Shinobu Nakamura

Induction of programmed cell death (apoptosis) by influenza virus infection in tissue culture cells.

The process of cell death caused by influenza virus infection in cultured MDCK and HeLa cells was analysed. This infection gave rise to nuclear fragmentation and chromatin condensation accompanied by chromosomal DNA fragmentation into oligonucleosomes. Chromosomal DNA fragmentation progressed concomitantly with cell lysis of MDCK cells and HeLa cells, producing high and low yields of virus particles, respectively, indicating that the extent of cell lysis was not proportional to the virus production. The endonuclease inhibitor zinc blocked DNA fragmentation in MDCK cells. Cycloheximide inhibited DNA fragmentation as well as cell lysis. Inhibition occurred when the drug was added to the medium within 2 h after infection but not efficiently at 4 h or later. Infection induced the Fas Ag gene, which encodes a possible apoptosis-mediating molecule, in the early infectious stage followed by the expression of Fas Ag on the cell surface. These results suggested that influenza virus infection causes apoptotic death of cultured cells, and their fate might be determined at an early stage of the infection by induction of an apoptotic gene.

Brain Natriuretic Peptide Is a Predictor of Anthracycline-Induced Cardiotoxicity

Anthracyclines are effective antineoplastic drugs, but they frequently cause dose-related cardiotoxicity. The cardiotoxicity of conventional anthracycline therapy highlights a need to search for methods that are highly sensitive and capable of predicting cardiac dysfunction. We measured the plasma level of brain natriuretic peptide (BNP) to determine whether BNP might serve as a simple diagnostic indicator of anthracycline-induced cardiotoxicity in patients with acute leukemia treated with a daunorubicin (DNR)-containing regimen. Thirteen patients with acute leukemia were treated with a DNR-containing regimen. Cardiac functions were evaluated with radionuclide angiography before chemotherapies. The plasma levels of atrial natriuretic peptide (ANP) and BNP were measured at the time of radionuclide angiography. Three patients developed congestive heart failure after the completion of chemotherapy. Five patients were diagnosed as having subclinical heart failure after the completion of chemotherapy. The plasma levels of BNP in all the patients with clinical and subclinical heart failure increased above the normal limit (40 pg/ml) before the detection of clinical or subclinical heart failure by radionuclide angiography. On the other hand, BNP did not increase in the patients without heart failure given DNR, even at more than 700 mg/m2. The plasma level of ANP did not always increase in all the patients with clinical and subclinical heart failure. These preliminary results suggest that BNP may be useful as an early and sensitive indicator of anthracycline-induced cardiotoxicity.

Effect of granulocyte colony‐stimulating factor on neutropenia due to chemotherapy for non‐Hodgkin's lymphoma

The authors administered recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) to 16 patients with advanced non‐Hodgkins lymphoma treated with combination chemotherapy. Groups of three to five patients were treated with 50, 100, 200, and 400 μ/m2 per day of rhG‐CSF by intravenous infusion for 14 days, beginning 3 days after chemotherapy. There was a strong linear relationship between the dose and the area under the curve over this dose range. The rhG‐CSF was rapidly cleared from serum, with a mean half‐life of 5.97 hours for the second phase (t1/2). In patients treated with a dose of more than 100 μg/m2 per day, the duration of neutropenia (P < 0.01) and the duration of fever (P < 0.05) were significantly decreased. The rhG‐CSF was well tolerated and the only clinical observation that appeared relating to rhG‐CSF administration was slight bone pain. This study strongly suggests that an optimum dose of rhG‐CSF in patients after chemotherapy is 100 to 200 μg/m2. Our study shows that rhG‐CSF is a clinically useful drug for patients treated with myelosuppressive chemotherapy.

Columnar cell carcinoma of the thyroid gland: A case report and review of the literature

A rare case of columnar cell carcinoma of the thyroid gland is reported. The tumor was characterized by a predominantly papillary proliferation of tall columnar cells with marked nuclear stratification with associated focal areas showing solid or microfollicular growth. The nuclei of the tumor cells did not have the ground-glass appearance that characterizes papillary thyroid carcinoma; rather their nuclear features resembled follicular carcinoma. The tumor was found in an advanced stage and the patient died of lung metastases 2.5 years after surgery. The unique histopathological features and highly aggressive nature of columnar cell carcinoma require that this variant be differentiated from common papillary carcinoma of the thyroid. We also reviewed the literature emphasizing the lethal biological nature of this variant.

Papillary thyroid carcinoma in Kanazawa, Japan : prognostic significance of histological subtypes

A retrospective analysis of 183 papillary thyroid carcinomas was made in order to assess the prognostic factors related to survival. The following factors were found to adversely affect the prognosis: trabecular subtype of papillary carcinoma, the extent of the primary tumour, regional lymph node involvement, the presence of distant metastases, old age, male sex and the extent of the neck dissection. The presence of the follicular variant of papillary carcinoma and the extent of the thyroidectomy did not influence the prognosis. The trabecular subtype of papillary carcinoma is characterized by a trabecular or solid arrangement of follicular cells with nuclei of ground‐glass appearance. Univariate and multivariate analysis indicated that patients with this type of thyroid tumour had a poorer prognosis than those with the well‐differentiated or follicular variants of papillary carcinoma. In our opinion the trabecular subtype of papillary carcinoma should be included as a separate entity in the WHO classification of thyroid tumours.

Deletion of the long arm of chromosome 20 in a patient with chronic neutrophilic leukemia: Cytogenetic findings in chronic neutrophilic leukemia

We encountered a 67‐year‐old female with chronic neutrophilic leukemia (CNL). Cytogenetic study showed she had a deletion in the long arm of chromosome 20. This finding indicates that CNL, in this case, is a clonal disorder. Most CNL patients have normal karyotypes, and only four patients with cytogenetic abnormalities, including two cases who received chemotherapy before the cytogenetic abnormality was detected, have been reported. Four of those cases, including our case, had abnormalities in the long arm of chromosome 20. This locus may be associated with the development of CNL. To our knowledge, this is the first case with CNL who showed deletion of the long arm of chromosome 20 before treatment was started. Am. J. Hematol. 54:72–75, 1997

Pathologic Assessment of Surgical Margins on Frozen and Permanent Sections in Breast Conserving Surgery

The diagnostic value of frozen section was evaluated in the histologic assessment of surgical margins obtained by wide excision of breast tumors. There were 87 patients with unilateral breast cancer, and 5 with bilateral breast cancers. The periphery of the excised breast tissue was peeled like an orange and histologically examined by frozen and permanent section. If eitherin situ or infiltrating microscopic tumor was found at the margin, it was considered positive. Using frozen sections, the margin was judged histologically positive or suspicious in 30 tumors (31%) and negative in 67 (69%) tumors. Positive surgical margins were histologically confirmed by permanent section in 20 (67%) of the 30 tumors diagnosed as positive or suspicious on frozen section. Another 10 tumors had negative margins. In 4 tumors, however, while the initial or re-excised margin was negative on frozen section, the margins were positive by permanent section. These surgical margins were positive due exclusively to the presence of ductal carcinomain situ (DCIS). Evaluation of surgical margins in breast cancer by frozen section, thus exhibited a diagnostic accuracy of 86%, a sensitivity of 83%, and a specificity of 86%. It is concluded that frozen sections are useful in the determination of involvement of surgical margins after the wide excision of breast cancer. It must be pointed out that frozen sections will often overestimate involvement of the surgical margins.

Monomorphic agranular natural killer cell lymphoma/leukemia with no Epstein-Barr virus association.

The conceptual view of natural killer (NK) cell malignancies has recently undergone a significant evolution. The majority of such diseases are associated with Epstein-Barr virus (EBV), while only a limited number of EBV-negative cases has been reported. We report an unusual case of NK cell lymphoma/leukemia showing a monomorphic histology, absence of intracytoplasmic azurophilic granules, and no EBV association. The patient was a 57-year-old woman who died 26 months after the diagnosis. Autopsy revealed tumor infiltration in the liver, spleen, lymph node, blood, and bone marrow. There was no involvement of the skin or nasal cavity throughout the clinical course. The tumor showed the monotonous proliferation of medium-sized cells without intracytoplasmic azurophilic granules. Phenotypic analysis showed CD2+, CD3/Leu4–, cytoplasmic CD3ε+, CD4–, CD5–, CD7+, CD8–, CD16–, CD38+, CD56+, CD57–, TdT–, granzyme B–, and TIA1+ phenotype. There were no detectable rearrangements of T cell receptor genes or immunogloublin heavy chain genes. Furthermore, there were no EBV-encoded small RNAs. These findings provide information to improve the understanding of poorly defined entities, i.e. aggressive NK cell lymphoma/leukemia and blastic NK cell lymphoma/leukemia.

Prognostic significance of immunoglobulin heavy chain gene rearrangement in patients with acute myelogenous leukemia.

Recently the immunoglobulin heavy chain (IgH) gene rearrangement in B cell malignancies has been analyzed. Clonality can be determined using the polymerase chain reaction (PCR). Little attention, however, has been given to the relationship between prognosis and IgH gene rearrangement in patients with acute myelogenous leukemia (AML). In this study, we examined IgH gene rearrangement in 35 untreated AML patients by PCR. PCR was performed using consensus heavy chain complimentarity-determining region (CDR)-3 primers. Clonal IgH gene rearrangement was detected in 14 patients (40%). Four of five patients (80%) who were positive for B cell markers had clonal IgH gene rearrangement. Ten of 30 B cell antigen-negative patients (33%) also showed IgH rearrangement. All patients were treated with a daunorubicin-based regimen, resulting in complete remission for 29 patients (83%). Sixty-four percent of those with IgH rearrangement and 95% of those without rearrangement had complete remission. Overall survival of IgH-PCR positive and negative patients at 25 months was 29 and 88%, respectively. IgH-PCR positivity may be a poor prognostic factor in AML.

Hemolysis due to high-dose intravenous gammaglobulin treatment for patients with idiopathic thrombocytopenic purpura

Two adult patients with chronic idiopathic thrombocytopenic purpura (ITP) were treated with high-dose intact immunoglobulin (high-dose IgG). Haptoglobin levels in both cases declined significantly during high-dose IgG, following the increase in platelet counts to normal level. In one of them apparent hemolytic anemia was observed. The findings strongly support the hypothesis that the effect of high-dose intact IgG treatment on ITP patients is due to sequestration of IgG-coated autologous red blood cells by the reticuloendothelial system and the saturation of the macrophages by red blood cells.