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J B Posner

Publications and source records attributed to J B Posner.

At least 37 records · Page 2Linked to original sources
PubMed1998

Anti-Hu immunolabeling as an index of neuronal differentiation in human brain tumors: a study of 112 central neuroepithelial neoplasms.

Anti-Hu is a polyclonal immunoglobulin G associated with a syndrome of paraneoplastic sensory neuropathy/encephalomyelitis that principally afflicts patients with small cell lung carcinoma. Anti-Hu antibodies, which identify a family of RNA-binding proteins that are normally neuron restricted and that appear to be integral to neuronal differentiation and maintenance, selectively label the nuclei (and, less strongly, the cytoplasm) of neurons throughout the human neuraxis. Small cell carcinomas of the lung and many neuroblastomas are also labeled. We screened 112 tumors of central neuroepithelial lineage for immunohistochemical evidence of Hu expression with anti-Hu immunoglobulin G that was purified from patient sera and with a recombinant Fab fragment (Fab GLN 495) selected from a patient-derived combinatorial antibody phage display library using a recombinant Hu protein (HuD). Both antibodies uniformly labeled, in addition to native neurons, the nuclei of central neurocytomas (6 of 6) and the neuronal components of "classic" (12 of 12) and desmoplastic infantile (2 of 2) gangliogliomas. Of 33 embryonal tumors, 29 were anti-Hu reactive, including 87% of medulloblastomas (26 of 30). Glial neoplasms (n = 59) were anti-Hu negative save for one "oligodendroglioma" (of 17 oligodendroglial/oligoastrocytic tumors) that may have been an extraventricular neurocytoma. Anti-Hu immunoglobulin G/Fab GLN 495 identifies neoplasms of differentiated neuronal type and embryonal tumors with neuronogenic potential.

Antibodies, Neoplasm↗
PubMed1998

Antibodies against the calcium channel beta-subunit in Lambert-Eaton myasthenic syndrome.

The sera of patients with Lambert-Eaton myasthenic syndrome (LEMS) contain autoantibodies against several extracellular and intracellular components of the voltage-gated calcium channel (VGCC)/synaptic vesicle release complex. An example of the latter are anti-beta-subunit antibodies (anti-MysB antibodies). We constructed a full-length cDNA clone of a human VGCC beta-subunit to produce purified beta-subunit fusion protein (MysB protein). Using this protein, we demonstrated that anti-beta-subunit antibodies are present in the sera of 23% of LEMS patients and only, in low titer, in 2% of small cell lung cancer patients without LEMS. The presence of anti-beta-subunit antibodies was closely associated with high titers of P/Q- and N-type VGCC antibodies. Immunization of rats with the purified MysB protein induced high antibody titers, but no signs of neurologic dysfunction were found. We conclude that anti-beta-subunit antibodies are not likely to interfere with ion channel function, but their presence could explain the cross-reactivity of LEMS sera with several subtypes of VGCCs and the lack of correlation between anti-VGCC antibody titer and clinical severity of disease.

Animals↗
PubMed1998

Absence of antibodies to non-NMDA glutamate-receptor subunits in paraneoplastic cerebellar degeneration.

OBJECTIVE: To determine whether patients with antineuronal antibody-associated paraneoplastic cerebellar degeneration (PCD) harbor antibodies to non-N-methyl-D-aspartate glutamate receptors (GluRs) in their serum. BACKGROUND: A recent study identified antibodies to GluRs in the serum of patients with PCD. METHODS: Sera of 35 patients with PCD (20 anti-Yo, 5 anti-Ri, 5 anti-Tr, and 5 anti-Hu) were examined by immunohistochemistry and immunoblot techniques. The expression of GluRs was obtained after transfection of 293T cells with cDNA plasmids corresponding to GluR1, GluR2, GluR3, GluR4, GluR6, and GluR7. The tumors of four patients with anti-Yo-associated PCD and nine ovarian carcinomas from patients without PCD were examined for the expression of GluRs. RESULTS: The expression of each GluR subunit was confirmed using affinity-purified antibodies against the corresponding GluRs and with whole sera from two rabbits immunized with GluR3. Thirty-two sera from patients with PCD were negative and 3 showed equivocal reactivity with 293T cells expressing different GluRs. None of the 35 sera had a pattern of reactivity characteristic of any GluR antibody on immunohistochemistry of sections of rat brain. Eleven of 14 tumors did not express GluRs; only some cells of one paraneoplastic tumor expressed GluRs. CONCLUSIONS: That patients with antibody-associated PCD (anti-Yo, -Ri, -Tr, and -Hu) harbor GluR antibodies in their sera is unlikely. GluR antibodies cannot be used as markers of paraneoplastic neurologic disorders.

Animals↗
PubMed1998

T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis.

OBJECTIVE: To analyze the T-cell receptor (TCR) repertoire in the inflammatory infiltrates of the nervous system and tumor of patients with anti-Hu associated paraneoplastic encephalomyelitis and sensory neuronopathy (PEM/SN). BACKGROUND: In PEM/SN, the pathogenic role of the infiltrating T cells is speculative. TCR analysis may establish whether these lymphocytes are attracted nonspecifically by a proinflammatory environment or are driven by a specific antigen or superantigen. METHODS: We examined frozen tissues of seven patients with PEM/SN using immunohistochemical and PCR analysis. Of 62 tissue blocks from seven patients, 19 blocks from five patients had >100 CD3+ cells per section infiltrating the nervous system or tumor. These infiltrates allowed screening of the TCR Vbeta family repertoire using a panel of 18 antibodies that recognize family-specific regions of most TCR Vbeta families against which antibodies have been generated. To distinguish between antigen-driven clonal and superantigen-driven family expansion, we extracted RNA from frozen tissue and performed reverse transcriptase (RT)-PCR analysis followed by subcloning and sequencing of the antigen-specific CDR3 region of the TCR Vbeta chain. RESULTS: All five patients showed a limited Vbeta repertoire. An overrepresentation (>10% of total CD3+) of certain Vbeta families was identified in three patients (as high as 45% of total CD3+), which consisted mainly of CD8 + cells. CDR3 sequences obtained from one patient revealed an in situ expansion of two clones in the amygdala (one at a frequency of 57%) and four clones in the tumor. CONCLUSION: These findings suggest that an antigen-driven oligoclonal cytotoxic T-cell response plays a role in the pathogenesis of anti-Hu associated PEM/SN.

Aged↗
PubMed1998

DNA vaccination with HuD inhibits growth of a neuroblastoma in mice.

Some patients with small cell lung cancer (SCLC) or neuroblastoma develop an immune response against HuD, a human homologue of the Drosophila protein, elav, which is expressed in the nucleus and to a lesser degree the cytoplasm of neurons and tumor cells. This immune response is characterized by antibodies (anti-Hu) that at high titers are associated with a disease called paraneoplastic encephalomyelitis/sensory neuronopathy, in which infiltrates of T cells are found in the tumor and nervous system. Although all SCLCs express HuD, anti-Hu antibodies are identified in only 17% of patients with SCLC, usually at low titers, and are associated with indolent tumor growth. To determine whether the anti-Hu immune response causes indolent tumor growth, we developed an animal model using HuD DNA immunization. We found that a plasmid coding for a secreted form of HuD induced a strong and specific anti-Hu response. Immunized animals were challenged by s.c. implantation of a neuroblastoma cell line that constitutively expresses HuD. When compared with controls, mice immunized with the secreted HuD showed significant tumor growth inhibition (51% reduction volume; P = 0.0012), and 14% of them had complete tumor rejection. Tumors from these animals showed three times more CD3+ lymphocytic infiltrates than those from control mice and had a higher CD8+:CD4+ ratio. None of the animals developed neurological deficits or neuropathological evidence of nervous system pathology. In this mouse model of neuroblastoma, DNA immunization with HuD resulted in tumor growth inhibition but did not induce neurological disease. This model closely mimics the clinical course of more indolent tumor growth seen in patients with the anti-Hu immune response.

Animals↗
PubMed1997

Serum anti-p53 antibodies and prognosis of patients with small-cell lung cancer.

BACKGROUND: Some patients with cancer develop antibodies against the p53 tumor suppressor protein. The presence of these antibodies in serum has been associated with the expression of mutant p53 by the tumor and in some studies with a poorer survival. PURPOSE: The goals of this study were to determine the prevalence of anti-p53 antibodies in the serum of patients with newly diagnosed small-cell lung cancer (SCLC) and to assess the clinical relevance of the presence of these antibodies in the serum, particularly their relationship with tumor response to treatment and with patient survival. METHODS: In this prospective study, serum was obtained from 170 patients at the time of diagnosis of SCLC who were to subsequently receive platinum- or doxorubicin-based chemotherapy at any one of four hospitals in Barcelona, Spain, from October 1991 through June 1994. Normal human sera from blood bank donors (n = 50) served as controls. The presence of anti-p53 antibodies was determined by western blot analysis with the use of purified recombinant p53 protein. As of January 1996, 96.5% of the patients had been treated and observed in the study, for a median follow-up time of 33.5 months. Survival was estimated by the Kaplan-Meier method. Cox proportional hazards regression and unconditional logistic regression analyses were conducted. All P values resulted from two-sided tests. RESULTS: Anti-p53 antibodies were detected in the serum of 27 (16%) of the 170 patients studied. None of 50 serum samples from normal individuals contained anti-p53 antibodies. Analysis of pretreatment clinical characteristics demonstrated that a weight loss of less than 5% (P = .025), a serum lactic acid dehydrogenase (LDH) level of less than 450 U/L (P = .002), and limited stage disease (i.e., tumor confined to one hemithorax, with local and regional lymph node positivity for tumor cells and/or ipsilateral pleural effusion allowed) (P < .001) were associated with a statistically significant complete response to therapy. The presence of serum anti-p53 antibodies was not associated with clinical characteristics, such as age (P = .622), functional status (P = 1.0), disease stage (P = .634), complete response to treatment (P = .572), and survival (P = .492) or with any laboratory parameters including known prognostic factors in SCLC, such as serum sodium or LDH concentration (P values of .731 and .246, respectively). CONCLUSIONS AND IMPLICATIONS: The presence of anti-p53 antibodies in the serum of patients with newly diagnosed SCLC was not associated with any clinical characteristics or prognostic markers, suggesting that, in this context, the measurement of anti-p53 antibodies is not a useful prognostic marker.

Aged↗
PubMed1997

Motor neuron syndromes in cancer patients.

Previous reports indicate that motor neuron disease (MND) may rarely be associated with systemic cancer. We have encountered 14 patients with MND and cancer who formed three distinct groups. Group 1: Three patients developed a rapidly progressive MND, less prominent symptoms of involvement of other areas of the nervous system, and anti-Hu antibodies. Group 2: Five women developed signs of upper motor neuron (UMN) disease, initially resembling primary lateral sclerosis (PLS), and breast cancer. In 4, symptoms of UMN occurred within 3 months of cancer diagnosis or tumor recurrence. They had no metastases or spinal cord compression. Serum anti-neuronal antibodies were negative. Three patients are alive (follow-up of 156, 15, and 12 months), and 2 remain without lower motor neuron signs. Group 3: Six patients developed MND resembling amyotrophic lateral sclerosis between 47 months before and 48 months after their cancer diagnosis. In group 1, the MND associated with the anti-Hu antibody is unequivocally paraneoplastic. In group 2, the proximate onset of MND with the diagnosis of cancer or its recurrence, its pure or long-lasting UMN signs, and its association with breast cancer, suggest that the disorder may be paraneoplastic. Although for most cancer patients who develop MND the occurrence of both disorders is probably coincidental, in some patients with MND a careful search for an underlying cancer is warranted (ie, patients in groups 1 and 2).

Aged↗
PubMed1997

Normalization of the tumor marker CA-125 after oophorectomy in a patient with paraneoplastic cerebellar degeneration without detectable cancer.

A 61-year-old woman developed severe subacute cerebellar degeneration in association with a neuronal antinuclear autoantibody. Neurologic investigations were remarkable only for mild CSF leukocytosis. Despite no radiographic evidence of cancer, a salpingo-oophorectomy was performed on the basis of an increased gynecologic cancer marker (CA-125) and the neurologic symptoms that were strongly suggestive of paraneoplastic cerebellar degeneration. Although no tumor was detected in the surgical specimen, CA-125 levels normalized after surgery. The patient remains stable 12 months after surgery with a severe cerebellar syndrome, no evidence of cancer, and persistent circulating antineuronal autoantibodies. An elevated tumor marker in a patient with a presumed paraneoplastic neurologic disorder should suffice as evidence of an occult neoplasm, and guide definitive treatment.

Autoantibodies↗
PubMed1997

Paraneoplastic anti-Hu serum: studies on human tumor cell lines.

Patients with low titers of anti-Hu, the paraneoplastic encephalomyelitis/sensory neuronopathy (PEM/PSN) antibody, have a better tumor prognosis that those who do not harbor these antibodies. Accordingly, we examined the effects of serum from patients with anti-Hu antibodies on human tumor cell lines, in order to determine: (1) if the serum was toxic (growth inhibition or cytolysis) to tumor cells with or without complement, and (2) if anti-Hu antibodies contributed to tumor toxicity. The serum of 14 patients with anti-Hu associated PEM/PSN, 22 patients with small-cell lung cancer (SCLC) without anti-Hu antibodies, and 20 normal individuals were studied. Three cell lines (NT-2, BE(2)-C, and SH.SY5Y) that express Hu proteins, and one cell line (SAOS-2) that does not, were studied. We examined the effects of whole serum, IgG-depleted serum, and purified IgG in the presence or absence of complement. A higher percentage of anti-Hu sera were toxic (71%) compared with sera from anti-Hu negative SCLC patients (23%) (p < 0.0001). No correlation existed between the titer of anti-Hu antibodies and toxicity. The toxic effects were observed in all tumor cell lines including the cell line that does not express Hu antigens. Toxicity persisted in serum depleted of IgG. Purified anti-Hu IgG in the presence and absence of complement, was not toxic. Our findings indicate that anti-Hu serum is toxic for human tumor cell lines, but this toxicity does not appear to be mediated by anti-Hu antibodies.

Antibodies↗
PubMed1997

Paraneoplastic syndromes.

Paraneoplastic syndromes (i.e. organ/tissue disorders associated with cancer) affecting the nervous system are thought to be the result of an autoimmune response triggered by specific cancer antigens. Several of these antigens have recently been identified and include the Hu, Yo and Ri proteins, with the Hu antigens being the best studied. Immunization of animals with HuD has been shown to retard the growth of HuD-positive neuroblastomas. In addition, the presence of anti-HuD antibody in humans with small-cell lung cancer predicts the slow growth of the tumor. The associated neurological disorders, however, limit the use of these and other antigens with similar characteristics in cancer vaccines.

Humans↗
PubMed1997

HuD, a neuronal-specific RNA-binding protein, is a potential regulator of MYCN expression in human neuroblastoma cells.

HuD is one of a family of neural antigens recognised by the sera of patients with antibody-associated paraneoplastic encephalomyelitis. Localised exclusively to neurons, these proteins are among the earliest markers of the developing nervous system. Sequence analysis suggests that HuD is an RNA-binding protein. Hu protein levels were determined for the three cell types characterising human neuroblastoma cell lines: sympathoadrenal neuroblasts (N), substrate-adherent Schwann/glial/melanoblastic precursors (S) and stem cells (I) which can give rise to both N and S cells. Western blot analysis showed similar levels of protein in three N-type cell lines; S cells have no detectable Hu protein. Northern blot analysis indicated that N cells express all three Hu genes, HuD, HuC and Hel-N1. N cells, mostly from MYCN-amplified cell lines, have consistently higher steady-state levels of MYCN mRNA than S cell counterparts. Nuclear run-on and mRNA half-life experiments revealed no differences in transcription rate or mRNA stability between N and S cells from the LA-N-1 cell line, implicating differences in post-transcriptional regulation. HuD is postulated to be instrumental in splicing/processing and/or stabilisation of mRNAs involved in cell growth and neuronal differentiation. As determined by gel-mobility shift assays, HuD fusion protein binds to the 3'UTR of human MYCN mRNA. Analysis of HuD deletion mutants has demonstrated that the first and second RNA-recognition motifs (RRMs) are required for binding. Whether HuD regulates MYCN expression and thereby influences tumour aggressiveness is of major interest.

Binding Sites↗
PubMed1997

Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome.

Several cancers, especially lung, ovarian and breast, can cause paraneoplastic cerebellar degeneration. The presence of different antineuronal antibodies associated with different cancers and paraneoplastic cerebellar degeneration suggests that several immunological mechanisms may result in the same neurological disorder. In patients with small-cell lung cancer, paraneoplastic cerebellar degeneration may occur with or without Hu antineuronal antibodies (HuAb), indicating that patients with the same tumour can develop paraneoplastic cerebellar degeneration by different immunological mechanisms. Furthermore, paraneoplastic cerebellar degeneration sometimes occurs in association with the Lambert-Eaton myasthenic syndrome. In order to try to understand the clinical implication of antineuronal antibodies in patients with small-cell lung cancer, we examined the serum of 57 patients with presenting symptoms of paraneoplastic cerebellar degeneration for the presence of HuAb and P/Q- and N-type voltage-gated calcium channel antibodies. Patients with paraneoplastic cerebellar degeneration who were HuAb positive were compared with HuAb negative patients with respect to neurological symptoms, course of the neurological disorder, response to treatment, tumour prognosis, pathological findings, and cause of death. The tumour outcome and serological findings of these patients were also compared with those of 109 small-cell lung cancer patients without paraneoplastic syndromes of the CNS. Titres of HuAb were classified as 'high' (immunoblot titre > 1:10,000) or 'low' (< 1:10,000), the latter similar to the antibody titres detected in some small-cell lung cancer patients without paraneoplastic symptoms. Twenty-five patients with paraneoplastic cerebellar degeneration (44%) had high titres of HuAb, four (7%) had low titres of HuAb, and 28 (49%) were HuAb negative; for clinical comparisons with the patients with high titres of HuAb, the four patients with low antibody titres were included in the HuAb negative cohort. None of the 109 small-cell lung cancer patients without paraneoplastic symptoms had high titres of HuAb. The presence of high titres of HuAb defined a subset of patients who differed from the HuAb negative paraneoplastic cerebellar degeneration cohort, HuAb positive patients were more likely to be female (P < 0.01), to have multifocal neurological disease (brainstem encephalopathy and sensory neuropathy being common extracerebellar manifestations) (P < 0.002), and be severely disabled (P < 0.005). A total of nine patients (16%) from both paraneoplastic cerebellar degeneration groups developed electrophysiologically confirmed Lambert-Eaton myasthenic syndrome. Seven of these nine patients had serum available for P/Q-type voltage-gated calcium channel antibody testing and all seven were positive. In addition, 20% of HuAb negative paraneoplastic cerebellar degeneration patients without clinically identified Lambert-Eaton myasthenic syndrome had P/Q-type voltage-gated calcium channel antibodies, while only 2% of small-cell lung cancer patients without paraneoplastic symptoms had these antibodies. Treatment of the tumour and/or immunomodulation did not alter the course of paraneoplastic cerebellar degeneration, but improved Lambert-Eaton myasthenic syndrome symptoms. At the time of death, in 60% of HuAb positive and 20% of HuAb negative paraneoplastic cerebellar degeneration patients, the tumour was either not evident or localized to the chest (P < 0.007); neurological disease was the cause of death of 65% HuAb positive paraneoplastic cerebellar degeneration and 10% HuAb negative paraneoplastic cerebellar degeneration patients (P < 0.001). (ABSTRACT TRUNCATED)

Age Distribution↗
PubMed1997

Paraneoplastic syndromes.

Most nervous system paraneoplastic syndromes probably result from an immune attack against antigens normally expressed only in the nervous system but aberrantly expressed in a cancer. Specific antibodies in serum and cerebrospinal fluid that react with the nervous system and the cancer can be used to characterize proteins usually restricted to the nervous system and to identify neurologic disorders as paraneoplastic caused by a specific tumor type.

Animals↗
PubMed1997

Spontaneous neurological improvement in anti-Hu associated encephalomyelitis.

Symptoms of anti-Hu associated paraneoplastic encephalomyelitis (PEM) and sensory neuropathy (PSN) are usually severe and irreversible. Two patients are reported whose symptoms improved spontaneously, and in one of them they resolved after resection of an inflammatory lesion of the lung. Spontaneous neurological improvement, although rare, should be considered in the evaluation of therapies for PEM/PSN.

Aged↗
PubMed1997

Paraneoplastic syndromes affecting the central nervous system.

Paraneoplastic syndromes affecting the nervous system are rare neurologic syndromes caused by cancer but not ascribable to metastases. Any portion of the nervous system may be involved in a paraneoplastic syndrome. The pathogenesis of these disorders appears to be an immune reaction against antigens shared by the cancer and the nervous system. Some disorders, such as the Lambert-Eaton myasthenic syndrome, are effectively treated by removal of autoantibodies directed against the presynaptic cholinergic synapse. In other disorders, such as paraneoplastic cerebellar degeneration or paraneoplastic sensory neuronopathy, neither removal of the autoantibody nor treatment of the cancer is effective.

Autoantibodies↗