Protracted infusion of 5-FU with weekly low-dose cisplatin as second-line therapy in patients with metastatic colorectal cancer who have failed 5-FU monotherapy.

Forty four patients who had documented progression of metastatic colorectal cancer while receiving 5-fluorouracil (5-FU) monotherapy were treated with continuous infusion 5-FU, 300 mg/mg2/day, plus weekly low-dose cisplatin, 20 mg/m2. Treatment was given in 12-week cycles, consisting of 8 weeks of chemotherapy followed by a 4-week rest period, and was well tolerated. Three of 23 patients (13%) who had failed bolus 5-FU but not been exposed previously to infusional 5-FU responded. Of 21 patients who had failed infusional 55-FU monotherapy, only one (5%) responded. Time to progression (5.7 vs. 1.8 months) and survival (12 vs. 5.5 months) were significantly longer for patients who had not previously received infusional 5-FU but who had failed bolus schedules, compared with patients who had previously failed infusional 5-FU (p less than .001).

Inherited incomplete deficiency of the fourth component of complement (C4) determined by a gene not linked to human histocompatibility leukocyte antigens.

We have studied a family in which the proband had systemic lupus erythematosus and selective incomplete deficiency of the fourth component of complement (C4) (2-5% of the normal level). An additional six healthy family members also had low C4 levels (2.4-24.1% of normal) but no evidence of lupus. This form of inherited C4 deficiency differs from that in previously reported families in that inheritance was autosomal dominant (rather than recessive), C4 levels were markedly reduced (but not undetectable), and there was no linkage to HLA, BF, or C4 structural loci, all known to be within the major histocompatibility complex.

Erythrocyte pyruvate kinase deficiency in the Ohio Amish: origin and characterization of the mutant enzyme.

We have identified eight individuals in an Amish population in Geauga County, Ohio, who have a congenital hemolytic anemia and red cell pyruvate kinase (PK) deficiency. The mutant enzyme is a low Km phosphoenolpyruvate (PEP) variant associated with a slower (77.5% of normal) electrophoretic mobility in starch gel. Because of the high consanguinity in this population, we assume the affected individuals are homozygous for the mutant gene. Genealogical records allow us to trace all eight cases back to a common ancestor who lived in Mifflin County, Pennsylvania. His sister was a common ancestor to all cases of PK deficiency originally described in the Pennsylvania Amish isolate. Therefore, all cases of PK deficiency in the Amish arose from a common ancestral pair.

Evidence for heterogeneity in hereditary hemochromatosis. Evaluation of 174 persons in nine families.

Hereditary hemochromatosis is an autosomal recessive disease in which the gene is linked to the HLA system. Investigation of nine unrelated probands and their family members has revealed distinct groups based on biochemical and clinical manifestations of the disease. Four different types of disease expression were identified: Group I--classic hereditary hemochromatosis with elevated transferrin saturation, serum ferritin levels, and liver iron content; Group II--severe iron overload, accelerated disease manifesting at an early age; Group III--elevated total body iron stores, normal transferrin saturation and serum ferritin levels; Group IV--markedly elevated findings on serum biochemical tests, e.g., transferrin saturation, serum ferritin levels, with minimal elevation in total body iron stores. This evidence for several clearly distinguishable modes of expression in different families suggests that more than one genetic lesion in iron metabolism may be responsible for iron overload in hereditary hemochromatosis. This genetic heterogeneity may be helpful in delineating the fundamental abnormalities in iron metabolism in this group of disorders.

Iron transport across brush-border membranes from normal and iron-deficient mouse upper small intestine.

We have studied Fe(III)-citrate and Fe(II)-ascorbate uptake by purified intestinal brush-border membrane vesicles from normal (iron-replete) and iron-deficient mice. In iron-replete mice using a final Fe(III) concentration of 1.43 microM, 25-30 pmol of Fe(III)/mg of protein were bound to the membranes versus 65-70 pmol in iron-deficient mice. Fe(II) uptake in normal mice using a final Fe(II) concentration of 1.79 microM was 1600-1800 pmol/mg of protein versus 3600-4000 pmol in iron-deficient mice. Evidence that Fe(II) was transported into the vesicles by a membrane carrier-mediated process was obtained by observing saturation kinetics under conditions of isotope exchange at equilibrium in mice rendered iron-deficient, but not in iron-replete mice. Eighty per cent of the transported Fe(II) could be removed by strong chelating agents. The remainder was exchangeable with Fe(II) in the medium when measured under equilibrium conditions. We can explain these results by the following model; iron uptake appears to be a 2-fold process. The first step is the transport of Fe(II) across the membrane by a carrier-mediated process which is biologically regulated. The second step is the subsequent binding of iron on the inside of the membrane. The number of binding sites is also regulated by the iron status of the mouse. The membrane binding affinity for Fe(II) appears to be weaker than that for dithiothreitol but stronger than for ascorbate.

Arthritis of hemochromatosis. Clinical spectrum, relation to histocompatibility antigens, and effectiveness of early phlebotomy.

Five patients who presented with arthritis as the sole manifestation of hereditary hemochromatosis and 51 family members were studied. Studies included clinical evaluation for the presence of arthritis and hemochromatosis, roentgenography of hands, knees, and pelvis, serum iron and serum ferritin measurements, complete HLA typing for 50 of the A and B loci, and, when indicated, liver biopsy. Arthritis occurred in 45 percent of persons with hemochromatosis. Although typical involvement of second and third metacarpophalangeal joints was observed in all five patients and some family members, two with typical arthritis did not have characteristic radiographic changes, two had constitutional symptoms without arthropathy, and one had unilateral hand changes. A specific HLA haplotype (A2/B17 in Family 1 and A29/B15 in Family 2) correlated with hereditary hemochromatosis but not with the arthropathy. Phlebotomy alleviated the early constitutional symptoms but did not help advanced arthritis. Anti-inflammatory drugs, intraarticular injections of glucocorticoids, and resection osteotomies of metacarpal heads were other treatment modalities.

Iron overload disorders: natural history, pathogenesis, diagnosis, and therapy.

Hemochromatosis is a syndrome which, when fully expressed, is manifested by melanoderma , diabetes mellitus, and liver cirrhosis, with iron overload involving parenchymal and reticuloendothelial cells in many organ systems. This clinical presentation may arise as a consequence of either hereditary or acquired abnormalities of iron overload, although the mechanisms are quite different. In hereditary hemochromatosis (also known as primary, or idiopathic, hemochromatosis), increased intestinal iron absorption leads to excessive accumulations of iron, throughout the body, particularly in parenchymal cells. In secondary forms of iron overload including transfusional hemosiderosis, alcoholic cirrhosis, thalassemia, sideroblastic anemia, and porphyria cutanea tarda, iron accumulates in the reticuloendothelial system initially, but with increasing amounts of total body iron, excessive iron deposits eventually accumulate in parenchymal cells throughout the body producing a picture indistinguishable from hereditary hemochromatosis. In this article, the course, prognosis, and therapy of iron overload will be reviewed in detail. Clinical and experimental data concerning the pathogenesis of the different forms of iron overload will be examined critically. In particular, information relating to possible abnormalities of reticuloendothelial function, intestinal mucosal iron transport, and alterations in serum and tissue isoferritin patterns in hereditary hemochromatosis will be analyzed, and possible directions for future research will be suggested. The mode of inheritance and linkage with the major histocompatibility (HLA) complex will be discussed. Theories on the pathogenesis of tissue damage by excess iron will be evaluated. Methods for measuring the extent of iron overload in clinical practice will be described, including measurements of serum iron, serum ferritin, iron absorption, cobalt excretion, desferrioxamine excretion, liver biopsy and tissue iron determinations, and HLA typing. Finally, unresolved problems in the understanding of the disease process, diagnosis, and therapy will be delineated.

Improved detection of Duchenne muscular dystrophy heterozygotes using discriminant analysis of creatine kinase levels.

We have assessed the sensitivity and specificity of tests to detect carriers of Duchenne muscular dystrophy by use of three serum enzymes (creatine kinase, pyruvate kinase, and aldolase) and discriminant analysis in 21 obligate heterozygotes and 28 normal controls. We found no significant age effects on enzyme levels. Each enzyme level considered separately was significantly higher in heterozygotes. Use of logs improved discrimination, and log CK was sufficient by itself as a discriminant (that is, addition of other enzymes did not significantly improve discrimination). We present procedures to generate posteriori probabilities for genetic counselling that incorporate prior probabilities and enzyme levels. Our results show both improved sensitivity (90%) and specificity (86%).

Magnetic-susceptibility measurement of human iron stores.

We made direct noninvasive magnetic measurements of hepatic iron stores with a specially designed superconducting quantum-interference-device (SQUID) susceptometer in 20 normal subjects and in 110 patients with liver disease, iron deficiency, hereditary hemochromatosis, or transfusional iron overload. Magnetic in vivo measurements of liver non-heme iron were closely correlated with chemical in vitro measurements in liver-biopsy specimens (r = 0.98, P less than 10(-5) up to 115 mumol per gram of liver tissue (wet weight) or more. Magnetically determined storage-iron concentrations were below 6.0 mumol per gram in iron-deficient patients and normal men and premenopausal women, but they were raised (9.7 to 31.4 mumol) in 12 of 67 patients with liver disease and were greatly increased (22.9 to 117.7 mumol) in patients with untreated hereditary hemochromatosis or transfusional iron overload. Magnetic measurements of iron stores provide a new quantitative technique for early detection of hereditary hemochromatosis and for rapid evaluation of treatment regimens for transfusional iron overload.

Diagnostic workup bias in the evaluation of a test. Serum ferritin and hereditary hemochromatosis.

Two studies report markedly divergent results about the usefulness of serum ferritin in diagnosing iron overload in relatives of patients with hereditary hemochromatosis. One study found the sensitivity of elevated serum ferritin to be 0%; another study found a sensitivity of 100%. Although different genetic abnormalities in iron or ferritin metabolism may explain the different results, our examination of these studies suggests that diagnostic workup bias also may explain the difference. In the study reporting a sensitivity of 100%, relatives with normal serum tests may have been excluded from consideration for liver biopsy, thus preventing detection of iron overload. The controversy may provide an empirical illustration of diagnostic workup bias.

Labile anticoagulant in a patient with lymphoma.

A patient with diffuse lymphocytic lymphoma and monoclonal IgM kappa immunoglobulin was found to have an unstable circulating anticoagulant. The anticoagulant inhibited phospholipid-dependent plasma coagulation reactions. Unlike previously described anticoagulants of this type, this plasma inhibitor was neutralized in vitro by products of platelet lysis but not by exogenous addition of other phospholipids or by intact platelets. Inhibitory activity seemed dependent on the monoclonal immunoglobulin, but isolated immunoglobulin fractions lacked anticoagulant activity, suggesting that the inhibitory function was dependent on an easily disrupted macromolecular aggregate. Recognition and characterization of other similar anticoagulants may provide a means of studying the role of phospholipids in normal hemostasis.

Premature cataracts in a family with hidrotic ectodermal dysplasia.

In a family with hidrotic ectodermal dysplasia affecting five members in three generations, bilateral premature cataracts have developed in four of the five affected individuals. To our knowledge, this represents the first report of a family in which bilateral premature cataracts appear to be inherited with hidrotic ectodermal dysplasia.

Bullous pemphigoid as a manifestation of chronic lymphocytic leukemia.

We describe a patient with chronic lymphocytic leukemia (CLL) and bullous pemphigoid. Initial treatment with high-dose prednisone (60 mg/day for 14 days) failed to prevent occurrence of new skin lesions. After the addition of chlorambucil, 6 mg/day, and tapering the prednisone dosage, no new skin lesions appeared, and the bullous lesions rapidly resolved. We were unable to isolate an antibody produced by leukemic lymphocytes that is directed against subepithelial basement membrane. Nevertheless, we believe that bullous pemphigoid can be a peripheral manifestation of an underlying disease such as CLL. Confirmation of this would be aided by the isolation of antibody produced by leukemic cells that is directed against subepithelial basement membrane.

Maternal homocystinuria: studies of an untreated mother and fetus.

A 20-year-old woman with untreated homocystinuria was examined when she was 18 weeks' pregnant. Amniocentesis was performed and raised levels of homocystine and methionine were present in the amniotic fluid. Assay of cystathionine synthetase activity in cultured amniotic fluid cells showed the carrier state for homocystinuria. An abortion was performed because of the possible adverse effects of continuing the pregnancy both for the mother and the fetus. No pathological abnormality was found in the aborted fetus. Further data are needed to assess the possible teratogenic effects of maternal homocystinuria and the adverse consequences of pregnancy in the affected mother.

The recurrence risk for neural tube defects in the United States: a collaborative study.

To determine the recurrence risk for patients with one prior pregnancy affected with neural tube defects (NTD), the authors have pooled data from eight testing centers. In 831 pregnancies studied because one sib was affected with an NTD, the recurrence rate was 3.0%, with 95% confidence limits of 2.0-4.3%, and 99% confidence limits of 1.8-4.8%. The recurrent lesion, whether spina bifida or anencephaly, tended to be concordant with the first to a significant degree. Only 12.2% of recurrent NTD were different from the first, with 95% confidence limits of 4.1-26.2%, and 99% confidence limits of 1.7-30.9%. Both an accurate recurrence risk and the information that a recurrent NTD lesions tends to be concordant with that in the first affected child are useful in the genetic counseling of patients in the United States and in the selection of appropriate prenatal diagnostic studies.

Prenatal diagnosis of classic hemophilia.

Prenatal diagnosis of classic hemophilia (hemophilia A) in mid-trimester was achieved by means of immunoradiometric assays for factor VIII on fetal plasma and amniotic-fluid mixtures obtained by fetoscopy. Samples were analyzed from six male fetuses at risk for severe hemophilia and from nine control fetuses for which fetoscopy was carried out to attempt prenatal diagnosis of other genetic disorders. The factor VIII coagulant-antigen values for the control (non-hemophilic) samples were 17 to 94, and the factor VIII related-antigen concentrations were 50 to 155 U per deciliter. Three of the fetuses at risk for hemophilia had factor VIII values in the control range, and these infants were normal at birth. The other three fetuses had low concentrations of factor VIII coagulant antigen but normal concentrations of factor VIII related antigen. These values and the diagnoses of severe hemophilia were confirmed with blood from the abortuses.

Methyprylon-induced bone marrow suppression in siblings. An inherited defect?

Transient bone marrow suppression in two sisters followed ingestion of the sedative-hypnotic drug methyprylon. No other pharmacologic or environmental inciting factor common to both patients was identified. The mechanisms responsible could not be defined; abnormal suppression fo granulocyte progenitors by the drug in vitro was not demonstrable. It is postulated that a pharmacogenetic interaction may have been responsible for methyprylon-related bone marrow suppression in these two siblings.

An autosomal dominant midline cleft syndrome resembling familial holoprosencephaly.

We have detected a previously unrecognized autosomal dominant syndrome characterized by: mental retardation, microcephaly; craniofacial anomalies including cleft lip and anterior cleft palate, hypotelorism and antimongoloid slant; skeletal anomalies, notably of the foot and spine; and chronic constipation. Despite similarities to familial holoprosencephaly, this disorder appears to be a distinct entity. Incomplete penetrance and variable expressivity accompany transmission of the abnormal allele through four generations of a large kindred. Three of the four affected males survived past 20 years of age; the fourth is an infant. All three affected females died very early in infancy.

HLA B27 in ankylosing spondylitis: differences in frequency and relative risk in American Blacks and Caucasians.

Twenty-eight HLA alleles of the A and B loci were determined in 23 American Blacks and 50 Caucasians with primary ankylosing spondylitis (AS). The prevalence of HLA B27 was significantly increased in American Black patients (48 per cent) vs Black controls (two per cent), but was much less than the 94 per cent found in Caucasian patients (controls eight per cent). The lower prevalence of B27 in American Black patients vs Caucasian patients was significant (p less than 0.001), and indicated that susceptibility to AS is not as closely associated with B27 in Blacks as in Caucasians. No other HLA antigen was significantly associated with AS in either racial group. Among B27 positive individuals, the relative risk of developing AS was significantly lower in American Blacks than in Caucasians. These data indicate that for diagnostic purposes, the absence of B27 is less important in ruling out AS in Blacks than in Caucasians.