Occurrence of cancer in Alzheimer and elderly control patients: an epidemiologic necropsy study.

Epidemiologic necropsy provides an accurate measure of the occurrence rates of diseases. To determine the occurrence of cancer in Alzheimer patients as well as in non-Alzheimer elderly controls, we examined autopsy reports of 575 control and 71 Alzheimer cases aged 50-100 years for histologic evidence of cancer. We compared expected rates of cancers calculated from the National Cancer Institute's Surveillance, Epidemiology and End Result (SEER) Program data to rates observed at autopsy using a chi-squared test. To determine whether there was an association between the occurrence of cancer and Alzheimer disease, we compared rates for all cancer and three specific cancers in Alzheimer and control patients using an odds ratio test. We found from fourfold to 98-fold more cancer in Alzheimer patients and controls than that expected from SEER data. There was no statistical difference in the autopsy incidence of total, lung, or prostate cancer between Alzheimer patients and controls. However, the occurrence of pancreatic cancer was 6.7-fold higher in Alzheimer patients than in control subjects. Controlling for multiple comparisons, the odds ratio for pancreatic cancer in Alzheimer's disease was significantly higher than in controls (p < 0.001). Our results indicate that cancer occurs more frequently than expected in both Alzheimer patients and control subjects. In addition, there may be an association between the occurrence of certain cancers and Alzheimer's disease.

Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer.

The serum and cerebrospinal fluid (CSF) of 8 women with ataxia, 6 of whom also had eye movement abnormalities believed to be opsoclonus, were found to contain a highly specific antineuronal antibody we call anti-Ri. Seven of the 8 women also had or developed cancer: carcinoma of the breast in 5, adenocarcinoma in an axillary lymph node in 1, and carcinoma of the fallopian tube in 1. Four patients presented with the neurological disorder; the cancer was diagnosed first in the other 4. Immunohistochemical studies using serum or CSF from all 8 patients revealed a highly specific antibody interaction with central nervous system neuronal nuclei but not with glial or other cells; the titer ranged from 1:5,000 to 1:320,000 in serum and from 1:2,000 to 1:16,000 in CSF. Biotinylated IgG from the patients' serum reacted with the tumors of 3 of 4 patients with anti-Ri antibody but not with breast cancers from patients without anti-Ri antibody. Immunoblots against cerebral cortex neuronal extracts identified protein antigens of 55-kd and 80-kd relative molecular mass. Serum titers by immunoblot ranged from 1:500 to more than 1:40,000 and CSF titers, from 1:10 to 1:2,000. The relative amount of anti-Ri was always higher in CSF than in serum. The antibody was not present in sera from normal individuals; patients with breast cancer without opsoclonus; other patients with opsoclonus; or patients with other paraneoplastic syndromes related to breast, ovarian, or small-cell lung cancer. We conclude that the presence of anti-Ri antibody identifies a subset of patients with paraneoplastic ataxia and eye movement disorders (opsoclonus) who usually suffer from breast or other gynecological cancer; the antibody when present is a useful marker for an underlying malignancy.

Parkinsonism induced by high-dose cytosine arabinoside.

We report a severe parkinsonian condition following high dose, parenteral cytosine arabinoside (Cytosar) that persisted for 8 weeks. The drug was used in a patient with acute myelogenous leukemia that was refractory to all other treatment. The syndrome was partially responsive to antiparkinsonian drugs and fortunately remitted completely within 12 weeks.

Purification and sequence of a presynaptic peptide toxin from Conus geographus venom.

A novel toxin, omega-conotoxin (omega-CgTX), from the venom of the fish-eating marine mollusc Conus geographus has been purified and biochemically characterized. Recently, this omega-conotoxin has been shown to inhibit the voltage-activated entry of Ca2+, thus providing a potentially powerful probe for exploring the vertebrate presynaptic terminal [Kerr, L. M., & Yoshikami, D. (1984) Nature (London) 308, 282-284]. The toxin is a basic 27 amino acid peptide amide with three disulfide bridges. An unusual feature is a remarkable preponderance of hydroxylated amino acids. The sequence of omega-CgTx GVIA is Cys-Lys-Ser- Hyp-Gly5-Ser-Ser-Cys-Ser-Hyp10-Thr-Ser-Tyr-Asn-Cys15-C ys-Arg-Ser- Cys-Asn20-Hyp-Tyr-Thr-Lys-Arg25-Cys-Tyr-NH2.

Conotoxin GI: disulfide bridges, synthesis, and preparation of iodinated derivatives.

The 13 amino acid toxic peptide from the marine snail Conus geographus, conotoxin GI, blocks the acetylcholine receptor at the neuromuscular junction. In this report, we describe a method for analyzing disulfide bonding in nanomole amounts of small cystine-rich peptides. The procedure involves partial reduction and a double-label alkylation of cysteine residues. Using this method, we show that the natural conotoxin GI has a (2-7, 3-13) disulfide configuration. The structure of conotoxin GI has been confirmed by chemical synthesis. The preparation and purification of molecularly homogeneous, iodinated derivatives of this toxin are also described. All derivatives, including the [diiodohistidine,diiodotyrosine]conotoxin GI, retained at least half of the biological activity of unmodified toxin. Since the tetraiodinated toxin, which is greater than 25% by weight iodine, retains considerable toxicity, unmodified histidine and tyrosine residues in conotoxin GI are not crucial for biological activity.