Acute leukemia during pregnancy: an investigative survey of the past 11 years.

INTRODUCTION: The management of pregnant women with acute leukemia is usually challenging. We collected data concerning pregnant women with acute leukemia in the Kanagawa area in Japan. METHODS: A questionnaire was sent to 24 institutions in the Kanagawa area. RESULTS: Data were obtained for 11 patients, median age of 31 years (range, 20-36). Eight patients had acute myeloid leukemia and three had acute lymphoblastic leukemia. Six patients were diagnosed in the first trimester of pregnancy, one in the second trimester, and four in the third trimester. Five of six patients diagnosed in the first trimester had abortions before chemotherapy, and one had an elective abortion after receiving chemotherapy. All patients diagnosed in the second or third trimester delivered live infants. Of the six patients diagnosed in the first trimester, two died of recurrent leukemia, and four remained in remission. Of the five patients diagnosed in the second or third trimester, four achieved complete remission and remained in remission. One patient died of sepsis 4 days after cesarean section. CONCLUSIONS: Careful surveillance and monitoring of the fetus and close co-operation among hematologists, gynecologists, and pediatricians are essential to successfully treat pregnant women with acute leukemia.

DHMEQ, a new NF-kappaB inhibitor, induces apoptosis and enhances fludarabine effects on chronic lymphocytic leukemia cells.

Chronic lymphocytic leukemia (CLL) is a low-grade lymphoid malignancy incurable with conventional modalities of chemotherapy. Strong and constitutive nuclear factor kappa B (NF-kappaB) activation is a characteristic of CLL cells. We examined the effects of a new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on CLL cells. Dehydroxymethylepoxyquinomicin completely abrogated constitutive NF-kappaB activity and induced apoptosis of CLL cells. Apoptosis induced by DHMEQ was accompanied by downregulation of NF-kappaB-dependent antiapoptotic genes: c-IAP, Bfl-1, Bcl-X(L) and c-FLIP. Dehydroxymethylepoxyquinomicin also inhibited NF-kappaB induced by CD40 and enhanced fludarabine-mediated apoptosis of CLL cells. Results of this study suggest that inhibition of constitutive and inducible NF-kappaB by DHMEQ in combination with fludarabine is a promising strategy for the treatment of CLL.

Spontaneous rupture of a left gastroepiploic artery aneurysm in a patient with autosomal-dominant polycystic kidney disease.

Autosomal-dominant polycystic kidney disease (ADPKD) has been known to be associated with a variety of vascular diseases. We present a hemodialysis patient with ADPKD who died of a massive intraperitoneal hemorrhage caused by the spontaneous rupture of a left gastroepiploic artery aneurysm. A 64-year-old male was admitted to our hospital with acute upper abdominal pain and hemorrhagic shock. An abdominal angiography showed three aneurysms and the source of hemorrhage was assumed to be the left gastroepiploic artery aneurysm. The patient died of severe metabolic acidosis and disseminated intravascular coagulation (DIC) on the second hospital day. At autopsy, there was massive bleeding into the abdominal cavity, and pathological examination of the left gastroepiploic artery aneurysm revealed a dissecting aneurysm. This is the first case describing a rupture of a gastroepiploic aneurysm in a patient with ADPKD.

Primary gastric T-cell lymphoma not associated with human T-lymphotropic virus type I: a case report and review of the literature.

Primary gastric T-cell lymphoma (PGTL) not associated with human T-lymphotropic virus type I (HTLV-I) is extremely rare and such a case is reported herein. The patient was a 58-year-old Japanese male presenting with submucosal tumor of the stomach identified on endoscopic examination. The lesion was diagnosed as non-Hodgkin's lymphoma by endoscopic biopsy and classified as peripheral T-cell lymphoma, unspecified, due to clonal rearrangement of the T-cell receptor beta (TCR) gene and expression of TCR beta protein in the absence of B-cell genotypes and phenotypes. Unlike previously reported cases of HTLV-I-unassociated PGTL, lymphoma in the current case was characterized histologically as "low grade" and phenotypically as CD4+, TIA-1+, granzyme B+, and CD103-. The lymphoma responded well to chemotherapy and radiation, and the patient was well with no detectable disease 10 months after initiation of therapy. A review of patients with PGTL in the literature revealed a few long-term survivors, and the investigation of therapeutic strategies for PGTL is, therefore, necessary.

Clinical significance of nm23-H1 proteins expressed on cell surface in non-Hodgkin's lymphoma.

The nm23 gene was isolated as a metastasis suppressor gene that exhibits low expression in high-level metastatic cancer cells. Its gene is related to the prognosis of acute myelogenous leukemia (AML) and non-Hodgkin's lymphoma (NHL). In this study, we examined the expression of nm23-H1 protein on the lymphoma cell surface of NHL. In 28 of 108 cases (25.9%), we observed > or = 20% of cell surface nm23-H1 protein expression and expression was especially high in peripheral T cell lymphomas and extranodal NK/T cell lymphomas. We also observed a significant correlation between serum nm23-H1 level and cell surface nm23-H1 expression levels. In patients with high levels of cell surface nm23-H1 expression, overall and progression-free survival rates were significantly lower than those in patients with low surface nm23-H1 expression levels. When surface nm23-H1 and serum nm23-H1 were combined, patients with high levels of both exhibited a poorer prognosis than patients with a high level of one or the other. These results indicate that in addition to serum nm23-H1, cell surface nm23-H1 may be used as a prognostic factor in planning a treatment strategy. The nm23-H1 protein appears to be intimately related to biological aggressiveness of lymphoma and, therefore, might be a molecular target of NHL treatment.

HHV-8 infection status of AIDS-unrelated and AIDS-associated multicentric Castleman's disease.

Multicentric Castleman's disease (MCD) is a clinicopathologically defined entity characterized by systemic lymphadenopathy with unique pathomorphology such as angiosclerosis, blood vessel proliferation in and around follicles, and plasmacytosis. While its pathogenesis has remained unclarified for many years, identification of the human herpesvirus 8 (HHV-8) in at least some MCD cases has opened new perspectives in this field. Because previous reports have described many inconsistencies regarding HHV-8 positivity in MCD, we intended to clarify this issue by the introduction of more convincing methodologies. For this investigation, we introduced two antibodies produced in our laboratories that recognize a latent gene product ORF73 and a lytic gene product ORF59, together with two well-recognized methods, in situ hybridization for the detection of lytic phase transcript T1.1/nut-1, and genomic polymerase chain reaction (PCR). Eighty-two cases of MCD were collected from Japan (n = 75) and France (n = 7). In three cases, the patients were suffering from acquired immunodeficiency syndrome (AIDS). Immunohistochemistry and in situ hybridization showed identical results: only three out of 82 cases were positively stained, and all the positive cases were found to be the patients with AIDS. Genomic PCR was done in 43 cases, and only one case produced positive results: the only AIDS case among the 43 cases studied by genomic PCR. Histopathologically, the HHV-8-positive cases showed the highest intensity of angiosclerosis and germinal center / perifollicular vascular proliferation, while plasmacytosis was not severe in the HHV-8-positive cases. Some of the HHV-8-negative MCD cases displayed similar histopathology, but at a far less intense level, except for the plasmacytosis. These results suggest that: (i) all three of the HHV-8-positive MCD patients in the present group are the patients with AIDS; and (ii) HHV-8-positive MCD patients develop typical but marked angiosclerosis and vascular proliferation that might be differentiated from HHV-8-negative MCD patients, who showed far less intense changes.

[Primary lymphoma of the vagina].

Primary vaginal non-Hodgkin's lymphomas (NHL) are rare, and are clinically difficult to differentiate from inflammatory diseases or vaginal cancer. Here, we present such a case in a 74-year-old woman complaining of fever and difficulty with urination. Pelvic examination revealed a tumor involving most of the vaginal wall, and pelvic MRI demonstrated vaginal wall thickening. A biopsy of this lesion confirmed NHL (diffuse large B-cell lymphoma), and the patient was admitted. Abdominal CT and MRI detected a vaginal tumor, and Ga scintigraphy confirmed accumulation in the pelvis, but no abnormalities were seen in other areas. Therefore, the patient was diagnosed as having NHL at clinical stage IB with low-intermediate risk (international prognosis index) (LDH 1,309 IU/L). The patient underwent three courses of CHOP therapy followed by radiotherapy, and complete remission was achieved. Primary vaginal NHL often affects women younger than 50 years of age, and abnormal hemorrhage is the initial symptom in many cases. There have been a number of reports of long-term survival following appropriate early chemotherapy and radiation therapy, suggesting that early diagnosis and treatment based on vaginal biopsy findings greatly influence the prognosis.

Molecular cloning and sequencing of myosin light chains in human megakaryoblastic leukemia cells.

Myosin light chain genes of hematopoietic cells have yet to be characterized. We cloned the full-length cDNAs of 20 kDa regulatory myosin light chain (MLC-2) and 17 kDa essential myosin light chain (MLC-3) from Meg-01, a human megakaryoblastic leukemia cell line. Both MLC-2 and MLC-3 gene are transcribed ubiquitously in various hematopoietic cells. The MLC-2 open reading frame of 516 nucleotides encoding a protein of 172 residues was detected in cloned cDNA of 967 nucleotides. The Ca2+-binding domain and five phosphorylation sites were highly conserved. The deduced amino acid sequence has a 99.4% and 100% homology with that of human fetus brain and human lymphocyte, respectively. The MLC-3 open reading frame of 453 nucleotides encoding a protein of 151 residues was detected in cloned cDNA of 742 nucleotide. The MLC-3 protein is 99.3% identical to that of human fibroblasts. These results suggest that hematopoietic myosin light chain proteins are similar to those of other nonmuscle cells and smooth muscle, thus differing from skeletal and cardiac muscles.

The tip of the coiled-coil rod determines the filament formation of smooth muscle and nonmuscle myosin.

Myosin II self-assembles to form thick filaments that are attributed to its long coiled-coil tail domain. The present study has determined a region critical for filament formation of vertebrate smooth muscle and nonmuscle myosin II. A monoclonal antibody recognizing the 28 residues from the C-terminal end of the coiled-coil domain of smooth muscle myosin II completely inhibited filament formation, whereas other antibodies recognizing other parts of the coiled-coil did not. To determine the importance of this region in the filament assembly in vivo, green fluorescent protein (GFP)-tagged smooth muscle myosin was expressed in COS-7 cells, and the filamentous localization of the GFP signal was monitored by fluorescence microscopy. Wild type GFP-tagged smooth muscle myosin colocalized with F-actin during interphase and was also recruited into the contractile ring during cytokinesis. Myosin with the nonhelical tail piece deleted showed similar behavior, whereas deletion of the 28 residues at the C-terminal end of the coiled-coil domain abolished this localization. Deletion of the corresponding region of GFP-tagged nonmuscle myosin IIA also abolished this localization. We conclude that the C-terminal end of the coiled-coil domain, but not the nonhelical tail piece, of myosin II is critical for myosin filament formation both in vitro and in vivo.

Tyrosine phosphorylation of proteins in primary human myeloid leukemic cells stimulated by macrophage colony-stimulating factor: analysis by disease type and comparison with normal human hematopoietic cells.

We investigated tyrosine phosphorylation of proteins in primary human leukemic cells stimulated by macrophage colony-stimulating factor (M-CSF) in 60 patients with acute myeloid leukemia (AML) and 5 patients with chronic myelomonocytic leukemia and compared the findings for leukemic cells with those of normal human monocytes and bone marrow immature hematopoietic cells. M-CSF induced tyrosine phosphorylation of p140-200, p110, p60, p44, and p42 frequently, and that of p95 and p55 less frequently, in primary myeloid leukemic cells, whereas M-CSF-induced phosphorylation of proteins was not detected in the normal human hematopoietic cells tested. Of these phosphoproteins, p140-200 was phosphorylated in all patients who responded to M-CSF and was considered to be almost identical to Fms, a product of the c-fms proto-oncogene. M-CSF-induced tyrosine phosphorylation was observed frequently (89%) in AML of French-American-British class M4 and infrequently in all other subtypes of AML, including M5. In chronic myelomonocytic leukemia, M-CSF-induced protein phosphorylation was prominent in blast crisis but was not detected in the chronic phase. Both bone marrow immature cells and mature monocytes showed low responsiveness to M-CSF. These findings for responsiveness to M-CSF were correlated with the amount of Fms in each type of cell. We also identified tyrosine phosphorylation of Vav, Shc, and extracellular signal-regulated kinase by M-CSF in some cases. These findings clarified an M-CSF-specific pattern of protein tyrosine phosphorylation and the responsiveness to M-CSF of primary human myeloid cells. Particularly, enhanced phosphorylation responses to M-CSF and increased amounts of Fms protein were observed in restricted human hematopoietic cells with a premature myelomonocytic character.

[Role of ultrasonography in diagnosis of neutropenic enteritis: a study of 4 cases].

Neutropenic enteritis is a septic or inflammatory disease of the colon. It is usually encountered in patients with hematological malignancy who have undergone chemotherapy, and it presents as fever, diarrhea, and abdominal pain, although the symptoms are not always specific. The diagnostic features of neutropenic enteritis revealed by barium enema, CT and ultrasonography have been reported previously. Here we report 4 cases of neutropenic enteritis in which ultrasound was used for diagnosis, and also for monitoring the clinical course of the disease. Because neutropenic enteritis is rapidly progressive, early diagnosis and therapeutic intervention are required. We believe that ultrasonography is a useful method for examining patients with neutropenic enteritis, being noninvasive, mobile, and providing rapid results in real time, thus aiding early diagnosis and clinical follow-up.

Acute respiratory failure due to "pulmonary calciphylaxis" in a maintenance haemodialysis patient.

Calciphylaxis is a rapidly developing, fatal process of vascular calcium deposition with prominent cutaneous manifestation. We treated a long-term haemodialysis patient who developed an analogous disorder limited to the lungs. A 57-year-old man was admitted for initiation of peritoneal dialysis because limited cardiac reserve precluded further haemodialysis. He was treated successfully for pneumonia until hypoxia and progressive hypercalcaemia developed. (99m)Tc-methylene disphosphonate scintigraphy showed diffusely increased pulmonary uptake. Death supervened despite aggressive and successful treatment of hypercalcaemia. Autopsy studies included immunohistochemistry and morphometric studies of bone. Alveolar capillary walls showed diffuse calcium deposition. Both gross and microscopical findings differed from those of typical metastatic calcification in dialysis patients. Immunoreactivity for parathyroid hormone-related protein was present in the lesions. Bone histomorphometry indicated mild osteitis fibrosa. Pneumonia is believed to have caused local synthesis of parathyroid hormone-related protein that, along with high calcium x phosphorus product, contributed to calcium deposition. By analogy with the cutaneous process we termed the deposition "pulmonary calciphylaxis".

Myosin light chain phosphorylation is correlated with cold-induced changes in platelet shape.

Chilling induces shape changes in platelets from disks to spheres with abundant filopodia. Such changes were time-dependent and correlated well with the phosphorylation of 20-kDa myosin light chain (LC20). Both the shape changes and the phosphorylation were reversible. After the platelets had been chilled, myosin became incorporated into the Triton X-insoluble fraction. When the chilled platelets were immunocytochemically stained, anti-myosin antibody was localized with filamentous structures inside the filopodia. These results suggest that LC20 phosphorylation and subsequent interactions with actin filaments play a crucial role in the cold-induced changes in platelet shape and in the formation of filopodia.

[Efficacy and safety of cefozopran (CZOP) monotherapy and combination therapy with CZOP and amikacin (AMK) for infections accompanying hematological diseases].

We evaluated efficacy and safety of monotherapy with CZOP (1-2 g x 2/day) and combination therapy with CZOP (1-2 g x 2/day) and AMK (200 mg x 2/day) for infections in patients with hematological diseases. Efficacy was evaluated in 71 patients of monotherapy group and 70 patients of combination therapy group. Underlying diseases were mostly leukemia and lymphoma. Infections included sepsis, suspected sepsis, pneumonia and so on. Efficacy in CZOP monotherapy was excellent in 21 patients (31.3%), good in 23 patients (34.3%), fair in 5 patients (7.5%) and the efficacy rate was 65.7%. On the other hand, in combination therapy, each was 14 patients (21.2%), 23 patients (34.8%), 12 patients (18.2%) and the efficacy rate was 56.1%. Side effects such as eruption were noted in 2 patients. Abnormal laboratory findings were noted in 9 patients. All side effects as well as abnormal laboratory findings were minimal. It was concluded that CZOP monotherapy was effective in the treatment of various infections accompanying hematological diseases.

Frequent expression of the variant CD30 in human malignant myeloid and lymphoid neoplasms.

We earlier identified a variant of CD30 (CD30v) that retains only the cytoplasmic region of the authentic CD30. This variant is expressed in alveolar macrophages. CD30v can activate the nuclear factor-kappaB (NF-kappaB) as CD30, and its overexpression in HL-60 induced a differentiated phenotype. To better understand the physiological and pathological functions of CD30v, expression of this variant was examined using a multiple approach to examine 238 samples of human malignant myeloid and lymphoid neoplasms. Screening by reverse transcriptase-polymerase chain reaction (RT-PCR) revealed expression of CD30v transcripts in 52 of 72, 7 of 11, 63 of 90, and 7 of 30 samples of acute myeloid leukemia (AML), myeloid blast crisis of myeloproliferative disorders (MBC), and lymphoproliferative disorders (LPDs) of B- and T-cell origin, respectively. CD30v expression was high in monocyte-oriented AMLs (FAB M4 and M5), B-cell chronic lymphocytic leukemia (B-CLL), and multiple myeloma (MM). Using the specific antibody HCD30C2, prepared using a peptide corresponding to the nine amino acids of the amino-terminal CD30v, expression of CD30v protein was detected in 10 of 25 and 2 of 10 AML and ALL samples, respectively. In AMLs, immunocytochemical detection of CD30v revealed the presence of loose clusters of CD30v-expressing cells dispersed amid a population of CD30v-negative blasts. Finally, the parallel expression of CD30v mRNA and protein, as evidenced by Northern and Western blotting, was confirmed in selected cases of AMLs and LPDs. A significant correlation was found between expressions of CD30v and CD30 ligand transcripts in AML and LPD (P = 0.02, odds ratio = 3.2). The association of CD30v with signal-transducing proteins, tumor necrosis factor receptor-associated factor (TRAF) 2, and TRAF5 was demonstrated by coimmunoprecipitation analysis, as was demonstrated for authentic CD30 protein. Expression of transcripts for TRAF1, TRAF2, TRAF3, and TRAF5, as demonstrated by RT-PCR, was noted in leukemic blasts that express CD30v. Collectively, frequent expression of CD30v along with TRAF proteins in human neoplastic cells of myeloid and lymphoid origin provide supportive evidence for biological and possible pathological functions of this protein in the growth and differentiation of a variety of myeloid and lymphoid cells.

Primary gastric T-cell lymphomas: report of two cases and a review of the literature.

To understand more fully the clinicopathological features of primary gastric T-cell lymphomas (PGTL), we report two cases of PGTL and review the literature. The present cases were not associated with human T-cell leukemia virus type 1 (HTLV-1) and were at clinical stage IIE. In both cases, T-cell origin of the lymphoma cells was diagnosed immunohistochemically. The clinical courses of these two cases were different: one followed a very aggressive clinical course and the patient died 6 months after the diagnosis, whereas the other patient survived more than 2 years without adjuvant chemotherapy. Clinicopathological features of 23 patients with PGTL are summarized with regard to their differences from primary small intestinal T-cell lymphomas (PSITL) and by association with HTLV-1. The median age at onset of PGTL was 58 years. The gender ratio was male-dominant (M:F = 2.3:1). About two-thirds (10 of 17) of PGTL cases had evidence of HTLV-1 infection. The most common presenting symptom for PGTL was upper abdominal discomfort and/or pain (76%), whereas that in PSITL was weight loss (61%) and diarrhea (42%). Typical lesions for PGTL were large ulcerations at the corpus to antrum. Neoplastic cells had no typical morphological characteristics for PGTL including HTLV-1-associated cases. CD3+4+8- was the most frequently observed surface phenotype of PGTL cells. Laboratory findings at diagnosis were not informative. Most patients were treated by gastrectomy with or without chemotherapy. PGTL, excluding that with HTLV-1, showed better prognosis than PSITL, although PGTL with HTLV-1 had a poorer prognosis.