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Biomedical subjects

J B Posner

Publications and source records attributed to J B Posner.

At least 109 records · Page 6Linked to original sources
PubMed1990

Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer--a quantitative western blot analysis.

We looked for the presence of the anti-Hu antibody in the sera from 50 normal subjects; 44 patients with small cell lung cancer, not associated with paraneoplastic disease; and 25 patients with small cell lung cancer associated with paraneoplastic sensory neuropathy, encephalomyelitis, or both. Using the avidin-biotin immunoperoxidase method and a highly sensitive quantitative Western blot analysis, the anti-Hu antibody was not detected in the 50 normal human sera. Seven of the 44 patients with small cell lung cancer but no paraneoplastic syndrome had detectable levels (average titer, 76 U/ml) of anti-Hu antibody on Western blot. These levels are significantly lower than the average titer of the 25 patients who had small cell lung cancer and paraneoplastic sensory neuropathy or encephalomyelitis (average titer, 4,592 U/ml). In the group with nonparaneoplastic small cell lung cancer (low anti-Hu titer) there was a predominance of women (5 women: 2 men), and all patients had "limited" disease when diagnosed. In the antibody-negative group the sex ratio was 16 women to 21 men and 51% of the patients had "extensive" disease. None of the 7 patients with a low-titer anti-Hu antibody developed a paraneoplastic syndrome by the time of writing. The anti-Hu antibody appears, when present, to be a good marker for small cell lung cancer and, when present at high titer, for small cell lung cancer associated with a paraneoplastic syndrome.

Adult↗
PubMed1990

Temporal effects of dexamethasone on blood-to-brain and blood-to-tumor transport of 14C-alpha-aminoisobutyric acid in rat C6 glioma.

We used quantitative autoradiography (QAR) to evaluate the effect of systemically administered dexamethasone on capillary permeability in brain tumors and surrounding brain. Rats bearing unilateral right hemispheric C6 gliomas were studied at one and twelve hours after 10 mg/kg of intraperitoneal dexamethasone. Capillary permeability was determined by measuring unidirectional blood-to-brain and blood-to-tumor transport of 14C-alpha aminoisobutyric acid (14C-AIB) over fifteen minutes. 14C-AIB entry into tumor, brain adjacent-to-tumor (BAT), and ipsilateral and contralateral cortices was determined and expressed as a unidirectional transfer constant, K. Nontreated tumor K was more than two-fold greater than K for BAT and ten-fold greater than ipsilateral cortical K, confirming substantial barrier disruption in tumor. In addition, the K for BAT was also significantly greater than K for cortex, indicating that the barrier in the peritumoral region was also disrupted. One hour after dexamethasone treatment, tumor K fell to 63% of its pretreatment value (p less than 0.025). By twelve hours post-treatment, tumor K fell to 25% of the untreated value (p less than 0.001) and to 47% of the one-hour value (p less than 0.005). BAT K fell to 29% of its untreated value (p less than 0.02) and to 46% of its one-hour value (p less than 0.02). By 12 hours, ipsilateral cortical K fell to 67% of the untreated cortical value (p less than 0.05). Compared to untreated values, there was no significant difference between contralateral cortical K at either one or twelve hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoisobutyric Acids↗
PubMed1990

Cerebellar degeneration-related antigen: a highly conserved neuroectodermal marker mapped to chromosomes X in human and mouse.

Cerebellar degeneration-related antigen (designated CDR34) was previously cloned by antibody screening of a cDNA library and was shown to be one of the target molecules recognized by autoantibodies in patients with paraneoplastic cerebellar degeneration. This molecule is distinctive in that it contains a tandem hexapeptide repetitive structure, presumably the basis for its high immunogenicity. In this study, we cloned the human CDR34 gene and proved that the entire repetitive sequence is encoded by a single exon without introns. We also showed that the nucleotide repeats are preserved only in the protein-coding sequences, suggesting evolutionary constraint in this region of the gene. Corresponding mouse cDNA clones were also isolated, which encoded a larger molecule with very similar hexapeptide repeating units. Comparison of the human and mouse repeats revealed a highly conserved Glu-Asp core in each unit, implicating the functional significance of this motif. Chromosomal mapping by somatic cell hybrid analysis mapped CDR34 to both human and mouse chromosomes X, and in situ hybridization further assigned CDR34 to human Xq24-q27.

Amino Acid Sequence↗
PubMed1990

Autoantibody synthesis in the central nervous system of patients with paraneoplastic syndromes.

We measured the activity of 2 highly specific autoantibodies (anti-Yo associated with paraneoplastic cerebellar degeneration and anti-Hu associated with paraneoplastic sensory neuronopathy-encephalomyelitis) in simultaneously procured samples of serum and CSF of 18 patients. We also measured the effect of plasma exchange on autoantibody activity in serum and CSF of 6 patients. In 11 patients with paraneoplastic cerebellar degeneration, the CSF/serum ratio of anti-Yo antibody varied between 0.74 and 63, with 8 of 11 patients having ratios substantially greater than 1. In 7 patients with paraneoplastic sensory neuronopathy-encephalomyelitis, the CSF/serum ratio of anti-Hu antibody varied from 0.6 to 44, with 6 of 7 patients having ratios greater than 1. Plasmapheresis reduced the level of the autoantibody in serum without affecting that in the CSF in 5 of 6 patients. These data indicate that autoantibodies in paraneoplastic syndromes are produced in the CNS. This is consistent with the hypothesis of autoimmunity as the pathogenic mechanism. Plasmapheresis failed to effectively remove the antibody from the CNS.

Adult↗
PubMed1990

Capillary permeability factor secreted by malignant brain tumor. Role in peritumoral brain edema and possible mechanism for anti-edema effect of glucocorticoids.

Conditioned media from two human malignant gliomas, C6 rat glioma, Walker 256 carcinosarcoma, and normal human glia were concentrated 50-fold to create a culture supernatant (SUP-C). The effect of SUP-C on rat brain capillary permeability was investigated by measuring the entry of 14C-aminoisobutyric acid (14C-AIB) by means of quantitative autoradiography. The SUP-C contained proteins with a molecular weight of 10 kD or greater. The SUP-C from all tumor cells markedly increased brain capillary permeability, indicating the presence of a permeability factor, whereas that from normal glial cells did not. Glioma cells produced more factor after incubation for 20 hours than 4 hours. The activity of capillary permeability factor in the SUP-C was inhibited by pretreatment of animals with BW755C (lipoxygenase inhibitor), but not with indomethacin (cyclo-oxygenase inhibitor). Pretreatment of animals with dexamethasone prior to intracerebral infusion of tumor SUP-C significantly reduced the factor-induced increase in capillary permeability. On the other hand, coincubating glioma cells with dexamethasone produced SUP-C with a permeability activity that was about one and a half times greater than that without dexamethasone. These results indicate that glucocorticoids produce their anti-edema effects by directly acting on capillary endothelial cells, possibly through the inhibition of phospholipase A2 activity, resulting in a decrease of lipoxygenase rather than cyclo-oxygenase products. The production of capillary permeability factor by tumor cells was not inhibited, but rather enhanced, by administration of glucocorticoids.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1989

Phenobarbital rheumatism in patients with brain tumor.

We reviewed the charts of 429 patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center to determine the frequency, clinical characteristics, and provocative factors involved in the development of the shoulder-hand syndrome. Five percent (20/429) of patients developed this syndrome, which was strongly associated with phenobarbital use (p less than 0.0001) and often produced more short-term disability than the brain tumor itself.

Brain Neoplasms↗
PubMed1989

The combined use of radiation therapy and lonidamine in the treatment of brain metastases.

Lonidamine is an indazole carboxylic acid that has been shown to be synergistic with radiotherapy (RT) in tissue culture and animal models. Clinical experience has shown that lonidamine is well-tolerated, and appears to potentiate the activity of conventional chemotherapy in the treatment of brain metastases. A prospective randomized trial was undertaken to evaluate the use of lonidamine in combination with RT in the treatment of brain metastases. All patients received 3000 cGy of whole brain radiotherapy (WBRT). Fifty eight patients were enrolled; 31 received lonidamine plus WBRT and 27 received WBRT alone. There was no significant difference in response rate or survival between the treatment groups. Lonidamine blood levels were measured in 30 of the 31 patients who received the drug, and were therapeutic (greater than or equal to 15 micrograms/ml) in 50%. Survival and response rate were unaffected by the presence or absence of a therapeutic lonidamine level. The most common side-effects of lonidamine were myalgia, testicular pain, anorexia, and ototoxicity; however, only 2 patients had to discontinue the drug because of intolerable myalgias. No serious organ toxicity or myelosuppression was observed.

Adult↗
PubMed1989

Acute effects of low-dose cranial irradiation on regional capillary permeability in experimental brain tumors.

To determine the acute effects of low-dose cranial irradiation (CRT) on regional capillary permeability (RCP) of normal brain, brain tumor and damaged brain surrounding the tumor, we used quantitative autoradiography (QAR) to measure regional blood-to-tissue transport (K) of [14C]aminoisobutyric acid (AIB) in experimental C6 brain tumors 3-4 h after a single dose of 3 Gy CRT. K increased 63% in cortex, 30% in basal ganglia and 31% in brain surrounding the tumor (BST) vs. controls (P less than 0.005). K did not change in the tumor or in the brain adjacent to the tumor (BAT), suggesting that capillaries of normal parenchyma are more sensitive to the acute effects of CRT than capillaries of damaged parenchyma or tumor.

Aminoisobutyric Acids↗
PubMed1989

Characterization of a cDNA encoding a 34-kDa Purkinje neuron protein recognized by sera from patients with paraneoplastic cerebellar degeneration.

Paraneoplastic cerebellar degeneration is a neurological disorder of unknown cause occurring in patients with an identified or occult cancer. An autoimmune etiology is likely since autoantibodies directed against the Purkinje cells of the cerebellum have been found in the serum and cerebrospinal fluid of some patients. Two Purkinje cell-specific antigens are recognized by these autoantibodies, a major antigen of 62 kDa (CDR 62, cerebellar degeneration-related 62-kDa protein) and a minor antigen of 34 kDa (CDR 34). Our previous studies have described the isolation and characterization of a human cerebellar cDNA that encodes an epitope recognized by sera from patients with paraneoplastic cerebellar degeneration. We have now established by two independent methods that this gene is uniquely expressed in Purkinje cells of the cerebellum and corresponds to the minor antigen CDR 34. This antigen is also expressed in tumor tissue from a patient with paraneoplastic cerebellar degeneration.

Autoantigens↗
PubMed1989

Experimental meningeal carcinomatosis selectively depresses local cerebral glucose utilization in rat brain.

Using quantitative autoradiography, we investigated the effect of meningeal carcinomatosis on local cerebral glucose utilization (LCGU). A rat model of meningeal carcinomatosis using Walker 256 tumor was used. LCGU was evaluated using 14C-2-deoxy-D-glucose according to the Sokoloff method. Thirty-one neuroanatomic structures were evaluated, both separately and as part of five functional or neuroanatomic groups: olfactory, auditory, visual, limbic, and white matter. The relationship between tumor and LCGU of underlying brain was examined. Compared with controls, there was no global change of LCGU in the experimental group that applied to all structures. However, mean LCGU was significantly depressed in olfactory cortex, temporal cortex, olfactory tubercle, amygdala, caudate/putaman, inferior colliculus, medial geniculate, anterior commissure, and corpus callosum, and the functional groups that make up the olfactory and auditory systems. There was no correlation between extent of regional tumor burden and degree of depression of LCGU in underlying structures. In meningeal carcinomatosis, tumor results in selective regional depression of LCGU. This occurs both in structures underlying tumor and those anatomically remote, but in certain cases, functionally related to structures subadjacent to tumor. These data may help to explain the diversity of neurologic dysfunction seen in patients with meningeal cancer.

Analysis of Variance↗
PubMed1989

Radiation-induced dementia in patients cured of brain metastases.

When a patient with cancer develops a brain metastasis, death is usually imminent, but aggressive treatment in some patients with limited or no systemic disease yields long-term survival. In such patients, delayed deleterious effects of therapy are particularly tragic. We report 12 patients who developed delayed complications of whole brain radiotherapy (WBRT) given as sole treatment (4 patients) or in combination with surgical resection (8 patients). Within 5 to 36 months (median, 14) all patients developed progressive dementia, ataxia, and urinary incontinence causing severe disability in all and leading to death in 7. No patient had tumor recurrence when neurologic symptoms began. Cortical atrophy and hypodense white matter were identified by CT in all. Contrast-enhancing lesions were seen in 3 patients; 2 of the lesions yielded radionecrosis on biopsy. Autopsies on 2 patients revealed diffuse chronic edema of the hemispheric white matter in the absence of tumor recurrence. Corticosteroids and ventriculoperitoneal shunt offered significant but incomplete improvement in some patients. The total dose of WBRT was only 2,500 to 3,900 cGy, but daily fractions of 300 to 600 cGy were employed. We believe that these fractionation schedules, several of which are used commonly, predispose to delayed neurologic toxicity, and that more protracted schedules should be employed for the safe and efficacious treatment of good-risk patients with brain metastases. The incidence of WBRT-induced dementia was only 1.9 to 5.1% in the 2 populations reviewed here; however, this underestimates the incidence because only severely affected patients could be identified from chart review.

Aged↗
PubMed1989

The role of postoperative radiotherapy after resection of single brain metastases.

To assess the value of whole brain radiotherapy (WBRT) after complete resection of a single brain metastasis we reviewed the records of 98 patients who had elective craniotomy between 1978 and 1985. Seventy-nine patients received postoperative WBRT (Group A) and 19 patients no radiotherapy (RT) (Group B). Neurological relapse was designated as local (i.e., at the site of the original metastasis) or distant (i.e., elsewhere in the brain). Postoperative WBRT significantly prolonged the time to any neurological relapse (P = 0.034) with a 1-year recurrence rate of 22% in Group A and 46% in Group B patients; however, it did not specifically control either local or distant cerebral recurrence. Recurrence of metastatic brain disease was not affected by location of the original lesion; however, meningeal relapse occurred in 38% of cerebellar lesions, but only in 4.7% of supratentorial metastases (P = 0.003). The total radiation dose or fractionation scheme of RT did not affect survival nor time to neurological relapse. The median survival was 20.6 and 14.4 months for Groups A and B, respectively (not statistically different). Forty-eight percent of Group A and 47% of Group B patients survived for 1 year or longer; however, 11% of patients who had received RT and survived 1 year developed severe radiation-induced dementia. All patients with radiation-related cerebral damage received hypo-fractionated RT with high daily fractions as commonly designed for rapid palliation of macroscopic brain metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

A dose-response study of dexamethasone in a model of spinal cord compression caused by epidural tumor.

In order to assess the clinical and biological effects of glucocorticoids in the therapy of epidural spinal cord compression, the T8-10 epidural space of 50 rats was implanted with Walker 256 tumor. The rats were studied 10 to 20 days later when they became paraparetic. The regional blood-spinal cord transport constant (K, a function of the blood-spinal cord barrier) of 14Carbon-labeled aminoisobutyric acid was measured with quantitative autoradiography 6 hours after intravenous injection of low-dose (0.1 mg/kg), intermediate dose (1 mg/kg), and high-dose (10 mg/kg) dexamethasone. The effects of dexamethasone in these doses on the clinical signs and water content of the compressed cord were also evaluated 40 hours after treatment began. The K factor increased 730% in compressed compared with noncompressed spinal cords (p less than 0.001). Dexamethasone induced a dose-related reduction of both K (p = 0.007) and water content of the compressed cord (p less than 0.0001). Stabilization or, more rarely, improvement of weakness at 24 and 40 hours posttreatment correlated with the dose of dexamethasone (r = 0.88, p less than 0.001). This study demonstrates that dexamethasone has a dose-related beneficial clinical effect associated with an improvement of blood-spinal cord barrier breakdown and a reduction of the water content of the compressed cord. This study supports the use of highdose dexamethasone for the initial treatment of epidural spinal cord compression.

Animals↗
PubMed1988

Expression of an antigen in small cell lung carcinoma lines detected by antibodies from patients with paraneoplastic dorsal root ganglionpathy.

We have identified an autoantibody that reacts with a neuronal nucleoprotein in the serum of patients with small cell lung carcinoma (SCLC) and the paraneoplastic syndrome, subacute sensory neuronopathy (SSN). A similar antigen has been found in the tumor from one of these patients. To determine the distribution of this antigen, immunoblots of a homogenate from the SCLC of another patient with SSN, six SCLC cell lines from patients without SSN, five non-SCLC cell lines, and one ovarian carcinoma cell line were reacted with serum from five patients with SCLC and SSN. Control sera were obtained from two patients with SSN without cancer, two patients with SSN associated with tumors other than SCLC, two patients with paraneoplastic cerebellar degeneration, and five patients with SCLC but no SSN. The sera from all five patients with SCLC and SSN identified a Mr 35,000 to 40,000 antigen in neurons, in all of six SCLC cell lines and in the SCLC tumor homogenate. The antigen was not detected in other tumor cell lines. Control sera did not react with these bands, in either neurons or SCLC cell lines. Bound IgG was eluted from the blot of one SCLC cell line after reaction with SSN serum. Eluates from the Mr 35,000 to 40,000 area reacted with neuronal nuclei in the cerebral cortex by an immunoperoxidase technique; eluates from other areas of the blot were negative. These findings support the hypothesis that the autoantibody in SSN arises in reaction to an antigen shared between SCLC and neuronal nuclei.

Antibodies, Neoplasm↗
PubMed1988

Distribution of brain metastases.

The number and site of brain metastases were identified on the computed tomographic scans of 288 patients. There was one brain metastasis in 49%, two in 21%, three in 13%, four in 6%, and five or more in 11% of scans. In patients with one metastasis, the posterior fossa was involved in 50% of patients when the primary tumor was pelvic (prostate or uterus) or gastrointestinal, but it was involved in only 10% of patients with other primary tumors. Hemispheral metastases preferred the anatomic "watershed areas" (29% of the brain surface contained 37% of the metastases), indicating that tumoral microemboli tend to lodge in the capillaries of the distal parts of the superficial arteries. The charts of 134 patients with brain metastases from a primary tumor originating outside the lung revealed that the incidence of lung and spine metastases was the same, whether the primary tumor was pelvic or gastrointestinal or from another site. These data suggest that the high incidence of subtentorial lesions in patients with pelvic and gastrointestinal primary tumors cannot be explained by arterial embolization alone, and that this peculiar distribution is probably not explained by seeding of the brain through Batson's plexus.

Brain Neoplasms↗
PubMed1988

An antineuronal autoantibody in paraneoplastic opsoclonus.

Sera from 7 patients with paraneoplastic opsoclonus were examined for antineuronal autoantibodies. An antibody against neuronal nuclei was found in serum from a patient with breast cancer, opsoclonus, and ataxia. This antibody recognized 53- to 61-kDa and 79- to 84-kDa antigens in immunoblots of neurons. Antineuronal antibodies were not found in other patients with paraneoplastic opsoclonus.

Adult↗
PubMed1988

The metabolic anatomy of paraneoplastic cerebellar degeneration.

Eleven patients with acquired cerebellar degeneration (10 of whom had paraneoplastic cerebellar degeneration [PCD]) were evaluated using neuropsychological tests and 18F-fluorodeoxyglucose/positron emission tomography to (1) quantify motor, cognitive, and metabolic abnormalities; (2) determine if characteristic alterations in the regional cerebral metabolic rate for glucose (rCMRGlc) are associated with PCD; and (3) correlate behavioral and metabolic measures of disease severity. Eighteen volunteer subjects served as normal controls. Although some PCD neuropsychological test scores were abnormal, these results could not, in general, be dissociated from the effects of dysarthria and ataxia. rCMRGlc was reduced in patients with PCD (versus normal control subjects) in all regions except the brainstem. Analysis of patient and control rCMRGlc data using a mathematical model of regional metabolic interactions revealed two metabolic pattern descriptors, SSF1 and SSF2, which distinguished patients with PCD from normal control subjects; SSF2, which described a metabolic coupling between cerebellum, cuneus, and posterior temporal, lateral frontal, and paracentral cortex, correlated with quantitative indices of cerebellar dysfunction. Our inability to document substantial intellectual impairment in 7 of 10 patients with PCD contrasts with the 50% incidence of dementia in PCD reported by previous investigators. Widespread reductions in PCD rCMRGlc may result from the loss of cerebellar efferents to thalamus and forebrain structures, a "reverse cerebellar diaschisis."

Adolescent↗