Gibbons G. Cornwell

Frequency and distribution of senile cardiovascular amyloid: A clinicopathologic correlation☆

Atrium, ventricle, aorta, lung, kidney, and rectum were removed at autopsy from 85 consecutive elderly patients (aged 80 years or older) and examined for amyloid with Congo red. All tissues containing amyloid were counterstained with an antiserum specific for amyloid fibril protein ASc1 and studied by immunofluorescence. Three distinct forms of amyloid were found: (1) all patients had senile aortic amyloid; (2) 78 percent of patients had isolated atrial amyloid; and (3) 25 percent of patients had senile cardiac amyloid of the ASc1 type. The cardiac amyloid deposits were small and widely scattered in more than 80 percent of patients with isolated atrial amyloid and in more than 50 percent of patients with ASc1-type amyloid. Of 21 patients with ASc1 amyloid, 19 had extracardiac involvement (lung in 81 percent of cases and rectum in 57 percent of cases). The kidney was not involved in any patient. The mean heart weight, frequency of atrial fibrillation, percentage of patients with heart failure, and frequency of myocardial infarction were increased in patients with cardiac amyloid, but these differences failed to reach statistical significance. There was no difference in the mean left ventricular wall thickness or degree of coronary atherosclerosis.

Evidence that the amyloid fibril protein in senile systemic amyloidosis is derived from normal prealbumin.

Familial amyloidosis in different kindreds is associated with a variety of point mutations in the prealbumin gene, resulting in prealbumin variants which are believed to be amyloidogenic, i.e. prone to form amyloid fibrils. In the most common amyloid-associated variant, there is a methionine for valine substitution in position 30. We have studied the prealbumin-derived amyloid protein ASc1 in the common age-related senile systemic amyloidosis. Evidence is presented that there is no abnormality in the primary structure of prealbumin in this disease and that, in addition to complete prealbumin, fibrils contain prealbumin fragments lacking a significant part of the N-terminus.

Combination chemotherapy and radiotherapy for acute lymphocytic leukemia in adults: results of CALGB protocol 7113.

Abstract One hundred and forty-nine adult patients with acute lymphocytic leukemia (ALL) were treated with protocol defined combination chemotherapy-radiotherapy by 25 member institutions of the Cancer and Leukemia Group B. Induction of remission was attempted with vincristine (V), prednisone (P), L-asparaginase (A), with or without intrathecal methotrexate (IT-MTX) and followed by daunorubicin (D) in those patients not in complete remission after 4 weeks. The overall complete remission (CR) rate was 72%; daunorubicin was needed to achieve CR in 20 of the 107 remitting patients. The administration of IT-MTX during remission induction, especially when given simultaneously with A, was found to increase toxicity without therapeutic benefit. Remissions were maintained with either parenteral courses of 6-mercaptopurine (6-MP), and methotrexate (MTX), plus intermittent doses of V, P, and bis-β-chloroethylnitrosourea(BCNU) or with daily oral 6-MP, weekly oral MTX, and periodic VP reinforcements. All patients remaining in remission for 3 months or longer received CNS chemoradiotherapy. Median remission duration was 15 months. Continuous oral maintenance proved at least equivalent to intermittent parenteral remission therapy. Median survival was 17 months for all patients and 29 months for qualified patients achieving CR. Frequency and duration of response, and duration of survival were independent of age between ages 30 and 60. Above age 60 the prognosis is significantly less good. Thirty-two percent of the responders (life table estimate) remain in continuous first remission at 5 y. Toxicity was acceptable, except for an excessive frequency and severity of infections: (1) when V, P. A, and IT-MTX were given simultaneously; and (2) early in remission when full doses of maintenance chemotherapy were employed prior to complete recovery of normal bone marrow function. Results of treatment of ALL in adults have improved markedly during the last decade but lag behind those observed in children for reasons as yet unexplained.

Chromosomal aberrations and neoplasm—a family study

A family is described in which four out of five siblings have chromosomal aberrations both in the myeloid and lymphoid cells. One of these died in the blastic phase of chronic myelogenous leukemia, another had myelofibrosis and carcinoma of the breast, a third had squamous cell carcinoma of the lip, and the other two siblings are normal. The mother had carcinoma or the breast. Two of the siblings have had occupational exposure to organic solvents. The relationship of genetic pre‐disposition to malignancy, chromosomal instability, and environmental stresses is discussed.

Comparison of oral melphalan, CCNU, and BCNU with and without vincristine and prednisone in the treatment of multiple myeloma. Cancer and leukemia group B experience

A total of 361 evaluable patients with previously untreated multiple myeloma were randomized to receive oral melphalan (0.15 mg/kg/day for seven days, followed by 0.05 mg/kg/day after recovery from the nadir of the leukocytes), BCNU (150 mg/m2 intravenously every six weeks) or CCNU (100 mg/m2 orally every six weeks). All patients received a tapering six‐week course of prednisone starting at 0.8 mg/kg for the first two weeks. At week 22, one‐half of the patients were randomized to receive vincristine (1 mg/m2) and prednisone (0.6 mg/kg for seven days) every two months in addition to previous therapy. The melphalan treated patients showed a significantly higher overall objective response frequency (59%), according to Myeloma Task Force criteria, when compared to those treated with BCNU (40%) or CCNU (42%). The survivals for all patients were not statistically different for the three treatment programs. However, the good‐risk patients treated with melphalan had significantly longer survival (P = 0.02) than the equivalent patients who received BCNU or CCNU. The addition of vincristine and prednisone at week 22 did not significantly increase the percentage of subsequent objective responses or prolong the subsequent survival of any treatment group. It is concluded that oral melphalan is superior to BCNU and CCNU in producing objective responses and in prolonging survival in good risk patients. Cancer 50:1669‐1675, 1982.

Reduced tissue factor (thromboplastin) activity in von Willebrand's disease

Abstract Identification of tissue factor in cultures of human skin fibroblasts permitted assessment of tissue factor activity in patients with bleeding disorders. Tissue factor activity was studied by means of a one-stage assay patterned after the prothrombin time and a two-stage test in which activation of factor X by tissue factor in the presence of factor VII was assessed. Tissue factor activity observed in cultured skin fibroblasts from five subjects with hemophilia A and B was not significantly different from that observed in pooled fibroblasts from normal controls. By contrast, tissue factor activity in cultured skin fibroblasts from four subjects with von Willebrands disease was significantly lower than that in the control. It is postulated that the observed tissue factor defect may be related to the pathogenesis of von Willebrands disease.

The Amino Acid Sequence of the Glycosylated Amyloid Immunoglobulin Light Chain Protein AL MS

The authors report on the amino acid sequence of the glycosylated amyloid protein AL MS. The amyloid fibrils were extracted from the spleen of a patient (MS.) with amyloidosis. The protein AL MS was purified from the amyloid fibrils by gel filtration. SDS–PAGE performed on the purified protein material showed glycosylated protein bands in the range of 22 to 32 kDa, corresponding to polymerization of N‐terminal fragments. The protein was characterized by amino acid analysis and Edman degradation. Tryptic digest combined with Staphylococcal V8 protease, chymotrypsin and pyroglutamate aminopeptidase digestion, as well as cleavage with BNPS‐skatole, established the complete amino acid sequence of 168 residues. The protein was compared to other proteins in the SWISSPROT databank, showing homology with the immunoglobulin light chain variable subgroup λI. AL MS showed some unique amino acid substitutions. Highly conserved residues Gly(57) and Arg(61), were exchanged to arginine and glutamine, respectively, possibly altering the three‐ dimensional structure of the protein.

Clinicopathologic Correlations in 109 Patients with Systemic Amyloidosis Studied by Immunocytochemistry

Tissues obtained by biopsy or at autopsy from 266 patients with systemic amyloid were studied with antibodies specific for amyloid fibril proteins. 109 tissues could be characterized as follows: AλI 28%, AλIII 7%, AλVI 5%, AλI 28%, AλIII 13%, AA 6%, ASc113%. The mean age for Aλ and AK patients was similar (60 yrs), but those with ASc1 fell into an older group (mean 86 yrs) with heart disease and a younger group (mean 61 yrs) with peripheral neuropathy. The λ/κ. ratio of the characterized patients (Group A) was significantly lower than that of the remaining patients with a monoclonal protein (Group B) (1.0 vs 2.4; p =. 003). There was a significantly higher frequency of nephrotic syndrome (p =. 005) and lower frequency of myeloma (p <. 0001) among the λ light chain patients in the total population, when adjustment was made for group membership.

Heparin Therapy for Heat Stroke

Excerpt To the editor: The role of disseminated intravascular coagulation and the fibrinolytic mechanism in heat stroke has been controversial (1-3). We recently observed a 17-year-old male with he...

Transfer RNA content of rat liver polysomes and microsomes and their capacity to associate with 3H-tRNA invitro

Summary The tRNA content of polysomes and microsomes was determined by polyacrylamide electrophoresis. Clean specimens of both preparations contained 1.2 to 1.5 tRNA molecules per ribosome. A comparison of the capacity of polysomes and microsomes to react with 3 H-tRNA in vitro indicated that ribosomes in both preparations contain two sites for tRNA attachment.