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CAP Home > CAP Reference Resources and Publications > CAP TODAY > CAP TODAY 2004 Archive > October 2004 Clinical Abstracts
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  Clinical Abstracts





cap today

October 2004

Michael Bissell, MD, PhD, MPH, Professor and Director of Clinical Services and Vice Chair, Department of Pathology, Ohio State University Medical Center, Columbus
Ronald Domen, MD, Professor of Pathology, Medicine, and Humanities, Penn State University College of Medicine, Hershey, Pennsylvania

Still no serum biomarker for melanoma
Lymphocyte subsets in patients with pulmonary tuberculosis
Cytokines and occurrence of aGvHD in cord blood transplantation
CCR5 and CCR2 polymorphisms and drug resistance in HIV-1
Revisiting the fasting glucose criterion for diagnosing hypoglycemia
D-dimer test in acute venous thrombosis and pulmonary embolism
Followup of Nipah virus infection
B cell depletion in systemic lupus erythematosus
Protease inhibitor-associated insulin resistance

Still no serum biomarker for melanoma

The CD95 receptor ligand (Fas ligand, Fas-L), a member of the tumor necrosis factor family, may be considered a marker for melanoma. It is first expressed on the plasma membrane of activated cytolytic T lymphocytes which are able to trigger apoptosis of melanoma cells that express its receptor (CD95, Fas) on their surface. Melanoma cells can develop several mechanisms to counterattack cytolytic T lymphocytes, one of which is the expression of Fas-L on the melanoma cell membrane. Fas-L can be cleaved, presumably by metalloproteinases, from the cell membrane and become soluble (soluble Fas-L, sFas-L). The soluble form has been demonstrated to be a serological marker for several Fas-L-expressing/releasing malignancies, in which it was detected significantly more often in the sera of melanoma patients than in the sera of controls. The authors investigated values of sFas-L in the sera of patients with melanoma and compared them to those in the sera of healthy controls to address whether sFas-L is a serological marker of melanoma (that is, it is significantly more represented in melanoma patients than in controls) and to assess whether sFas-L is useful for the early detection of melanoma. Serological sFas-L values in 114 patients with melanoma and 25 controls were measured using enzyme-linked immunosorbent assay. The sFas-L values in melanoma patients were not significantly higher than in the controls. They were not significantly different, moreover, when patient groups belonging to different clinical stages of disease were compared with the control group. Two patients affected with distant metastases had the highest sFas-L values. The authors concluded that sFas-L cannot be considered, within the limits of this study, to be a serological marker for detecting melanoma. Additional studies are needed to evaluate whether sFas-L can be used as a marker for disease progression or prediction of therapy outcome, or both.

Melzani G, Bugari G, Parrinello G, et al. Evaluation of soluble Fas ligand as a serological marker for melanoma. Dermatology. 2002;205:111-115.

Reprints: Dr. Giuseppe De Panfilis, Dept. of Dermatology, Parma University, I-43100 Parma, Italy;

Lymphocyte subsets in patients with pulmonary tuberculosis

T cell-mediated immunity plays an important role in eliminating mycobacteria. This is especially true with CD4+ T lymphocyte function. In advanced or disseminated tuberculosis, the number of circulating CD4+ T lymphocytes is reduced, while the number of CD8+ cells is increased. The authors previously reported increased lymphocyte and neutrophil percentages in BAL fluid from patients with active pulmonary tuberculosis. Bronchoalveolar T lymphocytes and their subpopulations may reflect the clinical course manifested as extent of pulmonary involvement, fever, or loss of body weight. Also, in patients with higher grades of pulmonary tuberculosis, more CD4+ T lymphocytes may be trapped in the infected lungs, reflecting a decreased circulating CD4+ T lymphocyte count. To explore these issues, the authors collected BAL fluid from 45 patients with active pulmonary tuberculosis and 14 healthy control subjects. The percentages for T lymphocyte subpopulations, including CD4+, CD8+, and CD3+ T cells, were measured using two-color flow cytometry. A higher percentage of CD3+ CD4+ T lymphocytes, with a relatively lower percentage of CD3+ CD8+ T lymphocytes, was revealed for the patients with a higher grade of pulmonary tuberculosis, compared with patients who had a lower grade of pulmonary tuberculosis. This resulted in an increased BAL fluid CD4+/CD8+ ratio. By contrast, a higher percentage of CD3+ CD8+ T lymphocytes with a relatively low percentage of CD3+ CD4+ T lymphocytes was demonstrated for those patients with a higher grade of pulmonary tuberculosis, resulting in a decreased peripheral blood CD4+/CD8+ ratio. The authors concluded that CD4+ T lymphocytes may be compartmentalized in the infected lungs of patients with higher grades of pulmonary tuberculosis.

Tsao TCY, Chen CH, Hong JH, et al. Shifts of T4/T8 T lymphocytes from BAL fluid and peripheral blood by clinical grade in patients with pulmonary tuberculosis. Chest. 2002;122:1285-1291.

Reprints: Dr. Thomas C.Y. Tsao, FCCP, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, 199 Tun-Hwa North Rd., Taipei, Taiwan;

Cytokines and occurrence of aGvHD in cord blood transplantation

Cord blood has emerged as an alternative source of hematopoietic stem cells, with more than 1,000 cord blood transplants having been performed. Although the majority of these grafts were HLA disparate at one to three antigens, the incidence and severity of acute graft-versus-host disease (aGvHD) has been remarkably low compared with unrelated bone marrow transplantation. The decreased incidence of acute and chronic GvHD in cord blood transplants (CBTs) is probably because of the relative immaturity of the immune cells within cord blood, which may allow tolerance to alloantigens. In addition, the differential profile of production of cord blood cytokines may aid in the reduced GvHD effects of CBT. It is well known that cytokines, especially interleukin (IL)-2, tumor necrosis factor (TNF)-α, interferon (IFN)-γ , IL-6, and IL-1, are involved in the "cytokine storm" culminating in the pathologic damage caused especially by IL-1 and (TNF)-α and observed as clinical GvHD. The authors investigated the influence of (TNF)-α and IL-10 cytokine gene polymorphisms and major and mHag disparities, including HY, HA-1, and CD31 codon 125, on the occurrence and severity of aGvHD after unrelated HLA-mismatched CBT. DNA samples from 115 cord blood recipients and their unrelated cord blood grafts were analyzed for genotypes associated with (TNF)-α (TNFd3/d3) and IL-10 (IL-10-1064) and for disparities in major histocompatibility antigens and three minor histocompatibility antigens-HY, HA-1, and CD31 codon 125. Results were correlated with the incidence of aGvHD grades II to IV. Neither the donor nor the recipient GvHD risk alleles TNFd3/d3 and IL-10-1064 were associated with the development of aGvHD grades II to IV and I to IV. Due to the heterogeneity of CBTs, the data were reanalyzed separately for patients with malignancies (n=83) or inborn errors (n=24). No significant association was observed between the severity of aGvHD and the possession of either TNFd3/d3 or IL-10 genotypes. Mismatches for the mHags HY, HA-1, and CD31 exon 125 between donor and recipient did not associate with aGvHD grades II to IV. The authors concluded that, in contrast to HLA-identical sibling bone marrow transplantation, in mismatched unrelated CBT, neither the cytokine genotypes TNFd3/d3 alone or in combination with IL-10-1064 alleles nor the minor histocompatibility antigens HY, HA-1, and CD31 exon 125 were associated with aGvHD grades II to IV. Further determination of the cytokine gene polymorphism genotypes in CBTs compared with bone marrow transplants may identify those polymorphisms that could be potential predictive markers for the occurrence of aGvHD.

Kögler G, Middleton PG, Wilke M, et al. Recipient cytokine genotypes for (TNF)-α and IL-10 and the minor histocom-patibility antigens HY and CD31 codon 125 are not associated with occurrence or severity of acute GvHD in unrelated cord blood transplantation. Transplantation. 2002;74: 1167- 1175.

Reprints: Dr. Gesine Kögler, Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine University Medical Center, Moorenstrasse 5, Bldg. 14.80, 40225 Düsseldorf, Germany;

CCR5 and CCR2 polymorphisms and drug resistance in HIV-1

HIV-1 infects cells expressing the CD4 receptor on their surfaces. Macrophage-tropic strains of HIV-1 also need CCR5 as a co-receptor to enter host cells. A 32bp deletion in the CCR5 gene (CCR5 C632) results in reduced expression of CCR5 on the cell surface. People who are homozygous for this polymorphism are almost completely protected against HIV-1 infection. Heterozygotes for the CCR5 C632 polymorphism progress more slowly from infection to AIDS. The 64I polymorphism in the gene for CCR2, a minor co-receptor for HIV, is not associated with protection against HIV-1 infection, but both heterozygotes and homozygotes for this polymorphism progress more slowly from infection to AIDS. The CCR2 64I polymorphism is in complete linkage disequilibrium with a single nucleotide polymorphism in the promotor region of the CCR5 gene (C927T) that has been associated with slower HIV-1 disease progression. Some studies report that CCR2 or CCR5 polymorphisms, or both, affect the virologic and immunologic treatment response to antiretroviral therapy, but others have found no significant differences in the response to treatment of individuals with these polymorphisms and the response of those without. The authors retrospectively investigated the influence of the CCR2 64I and CCR5 C632 polymorphisms on the virologic and immunologic response to highly active antiretroviral therapy (HAART), pooling data from four clinical studies. The prevalence of the CCR5 C632 polymorphism was 21 percent (27 of 130 subjects), and the prevalence of the CCR2 64I polymorphism was 15 percent (19 of 130 subjects). There were no major differences between subjects with and without polymorphisms in the CCR5 or CCR2 genes with respect to the rate of initial viral clearance, proportion of subjects with plasmas HIV-1 RNA levels below the lower limit of quantification, rate of virologic treatment failure, immunologic responses, and disease progression during 96 weeks of followup.

Wit FWNM, van Rij RP, Weverling GJ, et al. CC chemokine receptor 5 C632 and CC chemokine receptor 2 64I polymorphisms do not influence the virologic and immunologic response to antiretroviral combination therapy in human immunodeficiency virus type 1-infected patients. JID. 2002;186: 1726-1732.

Reprints: Dr. Ferdinand W.N.M. Wit, Dept. of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, National AIDS Therapy Evaluation Center, Academic Medical Center, Room T0-120, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands;

Revisiting the fasting glucose criterion for diagnosing hypoglycemia

Diagnosis of hypoglycemia is based on Whipple’s triad, as defined by the occurrence of symptoms consistent with hypoglycemia in association with a low plasma glucose concentration and relief of symptoms when the plasma glucose concentration is raised to normal levels. Symptoms of hypoglycemia are rather nonspecific and may be autonomic or neuroglycopenic (resulting from glucose deprivation of the central nervous system). Autonomic symptoms include sweating, pallor, tremulousness, palpitations, and tachycardia. Neuroglycopenic symptoms include somnolence, difficulty thinking or speaking, confusion, bizarre behavior, personality changes, or focal neurological deficits, and they may lead to loss of consciousness, seizures, or coma. A few symptoms, such as hunger, anxiety, dizziness, blurred vision, and weakness, cannot be clearly assigned to either group. The standard test for evaluating hypoglycemic disorders is the supervised 72-hour fast. The classical endpoint to terminate the 72-hour fast in the evaluation of hypoglycemic disorders is the occurrence of hypoglycemic symptoms in association with a low glucose level. However, neither the symptoms nor the plasma glucose cutoff value have been exactly defined. The authors assessed whether a glucose cutoff value to end the fast, irrespective of neuroglycopenic symptoms, can be defined prospectively. They conducted a single-center case-control study in a tertiary referral hospital in Switzerland. The authors performed a 72-hour fast in 23 consecutive patients (17 women and six men) following a standardized protocol between July 1999 and January 2002. The criterion to end the fast before 72 hours was defined by the occurrence of symptoms or signs typical for neuroglycopenia irrespective of plasma glucose levels. The main outcome measures were insulin levels and insulin-to-plasma glucose ratios in insulinoma patients and in individuals without insulin-secreting tumors at termination of the fast and at plasma glucose levels of 2.5 mmol/L or less prior to the occurrence of neuroglycopenic symptoms. The fast was terminated before 72 hours in seven patients because they developed neuroglycopenic symptoms. Insulin-secreting tumors were found and removed in these seven patients. Sixteen patients did not develop neuroglycopenic symptoms throughout the 72-hour fast, and an insulin-secreting tumor could be excluded in these 16 patients. Five of the 16 patients had plasma glucose levels of 2.5 mmol/L or less during the 72-hour fast. Insulin levels and insulin-to-glucose ratios in insulinoma patients and healthy individuals overlapped during as well as at termination of the fast. Before the occurrence of neuroglycopenic symptoms and at venous plasma glucose levels of 2.5 mmol/L or less, insulin-to-plasma glucose ratios dropped in insulinoma patients to values within the normal range on several occasions. The authors concluded that the presence of symptoms or signs typical for neuroglycopenia are the prerequisite criteria for ending the fast before 72 hours.

Wiesli P, Brändle M, Schwegler B, et al. A plasma glucose concentration below 2.5 mmol L-1is not an appropriate criterion to end the 72-h fast. J Int Med. 2002;252: 504-509.

Reprints: Dr. Peter Wiesli, Dept. of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Zurich, CH-8091 Zurich, Switzerland;

D-dimer test in acute venous thrombosis and pulmonary embolism

Despite the publication of numerous studies, the role of D-dimer in diagnosing deep venous thrombosis or pulmonary embolism is not clear. The authors of this study performed a systematic review of the literature to assess the sensitivity and specificity of D-dimer assays and to evaluate their usefulness for diagnosing deep venous thrombosis (DVT) and pulmonary embolism (PE). They performed a literature search of all published studies between 1983 and 2003. Eleven inclusion criteria were established, and studies were categorized into three tiers. Tier three studies lacked some of the inclusion criteria but were included in sensitivity analyses. Tier one studies compared an enzyme-linked immunosorbent assay with at least one other D-dimer assay. Tier two studies included those in tier one and all other studies that met all inclusion criteria. From 513 studies identified, 31 met the criteria for tier one, 78 studies were included in tier two analysis, and 109 studies were in tier three analysis. The authors found that, in general, the ELISA and quantitative rapid ELISA D-dimer were more clinically useful in ruling out DVT or PE when compared to quantitative latex agglutination, semi-quantitative latex agglutination, and whole blood agglutination assays. For DVT, the ELISA and quantitative ELISA assays had sensitivity values of 0.96; for PE, the sensitivity values for both were 0.95. These two assays also had negative likelihood ratios that yielded a high certainty for excluding DVT or PE. The authors concluded that a negative result on quantitative rapid ELISA is as diagnostically useful as a normal to near-normal lung scan or negative duplex ultrasonography finding for excluding PE or DVT.

Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism. Ann Intern Med. 2004;140:589-602.

Reprints: Dr. Paul D. Stein, Saint Joseph Mercy-Oakland, 44555 Woodward Ave., Suite 107, Pontiac, MI 48341;

Followup of Nipah virus infection

An outbreak of fatal encephalitis occurred among pig farmers in Malaysia in 1998 and 1999. In neighboring Singapore, which imported live pigs from Malaysia, the outbreak affected only abattoir workers. A newly discovered member of the Paramyxoviridae family, named the Nipah virus, was found to be the causative agent. Named after the village in Malaysia where the virus was first discovered, the Nipah virus is closely related to the Hendra virus, another recently isolated paramyxovirus responsible for disease in horses and humans in Australia. Because the Nipah virus is a novel pathogen, its long-term effects are unknown. In the Hendra virus outbreak, there was one case of fatal encephalitis after a 13-month latency period. Furthermore, there have been reports of neurological relapse and late onset encephalitis among Malaysian Nipah virus patients. The authors described the followup clinical and radiological findings in two groups of pig workers affected by the Nipah virus outbreak, including magnetic resonance imaging (MRI) findings in 22 affected subjects. Of 13 patients with encephalitis, one died, one was lost to followup, and seven recovered. Among the four remaining patients, one had residual sixth nerve palsy, another suffered from severe clinical depression, and another patient had evidence of retinal artery occlusion. One patient with delayed onset Horner syndrome had a single lesion in the cervical spinal cord. The brain MRI findings were stable or improved in nine patients over 18 months of followup. Among a second group of nine asymptomatic seropositive abattoir workers, MRI examination in seven subjects revealed discrete small lesions in the brain similar to those detected in encephalitis patients. These findings suggest that in addition to causing encephalitis, the newly discovered Nipah virus affects the spinal cord and retina. Late clinical and radiological findings can occur in Nipah virus infections as with other paramyxoviruses.

Lim CCT, Lee WL, Leo YS, et al. Late clinical and magnetic resonance imaging followup of Nipah virus infection. J Neurol Neurosurg Psychiatry. 2003;74:131-133.

Reprints: Dr. C.C.T. Lim, Dept. of Neuroradiology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433;

B cell depletion in systemic lupus erythematosus

B lymphocyte depletion using rituximab has been introduced for treating several autoimmune disorders, including rheumatoid arthritis, IgM-associated neuropathies, and immune thrombocytopenia. It is thought to lower autoantibody levels by reducing the generation of autoantibody-producing daughter plasma cells. Given the evidence for a probable direct pathogenic role for at least some autoantibodies in systemic lupus erythematosus (SLE), notably anti-double-stranded DNA, the authors undertook a study to determine whether B lymphocyte depletion might be of similar benefit in this condition. The first study subjects with SLE were treated with two 500-mg doses of rituximab in combination with two 750-mg doses of cyclophosphamide and high-dose oral prednisolone. Six female patients with active SLE resistant to standard immunosuppressive therapy were treated on an open-label basis. During a two-week period, each patient received two 500-mg infusions of rituximab, two 750-mg infusions of cyclophosphamide, and high-dose oral corticosteroids. No significant adverse events were observed during followup. Patient one had not improved at three months and was then lost to followup. At six months, all five remaining patients had improved. Manifestations of SLE, such as fatigue, arthralgia/arthritis, and serositis, responded particularly well to this protocol. Hemoglobulin levels increased in patients two, three, five, and six. The erythrocyte sedimentation rate decreased in patients two, three, four, and five and was stable in patient one. In patients four and five, the urinary protein-to-creatinine ratio decreased significantly. C3 serum levels increased in all five patients who had low levels at baseline; in patients two and five, C3 values were normal at six months. The variation in the level of anti-double-stranded DNA antibody was different in each patient. The authors concluded that B lymphocyte depletion therapy in SLE is feasible enough to justify a formal controlled trial.

Leandro MJ, et al. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum. 2002;46:2673-2677.

Reprints: Dr. Maria J. Leandro, Rheumatology, 4th floor, Arthur Stanley House, 40-50 Tottenham St., London W1T 4NJ, United Kingdom;

Protease inhibitor-associated insulin resistance

Protease inhibitors used as therapy for HIV-1 infection have been associated with metabolic side effects, such as peripheral fat wasting, central adiposity, hyperlipidemia, and insulin resistance. This metabolic disorder is known as the lipodystrophy syndrome. The underlying mechanism behind these metabolic effects remains unclear. Protease inhibitors might inhibit the cytoplasmatic retinoic acid-binding protein type 1 and the low-density lipoprotein receptor-related protein. This led to the hypothesis that interference with the action of one or both of these proteins could generate abnormalities in lipid metabolism. This syndrome can be recognized by the early appearance of an increase in serum triglyceride, cholesterol, and plasma-free fatty acid levels. High levels of plasma-free fatty acids inhibit glucose uptake, glucose oxidation, and glycogen synthesis, and enhance gluconeogenesis in humans. Conversely, inhibitors of fatty acid oxidation promote glucose oxidation and lower blood glucose in type 2 diabetics. The authors described an HIV-1- positive patient with lipodystrophy syndrome in whom a decline in serum triglycerides was seen along with a significant improvement in glucose uptake following treatment with bezafibrate for three months. This improvement may be a consequence of the Randle effect—that is, increased availability of plasma-free fatty acids is negatively correlated to glucose uptake. The authors also noted a significant improvement in endothelial-dependent, flow-mediated dilation after treatment with bezafibrate. The authors concluded that bezafibrate may be of clinical utility in lipodystrophy syndrome through its beneficial effects on insulin resistance, glucose uptake, and endothelial dysfunction.

Nyström T, et al. Bezafibrate-induced improvement in glucose uptake and endothelial function in protease inhibitor-associated insulin resistance. J Int Med. 2002;252L:570-574.

Reprints: Dr. Thomas Nyström, VO Medicine, South Hospital (Södersjukhuset), Ringvãgen 52, SE-118 83 Stockholm, Sweden;




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