotinylated IgG from the patients' serum reacted with the tumors of 3 of 4 patients with anti-Ri antibody but not with breast cancers from patients without anti-Ri antibody. Immunoblots against cerebral cortex neuronal extracts identified protein antigens of 55-kd and 80-kd relative molecular mass. Serum titers by immunoblot ranged from 1:500 to more than 1:40,000 and CSF titers, from 1:10 to 1:2,000. The relative amount of anti-Ri was always higher in CSF than in serum. The antibody was not present in sera from normal individuals; patients with breast cancer without opsoclonus; other patients with opsoclonus; or patients with other paraneoplastic syndromes related to breast, ovarian, or small-cell lung cancer. We conclude that the presence of anti-Ri antibody identifies a subset of patients with paraneoplastic ataxia and eye movement disorders (opsoclonus) who usually suffer from breast or other gynecological cancer; the antibody when present is a useful marker for an underlying malignancy.

370 citations

Journal ArticleDOI
TL;DR: It is recommended that patients with malignant glioma be treated by parallel opposed fields with a margin that is 4 cm beyond the edge of the preoperative enhancing tumor, as seen on computerized tomography scan.
Abstract: Pre- and postoperative computerized tomography scans, simulator films, and computerized tomography scans documenting tumor recurrence were analyzed on 70 patients with supratentorial malignant glioma treated with whole brain plus boost radiation therapy to determine sites of recurrence in relation to the boost. The boost was planned using the postoperative computerized tomography scan. Tumor recurred in 53 patients--within the boost in 38 (72%), partly outside the boost in 12 (23%), outside the boost but within the brain in one (2%), in the boost and in the spinal cord in one (2%), and in the spinal cord only in one (2%). All recurrences confined to the brain were found within 4 cm of the enhancing tumor as defined by the preoperative computerized tomography scan. Recurrences outside the boost were more common with inadequate boost margins, small boost volumes, temporal lobe tumors, and homolateral wedge pair technique. Survival was not adversely affected by recurrence outside the boost. We recommend that patients with malignant glioma be treated by parallel opposed fields with a margin that is 4 cm beyond the edge of the preoperative enhancing tumor, as seen on computerized tomography scan.

276 citations

Journal ArticleDOI
TL;DR: A distinct subgroup of brain tumour consists of transformed yet pre-immortal cells that follow different pathways of neoplastic progression, according to analysis of telomerase activity in 90 human gliomas.

219 citations


Cited by
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Journal ArticleDOI
TL;DR: Specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood–brain barrier function are explored to lead to the development of new protective and restorative therapies.
Abstract: The blood-brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood-brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.

4,578 citations

Journal ArticleDOI
TL;DR: All major types of cancer have been screened and the presence of telomerase activity has been detected in the vast majority of cases, and a summary, in table form, of the current data is provided.

2,762 citations

Journal ArticleDOI
TL;DR: A general method for the covalent labeling of fusion proteins in vivo that complements existing methods for noncovalentlabeling of proteins and that may open up new ways of studying proteins in living cells is described.
Abstract: Characterizing the movement, interactions, and chemical microenvironment of a protein inside the living cell is crucial to a detailed understanding of its function. Most strategies aimed at realizing this objective are based on genetically fusing the protein of interest to a reporter protein that monitors changes in the environment of the coupled protein. Examples include fusions with fluorescent proteins, the yeast two-hybrid system, and split ubiquitin. However, these techniques have various limitations, and considerable effort is being devoted to specific labeling of proteins in vivo with small synthetic molecules capable of probing and modulating their function. These approaches are currently based on the noncovalent binding of a small molecule to a protein, the formation of stable complexes between biarsenical compounds and peptides containing cysteines, or the use of biotin acceptor domains. Here we describe a general method for the covalent labeling of fusion proteins in vivo that complements existing methods for noncovalent labeling of proteins and that may open up new ways of studying proteins in living cells.

1,702 citations

Journal ArticleDOI
TL;DR: The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use.
Abstract: Objective To attempt to determine the relative value of preclinical cardiac electrophysiology data (in vitro and in vivo) for predicting risk of torsade de pointes (TdP) in clinical use. Methods Published data on hERG (or I(Kr)) activity, cardiac action potential duration (at 90% repolarisation; APD(90)), and QT prolongation in dogs were compared against QT effects and reports of TdP in humans for 100 drugs. These data were set against the free plasma concentrations attained during clinical use (effective therapeutic plasma concentrations; ETPC(unbound)). The drugs were divided into five categories: (1) Class Ia and III antiarrhythmics; (2) Withdrawn from market due to TdP; (3) Measurable incidence/numerous reports of TdP in humans; (4) Isolated reports of TdP in humans; (5) No reports of TdP in humans. Results Data from hERG (or I(Kr)) assays in addition to ETPC(unbound) data were available for 52 drugs. For Category 1 drugs, data for hERG/I(Kr) IC(50), APD(90), QTc in animals and QTc in humans were generally close to or superimposed on the ETPC(unbound) values. This relationship was uncoupled in the other categories, with more complex relationships between the data. In Category 1 (except amiodarone), the ratios between hERG/I(Kr) IC(50) and ETPC(unbound) (max) ranged from 0.1- to 31-fold. Similar ranges were obtained for drugs in Category 2 (0.31- to 13-fold) and Category 3 (0.03- to 35-fold). A large spread was found for Category 4 drugs (0.13- to 35700-fold); this category embraced an assortment of mechanisms ranging from drugs which may well be affecting I(Kr) currents in clinical use (e.g. sparfloxacin) to others such as nifedipine (35700-fold) where channel block is not involved. Finally, for the majority of Category 5 drugs there was a >30-fold separation between hERG/I(Kr) activity and ETPC(unbound) values, with the notable exception of verapamil (1.7-fold), which is free from QT prolongation in man; this is probably explained by its multiple interactions with cardiac ion channels. Conclusions The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use. A 30-fold margin between C(max) and hERG IC(50) may suffice for drugs currently undergoing clinical evaluation, but for future drug discovery programmes, pharmaceutical companies should consider increasing this margin, particularly for drugs aimed at non-debilitating diseases. However, interactions with multiple cardiac ion channels can either mitigate or exacerbate the prolongation of APD and QT that would ensue from block of I(Kr) currents alone, and delay of repolarisation per se is not necessarily torsadogenic. Clearly, an integrated assessment of in vitro and in vivo data is required in order to predict the torsadogenic risk of a new candidate drug in humans.

1,411 citations

Journal ArticleDOI
TL;DR: In this paper, the authors discuss mechanisms of glioma invasion, characteristics of the invasive cell, and consequences of this cellular phenotype for surgical resection, oncologic treatments, and future perspectives for anti-invasive strategies.
Abstract: Tumors of glial origin consist of a core mass and a penumbra of invasive, single cells, decreasing in numbers towards the periphery and still detectable several centimeters away from the core lesion. Several decades ago, the diffuse nature of malignant gliomas was recognized by neurosurgeons when super-radical resections using hemispherectomies failed to eradicate these tumors. Local invasiveness eventually leads to regrowth of a recurrent tumor predominantly adjacent to the resection cavity, which is not significantly altered by radiation or chemotherapy. This raises the question of whether invasive glioma cells activate cellular programs that render these cells resistant to conventional treatments. Clinical and experimental data demonstrate that glioma invasion is determined by several independent mechanisms that facilitate the spread of these tumors along different anatomic and molecular structures. A common denominator of this cellular behavior may be cell motility. Gene-expression profiling showed upregulation of genes related to motility, and functional studies demonstrated that cell motility contributes to the invasive phenotype of malignant gliomas. There is accumulating evidence that invasive glioma cells show a decreased proliferation rate and a relative resistance to apoptosis, which may contribute to chemotherapy and radiation resistance. Interestingly, interference with cell motility by different strategies results in increased susceptibility to apoptosis, indicating that this dynamic relationship can potentially be exploited as an anti-invasive treatment paradigm. In this review, we discuss mechanisms of glioma invasion, characteristics of the invasive cell, and consequences of this cellular phenotype for surgical resection, oncologic treatments, and future perspectives for anti-invasive strategies.

1,135 citations