Treatment of bleeding in acquired hemophilia A with the proper administration of recombinant activated factor VII: single-center study of 7 cases.

Recombinant activated factor VII (rFVIIa) is the bypassing agent used in the first-line hemostatic therapy for acquired hemophilia A (AHA); however, the occurrence of thrombotic complications in rFVIIa-treated AHA patients was recently reported to be 2.9-6.5%. Therefore, the investigation of the proper administration of rFVIIa for AHA is needed. In the present study, we retrospectively investigated the clinical features of AHA with regards to the use of rFVIIa (presence or absence of use and total amount) in 7 AHA patients encountered in our department for 7 years between January 2008 and December 2014. Ages were 63-89 years old (median: 79 years old), and there were 5 male and 2 female patients. The coexistence of cardiovascular risk factors and arteriosclerotic diseases, such as hypertension, diabetes mellitus, and cerebral infarction were present in 6 patients. Anemia progressed to less than 7 g/dL of hemoglobin and required red blood cell transfusion in 5 patients, showing "severe" hemorrhage. Factor VIII inhibitors were removed by immunological treatments in 6 patients. As a hemostatic therapy, rFVIIa was used in 4 patients. rFVIIa was not administered or was administered at a very low dose (20 mg) to 3 and 1 patient, respectively, and bleeding stopped as inhibitor titers decreased and disappeared in these patients. Inhibitors did not disappear in 1 patient and the control of hemostasis became poor and was accompanied by intestinal hemorrhage. Although a large amount of rFVIIa (265 mg in total) was administered, the patient bled to death. Therefore, bleeding may be stopped without the administration of rFVIIa in some AHA cases, while the dose of rFVIIa is not necessarily related to hemostatic effects in other cases. Since the main aim of AHA treatments is the removal of inhibitors, caution is needed to ensure that more than the necessary amount of rFVIIa is not administered.

¹8F-FDG PET/CT imaging for a gastrointestinal mantle cell lymphoma with multiple lymphomatous polyposis.

Multiple lymphomatous polyposis (MLP) is an uncommon type of gastrointestinal lymphoma characterized by the presence of multiple polyps along the gastrointestinal tract. Most of this entity is in fact considered the counterpart of gastrointestinal tract involvement for mantle cell lymphoma (MCL). To our knowledge, there have been no reports on [fluorine-18]-fluorodeoxy-glucose ((18)F-FDG)-positron emission tomography (PET)/computed tomography (CT) imaging for gastrointestinal MCL with MLP. We present the results of (18)F-FDG PET/CT imaging in a patient with gastrointestinal tract involvement of MCL showing continuous MLP from the stomach to the rectum and intestinal intussusception. FDG-PET/CT findings were false negative in typical MLP spreading widely over the gastrointestinal tract, but uptake was noted in large lesions with deep infiltration considered atypical as MLP. On FDG-PET/CT imaging, the Ki-67 proliferative index, which is a cell proliferation marker, showed neither correlation with the presence of uptake nor the maximum standardized uptake value.

[Intestinal bleeding in patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors].

Tyrosine kinase inhibitors (TKIs) are highly effective in the treatment of chronic myelogenous leukemia (CML), but there have been a few adverse event reports describing gastrointestinal bleeding. We clinically analyzed two patients who developed intestinal bleeding during the administration of TKIs for CML. Platelet counts of both patients were normal. The patients showed endoscopic findings characterized by mildly hemorrhagic mucosa. The imatinib patient was diagnosed by capsule endoscopy of the small intestine, and required frequent blood transfusions. The dasatinib patient showed occult bleeding due to CD8-positive colitis. We should adequately recognize that gastrointestinal bleeding may occur during the administration of TKIs.

In Japanese patients with type A gastritis with pernicious anemia the condition is very poorly associated with Helicobacter pylori infection.

There are conflicting views about the association between type A gastritis with pernicious anemia (PA) and infection with Helicobacter pylori, and currently, no definite conclusion has been reached. In this study, we evaluated H. pylori infection in patients with type A gastritis who developed PA. The study included a total of 25 Japanese patients (13 males and 12 females) who had been diagnosed with PA at our department, with a mean age of 71.2 years. We diagnosed infection with H. pylori by measuring serum H. pylori-IgG antibodies in all 25 patients, and we performed gastric biopsy in 17 patients. They were all negative for H. pylori-IgG antibody (0/25) and H. pylori on gastric biopsy (0/17). Although the prevalence of H. pylori infection (70-80 %) in our age-matched controls in Japan is higher than the prevalence in similar populations in western countries, we believe that type A gastritis with PA is very poorly associated with H. pylori infection.

Biphenotypic Acute Leukemia with t(15;17) Lacking Promyelocytic-retinoid Acid Receptor α Rearrangement.

Biphenotypic acute leukemias (BAL) account for less than 4% of all cases of acute leukemia. Philadelphia chromosome and 11q23 rearrangement are the most frequently found cytogenetic abnormalities. Since t(15;17) is almost always associated with acute promyelocytic leukemia, t(15;17) in BAL cases is extremely uncommon. We report here a rare and instructive case of BAL with t(15;17) and the successful treatment approach adopted. A 55-year old woman was referred to our hospital for an examination of elevated white blood cell (WBC) counts with blasts (WBC 13.4×10(9)/L; 76% blasts). The blasts with acute lymphoblastic leukemia (ALL-L2, FAB) morphology co-expressed B-lymphoid and myeloid lineages, and a cytogenetic study revealed 4q21 abnormalities and t(15;17). However, promyelocytic-retinoid acid receptor α rearrangement was not detected by fluorescence in situ hybridization on interphase nuclei. Our patient was treated with chemotherapy for ALL and gemtuzumab ozogamicin without all-trans-retinoic acid, and has remained in hematologic first complete remission for more than 3.7 years.

Epstein-Barr virus-positive ileal extraosseous plasmacytoma containing plasmablastic lymphoma components with CD20-positive lymph node involvement.

We report a case of Epstein-Barr virus (EBV)-positive ileal extraosseous plasmacytoma containing plasmablastic lymphoma components with CD20-positive lymph node involvement. A 34-year-old healthy Japanese male developed intussusception due to an ileal plasmacytoma. The lesion was positive for EBV-encoded small nuclear RNA in in situ hybridization, with the surrounding lymph nodes showing the expression of CD20. Tumor cells in the ileal and lymph node lesions contained high-grade malignant features compatible with plasmablastic lymphoma. Because his abdominal lymph nodes recurred 6 months after resection, he received six cycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), and had a complete remission. Although his case was complicated by acute promyelocytic leukemia, he has so far survived, recurrence-free, for more than 7.5 years after chemotherapy for extraosseous plasmacytoma.

[Clinical evaluation of three elderly cases with acquired hemophilia A].

In this paper we report our clinical investigation of three cases with acquired hemophilia A treated in our department. These patients were all elderly males (79, 77, and 68 years old), and presented with subcutaneous bleeding, a prolonged activated partial thromboplastin time (APTT), and anemia. On the basis of these findings as well as decreased factor VIII activities (0.9~3.1%) and the presence of factor VIII inhibitors (57.1~173 BU/ml), we made a diagnosis of acquired hemophilia A. In cases 1 and 2, a recombinant activated factor VII was used to achieve hemostasis. The factor VIII inhibitor disappeared with prednisolone (PSL) alone in case 1 and a combination of PSL and cyclophosphamide in case 2. In case 3, treatment involving five courses of weekly rituximab (RTX) reduced the activity of factor III inhibitor to 3.5 BU/ml (and subsequently to zero). During this time, the patient achieved hemostasis without using a specific hemostatic agent, and was again referred to the previous hospital for the treatment of hepatocellular carcinoma. Although PSL is often chosen as a first-line therapy to suppress the production of factor VIII inhibitor, which may cause acquired hemophilia A, RTX may be another therapeutic option in some patients.

Endoscopic follow-up of 3 cases with gastrointestinal tract involvement of mantle cell lymphoma.

Gastrointestinal (GI) tract involvement of mantle cell lymphoma (MCL) presents as a variety of forms, ranging from multiple lymphomatous polyposis (MLP) to a slight mucosal change. We report 3 cases with GI tract involvement of MCL who were followed-up by endoscopy. The present study shows three new informations. MLP of the esophagus is rare, but it was observed in two of 3 patients who were extensively involved by MCL. Endoscopic follow-up in one patient suggested that lymphoma cells of MCL had invaded the lamina propria to submucosal layer before MLP developed. Two of the 3 cases showed a favorable clinical course with single-agent rituximab therapy.

[Massive hepatic infarction occurred during the myelosuppression after re-induction chemotherapy for acute myeloid leukemia].

Since the liver has a duplicate blood supply through the hepatic artery and portal vein, hepatic infarction is considered a rare disease. A 51-year-old male with acute myeloid leukemia and diabetes mellitus developed fulminant hepatic infarction only a few days after administration of FLAGM chemotherapy. Our case was considered to have been caused by the almost complete obstruction of both the hepatic artery and portal vein by thrombi during a short period. Hepatic infarction should be recognized as a complication that may develop after salvage chemotherapy such as FLAGM inducing marked myelosuppression. Hepatic infarction after chemotherapy requires further analysis by evaluating a larger number of cases.

[Therapy-related acute myeloid leukemia with 11q23 abnormality due to paclitaxel coexisting with bone marrow metastasis of breast cancer].

Among cases of therapy-related acute myeloid leukemia (t-AML) due to DNA topoisomerase II inhibitors, 11q23 abnormality is often detected. The usefulness of paclitaxel as a key drug in chemotherapy for breast cancer has been demonstrated. Few studies have reported t-AML due to paclitaxel. In this study, we report a patient who developed t-AML with 11q23 abnormality and bone marrow metastasis after breast cancer treatment with paclitaxel. The patient was a 61-year-old female who developed breast cancer at the age of 54 years. Four years after resection, lung and bone metastases were detected. Weekly therapy with paclitaxel at 80 mg/m2 was administered for 10 weeks (total dose: 1,200 mg), and radiotherapy was performed; thereafter, the extent of bone metastasis increased. Pancytopenia was noted 3 years after paclitaxel therapy. Bone marrow aspiration suggested AML (M4) with (11;19)(q23;p13) chromosome abnormalities. Histopathologically, bone marrow metastasis from breast cancer was detected in the same bone marrow specimen. This patient had not received any other anticancer drugs. Based on the clinical course, t-AML may have developed after paclitaxel therapy.

[Helicobacter pylori infection is not associated with pernicious anemia in Japan].

At present, the etiologic relationship between pernicious anemia and H. pylori infection remains unknown because different rates of positivity have been reported. To investigate the relationship of these two entities, 16 Japanese patients diagnosed with pernicious anemia were examined for H. pylori infection. Serological tests for H. pylori-IgG antibody and gastric biopsy were performed. These 16 patients ranged in age from 34 to 93 years, with a mean age of 68.1 years. They were all negative for H. pylori-IgG antibody and H. pylori on gastric biopsy. Considering that the H. pylori-positive rate in the Japanese population of the same age (60 years) is 70-80%, the findings of this study suggest that the rate of H. pylori positivity in patients with pernicious anemia is low.

[Clinical analysis of predictive factors for the response to antithymocyte globulin in patients with aplastic anemia].

We report the results of a retrospective study of antithymocyte globulin (ATG) treatment in 17 adult patients with aplastic anemia (AA). We evaluated 24 ATG treatments which included re-treatment with ATG in patients who had not responded to the first ATG treatment or who had relapsed after the first remission. The median age was 66 years, and the median follow-up period was 52 months. The response and relapse rates of ATG treatment were 70.8% and 23.1%, respectively. The response rate of ATG re-treatment was 57.1%. Overall survival and event-free survival at 10 years were 66.7% and 50.7%, respectively. The shorter duration from diagnosis to ATG treatment, the higher reticulocyte count before ATG treatment, and being female independently correlated with the efficacy of ATG treatment. Two patients developed monosomy 7 clonal abnormality. These results suggest that ATG treatment can achieve a high response rate and long-term survival among patients with adult AA. However, we have to pay attention to the development of the clonal diseases.

[Hypercalcemia and multiple osteolytic lesions associated with proinflammatory cytokines in a patient with acute lymphoblastic leukemia].

A 70-year-old man was admitted to the hospital with left ankle pain, also exhibiting severe consciousness disturbance. Laboratory findings showed not only hypercalcemia, but also increased serum levels of PTHrP and a few of proinflammatory cytokines, such as TNF-alpha, and IL-6. The X-ray and CT examinations revealed multiple osteolytic lesions, including the left tibia and fibula. Bone marrow aspiration revealed increased lymphoblasts (48%), and the patient was diagnosed as having acute lymphoblastic leukemia (ALL, L2). The hypercalcemia was successfully treated with calcitonin and bisphosphonate, and subsequently his consciousness status recovered rapidly. The bone marrow lymphoblast count decreased following combination chemotherapy, and a tendency towards improvement of the left ankle pain was also noted. However, he died of acute pneumonia and gastrointestinal bleeding. The postmortem findings showed leukemic cell involvement of the left tibia. The present case suggested that not only humoral hypercalcemia or local osteolytic hypercalcemia, but also proinflammatory cytokines were associated with multiple osteolysis and hypercalcemia.

Primary gastric Hodgkin's lymphoma expressing a B-Cell profile including Oct-2 and Bob-1 proteins.

Classic Hodgkin's lymphoma (cHL) most often involves lymph nodes, and gastric involvement is rare. Hodgkin's and Reed-Sternberg (H-RS) cells in cHL are known to often lack expression of several B-lineage markers, such as CD20, CD79a, Oct-2, and Bob-1. We present an extremely rare case of mixed-cellularity cHL in the stomach in which expression of these B-cells was detected immunohistochemically. The patient was an 83-year-old Japanese woman who developed a sensation of abdominal fullness and appetite loss. Endoscopic and abdominal computed tomography examinations revealed a gastric ulcer lesion and swelling of para-aortic lymph nodes, respectively. A subtotal gastrectomy was performed, and the histopathologic diagnosis was established as a typical cHL compatible with stomach origin. The patient underwent postoperative chemotherapy of 3 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and has since been in complete remission. Immunohistochemically, the H-RS cells in the cHL were positive not only for CD30 but also for CD20, CD79a, Oct-2, and Bob-1, whereas they were negative for CD3, CD15, CD45, EMA, and ALK1. Our patient may have had an intermediate cHL disease overlapping that of non-Hodgkin's peripheral B-cell lymphoma, possibly reflecting derivation from germinal-center B-cells.

[Current status of treatment for patients with idiopathic thrombocytopenic purpura in the Hokkaido area (evaluation of Helicobacter pylori eradication)].

Treatment guidelines for patients with idiopathic thrombocytopenic purpura (ITP) have been changed recently due to the clinical application of Helicobacter pylori (H. pylori) eradication but there has been no detailed multi-center analysis of the hematological effects of H. pylori eradication. The Clinical Hematology Forum consists of 11 large hematological departments and divisions in the Hokkaido area. We sent questionnaires to these 11 hematological departments and divisions in March 2003 to obtain information on current treatment strategies for patients with ITP and hematological results after the eradication of H. pylori. Questionnaires were returned by 9 (81.8%) of the 11 departments. Doctors in all hospitals had experience in diagnosis and treatment of H. pylori infection. Diagnostic examinations for H. pylori infection were performed in 54.3% of the registered cases. H. pylori infection was detected in 68.1% of the examined cases, and eradication treatment was performed in 87.7% of H. pylori-positive patients. H. pylori was eradicated in 52 (83.9%) of the 62 patients in whom the results of treatment could be evaluated. Among the patients whose platelet counts were less than 10.0 x 10(4)/microl, platelet recovery was observed in 48.8% of cases with successful eradication, a percentage similar to previously reported percentages in Japan. There was no prognostic factor to predict good responders before eradication treatment. Since the side effects of eradication treatment, including gastrointestinal symptoms and skin eruptions, were not serious, this method might become a front-line treatment for patients with ITP. Patient selection for eradication as an up-front treatment, analysis of the pathophysiology of platelet recovery after eradication and long-term effects should be investigated to make new treatment guidelines for newly diagnosed patients with ITP.