Paraneoplastic and autoimmune encephalopathies.

Immune-mediated encephalitis is an increasingly recognized cause of neurologic dysfunction including behavioral change, psychosis, movement disorders, seizures, autonomic instability, and coma. Associated antineuronal antibodies are of two main subtypes, those targeting neuronal cell surface antigens, which are pathogenic, and nonpathogenic antibodies targeting intracellular antigens. Antibody identification aids in screening for underlying cancers and prediction of outcome. Cancer is found most commonly with antibodies targeting intracellular neural components. Certain cancers, such as small-cell lung carcinoma, and breast and ovarian cancer are particularly immunogenic. When cancer is detected, oncologic treatment should be followed with immunotherapy. Nonpathogenic antibody disorders respond poorly to treatment, whereas pathogenic antibodies predict a favorable response to immune treatment. If no cancer is identified, then ongoing surveillance is recommended for 5 years after detection of most antineuronal antibodies.

Neurolymphomatosis: a case study of diffuse large B-cell lymphoma.

Neurologic changes can be seen during treatment for hematologic malignancies such as lymphoma and leukemia. Differential diagnoses for neurologic changes remain vast, and etiologies may result from malignant, nonmalignant, and paraneoplastic syndromes. This article describes a case study of a man with neurolymphomatosis, a rare neurologic manifestation seen in B-cell and non-Hodgkin lymphoma and acute leukemias.

Assessment of gonadal function in boys and adolescents at the diagnosis of neoplastic disease.

OBJECTIVE: We assessed the gonadal function in boys with a newly diagnosed neoplastic disease prior to chemotherapy. Eighty-four boys (48 prepubertal and 36 pubertal) were evaluated, including 50 with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL), 10 with Hodgkin lymphoma (HL), and 24 with solid tumors. The control group consisted of 24 healthy prepubertal and 24 pubertal boys. The levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin B, and testosterone were determined, and testicular volumes were measured. RESULTS: Patients in prepuberty and early puberty (Tanner stages 1-3) diagnosed with ALL/NHL or solid tumor presented normal serum reproductive hormone levels, whereas in ALL/NHL patients in Tanner stages 4-5, the mean values of inhibin B were significantly lower (45.18 +/- 33.85 vs. 153.57 +/- 71.44 ng/L, p = 0.0027). In patients with HL in Tanner stages 4-5, a statistically significant lower mean inhibin B level (100.44 +/- 67.45 versus 153.57 +/-71.44 ng/L, p = 0.0027), higher mean FSH level (6.3 +/- 3.6 versus 4.6 +/- 2.2 mIU/mL, p = 0.05), and higher mean LH level (5.9 +/- 4.0 versus 3.6 +/- 1.8 mIU/mL, p = 0.05) were observed. No statistically significant differences were noted in assessed hormones in patients with solid tumors, independently of Tanner stage. CONCLUSION: Our analysis indicates that adolescents with ALL/NHL and HL prior to treatment, exhibit reduced levels of inhibin B, which indirectly suggests the possibility of spermatogenesis dysfunction.

Bilateral vagus nerve neurolymphomatosis diagnosed using PET/CT and diffusion-weighted MRI.

In neurolymphomatosis, malignant lymphocytes infiltrate the peripheral nervous system in the presence of a known or unknown hematological malignancy. This report describes the findings of diffusion-weighted MRI and F-FDG PET/CT in a 65-year-old man with hoarseness. Results revealed a mass with restricted diffusion on diffusion-weighted imaging in the right visceral vascular space, increased uptake of F-FDG, and other masses at distant peripheral nerves. Restaging PET/CT showed involvement of the right brachial plexus and right sciatic nerve. Biopsy and immunohistochemistry of the right vagus nerve and cervical lymphadenopathy revealed a diffuse large B-cell non-Hodgkin lymphoma.

Deadly teamwork: neural cancer stem cells and the tumor microenvironment.

Neural cancers display cellular hierarchies with self-renewing tumorigenic cancer stem cells (CSCs) at the apex. Instructive cues to maintain CSCs are generated by both intrinsic networks and the niche microenvironment. The CSC-microenvironment relationship is complex, as CSCs can modify their environment and extrinsic forces induce plasticity in the cellular hierarchy.

Reduction in Size of a Large Rathke's Cleft Cyst on Treatment with Low Dose of Corticosteroid.

Rathke's cleft cyst is a non-neoplastic sellar cyst, which is increasingly reported on radiological investigation performed for unrelated intra-cranial pathology. When symptomatic, it is associated with headache, visual symptoms, and pituitary dysfunction. We report a case of an 18 year-old male patient with Rathke's cleft cyst, who presented with failing vision, headache, and hypocortisolism. After defaulting on planned surgery, the patient continued to take a replacement dose of prednisolone for a year. He reported significant improvement in vision and remarkable reduction in cyst size on repeat imaging after a year. Surgery was later performed in view of persisting severe headache. The authors discuss the reduction in cyst size in relation to long-term usage of replacement steroid. They postulate that selected patients with Rathke's cleft cyst with radiological evidence of inflammatory fluid can be given a trial of glucocorticoids and assessed for cyst shrinkage and changes in imaging characteristics.

Neurofibromatosis and lessons for the war on cancer.

In the war on cancer, a great deal of attention is being paid to knowing the 'enemy'. It is widely believed that by understanding the driving forces underlying cancer, researchers can develop better ways to target the disease. Currently, large-scale efforts have been under taken to completely characterize molecular changes in common human cancers (http://cancergenome.nih.gov/) (Collins & Barker, 2007). However, as more is learned about cancer, the debate increases on what exactly the enemy is: cells making up the bulk of the tumour, rare tumour stem cells that can regrow the tumour, tumour microenvironment, the subset of cancer cells with metastatic potential, etc. Studies of the cancers associated with Neurofibromatosis type 1 (NF1) are helping to define the relationship between many of these different cell types. It is still unclear how these different enemies are related to each other and how they interact to wage cancer's war on the patient. 'If you know the enemy and know yourself you need not fear the results of a hundred battles.' - Sun Tzu, The Art of War, c. 500 B.C.

Endocrine manifestations of the rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor syndrome in childhood.

CONTEXT: Rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor (ROHHADNET) is a newly described syndrome that can cause cardiorespiratory arrests and death. It mimics several endocrine disorders or genetic obesity syndromes during early childhood and is associated with various forms of hypothalamic-pituitary endocrine dysfunctions that have not yet been fully investigated. OBJECTIVE: The current report aspires to facilitate the earlier recognition and appropriate treatment of the ROHHADNET syndrome when children present with various endocrine manifestations, such as early obesity, growth failure, pseudo-Cushing's syndrome, glucocorticoid insufficiency, congenital hypopituitarism, or adrenal tumors. A more widespread knowledge of the syndrome will help characterize its molecular origin. DESIGN: Endocrine studies were performed in six patients admitted for seemingly common early-onset obesity associated with growth failure in five of them. The six patients later showed distinctive features of the ROHHADNET syndrome. RESULTS: Abnormalities of the pituitary adrenal axis ranged from a true Cushing-like profile (one of six), to glucocorticoid deficiency with normal ACTH (two of six). Complete GH deficiency with low IGF-I was observed in four of six, hypogonadotropic hypogonadism in four of six, hyperprolactinemia in six of six, and various degrees of TSH/T(4) abnormalities in five of five patients. All had increased natremia without diabetes insipidus. Five children had unilateral macroscopic adrenal ganglioneuroma. Two patients died at 8.5 and 12 yr of age. CONCLUSIONS: Various hypothalamic-pituitary endocrine dysfunctions are associated with ROHHADNET, carrying a risk of misdiagnosis until other elements of the syndrome make it more easily recognizable. Given its severity, ROHHADNET syndrome should be considered in all cases of isolated, rapid, and early obesity.

The role of protein kinase C-alpha in malignancies of the nervous system and implications for the clinical development of the specific PKC-alpha inhibitor aprinocarsen (Review).

Antisense oligonucleotide (ASO) technology offers a novel approach for the development of anti-cancer drugs. For example, the ASO aprinocarsen has been developed to specifically inhibit the intracellular signal transduction protein, protein kinase C-alpha (PKC-alpha). The clinical development of such specific or "new targeted" agents in cancer requires a comprehensive understanding of the target protein. This understanding is expected to improve the identification of patients who most likely will benefit from treatment with a specific inhibitor, such as aprinocarsen. In order to better understand the role of PKC-alpha in nervous system malignancies we here review the published literature on PKC-alpha expression in nervous system tumors, including glioblastoma multiforme. In pre-clinical experiments aprinocarsen had demonstrated anti-tumor activity, in particular in animal models of glioblastoma. Thus, clinical study CS10 with aprinocarsen was undertaken in patients with central nervous system (CNS) malignancies. The results of this study and considerations for future clinical studies in CNS tumors are reviewed.

Characteristics of stem cells from human neuroblastoma cell lines and in tumors.

Cellular heterogeneity is a hallmark of human neuroblastoma tumors and cell lines. Within a single neuroblastoma are cells from distinct neural crest lineages whose relative abundance is significant for prognosis. We postulate that a self-renewing multipotent tumor stem cell, which gives rise to diverse cell lineages, is the malignant progenitor of this cancer. To test this hypothesis, we have established 22 cloned, phenotypically homogeneous populations of the three major cell types from 17 neuroblastoma cell lines. In vitro, malignant neuroblastoma stem cells, termed I-type (intermediate type), have distinct morphologic, biochemical, differentiative, and tumorigenic properties. I-type cells express features of both neuroblastic (N) cells (scant cytoplasm, neuritic processes, neurofilaments, pseudoganglia, and granin and neurotransmitter enzyme expression) and substrate-adherent (S) cells (extensive cytoplasm and vimentin and CD44 expression). Moreover, they show bidirectional differentiation to either N or S cells when induced by specific agents. I-type cells are significantly more malignant than N- or S-type cells, with four- to five-fold greater plating efficiencies in soft agar and six-fold higher tumorigenicity in athymic mice. Differences in malignant potential are unrelated to N-myc amplification/overexpression or the ability to digest and migrate through the extracellular matrix. Immunocytochemical analyses of a small series of tumors reveal that frequency of cells coexpressing N and S cell markers correlates with poor prognosis. Thus, I-type stem cells may be instrumental in the genesis and growth of tumors in the patient. Their unique biology deserves attention and further investigation.

Class III beta-tubulin in human development and cancer.

The differential cellular expression of class III beta-tubulin isotype (betaIII) is reviewed in the context of human embryological development and neoplasia. As compared to somatic organs and tissues, betaIII is abundant in the central and peripheral nervous systems (CNS and PNS) where it is prominently expressed during fetal and postnatal development. As exemplified in cerebellar and sympathoadrenal neurogenesis, the distribution of betaIII is neuron-associated, exhibiting distinct temporospatial gradients according to the regional neuroepithelia of origin. However, transient expression of this protein is also present in the subventricular zones of the CNS comprising putative neuronal- and/or glial precursor cells, as well as in Kulchitsky neuroendocrine cells of the fetal respiratory epithelium. This temporally restricted, potentially non-neuronal expression may have implications in the identification of presumptive neurons derived from embryonic stem cells. In adult tissues, the distribution of betaIII is almost exclusively neuron-specific. Altered patterns of expression are noted in cancer. In "embryonal"- and "adult-type" neuronal tumors of the CNS and PNS, betaIII is associated with neuronal differentiation and decreased cell proliferation. In contrast, the presence of betaIII in gliomas and lung cancer is associated with an ascending histological grade of malignancy. Thus, betaIII expression in neuronal tumors is differentiation-dependent, while in non-neuronal tumors it is aberrant and/or represents "dedifferentiation" associated with the acquisition of progenitor-like phenotypic properties. Increased expression in various epithelial cancer cell lines is associated with chemoresistance to taxanes. Because betaIII is present in subpopulations of neoplastic, but not in normal differentiated glial or somatic epithelial cells, the elucidation of mechanisms responsible for the altered expression of this isotype may provide insights into the role of the microtubule cytoskeleton in tumorigenesis and tumor progression.

Cancer and the nervous system.

Brain tumours should be considered when patients present with headache with diurnal variation, seizures, or progressive neurological symptoms. Spinal cord compression by tumour is a medical emergency. Prognosis for patients with glioma is better in those with tumours of low grade, and in patients younger than 50 years and with higher functional levels. Surgery, radiotherapy and chemotherapy can improve survival for patients. Anticancer therapies can have neurotoxic side effects.