Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02.

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.

Non-invasive assessment of tumor proliferation using triple quantum filtered 23/Na MRI: technical challenges and solutions.

We address the development of triple-quantum-filtered sodium MRI as a non-invasive surrogate measure for cell proliferation in brain tumors. We demonstrate that through careful consideration of the theoretical description of the signal, triple-quantum-filtered sodium images of adequate signal-to-noise ratio (SNR) can be acquired in clinically acceptable imaging times.

Bilateral optic neuropathy with IgGkappa multiple myeloma improved after myeloablative chemotherapy.

A 49-year-old woman with immunoglobulin GK multiple myeloma developed progressive visual loss with bilateral upper and lower central arcuate scotomas. Funduscopic and electrophysiologic studies indicated bilateral optic neuropathy. The immunoglobulin G fraction of the patient's serum reacted with retinal ganglionic cells in bovine retina. The visual abnormalities remitted after myeloablative chemotherapy and disappearance of the paraprotein.

Inflammatory infiltrates and complete absence of Purkinje cells in anti-Yo-associated paraneoplastic cerebellar degeneration.

We studied the nervous systems and tumors of two patients with anti-Yo-associated paraneoplastic cerebellar degeneration (PCD). In both patients the underlying tumor was an ovarian adenocarcinoma that expressed Yo antigens and contained extensive infiltrates of lymphocytes and plasma cells. The major central nervous system findings were a complete loss of cerebellar Purkinje cells with Bergmann astrogliosis. One patient had inflammatory infiltrates in the medulla and pons, and moderate axonal loss and demyelination involving the spinal cord. No inflammatory infiltrates were identified in the cerebrum, cerebellum or brain-stem of the other patient. Using quantitative Western blot analysis, deposits of anti-Yo IgG could not be demonstrated in the nervous system, possibly as a result of the loss of cells expressing Yo antigens. The detection of the anti-Yo antibody as a common marker of PCD in one patient with inflammatory infiltrates and another without infiltrates suggests that some PCD pathologically classified as "non-inflammatory" may represent a final burn-out stage of a cellular immune-mediated disorder. Our findings indicate that Purkinje cells are the main, but not necessarily the exclusive, targets of this disorder.

Inhibition of proliferation and induction of differentiation in medulloblastoma- and astrocytoma-derived cell lines with phenylacetate.

The authors investigated the effects of a nontoxic differentiation inducer, phenylacetate (PA), on neuroectodermal tumor-derived cell lines. Treatment of medulloblastoma (Daoy and D283 MED) and glioma (U-251MG, C6, and RG2) cell lines resulted in a dose-dependent decline in DNA synthesis and cell proliferation, associated with accumulation in the G0/G1 phase of the cell cycle. Phenylacetate decreased transforming growth factor (TGF)-beta 2 production by medulloblastoma Daoy cells. Neutralizing antibodies against either TGF beta 2 or TGF beta 1 failed to block the growth arrest observed. This suggests that, unlike other differentiation agents, such as retinoic acid, the effect of PA on medulloblastoma proliferation is not mediated by a TGF beta pathway. In addition to cytostasis, PA induced marked morphological changes in U-251MG and C6 glioma cells associated with increased abundance of glial fibrillary acidic protein-positive processes. Although the morphology of PA-treated medulloblastoma cells was not significantly altered, the D283 MED cells exhibited increased expression of neurofilament proteins and Hu antigen, indicative of differentiation along a neuronal pathway. The effects of PA on the medulloblastoma cell lines were compared to its effects on the human neuroblastoma cell line BE(2)C, which is capable of a bidirectional differentiation toward a neuronal or a glial/schwann cell pathway. In BE(2)C cells, PA induced differentiation toward a schwann/glial cell-like phenotype, suggesting that the choice of differentiation pathway is cell type and agent specific. These in vitro antiproliferative and differentiation inducing effects of PA suggest that this agent warrants further evaluation as a potential therapeutic modality for the treatment of medulloblastoma and malignant glioma in humans.

Nuclear localization of anti-Hu antibody is not associated with in vitro cytotoxicity.

IgG fractions of sera containing anti-Hu antibodies or control sera were incubated with Hu-positive and Hu-negative cell lines. Anti-Hu IgG specifically localized in the nucleus of Hu-positive cells. Anti-Hu-positive and control sera were incubated with Hu-positive cells and human complement or peripheral blood mononuclear cells. Hu antibody caused neither complement-mediated lysis nor augmented antibody-dependent cell-mediated cytotoxicity. Anti-Hu IgG did not affect proliferation of Hu-positive cells. Anti-Hu antibodies may not play a direct role in tissue injury in patients with paraneoplastic encephalomyeloneuropathy and anti-Hu antibodies.

Anti-histone antibodies in subacute sensory neuropathy.

We investigated the levels of anti-histone antibodies in the sera of 7 patients with subacute sensory neuropathy. IgG antibodies to histones H1 and H3 were significantly elevated in 4 of these patients. The anti-H1 antibodies reacted mainly with determinants located in the central globular and the carboxy-terminal domain of the H1 molecule. We also observed reactivity of these sera with histone H1 zero, a variant found in terminally-differentiated cells such as neurons. This study suggests a potential for histones to serve as autoantigens in humorally-mediated paraneoplastic diseases.

Vitamin E deficiency and neurologic disease in adults with cystic fibrosis.

We report the cases of two adult patients with cystic fibrosis affecting the pancreas and liver, who also had severe vitamin E deficiency and neurologic disease. The most prominent clinical features were abnormal eye movements, diminished reflexes, decreased vibratory and position sense, ataxia, and muscle weakness. Treatment with intramuscular injections of vitamin E partially corrected the neurologic deficits. Vitamin E absorption tests documented severe malabsorption, which was later alleviated by the addition of dessicated ox bile to the regimen of alpha-tocopheryl acetate. These studies suggest that a decreased intraluminal concentration of bile salts is an important factor in the development of severe vitamin E deficiency and in the poor response to oral replacement therapy that is seen in some patients with cystic fibrosis.

Psychotherapy and the clinical social worker.

Social work's long and historical involvement in psychotherapy has resulted in many significant contributions to practice such as the use of time, family and group therapy, the development of innovative settings and practices, and skill in using action communication. In addition, social workers have developed expertise in working with many that others have considered unsuitable for psychotherapy. Differences between psychiatric social work and the present more commonly used term, clinical social work, are related to issues of identity and autonomy, and essential practices and values that differentiate the clinical social worker from other professionals. These are a preference for the term client rather than patient, an emphasis upon person-in-situation, and a valued belief in client self-determination. However, special educational preparation is needed for the practice of psychotherapy which is considered a specialty within social work.

Pattern of reactivity of IgM from the sera of eight patients with IgM monoclonal gammopathy and neuropathy with components of neural tissues: evidence for interaction with more than one epitope.

It has been postulated that binding of monoclonal IgM from the sera of some patients with IgM monoclonal gammopathy and neuropathy to components of peripheral nerve may play a key role in the pathogenesis of the neuropathy. Serum IgM from these patients has been shown to bind to antigenic determinants shared by the myelin-associated glycoprotein (MAG) and a polar glycolipid from peripheral nerve. Here we describe a study of sera from eight patients with IgM monoclonal gammopathy and neuropathy. Five of the patients had serum IgM directed both against MAG and one or two polar glycolipids from peripheral nerve. One of the patients had serum IgM that bound to a peripheral nerve glycolipid but not to MAG; no one had serum IgM that bound to MAG but not to a peripheral nerve glycolipid. The relative affinity of IgM from the sera of the patients for proteins in peripheral nerves of chickens, dogs, and humans varied from patient to patient. These data indicate that the epitope against which the serum IgM from these patients is directed is not necessarily the same in all of the cases.

Selective inhibition of two soluble adenosine cyclic 3',5'-phosphate phosphodiesterases partially purified from calf liver.

"Low Km" cAMP phosphodiesterase and cGMP-stimulated cyclic nucleotide phosphodiesterase activities were partially purified from calf liver supernatant by chromatography on DEAE-cellulose and DEAE-Sepharose and ammonium sulfate precipitation. The low Km phosphodiesterase was not retained on N6-H2N(CH2)2-cAMP-agarose and could be separated from the cGMP-stimulated phosphodiesterase which was absorbed by this matrix. From the proteins that did not bind, two distinct low Km cAMP phosphodiesterases were separated on Ultrogel AcA 34. One form (fraction C) hydrolyzed cAMP with an apparent Km of approximately 0.5 microM and was very sensitive to inhibition by cGMP. Lineweaver-Burk plots of cAMP hydrolysis by a second form (fraction B) were nonlinear, with an apparent low Km component of approximately 2 microM. This form was rather insensitive to inhibition by cGMP. With both fractions, hydrolysis of cAMP relative to cGMP was much greater at low (approximately 1 microM) than at high (approximately 100 microM) substrate concentrations. Maximal velocities for cAMP and cGMP were similar. From sedimentation equilibrium, the apparent weight-average molecular weight of fraction B was estimated as 174000, and that of fraction C was 85000. Another fraction (A) of cAMP phosphodiesterase eluted at the void volume of the AcA 34 column. On the basis of the relative affinities for cAMP and cGMP and inhibition by cGMP, fraction A is most likely an aggregated form of fraction B. No apparent interconversion of fractions A, B, or C was observed on high-performance liquid chromatography.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in cyclic AMP phosphodiesterase activities during differentiation of 3T3-L1 cells.

3T3-L1 cells contain multiple forms of cyclic nucleotide phosphodiesterase in both supernatant (100,000 X g, 40 min) and particulate fractions. Supernatant fractions from both undifferentiated and differentiated cells contained calmodulin-sensitive activity. In undifferentiated 3T3-L1 cells, only a small fraction of the total cAMP phosphodiesterase activity was found in the particulate fraction and the specific activity of the particulate was lower than the supernatant. With differentiation the specific activity of the particulate doubled, and there was a dramatic increase in total activity in this fraction, while in the supernatant total cAMP phosphodiesterase activity increased less and specific activity decreased. The particulate fraction accounted for approximately 70% of the total cAMP phosphodiesterase activity in differentiated cells in contrast to about one-third in undifferentiated cells. In addition, there was a qualitative change in particulate phosphodiesterase activity. In fractions from 3T3-L1 adipocytes, with either cAMP or cGMP as substrate, Lineweaver-Burk plots were nonlinear, with low Km components of less than 1 microM, and cGMP inhibited cAMP hydrolysis. In particulate fractions from undifferentiated cells, cGMP did not inhibit and often enhanced hydrolysis of cAMP. With differentiation, there was also a marked increase in particulate cGMP phosphodiesterase activity. cAMP and cGMP phosphodiesterase activities solubilized from particulate fraction of differentiated cells coeluted from DEAE-Biogel and exhibited kinetic properties similar to the crude particulate fractions. During differentiation, there seems to be an alteration in the distribution of phosphodiesterase activity as well as the appearance of a particulate phosphodiesterase with kinetic properties similar to a particulate phosphodiesterase found in mature rat adipocytes.