Mark T. Jennings

Carboplatin and recurrent childhood brain tumors.

Carboplatin, a cisplatin analogue, was administered as an intravenous (IV) one-hour infusion in a 4-consecutive weekly dose schedule to 44 patients with recurrent childhood brain tumors. Twenty-four patients were registered on our phase I, and 20 on our phase II studies. The maximum tolerable dose derived from our phase I study was 210 mg/m2/wk in patients with solid tumors, and the recommended dose for subsequent pediatric phase II studies was 175 mg/m2/wk. This dose was administered to 14 patients in the phase I and all 20 patients in the phase II study. Nine of 36 (25%) evaluable patients in the combined studies experienced objective responses for a median duration of 10+ months. Seven of nine responders had received prior cisplatin. Disease-specific response rates were as follows: medulloblastoma, six of 14 (43%) with three complete (CR) and three partial responses (PR); pineoblastoma, one of one (PR); germinoma, one of two (CR); and brainstem glioma, one of eight (13%) (PR). Carboplatin had mild emetic effects but no significant auditory or renal toxicity. Thrombocytopenia (less than 49,000) was encountered in nine of 28 (32%) evaluable trials at a dose of 175 mg/m2/wk. Because of its low potential for auditory, renal, and emetic toxicity, ease of administration, and high disease-specific activity, carboplatin deserves further study in multiagent phase II and III trials, especially in chemotherapy-sensitive diseases such as medulloblastoma.

Strategies in the treatment of diffuse pontine gliomas: the therapeutic role of hyperfractionated radiotherapy and chemotherapy

This article will review the current treatment of pediatric patients with diffuse pontine gliomas (DPG) and discuss three potential avenues of therapeutic research including (i) radiotherapy (RT) in combination with radiation sensitizers, (ii) dose-intensive, induction chemotherapy with hematopoietic support followed in sequence with RT applied as a ‘consolidation’ therapy, and (iii) the interleafed application of phase-specific chemotherapeutic agents and hyperfractionated external beam radiotherapy (HFEBRT) referred to as ‘chemoradiotherapy’.

Transforming growth factor-β in neural embryogenesis and neoplasia

Abstract The transforming growth factor-β (TGF-β) family of polypeptides includes three structurally and functionally related mammalian isoforms that influence cell proliferation, differentiation, and extracellular matrix production. Recent identification of these isoforms in the embryonic murine central nervous system suggests that these factors may regulate proliferation and differentiation of meningeal and neuroepithelial cells during development. Predominant expression of TGF-β1 in the leptomeninges compared with the brain of the murine and human central nervous system implicates this isoform in regulation of that mesodermal tissue. Thus, defective TGF-β regulation may contribute to neoplastic transformation. Failure to activate latent TGF-βs may contribute to the loss of autocrine regulation seen in meningiomas. Expression of TGF-β2 and TGF-β3 primarily in embryonic murine radial glia and adult human astrocytes suggests other roles for these isoforms, including glioblast differentiation and guidance of neuroblast migration. Although inhibitory to “normal” astrocyte proliferation, TGF-βs demonstrate autocrine growth stimulation in vitro among hyperdiploid malignant gliomas, medulloblastomas, primitive neuroectodermal tumors, and anaplastic ependymomas. Hence, synthesis and release of active TGF-βs by malignant brain tumors may create aberrant stimulatory autocrine loops. The mechanism of TGF-β-induced growth stimulation is poorly understood. Future studies with likely clarify and identify additional roles for the TGF-β isoforms in neuro-embryogenesis and neoplasia.

TGFβ1 and TGFβ2 are potential growth regulators for medulloblastomas, primitive neuroectodermal tumors, and ependymomas: Evidence in support of an autocrine hypothesis

Our previous investigations of transforming growth factor types beta 1 and beta 2 (TGF beta s) showed negative or positive autocrine growth regulation of gliomas in vitro. Near-diploid gliomas were inhibited by the TGF beta s, whereas a stimulatory response correlated with progressive anaplasia and karyotypic divergence. We have tested the hypothesis that cytogenetic aberrations may be associated with conversion of TGF beta autoregulation from inhibitory to stimulatory among other cultured neuroectodermal tumors. Anchorage-independent growth and karyotypic aberrations supported the malignant nature in vitro of two medulloblastoma (MBL), two primitive neuroectodermal tumor (PNET), and two ependymoma (EPD) cultures. Transforming growth factor type beta 1 and/or TGF beta 2 RNA was evident by Northern blot analysis among these cell cultures. By radioreceptor assay active TGF beta was present in conditioned medium in concentrations of 0 to 14 ng/mL, whereas the total amount of active and latent TGF beta secreted was in the range of 3 to 118 ng/mL. Expression of the TGF beta radioreceptor (TGF beta-R) types I and II was shown by cross-linking assay. Responses to exogenous TGF beta were determined by [3H]-thymidine incorporation, cell counts, and anchorage-independent clonogenicity. Exogenous TGF beta was growth inhibitory for the near-diploid MBL, PNET, and EPD in vitro, as well as antagonistic to the mitogenic effect of epidermal growth factor (EGF) and insulin. In contrast, MBL, PNET, and EPD with a hyperdiploid subpopulation were stimulated to proliferate in monolayer culture or soft agar by TGF beta 1 and TGF beta 2. The growth response did not correlate with TGF beta-R type. Autocrine regulation was supported by antibody neutralization experiments performed with quiescent cells in the absence of exogenous TGF beta. Anti-TGF beta antisera enhanced the growth of TGF beta-inhibited cultures, whereas the TGF beta-stimulated cultures were inhibited by the antisera. Karyotypic divergence seemed to predict response as MBL, PNET, and EPD with hyperdiploid elements exhibited autocrine TGF beta-stimulation. In contrast, the near-diploid cultures were inhibited by the TGF beta s. By analogy with the gliomas, conversion of TGF beta autocrine regulation from inhibition to stimulation may be a late progression marker of anaplasia among MBL, PNET, and EPD. Secretion of this TGF, which serves both as a mitogen and immunosuppressive agent may contribute to the adverse prognosis of hyperdiploid neuroectodermal neoplasms of the central nervous system (CNS).

In vitro karyotypic and immunophenotypic characterisation of primitive neuroectodermal tumours: Similarities to malignant gliomas☆

Monoclonal antibody (Mab) mediated immunotherapy of brain tumours requires the identification of tumour-restricted cell surface antigens. We have characterised four primitive neuroectodermal tumours, which included pineoblastoma, medulloblastoma and ependymoblastoma cultures, that demonstrated in vitro evidence of malignant behaviour (anchorage-independent growth and nu/nu xenograft tumour formation). The cytogenetic findings ranged from normal G-banded and Q-banded karyotypes through mixed near-diploid/hyperdiploid. These cultures resembled the cell surface immunophenotypic spectrum of malignant gliomas. They were distinguished from normal glia in vitro by the expression of restricted fetal mesenchymal, neuronal, myoblastic, melanocytic, epidermal, chondrocytic, lymphoid and epithelial antigens. Certain antigens appeared sufficiently represented among central nervous system (CNS) neoplasms to afford potential targets for Mab-mediated immunotherapy.

Transforming growth factor b as a potential tumor progression factor among hyperdiploid glioblastoma cultures: Evidence for the role of platelet-derived growth factor

Among early-passage, near-diploid gliomas in vitro, transforming growth factor type β (TGFβ) has been previously shown to be an autocrine growth inhibitor. In contrast, hyperdiploid (≥ 57chromosomes/metaphase) glioblastoma multiforme (HD-GM) cultures were autocrinely stimulated by the TGFβ. The mechanism of this ‘conversion’ from autocrine inhibitor to mitogen is not understood; previous studies have suggested that platelet-derived growth factor (PDGF) might be modulated by TGFβ. The similar expression of TGFβ types 1—3, PDGF-AA, — BB, as well as the PDGF receptor α and β subunits (a/βPDGFR) between biopsies of the HD-GM and near-diploid, TGFβ-inhibited glioblastomas (GM) by immunohistochemistry did not explain the discrepancy in their regulatory responses. Flowcytometry demonstrated that TGFβs mitogenic effect was selective for the aneuploid subpopulations of two of three selected HD-GM cultures,while the diploid cells were inhibited. Among the HD-GM, TGFβ1 induced the RNA of PDGF-A, c-sis and TGFβ1. The amount of PDGF-AA secreted following TGFβ treatment was sufficient to stimulate the proliferation of a HD-GM culture. Antibodies against PDGF-AA, -BB, -AB,αPDGFR and/or βPDGFR subunits effectively neutralized TGFβs induction of DNA synthesis among the HD-GM cell lines, indicating that PDGF served as the principal mediator of TGFβs growth stimulatory effect. By comparison, TGFβ induced only the RNA of PDGF-A and TGFβ1 among the near-diploid GM; c-sis was not expressed at all. However, the amount of PDGF-A which was secreted in response to TGFβ1 was insufficient to prevent TGFβs arrest of the near-diploid cultures in G1 phase. Thus, the emergence of hyperdiploidy was associated with qualitative and quantitative differences in TGFβs modulation of PDGF-A and c-sis, which provided a mechanism by which the aneuploid glioma cellsmight achieve ‘clonal dominance’. We hypothesize that TGFβ may serve as an autocrine promoter of GM progression by providing a selective advantage to the hyperdiploid subpopulation through the loss of a tumor suppressor gene which mediates TGFβs inhibitory effect.

Oligodendroglial Ganglioglioma with Anaplastic Features Arising from the Thalamus

Anaplastic gangliogliomas with an oligodendroglial component are exceedingly rare tumors of uncertain growth potential. We report a 17-year-old female with a massive ganglioglioma containing anaplastic oligodendroglioma apparently arising from the thalamus. Two weeks after partial resection, she was started on a regimen including escalated doses of topotecan in combination with a fixed-dosage intensification regimen of cisplatin, cyclophosphamide and vincristine with subsequent hyperfractionated external beam radiotherapy. She currently has stable disease.

Ganglioglioma of the pineal gland: clinical and radiographic response to stereotactic radiosurgical ablation.

Case Report This 10-year-old, right-handed male third grader presented with a 3month history of behavioral changes followed by abulia, &dquo;dizziness,&dquo; ataxia, and urinary incontinence. His apathy and inactivity were initially attributed to a grief reaction after the death of a great-grandfather. However, a week before admission, his ataxia worsened, impairing safe ambulation. He had urinary incontinence for 1 to 2 days before admission. He did not complain of headache or double vision. His medical history was otherwise noncontributory. On examination, he was afebrile and normotensive. Abnormal findings were confined to the neurologic examination. He was inattentive, with flat affect and no spontaneous movements. Although disoriented to date and place, memory was intact. The cranial nerve examination revealed swollen optic discs. His color vision was significantly impaired bilaterally, and he had no stereopsis (by Titmus test). Confrontation fields showed a generalized constriction bilaterally, worse nasally. Regarding ocular motility, he was orthotropic but had impaired pursuit bilaterally. He had normal horizontal and vertical saccades, with no impairment of upgaze. Convergence was present but a little slow. His pupils reacted briskly to light. There was a limited upward gaze, and gaze evoked nystagmus in all directions. Cerebellar signs revealed severe axial ataxia with a positive Romberg sign. The sensory examination was indeterminate. There was no corticospinal tract deficit. Visual acuity, without correction, was 9/200 and 6/200, there was no improvement with pinhole, and his near vision was worse than J14 OU. Analysis of the cerebrospinal fluid revealed no cells or elevations in a-fetoprotein, #-human choriogonadotropin, chorioembryonic antigen, the lactate dehydrogenase 5 isoenzyme, or placental alkaline phosphatase. Neurodiagnostic imaging demonstrated a 2.7-cm mass in the

Differential responsiveness among High risk pediatric brain tumors in a pilot study of dose-intensive induction chemotherapy

These factors have been predictive for progressive disease on therapy (PDOT) among pediatric brain tumors: >1.5 cm2 unresectable tumor, glioblastoma, supratentorial primitive neuroectodermal tumor, and metastatic medulloblastoma (MBL). This pilot study sought to correlate cytoreductive response with progression free survival.

The molecular genetics of therapeutic resistance in malignant astrocytomas.

The adverse prognosis associated with malignant astrocytomas (MA) is due in part to the development of resistance by the tumor to chemo- and radiotherapy-induced cytotoxic damage. The mechanisms of resistance are poorly understood but function at the level of the endothelial cell, the blood-brain barrier and the neoplastic cell itself. The classic examples of drug resistance proteins, such as the p-glycoprotein/multidrug resistance protein 1, have been identified within MA biopsy specimens. However, it is questionable to what degree, if at all, these proteins contribute directly to the evolution and prognosis of the MA. Surprisingly, there are specific genes, not traditionally associated with resistance, which appear increasingly relevant to both tumor progression and insensitivity to cytotoxic damage. These genes are involved in cell cycle regulation, and include the retinoblastoma susceptibility gene (Rb), the tumor suppressor gene p53, as well as those encoding the cyclins, their kinases and inhibitors. The interaction between the products of these genes and intratumoral environmental factors appears to involve a dynamic and prognostically adverse selection process. It is from this perspective that the mechanism(s) of hypoxic-ischaemic selection for resistance and its therapeutic repercussions will be analyzed.