IP-10/CXCL10 and MIG/CXCL9 as novel markers for the diagnosis of lymphoma-associated hemophagocytic syndrome.

Lymphoma-associated hemophagocytic syndrome (LAHS) is a serious disorder, and its early diagnosis and treatment with appropriate chemotherapy are very important. However, reliable markers for early diagnosis of LAHS have not been identified. We screened serum cytokines using a newly introduced assay system, cytometric bead array (CBA), and identified interferon-inducible protein 10 (IP-10)/CXCL10 and monokine induced by interferon gamma (MIG)/CXCL9 as useful markers. Serum concentrations of IP-10 and MIG at the time of LAHS diagnosis were greater than 500 and 5,000 pg/ml, respectively. The sensitivity and specificity for LAHS diagnosis were 100 and 95 %, respectively, when we set the above values as the cut-off levels. Serum levels of these two chemokines were already elevated at the time of admission and significantly decreased after successful treatment, indicating their usefulness for both the diagnosis and therapeutic outcomes for LAHS. IP-10 and MIG were also useful in distinguishing severe from moderate/mild LAHS, and B-cell-type LAHS from T-cell/natural killer cell-type LAHS. Furthermore, IP-10 and MIG were of use to distinguish LAHS from sepsis in patients with hematologic malignancies. Rapid measurement of IP-10 and MIG by CBA appeared to be important for early diagnosis and treatment of LAHS.

Successful treatment of γ-heavy-chain disease with rituximab and fludarabine.

An 84-year-old Japanese man was admitted because of pancytopenia. The bone marrow was hypoplastic with a predominance of abnormal small lymphocytes and grape cells, which were positive for CD19 and CD20, and partially for the surface ĸ-light chain. Systemic CT scanning showed neither lymph node swelling nor hepatosplenomegaly. Serum immunoelectrophoresis and rocket immunoselection assays showed the presence of monoclonal IgG protein without a corresponding light chain and faint IgMĸ monoclonal protein. Histologic analysis of the clot preparation of the bone marrow aspirate facilitated a diagnosis of lymphoplasmacytic lymphoma (LPL). PCR analysis of the marrow cells demonstrated a clonal rearrangement of the immunoglobulin heavy-chain gene. From these results, we made a final diagnosis of γ-heavy-chain disease (γ-HCD) with underlying LPL localized in the bone marrow. We performed only a single course of immunochemotherapy (rituximab and fludarabine) in view of severely impaired hematopoiesis, which resulted in marked reduction of lymphoma cells and improvement of hematopoiesis. This report suggests the efficacy of rituximab plus fludarabine therapy for LPL-associated γ-HCD.

[Two year investigation of glycosylation profiles in serum IgG from a patient with multiple myeloma].

Although abnormalities of glycosylation profile in serum IgG have been demonstrated in a variety of inflammatory autoimmune diseases such as rheumatoid arthritis, there are only a few reports describing long term monitoring of N-glycosylation profiles in such patients. Here we report the serial finding of N-glycosylation profiles of IgG-kappa M-protein in a patient with multiple myeloma monitored for two years. In this patient, serum formed a gel precipitation upon exposure to air. The HPLC mapping method demonstrated that IgG M-protein in the patient exhibited a significant decrease in the ratio of fucosyl to afucosyl N-glycans compared with that in a healthy control. With remission, the IgG M-protein showed an increase in this ratio, becoming closer to that in the healthy control. However, the gel-precipitation persisted. This finding suggested that this unique property of serum may not be related to the glycosylation profile of the M-protein.

[Simultaneous presence of macroamylase and macrolipase in a patient with celiac disease].

Celiac disease is a permanent intolerance to ingested gluten that results in immunologically mediated inflammatory damage of the small intestinal mucosa. Here we report the case of a patient with Celiac disease demonstrating simultaneous macroamylasemia and macrolipasemia. The patient showed persistently elevated levels of serum amylase and lipase. Amylase and lipase in normal serum were eluted from a Superdex-200 column after the 4S protein. These enzymes in the serum from this patient were eluted in the 19S protein. This finding indicated that these enzymes from this patient had a molecular weight greater than that of normal amylase and lipase. Immunoprecipitation assay showed that amylase was bound to polyclonal IgG and IgA, whereas lipase was bound to polyclonal IgA. To our knowledge, the simultaneous presence of macroamylase and macrolipase in the same patient has been previously reported in only four cases. Interestingly, two of those patients had Celiac disease. If macroamylase and macrolipase are present, the possibility of Celiac disease should be considered.

[Immunochemical properties of free mu-chain protein in a patient with mu-heavy chain disease].

We report a case of mu-heavy chain disease. A 56-year-old woman presented with anemia and hemorrhagic diathesis. The serum of the patient was found to have free mu-heavy chain. The patient also had a kappa type-Bence Jones protein in serum and urine. Immunoelectrophoresis showed an abnormal precipitin line in the alpha 2-globulin region which reacted with antiserum to mu-chain but not with antiserum for light chains. The molecular weight of the monomer of the patient's mu-heavy chain protein was approximately 67,000 daltons less than that of the normal mu-heavy chain protein.

Hepatic encephalopathy in primary human immunodeficiency virus type 1 (HIV-1) infection.

Primary infection of human immunodeficiency virus type 1 (HIV-1) is occasionally associated with common cold-like symptoms, and rarely with a self-limited illness resembling infectious mononucleosis. We report a 32-year-old man who presented with infectious mononucleosis-like blood picture on admission. Five days after admission he developed hepatic encephalopathy, which was ameliorated by administration of bolus corticosteroid. Based on the results of serologic studies, we diagnosed that he had primary HIV-1 infection. To our knowledge, this is the first published report of hepatic encephalopathy as a clinical manifestation of primary HIV-1 infection.

[Studies on the mechanism of elevation of serum PIVKA-II levels in alcoholic liver cirrhosis].

We measured serum PIVKA-II concentrations in 18 patients with alcoholic liver cirrhosis. Alcoholic liver disease was diagnosed by the history of ethanol intake of more than 900 ml/day for over 10 years. Liver cirrhosis was diagnosed histologically. Infections with hepatitis B and C viruses were ruled out by assaying serum virus markers. No tumor was detected in liver by ultrasonography and computed tomography during observation period. None of the patients studied were positive for alpafetoprotein (AFP). Eight out of 18 (44.4%) patients with alcoholic liver cirrhosis showed elevated serum PIVKA-II levels. In contrast, only eight out of 93 (8.6%) patients with nonalcholic liver cirrhosis had elevated serum PIVKA-II levels. PIVKA-II is well known as a tumor marker of hepatocellular carcinoma (HCC). The rates of positive PIVKA-II found in alcoholic liver cirrhosis approached its rates in HCC. However, the time course for the elevation of serum PIVKA-II levels was different each other in alcoholic liver cirrhosis and HCC. In HCC, serum PIVKA-II "levels" continued to elevate until therapy. In contrast, its elevation was transient and its levels returned to baseline in alcoholic liver cirrhosis. The values of ALT (GPT), gamma-GTP, and ALP correlated poorly with serum PIVKA-II levels in patients with alcoholic liver cirrhosis. To investigate the mechanism by which elevation of serum PIVKA-II levels in patients with alcoholic liver cirrhosis occurred, we studied the effect of vitamin K on production of PIVKA-II and AFP by hepatocytes. Hepatocytes(Alexander PLC/PRF/F cell line) were cultured in the presence of various concentrations of vitamin K (Kaytwo, Eisai, Tokyo). Vitamin K had no effect on AFP production. In contrast, PIVKA-II production was inhibited by addition of vitamin K in a dose dependent manner. Moreover, elevation of serum PIVKA-II levels in patients with alcoholic liver cirrhosis was suppressed by administration of vitamin K (Kaytwo) to these patients. Taken together, these results suggest that vitamin K may have a role in the mechanism of PIVKA-II elevation in sera of these patients. Then, we measured serum concentrations of vitamin K(PK, MK-4, MK-7) in these patients. There was no correlation observed between vitamin K and PIVKA-II in these patients. This result suggests that elevation of serum PIVKA-II in these patients may not be due to vitamin K deficiency. One question not answered here is how serum PIVKA-II levels in these patients are suppressed by treatment with vitamin K (Kaytwo). More detailed analysis of the mechanism of elevation of serum PIVKA-II levels in patients with alcoholic liver cirrhosis is needed.

[A case with multiple myeloma in which serum forms gel precipitation upon exposure to air].

We present the case of a 69-years-old man who was admitted to hospital with multiple myeloma. IgG-kappa type monoclonal protein was detected in the serum. When we separated the serum obtained from blood sample of the patient and the lid of the collecting tube was opened, the patient's serum became gelled immediately. When the lid of the collecting tube remained closed, the patient's serum did not become gelled even at 4 degrees C. Moreover, the gelled serum of the patient did not resolve at 56 degrees C. Taken together, these results indicated that gel formation of the patient's serum may not be due to cryoglobulin. It was found that the pH of the patient's serum elevated to pH 8.0 quickly after exposed to air. It was also found that the patient's serum, but not the sera of other IgG-kappa multiple myeloma patients, became gelled as soon as PBS of pH 8.0 was added. These results highly suggest that the patient's serum becomes gelled at pH 8.0. However, the isoelectric focusing of isolated precipitation in the patient showed fractions around the pH 8.5-8.7 zone, which was different from the pH at which the precipitation began to form. We think that this may be the first report of a multiple myeloma patient whose serum becomes gelled after exposed to air.