Research IndicatorsGraph generated 15 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (1)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: AMPH (cancer-related)
BACKGROUND: Some so-called "non-classical" paraneoplastic neurological syndromes (PNS), namely optic neuritis and myelitis, clinically overlap with neuromyelitis optica spectrum disorders (NMOSD), and conversely, in cancer-associated NMOSD, a paraneoplastic etiology has been suggested in rare cases. Therefore, we retrospectively investigated the prevalence of onconeural antibodies, which are highly predictive for a paraneoplastic etiology, and the prevalence of malignancies in NMOSD patients.
METHODS: We retrospectively screened 23 consecutive patients from our clinic with NMOSD (13 were anti-aquaporin-4 [AQP4] antibody positive, 10 were AQP4 negative) for onconeural antibodies using an immunoblot.
RESULTS: All patients were negative for a broad spectrum of antibodies targeting intracellular onconeural antigens (Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2, Zic4, SOX1, Tr, and amphiphysin). Notably, only two patients had a malignancy. However, neoplastic entities (astrocytic brain tumor and acute myeloid leukemia) were not typical for PNS.
CONCLUSIONS: Our data suggest that there is no need to routinely screen anti-AQP4 antibody positive NMOSD patients with a typical presentation for onconeural antibodies. Furthermore, absence of these antibodies in NMOSD, which is typically non-paraneoplastic, confirms their high specificity for PNS.
Inuzuka T[Autoimmune Encephalitis Associated with Malignant Tumors].
Brain Nerve. 2016; 68(9):1049-1055 [PubMed
] Related Publications
Autoimmune encephalitis consists of limbic symptoms and signs associated with antibodies against neuronal cell-surface antigens or intracellular antigens. Some cases are known to be associated with anti-channel or anti-receptor-related molecule antibodies. Whether these cases are paraneoplastic depends on the kinds of antigens that the antibodies are produced against. Other cases due to well-characterized onco-neural antibodies are almost always paraneoplastic and are generally resistant to anti-tumor therapy and/or immunotherapy. An exception is anti-Ma2 antibody-positive encephalitis associated with a testicular tumor. Antibodies for intracellular antigens are considered not to be pathogenic. Rather, the T-cell response is thought to be responsible. These antibodies are useful markers for the diagnosis of paraneoplastic disorders and in the search for underlying cancer, as neurological symptoms often precede tumor diagnosis. There is a relationship among onco-neural antibodies, clinical features, tumor types, and response to immunotherapy. Here we describe the characteristics of autoimmune encephalitis cases with antibodies against different intracellular antigens, such as Hu, Ma2, CRMP5, or amphiphysin.
Tebo AE, Haven TR, Jackson BRAutoantibody diversity in paraneoplastic syndromes and related disorders: The need for a more guided screening approach.
Clin Chim Acta. 2016; 459:162-9 [PubMed
] Related Publications
BACKGROUND: Significant progress has been made in understanding the role and diversity of autoantibodies in the pathogenesis, diagnosis and management of paraneoplastic syndrome (PNS) and related autoimmune neurologic diseases. We evaluated the positivity rates for diverse autoantibody panels to rationalize testing strategies and utilization.
METHODS: The result patterns for different autoantibody panels for PNS offered at 2 reference laboratories in the U.S. were retrospectively reviewed for the same period. The positivity rates were evaluated and compared for specific autoantibodies within panels offered at both laboratories.
RESULTS: For the Hu, Ri, Yo, and amphiphysin antibodies offered by both laboratories, no significant difference in positivity rates was observed. The positivity rates for non-classic PNS markers were 0% [AGNA and PCCA-Tr], and 0.06% [ANNA-3 and PCAC-2] while the prevalence of antibodies associated with neuromuscular autoimmunity varied from 1.40% to 4.44% [Striated muscle, AChR binding, ganglionic AChR, VGCC, P/Q- and N-type VGCC].
CONCLUSIONS: The data suggest that test utilization could be substantially improved based on ordering practice geared towards clinical manifestations and prevalence of autoantibodies. Concerted efforts towards streamlining diagnostic algorithms based on risk, clinical manifestations, characterization of autoantibodies and their associations as well as therapeutic strategies are needed.
Galassi G, Ariatti A, Rovati R, et al.Longitudinally extensive transverse myelitis associated with amphiphysin autoimmunity and breast cancer: a paraneoplastic accompaniment.
Acta Neurol Belg. 2016; 116(3):395-7 [PubMed
] Related Publications
BACKGROUND: Development of the intestinal subtype of gastric adenocarcinoma is marked by a progression of histopathologic lesions. Residents of the Andean regions of Colombia are at high risk for gastric cancer.
METHODS: A cohort of 976 Colombian subjects was followed over 16 years examining effects of Helicobacter pylori eradication and treatment with antioxidants on progression of lesions. We performed methylation analysis of DNA from baseline antral biopsies from 104 subjects for whom follow-up data were available for at least 12 years. Methylation was quantitated for AMPH, CDKN2A, CDH1, EN1, EMX1, NKX6-1, PCDH10, RPRM, RSPO2, SORCS3, ZIC1, and ZNF610 genes, using Pyrosequencing.
RESULTS: Levels of DNA methylation were associated with baseline diagnosis for AMPH, EMX1, RPRM, RSPO2, SORCS3, and ZNF610. After adjusting for baseline diagnosis and H. pylori infection, methylation levels of AMPH, PCDH10, RSPO2, and ZNF610 had progression coefficients that increased and P values that decreased over 6, 12, and 16 years. Methylation for SORCS3 was associated with progression at all 3 time points but without the continual strengthening of the effect. Scores for mononuclear leukocytes, polymorphonuclear leukocytes, or intraepithelial lymphocytes were unrelated to progression.
CONCLUSIONS: Methylation levels of AMPH, PCDH10, RSPO2, SORCS3, and ZNF610 predict progression of gastric lesions independent of the effect of duration of H. pylori infection, baseline diagnosis, gender of the patient, or scores for mononuclear leukocytes, polymorphonuclear leukocytes, or intraepithelial lymphocytes.
IMPACT: DNA methylation levels in AMPH, PCDH10, RSPO2, SORCS3, and ZNF610 may contribute to identification of persons with gastric lesions likely to progress.
OBJECTIVE: To determine the frequency and range of paraneoplastic neurologic disorders (PNDs) and neuronal antibodies in small cell lung carcinoma (SCLC).
METHODS: Two hundred sixty-four consecutive patients with biopsy-proven SCLC were recruited at the time of tumor diagnosis. All patients underwent full neurologic examination. Serum samples were taken prior to chemotherapy and analyzed for 15 neuronal antibodies. Thirty-eight healthy controls were analyzed in parallel.
RESULTS: PNDs were quite prevalent (n = 24, 9.4%), most frequently Lambert-Eaton myasthenic syndrome (3.8%), sensory neuronopathy (1.9%), and limbic encephalitis (1.5%). Eighty-seven percent of all patients with PNDs had antibodies to SOX2 (62.5%), HuD (41.7%), or P/Q VGCC (50%), irrespective of their syndrome. Other neuronal antibodies were found at lower frequencies (GABAb receptor [12.5%] and N-type VGCC [20.8%]) or very rarely (GAD65, amphiphysin, Ri, CRMP5, Ma2, Yo, VGKC complex, CASPR2, LGI1, and NMDA receptor [all <5%]).
CONCLUSIONS: The spectrum of PNDs is broader and the frequency is higher than previously appreciated, and selected antibody tests (SOX2, HuD, VGCC) can help determine the presence of an SCLC.
Berger B, Bischler P, Dersch R, et al."Non-classical" paraneoplastic neurological syndromes associated with well-characterized antineuronal antibodies as compared to "classical" syndromes - More frequent than expected.
J Neurol Sci. 2015; 352(1-2):58-61 [PubMed
] Related Publications
OBJECTIVES: Paraneoplastic neurological syndromes (PNSs) are rare disorders in association with cancer and sub-divided into "classical" and "non-classical" syndromes according to a 2004 consensus paper proposed by a panel of PNS experts. "Classical" PNSs are regarded to account for the vast majority of cases. However, systematic reports on clinical PNS manifestations are rare. Therefore, we analyzed the spectrum of PNS in our clinic.
METHODS: We retrospectively investigated medical records from consecutive patients diagnosed with definite PNS and serological evidence of well-characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2, and amphiphysin) analyzed between 1991 and 2014 in our clinic.
RESULTS: Of the 50 patients identified with onconeural antibody-positive PNS, 28 patients (56.0%) had "classical" PNS, and 22 (44.0%) "non-classical" PNS. Subacute cerebellar degeneration was the most frequent "classical" syndrome, brainstem encephalitis and subacute sensorimotor neuronopathy the most frequent "non-classical" syndromes. Anti-Hu antibodies were most frequent in both groups. 86.1% of patients developed neurological symptoms before the cancer was known. No differences between "classical" and "non-classical" syndromes were detected with respect to age, tumor entities and median time to diagnosis. However, whereas most patients with "classical" syndromes were females, there was no gender predominance in patients with "non-classical" PNS and the latter had significantly more frequent peripheral neurological syndromes.
CONCLUSIONS: The so-called "non-classical" PNSs in association with well-characterized onconeural antibodies were more common in our patient population than expected. Therefore, in neurological disorders of unclear etiology with a subacute onset and atypical presentation further diagnostic work-up including investigation of onconeural antibodies is necessary.
Nakanishi Y, Akiyama N, Tsukaguchi T, et al.Mechanism of Oncogenic Signal Activation by the Novel Fusion Kinase FGFR3-BAIAP2L1.
Mol Cancer Ther. 2015; 14(3):704-12 [PubMed
] Related Publications
Recent cancer genome profiling studies have identified many novel genetic alterations, including rearrangements of genes encoding FGFR family members. However, most fusion genes are not functionally characterized, and their potentials in targeted therapy are unclear. We investigated a recently discovered gene fusion between FGFR3 and BAI1-associated protein 2-like 1 (BAIAP2L1). We identified 4 patients with bladder cancer and 2 patients with lung cancer harboring the FGFR3-BAIAP2L1 fusion through PCR and FISH assay screens. To investigate the oncogenic potential of the fusion gene, we established an FGFR3-BAIAP2L1 transfectant with Rat-2 fibroblast cells (Rat-2_F3-B). The FGFR3-BAIAP2L1 fusion had transforming activity in Rat2 cells, and Rat-2_F3-B cells were highly tumorigenic in mice. Rat-2_F3-B cells showed in vitro and in vivo sensitivity in the selective FGFR inhibitor CH5183284/Debio 1347, indicating that FGFR3 kinase activity is critical for tumorigenesis. Gene signature analysis revealed that FGFR3-BAIAP2L1 activates growth signals, such as the MAPK pathway, and inhibits tumor-suppressive signals, such as the p53, RB1, and CDKN2A pathways. We also established Rat-2_F3-B-ΔBAR cells expressing an FGFR3-BAIAP2L1 variant lacking the Bin-Amphiphysin-Rvs (BAR) dimerization domain of BAIAP2L1, which exhibited decreased tumorigenic activity, FGFR3 phosphorylation, and F3-B-ΔBAR dimerization, compared with Rat-2_F3-B cells. Collectively, these data suggest that constitutive dimerization through the BAR domain promotes constitutive FGFR3 kinase activation and is essential for its potent oncogenic activity.
Amphiphilic gold nanoparticles (amph-NPs), composed of gold cores surrounded by an amphiphilic mixed organic ligand shell, are capable of embedding within and traversing lipid membranes. Here we describe a strategy using crosslink-stabilized lipid nanocapsules (NCs) as carriers to transport such membrane-penetrating particles into tumor cells and promote their transfer to intracellular membranes for enhanced radiotherapy of cancer. We synthesized and characterized interbilayer-crosslinked multilamellar lipid vesicles (ICMVs) carrying amph-NPs embedded in the capsule walls, forming Au-NCs. Confocal and electron microscopies revealed that the intracellular distribution of amph-NPs within melanoma and breast tumor cells following uptake of free particles vs Au-NCs was quite distinct and that amph-NPs initially delivered into endosomes by Au-NCs transferred over a period of hours to intracellular membranes through tumor cells, with greater intracellular spread in melanoma cells than breast carcinoma cells. Clonogenic assays revealed that Au-NCs enhanced radiotherapeutic killing of melanoma cells. Thus, multilamellar lipid capsules may serve as an effective carrier to deliver amphiphilic gold nanoparticles to tumors, where the membrane-penetrating properties of these materials can significantly enhance the efficacy of frontline radiotherapy treatments.
Moon J, Lee ST, Shin JW, et al.Non-stiff anti-amphiphysin syndrome: clinical manifestations and outcome after immunotherapy.
J Neuroimmunol. 2014; 274(1-2):209-14 [PubMed
] Related Publications
Amphiphysin antibody causes paraneoplastic stiff-person syndrome and can also result in a variety of neurological manifestations. Here, we investigated the clinical spectrum of 20 patients with non-stiff anti-amphiphysin syndrome and their responses to immunotherapy. The most common neurological manifestation was limbic encephalitis (n=10), followed by dysautonomia (n=9), and cerebellar dysfunction (n=6). Cancer was detected in only seven patients. Intravenous immunoglobulin or steroid treatment was effective in most patients, but three improved only after rituximab treatment. Our study suggests that anti-amphiphysin syndrome can manifest as non-stiff encephalomyelitis and is only partially associated with cancer. Active immunotherapy, including rituximab, would be beneficial.
Neshige S, Hara N, Takeshima S, et al.[Anti-amphiphysin antibody-positive paraneoplastic neurological syndrome with a longitudinally extensive spinal cord lesion of the dorsal column].
Rinsho Shinkeigaku. 2014; 54(7):572-6 [PubMed
] Related Publications
A 53-year-old woman was admitted to our hospital because of gait disturbance and paresthesia of the lower extremities. She also had marked deep sense impairment in her lower limbs. Cervical MRI showed a longitudinally extensive spinal cord lesion of the dorsal column at levels C1-T11. The findings of cerebrospinal fluid examination, including the IgG index (0.65), were normal. Serum anti-AQP4 antibody was negative, but anti-amphiphysin antibody was positive. Electrophysiological examinations suggested the presence of lesions in the dorsal column of the spinal cord and dorsal root ganglion (DRG). Enlargement of and fluorodeoxyglucose accumulation in her left parasternal lymph node was observed on contrast-enhanced CT and PET-CT, respectively. The lymph node biopsy was underwent by using thoracoscopy. The metastasis of carcinoma was pathologically confirmed. Although the primary tumor was not detected on PET-CT re-examination, immunostaining of the biopsied lymph node specimen was positive for both the progesterone receptor and estrogen receptor. On the basis of these findings, the patient was diagnosed with paraneoplastic neurological syndrome due to potential breast cancer. The disorder is an immunological subacute sensory neuropathy with a longitudinally extensive spinal cord lesion of the dorsal column and a DRG lesion.
Horta ES, Lennon VA, Lachance DH, et al.Neural autoantibody clusters aid diagnosis of cancer.
Clin Cancer Res. 2014; 20(14):3862-9 [PubMed
] Related Publications
PURPOSE: Clustering of neural autoantibodies in patients with paraneoplastic neurologic disorders may predict tumor type. A mathematical analysis of neural autoantibody clusters was performed in 78,889 patients undergoing evaluation for a suspected paraneoplastic autoimmune neurologic disorder. Tumor predictive autoantibody profiles were confirmed in sera from patients with histologically proven tonsillar cancer, thymoma, and lung cancer.
PATIENTS AND METHODS: Of note, 78,889 patient sera were tested for 15 defined neural autoantibodies (1.2 million tests). The observed and hypothesized frequencies of autoantibody clusters were compared and their tumor associations defined. A tumor validation study comprised serum from 368 patients with a variety of tumors (thymoma, lung, or tonsil).
RESULTS: Informative oncological associations included (i) thymoma in 85% of patients with muscle striational, acetylcholine receptor antibodies plus CRMP5 autoantibodies; (ii) lung carcinoma in 80% with both P/Q-type and N-type calcium channel antibodies plus SOX1-IgG; and (iii) in men, prostate carcinoma frequency more than doubled when striational and muscle AChR specificities were accompanied by ganglionic AChR antibody. In women, amphiphysin-IgG alone was associated commonly with breast carcinoma, but amphiphysin-IgG, coexisting with antineuronal nuclear autoantibody-type 1 or CRMP5-IgG, was associated with lung cancer (P < 0.0001). In the validation cohorts, many tumor-associated profiles were encountered that matched the clusters identified in the screening study (e.g., 15% of thymoma patients had striational, acetylcholine receptor antibodies plus collapsin response-mediator protein-5 autoantibodies).
CONCLUSIONS: Neural autoantibodies commonly coexist in specific clusters that are identifiable by comprehensive screening. Signature autoantibody clusters may predict a patient's cancer risk and type.
Prokic I, Cowling BS, Laporte JAmphiphysin 2 (BIN1) in physiology and diseases.
J Mol Med (Berl). 2014; 92(5):453-63 [PubMed
] Related Publications
Amphiphysin 2, also named bridging integrator-1 (BIN1) or SH3P9, has been recently implicated in rare and common diseases affecting different tissues and physiological functions. BIN1 downregulation is linked to cancer progression and also correlates with ventricular cardiomyopathy and arrhythmia preceding heart failure. Increased BIN1 expression is linked to increased susceptibility for late-onset Alzheimer's disease. In addition, altered splicing may account for the muscle component of myotonic dystrophies, while recessive germinal mutations cause centronuclear myopathy. Despite undoubtedly underlining the relevance of BIN1 in human diseases, the molecular and cellular bases leading to such different diseases are unclear at present. BIN1 is a key regulator of endocytosis and membrane recycling, cytoskeleton regulation, DNA repair, cell cycle progression, and apoptosis. In light of the recent findings on the molecular, cellular, and physiological roles of BIN1, we discuss potential pathological mechanisms and highlight common disease pathways and also tissue-specific regulation. Next challenges will be to validate BIN1 both as a prognostic marker for the related diseases and as a potential therapeutic target.
The 20 amino acid (AA) N-terminus of the vesicular monoamine transporter 2 (VMAT2) was examined as a regulator of VMAT2 function. Removal of the first 16 or 19 AAs of the N-terminus resulted in a molecule with reduced ability to sequester [(3)H]-5HT. A glutathione-S-transferase-construct of the N-terminus underwent phosphorylation in the presence of PKC at serines 15 and 18. These putative phosphorylation sites were examined for effects on function. Phospho-mimetic substitution of serines 15 and 18 with aspartate in the full-length VMAT2 resulted in reduced [(3)H]-5HT sequestration and reduced methamphetamine (METH)-stimulated efflux of preloaded [(3)H]-5HT. In contrast, mutation of serines 15 and 18 to alanines maintained intact net substrate sequestration but eliminated METH-stimulated efflux of pre-accumulated [(3)H]-5HT. In summary, these data suggest a model in which the VMAT2 N-terminus regulates monoamine sequestration.
Yanagihashi M, Kawabe K, Ikeda KPresence of paraneoplastic antibodies in non-carcinomatous patients with neurological involvements of unknown cause.
J Neurol Sci. 2013; 335(1-2):197-200 [PubMed
] Related Publications
BACKGROUND: Paraneoplastic antibodies (PAs) play a crucial role in the diagnostic approach of paraneoplastic neurological syndrome (PNS). We clarified the frequency and the clinical profile of PA-positive non-carcinomatous patients with neurological involvements of unknown cause.
METHODS: PAs were analyzed in sera of 222 consecutive non-carcinomatous patients (122 men and 100 women) defined as acute or subacute onset of unknown-causative symptoms involving the neuromuscular junction, the central and/or the peripheral nervous system between 2006 and 2009. PAs contained antineuronal nuclear autoantibody type 1, 2, 3, Purkinje cell cytoplasmic autoantibody type 1, 2, anti-Tr, amphiphysin, CRMP-5, P/Q-type, N-type voltage-gated calcium channels (VGCC), voltage-gated potassium channel complex (VGKCC) and neuronal acetylcholine receptor (nAChR) antibodies. PA-seropositive patients received detailed examination of carcinoma in the whole body for the following 2 years.
RESULTS: Nine patients were PA-positive. VGKCC antibodies were found in four patients, P/Q-type VGCC antibodies in two, N-type VGCC antibodies in two and nAChR antibodies in one. Neurological features revealed limbic encephalitis in four patients, sensorimotor neuropathy in three and Lambert-Eaton myasthenic syndrome in two. One year later, 2 patients developed myelodysplastic syndrome and lung adenocarcinoma (one patient each).
CONCLUSION: We conclude that PA-seropositive frequency is 4.1% in non-carcinomatous neurological patients at examination. VGKCC, P/Q-type and N-type VGCC, and nAChR antibodies have benefits for screening non-carcinomatous PNS patients with acute or subacute neurological deficits of unknown cause.
OBJECTIVE: To report the clinical features of 20 newly diagnosed patients with GABAB receptor (GABABR) antibodies and determine the frequency of associated tumors and concurrent neuronal autoantibodies.
METHODS: Clinical data were retrospectively obtained and evaluated. Serum and CSF samples were examined for additional antibodies using methods previously reported.
RESULTS: Seventeen patients presented with seizures, memory loss, and confusion, compatible with limbic encephalitis (LE), one patient presented with ataxia, one patient presented with status epilepticus, and one patient presented with opsoclonus-myoclonus syndrome (OMS). Nineteen (95%) patients eventually developed LE during the course of the disease. Small-cell lung cancer (SCLC) was identified in 10 (50%) patients, all with LE. Treatment and outcome was available from 19 patients: 15 showed complete (n = 7) or partial (n = 8) neurologic improvement after steroids, IV immunoglobulins, or plasma exchange and oncologic treatment when indicated; 1 patient died of tumor progression shortly after the first cycle of immunotherapy, and 3 were not treated. Five patients with SCLC had additional onconeuronal antibodies (Ri, amphiphysin, or SOX1), and 2 without tumor had GAD65 and NMDAR antibodies, respectively. GABABR antibodies were not detected in serum of 116 patients with SCLC without neurologic symptoms.
CONCLUSION: Our study confirms GABABR as an autoantigen of paraneoplastic and nonparaneoplastic LE and expands the phenotype of GABABR antibodies to ataxia, OMS, and status epilepticus. The long-term prognosis is dictated by the presence of a tumor. Recognition of syndromes associated with GABABR antibodies is important because they usually respond to treatment.
Chou IJ, Wang HS, Lin JJ, et al.Limbic encephalitis in Taiwanese children and adolescence: a single center study.
Pediatr Neonatol. 2013; 54(4):246-53 [PubMed
] Related Publications
BACKGROUND: Non-viral limbic encephalitis, which may be paraneoplastic or idiopathic, is increasingly recognized in adults and children. Early identification of potential patients, who have neuronal autoantibodies to intracellular or neuronal surface antigens in order to give appropriate immunotherapy, is key to improving the prognosis. This cross-sectional study describes the clinical manifestation and the serological evidence of the presence of neuronal antibodies in Taiwanese children with limbic encephalitis.
METHOD: We enrolled children and adolescents who had been hospitalized due to nonviral limbic encephalitis. Serum samples from these patients were collected to screen antibodies against intracellular antigens [amphiphysin, Ma2, Ri, Yo, Hu and antiglutamic acid decarboxylase (GAD)] and neuronal surface antigens [N-methyl-d-aspartate (NMDA) receptor, γ-amino butyric acid (GABAB) receptor and voltage-gated potassium channel complexes (VGKCs)].
RESULTS: All of the 10 enrolled patients had acute onset of fever and rapid clinical deterioration. They had persistent neuropsychiatric symptoms and 90% developed refractory epilepsy, despite six patients having been treated with methylprednisolone pulse therapy or intravenous immunoglobulin (IVIG) at the acute stage. In the laboratory findings, half of the cases were positive for antibodies with regards to intracellular antigens (amphiphysin or GAD). The general outcomes, assessed by Glasgow Outcome Scale, were similar between patients with and those without the antibodies (Mann-Whitney U test, p = 0.43). One patient, who was positive for antibodies to amphiphysin 10 years after disease onset, still had a significant response to oral prednisolone therapy. At the end of the follow-up period, no cancer or insulin-dependent diabetes mellitus was detected in any of the patients.
CONCLUSION: This study provides evidence for a potential association between antibodies and limbic encephalitis. The presence of antibodies, especially antibodies to GAD, may serve as an indicator for immunotherapy.
Maat P, Brouwer E, Hulsenboom E, et al.Multiplex serology of paraneoplastic antineuronal antibodies.
J Immunol Methods. 2013; 391(1-2):125-32 [PubMed
] Related Publications
Paraneoplastic neurological syndromes (PNS) are devastating neurological disorders secondary to cancer, associated with onconeural autoantibodies. Such antibodies are directed against neuronal antigens aberrantly expressed by the tumor. The detection of onconeural antibodies in a patient is extremely important in diagnosing a neurological syndrome as paraneoplastic (70% is not yet known to have cancer) and in directing the search for the underlying neoplasm. At present six onconeural antibodies are considered 'well characterized' and recognize the antigens HuD, CDR62 (Yo), amphiphysin, CRMP-5 (CV2), NOVA-1 (Ri), and Ma2. The gold standard of detection is the characteristic immunohistochemical staining pattern on brain tissue sections combined with confirmation by immunoblotting using recombinant purified proteins. Since all six onconeural antibodies are usually analyzed simultaneously and objective cut-off values for these analyses are warranted, we developed a multiplex assay based on Luminex technology. Reaction of serial dilutions of six onconeural standard sera with microsphere-bound antigens showed lower limits of detection than with Western blotting. Using the six standard sera at a dilution of 1:200, the average within-run coefficient of variation (CV) was 4% (range 1.9-7.3%). The average between-run within-day CV was 5.1% (range 2.9-6.7%) while the average between-day CV was 8.1% (range 2.8-11.6%). The shelf-life of the antigen coupled microspheres was at least two months. The sensitivity of the multiplex assay ranged from 83% (Ri) to 100% (Yo, amphiphysin, CV2) and the specificity from 96% (CV2) to 100% (Ri). In conclusion, Luminex-based multiplex serology is highly reproducible with high sensitivity and specificity for the detection of onconeural antibodies. Conventional immunoblotting for diagnosis of onconeural antibodies in the setting of a routine laboratory may be replaced by this novel, robust technology.
Tanriverdi O, Meydan N, Barutca S, et al.Anti-Yo antibody-mediated paraneoplastic cerebellar degeneration in a female patient with pleural malignant mesothelioma.
Jpn J Clin Oncol. 2013; 43(5):563-8 [PubMed
] Related Publications
Paraneoplastic cerebellar degeneration is a rare non-metastatic complication of malignancies. It presents with acute or subacute onset of ataxia, dysarthria and intention tremor. Paraneoplastic cerebellar degeneration is most commonly associated with malignancies of the ovary, breast and lung. The anti-Yo (anti-Purkinje cells) antibodies that specifically damage the Purkinje cells of the cerebellum are found in the serum and cerebrospinal fluid. Anti-Yo-related paraneoplastic cerebellar degeneration is most commonly found in women with gynecological and breast cancers, but it is reported in other malignancies. Patients with paraneoplastic syndromes most often present with neurologic symptoms before an underlying cancer is detected. We report a case of anti-Yo-related paraneoplastic cerebellar degeneration associated with pleural malignant mesothelioma in a 51-year-old female patient. She presented to our department with a 2-week history after the last chemotherapy of progressive dizziness related to head movement, nausea, vomiting, ataxia and unsteady gait. A western blot assay was negative for anti-Hu, anti-Ri, anti-Ma2, anti-CV2 and anti-amphiphysin paraneoplastic antibody markers but positive for anti-Yo. In conclusion, we report a case of paraneoplastic cerebellar degeneration in a patient with pleural malignant mesothelioma because of the rarity of this neurologic presentation after the diagnosis of malignant mesothelioma and of the association with anti-Yo antibodies.
Krishna VR, Knievel K, Ladha S, Sivakumar KLower extremity predominant stiff-person syndrome and limbic encephalitis with amphiphysin antibodies in breast cancer.
J Clin Neuromuscul Dis. 2012; 14(2):72-4 [PubMed
] Related Publications
A 54-year-old woman presented with several weeks of psychiatric symptoms, partial-onset seizures, and painful spasms of the lower extremities. On examination, she exhibited severe stiffness and intermittent extensor spasms of the lower extremities. Magnetic resonance imaging of the brain showed T2 hyperintensity in the left temporal lobe with enhancement after gadolinium administration on T1-weighted images. Amphiphysin antibodies were present in the serum. Radiographic screening for malignancy disclosed a metastatic breast cancer. The case is a unique example of amphiphysin autoimmunity, illustrating the possibility of paraneoplastic stiff-person syndrome and limbic encephalitis coexisting in a patient with a "classical" presentation of stiff-person syndrome confined to the lower extremities.
PURPOSE OF REVIEW: This review describes relevant advances in paraneoplastic neurological syndromes (PNS) with emphasis on particular syndromes and the impact of antibodies against surface antigens in their management.
RECENT FINDINGS: PNS may present with symptoms that do not raise the suspicion of a paraneoplastic origin. The best example is anti-N-methyl-D-aspartate receptor encephalitis that in adult women frequently associates with ovarian teratoma. An electroencephalogram pattern described as 'extreme delta brush' was recently identified in 30% of patients with this disorder. Isolated myelopathy may have a paraneoplastic origin associated with amphiphysin or CV2 (CRMP5) antibodies. Jaw dystonia and laryngospasm can be the predominant symptom of the brainstem encephalitis associated with Ri antibodies. γ-Aminobutyric acid (GABA)(B) receptor antibodies are the most common antibodies found in patients with limbic encephalitis and small cell lung cancer, and contactin-associated protein 2 antibodies in patients with Morvan's syndrome and thymoma. Lastly, a recent study identified delta/notch-like epidermal growth factor-related receptor (DNER) as the target antigen of Tr antibodies, a marker of cerebellar ataxia and Hodgkin's lymphoma.
SUMMARY: The number of antibodies relevant to PNS is now expanded to those against surface antigens. These antibodies do not confirm the paraneoplastic origin of the syndrome but predict a better response to immunotherapy.
Byrne TN, Isakoff SJ, Rincon SP, Gudewicz TMCase records of the Massachusetts General Hospital. Case 27-2012. A 60-year-old woman with painful muscle spasms and hyperreflexia.
N Engl J Med. 2012; 367(9):851-61 [PubMed
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Kawanishi K, Ohyama Y, Kanai Y, et al.Sub-acute demyelinating polyradiculoneuropathy as an initial symptom of peripheral T cell lymphoma, not otherwise specified (PTCL-NOS).
Intern Med. 2012; 51(15):2015-20 [PubMed
] Related Publications
Here we report the first case of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), who initially presented with peripheral neuropathy. Nerve conduction, cerebral spinal fluid studies and his clinical course were compatible with sub-acute demyelinating polyradiculoneuropathy. In addition, left cervical lymph node swelling was observed on admission. Diagnosis of PTCL-NOS was made by the histological, immunohistochemical, and Southern blot analyses on the biopsy specimen from the enlarged lymph node. Combination chemotherapy composed of cyclophosphamide, vincristine, doxorubicin and prednisolone (CHOP) was effective for polyneuropathy as well as for lymphoma. Several antibodies relating to paraneoplastic syndrome such as Ma1, Ma2, Amphiphysin, CV2, Ri, Yo and Hu were all negative. Because sural nerve biopsy performed prior to CHOP therapy revealed no infiltration of lymphoma cells, immune dysfunction mediated by some cytokine or unidentified autoantibody related to PTCL-NOS was thought to be involved in the polyradiculoneuropathy.
Kwok E, Everingham S, Zhang S, et al.FES kinase promotes mast cell recruitment to mammary tumors via the stem cell factor/KIT receptor signaling axis.
Mol Cancer Res. 2012; 10(7):881-91 [PubMed
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KIT receptor is required for mast cell development, survival, and migration toward its ligand stem cell factor (SCF). Many solid tumors express SCF and this leads to mast cell recruitment to tumors and release of mediators linked to tumor angiogenesis, growth, and metastasis. Here, we investigate whether FES protein-tyrosine kinase, a downstream effector of KIT signaling in mast cells, is required for migration of mast cells toward SCF-expressing mammary tumors. Using a novel agarose drop assay for chemotaxis of bone marrow-derived mast cells (BMMC) toward SCF, we found that defects in chemotaxis of fes-null BMMCs correlated with disorganized microtubule networks in polarized cells. FES displayed partial colocalization with microtubules in polarized BMMCs and has at least two direct microtubule binding sites within its N-terminal F-BAR and SH2 domains. An oligomerization-disrupting mutation within the Fer/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain had no effect on microtubule binding, whereas microtubule binding to the SH2 domain was dependent on the phosphotyrosine-binding pocket. FES involvement in mast cell recruitment to tumors was tested using the AC2M2 mouse mammary carcinoma model. These tumor cells expressed SCF and promoted BMMC recruitment in a KIT- and FES-dependent manner. Engraftment of AC2M2 orthotopic and subcutaneous tumors in control or fes-null mice, revealed a key role for FES in recruitment of mast cells to the tumor periphery. This may contribute to the reduced tumor growth and metastases observed in fes-null mice compared with control mice. Taken together, FES is a potential therapeutic target to limit the progression of tumors with stromal mast cell involvement.
Maat P, VanDuijn M, Brouwer E, et al.Mass spectrometric detection of antigen-specific immunoglobulin peptides in paraneoplastic patient sera.
J Autoimmun. 2012; 38(4):354-60 [PubMed
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Paraneoplastic neurological syndromes (PNS) are severe immune mediated effects of cancer. The presence of IgG autoantibodies against onconeural antigens in serum is a hallmark of the disease. Multiple paraneoplastic antibodies have been described, including antibodies against HuD, Yo, amphiphysin and CV2. In this study, we test the hypothesis that primary amino-acid structures of the antigen binding part of antibodies from various individuals share common sequences that are specific for each auto-antigen. We selected 60 patients with PNS, associated with antibodies against HuD, Yo, Amp or CV2. Affinity purified IgG was separated using SDS-PAGE and IgG heavy chains were excised, trypsinized and subjected to tandem mass spectrometry. We selected masses that uniquely identified a PNS autoantibody group, and used MS/MS fragmentation spectra to obtain information on peptide sequences. Out of 19,173 unique masses, 28 immunoglobulin-derived peptides were found exclusively in samples from a single autoantibody defined PNS group. Our results confirm that specific peptide structures exist in the antigen binding site of IgG that are shared between individuals harboring autoantibodies against the same onconeural antigen. Thus, the immune response in these patients followed converging paths during the rearrangement, selection and maturation of immunoglobulin sequences. The identified peptides can be applied in the diagnosis of PNS, but these data also indicate that a similar approach in a variety of other diseases involving an immune response would have an appealing outlook.
McKeon A, Robinson MT, McEvoy KM, et al.Stiff-man syndrome and variants: clinical course, treatments, and outcomes.
Arch Neurol. 2012; 69(2):230-8 [PubMed
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BACKGROUND: Little information is available about the incidence of stiff-man syndrome (SMS) (the classic form or its variants) or about long-term treatment responses and outcomes.
OBJECTIVE: To comprehensively describe the characteristics of a cohort of patients with SMS.
DESIGN: Observational study.
SETTING: Mayo Clinic, Rochester, Minnesota.
PATIENTS: Ninety-nine patients with classic SMS vs variants of the disorder, both glutamic acid decarboxylase 65 kD isoform (GAD65) antibody seropositive and seronegative.
MAIN OUTCOME MEASURES: Neurological, autoimmune, serological, and oncological findings; treatments; and outcomes between January 1984 and December 2008.
RESULTS: The median follow-up duration was 5 years (range, 0-23 years). Seventy-nine patients (59 having classic SMS, 19 having partial SMS, and 1 having progressive encephalomyelitis with rigidity and myoclonus [PERM]) were GAD65 antibody seropositive. Sixty-seven percent (53 of 79) of them had at least 1 coexisting autoimmune disease, and 4% (3 of 79) had cancer. GAD65 antibody values at initial evaluation were significantly higher among patients with classic SMS (median value, 623 nmol/L) than among patients with partial SMS (median value, 163 nmol/L) (P < .001). The initial GAD65 antibody value was positively correlated with the last follow-up Rankin score (P = .03). Among 20 patients who were GAD65 antibody seronegative (6 with classic SMS, 12 with partial SMS, and 2 with PERM), 15% (3 of 20) had at least 1 coexisting autoimmune disease, and 25% (5 of 20) had cancer (3 with amphiphysin autoimmunity and breast carcinoma and 2 with Hodgkin lymphoma). Excluding patients with PERM, all patients but 1 had sustained improvements with at least 1 γ-aminobutyric acid agent, usually diazepam; the median dosage for patients with classic SMS was 40.0 mg/d. Additional improvements occurred among 14 of 34 patients (41%) who received immunotherapy (intravenous immune globulin, azathioprine, prednisone, mycophenolate mofetil, or cyclophosphamide). Sixteen of 25 patients (64%) with extended follow-up duration remained ambulatory.
CONCLUSIONS: Recognition of classic SMS vs variants is important because appropriate therapy improves symptoms in most patients. Classification by anatomical extent and by GAD65 antibody serostatus gives important diagnostic and prognostic information.
Missing in metastasis (MIM) is a member of newly emerged inverse Bin-Amphiphysin-Rvs (BAR) domain protein family and a putative metastasis suppressor. Although reduced MIM expression has been associated with bladder, breast and gastric cancers, evidence for the role of MIM in tumor progression remains scarce and controversial. Herein we characterized a MIM knockout mouse strain and observed that MIM-deficient mice often developed enlarged spleens. Autopsy and histological analysis revealed that nearly 78% of MIM(-/-) mice developed tumors with features similar to diffuse large B lymphoma during a period from 1 to 2 years. MIM(-/-) mice also exhibited abnormal distribution of B cells in lymphoid organs with decrease in the spleen but increase in the bone marrow and the peripheral blood. Furthermore, the bone marrow of MIM(-/-) mice contained a higher percentage of pre-B2 cells but fewer immature B-cells than wild-type mice. In response to CXCL13, a B-cell chemokine released from splenic stromal cells, MIM-deficient B-cells did not undergo chemotaxis or morphological changes in response to the chemokine and also did not internalize CXCR5, the receptor of CXCL13. Microarray analyses demonstrated that MIM is the only member of the I-BAR domain family that was highly expressed in human B cells. However, low or absent MIM expression was common in either primary B-cell malignancies or established B-cell acute lymphocytic leukemia or lymphomas. Thus, our data demonstrate for the first time an important role for MIM in B-cell development and suggest that predisposition of MIM-null mice to lymphomagenesis may involve aberrant interactions between B lineage cells and the lymphoid microenvironment.
Matsusaka K, Kaneda A, Nagae G, et al.Classification of Epstein-Barr virus-positive gastric cancers by definition of DNA methylation epigenotypes.
Cancer Res. 2011; 71(23):7187-97 [PubMed
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Epstein-Barr virus (EBV) is associated with Burkitt lymphoma, nasopharyngeal carcinoma, opportunistic lymphomas in immunocompromised hosts, and a fraction of gastric cancers. Aberrant promoter methylation accompanies human gastric carcinogenesis, though the contribution of EBV to such somatic methylation changes has not been fully clarified. We analyzed promoter methylation in gastric cancer cases with Illumina's Infinium BeadArray and used hierarchical clustering analysis to classify gastric cancers into 3 subgroups: EBV(-)/low methylation, EBV(-)/high methylation, and EBV(+)/high methylation. The 3 epigenotypes were characterized by 3 groups of genes: genes methylated specifically in the EBV(+) tumors (e.g., CXXC4, TIMP2, and PLXND1), genes methylated both in EBV(+) and EBV(-)/high tumors (e.g., COL9A2, EYA1, and ZNF365), and genes methylated in all of the gastric cancers (e.g., AMPH, SORCS3, and AJAP1). Polycomb repressive complex (PRC) target genes in embryonic stem cells were significantly enriched among EBV(-)/high-methylation genes and commonly methylated gastric cancer genes (P = 2 × 10(-15) and 2 × 10(-34), respectively), but not among EBV(+) tumor-specific methylation genes (P = 0.2), suggesting a different cause for EBV(+)-associated de novo methylation. When recombinant EBV was introduced into the EBV(-)/low-methylation epigenotype gastric cancer cell, MKN7, 3 independently established subclones displayed increases in DNA methylation. The promoters targeted by methylation were mostly shared among the 3 subclones, and the new methylation changes caused gene repression. In summary, DNA methylation profiling classified gastric cancer into 3 epigenotypes, and EBV(+) gastric cancers showed distinct methylation patterns likely attributable to EBV infection.
Stich O, Klages E, Bischler P, et al.SOX1 antibodies in sera from patients with paraneoplastic neurological syndromes.
Acta Neurol Scand. 2012; 125(5):326-31 [PubMed
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OBJECTIVES: SOX1 antibodies have been described in patients with Lambert-Eaton myasthenic syndrome (LEMS) in association with voltage-gated calcium channel antibodies as serological markers of small cell lung cancer (SCLC). This study was aimed to screen for additional SOX1 autoimmunity in onconeural antibody-positive sera from patients with paraneoplastic neurological syndromes (PNS) other than LEMS and to identify the clinical-immunological profile and associated tumours of patients with coexisting SOX1 antibodies.
METHODS: We retrospectively analysed sera from 55 patients with different PNS positive for well-characterized antineuronal antibodies for the presence of SOX1 antibodies by recombinant ELISA and immunoblot.
RESULTS: Eight (14.5%) patients showed additional SOX1 antibodies in the ELISA and the recombinant immunoblot. Five patients had coexisting Hu antibodies, while the other three showed coexisting CV2/CRMP5, amphiphysin, and coexisting CV2/CRMP5 and Hu antibodies, respectively. PNS included (partially overlapping) subacute sensory neuropathy, subacute sensorimotor neuropathy, cerebellar degeneration, brainstem encephalitis, encephalomyelitis and limbic encephalitis. No tumour was detected in two patients, while the others had lung cancer (four SCLC and two non-SCLC). One patient showed SOX1-specific intrathecal antibody synthesis.
CONCLUSIONS: We describe SOX1 reactivity for the first time overlapping with CV2/CRMP5 and amphiphysin antibodies. SOX1 reactivity is predominantly associated with Hu antibodies and SCLC, but can occur also in other types of lung cancer. Neurological manifestations present in patients with coexisting SOX1 antibodies and well-characterized antineuronal antibodies do not differ from those previously described in patients positive for antineuronal antibodies but no SOX1-specific anti-glial antibodies.
Raspotnig M, Vedeler CA, Storstein AOnconeural antibodies in patients with neurological symptoms: detection and clinical significance.
Acta Neurol Scand Suppl. 2011; (191):83-8 [PubMed
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BACKGROUND: Onconeural antibodies are strongly associated with cancer and paraneoplastic neurological syndromes (PNS). Most of these antibodies are well-characterized (antibodies against Hu, Yo, Ri, CRMP5, amphiphysin, Ma2 and Tr) and are in common use for the diagnosis of definite PNS.
MATERIALS AND METHODS: Literature on detection and clinical significance of onconeural antibodies were identified by using relevant search terms in PubMed and reviewed.
CONCLUSIONS: The onconeural antibodies are directed against intracellular antigens and their pathogenic role is still largely unknown. They are highly specific markers of paraneoplastic aetiology in patients with neurological symptoms. Detection of an onconeural antibody in a patient with neurological symptoms should lead to prompt investigation for cancer. However, absence of detectable onconeural antibodies does not exclude the PNS diagnosis. In particular, failure to detect antibodies in patients without classical PNS symptoms may result in less vigorous cancer screening and diagnostic delay. Neuronal antibodies that are directed to synaptic proteins or proteins of the cell membrane are also associated with neurological symptoms, and probably have pathogenic effects. The association between these antibodies and cancer is less robust, and they are usually not included among the onconeural antibodies.