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.

Plasma volume in cirrhosis of the liver: its relation of portal hypertension, ascites, and renal failure.

Plasma volume was measured by using albumin-(131)I- and (51)Cr-labeled erythrocytes in 24 control subjects, 140 patients with hepatic cirrhosis, and 10 patients with various portal-systemic shunts for the relief of noncirrhotic portal hypertension. The cirrhotic patients included subgroups with ascites, functional renal failure, and portacaval anastomoses. Elevated values for plasma volume, by both methods, were found in each group of patients.The lymph space drained by the thoracic duct was measured by a radioisotopic technique in six patients with cirrhosis and ascites. The amount of radioactivity in this space was found to be negligible in accounting for the elevated plasma volume. Similar results were obtained when the degree of leakage of albumin-(131)I into the ascites was determined in 10 patients with cirrhosis.The plasma volume was unusually elevated in patients who had bled from esophageal varices, and paired comparisons before and after portacaval shunt normal values. There was a statistically significant correlation between normal values. There was a statistically significant correlation between plasma volume and wedged hepatic venous pressure measured in 36 patients.We concluded that the elevated values for plasma volume in cirrhosis are valid and are not artifacts due to leakage of albumin-(131)I from the circulation during mixing. We also concluded that portal hypertension is responsible for the plasma volume expansion; however, we were unable on this basis to explain the failure of portacaval shunting to return the plasma volume to normal, unless the shunt or some other factor keeps the plasma volume elevated.

Effective plasma volume in cirrhosis with ascites. Evidence that a decreased value does not account for renal sodium retention, a sponteneous reduction in glomerular filtration rate (GFR), and a fall in GFR during drug-induced diuresis.

A reduction in effective (nonportal) plasma volume is considered the basis for renal sodium retention, a spontaneous reduction in glomerular filtration rate (GFR), and a fall in GFR occurring during drug-induced diuresis in patients with cirrhosis and ascites. In the present study the concept of a reduced effective plasma volume in cirrhosis is challenged by two lines of evidence, even though effective plasma volume itself could not be measured. (a) Total plasma volume failed to rise in 10 patients with the spontaneous loss of ascites, the appearance of sodium in the urine, and a rise in GFR. Portal pressure remained constant in these patients as ascites left, suggesting that effective plasma volume had not increased while portal plasma volume decreased. (b) Reduction of GFR could not be prevented in five patients with cirrhosis and ascites while total plasma volume was prevented from falling with albumin infusions during drug-induced diuresis. Reduction of GFR during drug-induced diuresis in 15 patients with cirrhosis and ascites was completely reversed with saline infusion despite continued diuresis with the identical drugs, excluding drug nephrotoxicity as the cause for the reduced GFR. The ascites of cirrhosis might no longer be regarded as a cause of effective plasma volume contraction, stimulating renal sodium retention and a reduction in GFR. More likely, this form of ascites is a result of plasma volume expansion and sodium retention. The causes for renal sodium retention and a spontaneous reduction in GFR remain unknown. The cause for a fall in GFR during drug-induced diuresis also remains unknown, but effective plasma volume contraction and drug nephrotoxicity seem excluded.

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.

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.

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.

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.

Advantages of treatment of ascites without sodium restriction and without complete removal of excess fluid.

Two modifications of the standard method of treatment of ascites in chronic liver disease were investigated in three separate randomised trials involving a total of 201 patients. These modifications were (1) an unrestricted sodium intake and (2) limitation of diuresis to partial removal of ascites, to the point of relief of abdominal tension. Mean serum sodium fell significantly in all patient groups receiving the low sodium diet and did not fall in the groups given an unrestricted diet. Mean serum urea nitrogen rose significantly in the patient groups undergoing complete diuresis and did not change in the groups undergoing partial diuresis. Mean serum uric acid rose only in the groups undergoing complete diuresis. We concluded that the advantages of these two modifications of therapy of ascites were increased dietary palatability and decreased likelihood of hyponatraemia and of rise in serum urea nitrogen and uric acid. Disadvantages included dissatisfaction of patients over incomplete clearing of ascites, occasional difficulty in performing diagnostic studies because of prolonged ascites, and unsuitability of a high sodium intake in patients whose ascites is highly refractory to treatment.

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)