Hiroyasu Kaya

Primary gastrointestinal follicular lymphoma involving the duodenal second portion is a distinct entity: A multicenter, retrospective analysis in Japan

We conducted a multicenter, retrospective study to determine the anatomical distribution and prognostic factors of gastrointestinal (GI) follicular lymphoma (FL). This study included 125 patients with stage I and II1 GI–FL. Of the 125 patients, the small intestine was examined in 70 patients, with double‐balloon endoscopy and/or capsule endoscopy. The most frequently involved GI–FL site was the duodenal second portion (DSP) (81%), followed by the jejunum (40%); 85% of patients with involvement of the DSP also had jejunal or ileal lesions. The absence of abdominal symptoms and macroscopic appearance of multiple nodules were significantly present in the DSP‐positive group. During a median follow up of 40 months, six patients showed disease progression. Patients with involvement of the DSP had better progression‐free survival (PFS) than those without such involvement (P = 0.001). A multivariate analysis revealed that male sex, the presence of abdominal symptoms, and negative involvement of the DSP were independently associated with poor PFS. In conclusion, most patients with GI–FL have duodenal lesions associated with multiple jejunal or ileal lesions. Gastrointestinal follicular lymphomas involving the DSP might be a distinct entity showing a favorable clinical course. (Cancer Sci 2011; 102: 1532–1536)

Immunophenotypic analysis of Epstein–Barr virus (EBV)‐infected CD8+ T cells in a patient with EBV‐associated hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a severe and often fatal condition characterized by uncontrolled activation of T cells and macrophages. In Epstein–Barr virus (EBV)‐associated HLH (EBV‐HLH), the pathogenic roles of ectopic EBV infection in the T‐cell population and of clonal proliferation of EBV‐infected T cells has been described. However, the immunophenotype of EBV‐infected T cells has not been fully characterized. Here we describe a case of EBV‐HLH presenting with a massive clonal proliferation of CD8+ T cells with TCR VB14. Analysis of in situ hybridization for EBV‐encoded small RNA1 showed that only CD8+ T cells harbored EBV in this patient. The EBV‐infected TCR VB14+ CD8+ T cells exhibited unique immunophenotypic features including lacked CD5 expression and a markedly bright expression of HLA‐DR. After initiation of treatment with prednisolone, etoposide, and cyclosporin A, the percentage of infected cells declined progressively in parallel with other serum markers such as ferritin. These findings suggest that lacking expression of CD5 on CD8+ T cells with specific TCR VB may serve as a useful marker of dysregulated T‐cell activation and proliferation in EBV‐HLH.

Unmanipulated Haploidentical Reduced-Intensity Stem Cell Transplantation Using Fludarabine, Busulfan, Low-Dose Antithymocyte Globulin, and Steroids for Patients in Non–Complete Remission or at High Risk of Relapse: A Prospective Multicenter Phase I/II Study in Japan

This prospective, multicenter phase I/II study of unmanipulated HLA-haploidentical reduced-intensity stem cell transplantation using a low dose of anti-T lymphocyte globulin (ATG) and steroid was conducted in 5 institutions in Japan. Thirty-four patients with hematologic malignancies who were in an advanced stage or at a high risk of relapse at the time of transplantation were enrolled. Among them, 7 patients underwent transplantation as a second transplantation because of relapse after the previous allogeneic stem cell transplantation. The conditioning regimen consisted of fludarabine, busulfan, and ATG (Fresenius, 8 mg/kg), and graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). All patients except 1 (97.1%) achieved donor-type engraftment. Rapid hematopoietic engraftment was achieved, with neutrophils > .5 × 10(9)/L on day 11 and platelets > 20 × 10(9)/L on day 17.5. Treatment was started for ≥grade I GVHD, and the cumulative incidences of acute grade I and grade II to IV GVHD were 27.5% and 30.7%, respectively. The incidence of chronic GVHD (extensive type) was 20%. Fourteen patients (41.2%) had a relapse. The cumulative incidence of transplantation-related mortality at 1 year after transplantation was 26.5%. The survival rate at day 100 was 88.2%. The survival rates at 1 year for patients with complete remission (CR)/chronic phase (n = 8) and non-CR (n = 26) status before transplantation were 62.5% and 42.3%, respectively. In the multivariate analysis, non-CR status before transplantation was the only factor significant prognostic factor of increased relapse (P = .0424), which tended to be associated with a lower survival rate (P = .0524). This transplantation protocol is safe and feasible, if a suitable donor is not available in a timely manner. As the main cause of death was relapse and not GVHD, more intensified conditioning or attenuation of GVHD prophylaxis and/or donor lymphocyte infusion may be desirable for patients with non-CR status.

BCR-ABL1 mutations in patients with imatinib-resistant Philadelphia chromosome-positive leukemia by use of the PCR-Invader assay

BCR-ABL1 kinase domain mutations were evaluated in 60 imatinib-resistant patients with Philadelphia-positive (Ph(+)) leukemia using PCR-Invader assay and direct sequencing. In chronic myelogenous leukemia (CML)--chronic phase (CP), 5 had P-loop mutations and 3 had T315I mutations. CML-CP patients with high Sokal score showed significantly higher incidence of mutations. P-loop mutations were associated with higher risk of disease progression. In CML-advanced phase, P-loop mutations and T315I mutation were associated with significantly shorter survival. In Ph(+) acute lymphoblastic leukemia, overall survival was poor irrespective of mutational status. The PCR-Invader assay is useful for screening of mutations and prediction of prognosis.

Acute Nonlymphocytic Leukemia Complicated by Garcin’s Syndrome

A 15-year-old girl was diagnosed as having acute nonlymphocytic leukemia (ANLL, FAB M2) in January 1990 and achieved complete remission with chemotherapy. She was readmitted to our hospital with a hearing disturbance and hoarseness in October 1990. A suprapharyngeal tumor was found on cranial MRI, and bone marrow leukemic cells were slightly increased in number. Involvement of leukemic cells was proven by biopsy of the tumor. Therefore, we made a diagnosis of ANLL relapse with Garcins syndrome. To our knowledge, this is the first reported case of leukemia complicated by Garcins syndrome.

Prevention of doxorubicin-induced cardiotoxicity by recombinant interleukin-1 in hamsters. Doxorubicin cardiotoxicity and interleukin-1

The major factor contributing to doxorubicin (DXR)-induced cardiotoxicity is the insufficiency of antioxidant defense mechanisms. As a model of acute cardiotoxicity with DXR, ten-week-old golden hamsters were given DXR (5 mg/kg) intravenously, and the toxicity was investigated by monitoring ECG changes. Complete A-V block and cardiac arrest on the ECG were observed in DXR-treated hamsters. DXR-induced edema and fragmentation of myofibrils were observed by electron-micrograph. Pretreatment with interleukin-1β(10 or 1μg/body) 12 or 24 hrs before prevented these changes, but pretreatment with tumor necrosis factorα had no effect.

Usefulness of Aspergillus Galactomannan Antigen Testing and the Prediction of an Outbreak during Hospital Reconstruction

Objective This study retrospectively evaluated fungal dissemination due to hospital reconstruction and explored effective methods of predicting an outbreak. Methods Patients suspected of having invasive aspergillosis were tested for Aspergillus galactomannan antigen before and after reconstruction, and the mean values of three months of testing for positive patients were determined. The characteristics of patients with aspergillosis during this period were also assessed. Results Forty-five patients were positive for Aspergillus antigen (>0.5 cut-off index) from January 2013 to December 2014. Mean Aspergillus antigen values significantly increased following reconstruction (p<0.05). Three patients developed pneumonia due to Aspergillus and were diagnosed with “probable” invasive aspergillosis according to the European Organization for Research and Treatment of Cancer and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. We also discovered that the anteroom to contain dust was not prefabricated and a negative pressure system to remove dust was not used. After construction of the unit, no new cases of aspergillosis were diagnosed. Conclusion Many Aspergillus spores may be transiently floating during hospital reconstruction. Therefore, monthly surveillance with frequent serum galactomannan antigen testing to predict outbreaks is necessary. Surveillance of all patients in the hematology ward is especially important. Reconsideration of prophylactic antifungals may also be necessary during hospital reconstruction.

Trisomy 14 with thrombocytosis and monocytosis.

It has been reported that trisomy 14 is associated with myeloid malignancies, but a case with increased platelet count has also been reported. However, the clinical significance of trisomy 14 is still uncertain. We report a patient with trisomy 14 with thrombocytosis and a gradual increase in monocytosis. He was treated with hydroxyurea, cytarabine and aclarubicin in low doses and his quality of life was maintained for a period of about 1 year from blastic crisis. Hydroxyurea, cytarabine or aclarubicin in low doses may be the treatment of choice for trisomy 14 patients with respect to the patients’ quality of life.

Multidrug resistance P-glycoprotein expression on leukemic cells at diagnosis.

糖蛋白の発現による多剤耐性 (MDR) については種々の報告があるが, われわれは44人の未治療の白血病患者の骨髄あるいは末梢血の腫瘍細胞をAPAAP法を使い, C219モノクローナル抗体で染色した.各検体につきそれぞれ1000個の腫瘍細胞を観察し, 強陽性に染まる細胞の割合を求めた.急性非リンパ性白血病 (ANLL) のM4および急性混合性白血病 (AMixL) において発現頻度および平均陽性率が高かった.細胞表面抗原についてはCD7やCD34がMDRと相関があることは報告されてはいるが, 本研究では有意な相関はなかった.また, 細胞形態からも, 幹細胞から単球系にやや分化した段階で陽性となりやすいと推測された.染色体異常については7番染色体異常のある群で50%が, ない群で25%がP糖蛋白陽性であった.しかし, 有意な相関はなかった.MDRと病型および臨床経過に関しては種々の結果が報告されているが, 今回のわれわれのC219モノクローナル抗体を使った免疫染色法でも, これまでの報告と多少異なった結果となった.今後, 統一された方法で症例を蓄積し, 検討していくべきであろう.

A recombinant human interleukin-1β protects adriamycin-induced toxicity

Pretreatment with recombinant human interleukin-1β (IL-1) protected normal BALB/c mice from the lethal effect adriamycin (ADM) of related to dose and frequency of administration. Posttreatment with IL-1 failed to protect. Neutrophil and platelet counts after the administration of ADM (16mg/kg) did not differ between the group with and that without IL-1 pretreatment, whereas lipid peroxide levels in the heart were reduced in the group pretreated with IL-1. It appears that the chemoprotection mechanism of IL-1 lies in the prevention of cardiotoxicity due to ADM-induced free radicals.Pretreatment with recombinant human interleukin-1 beta (IL-1) protected normal BALB/c mice from the lethal effect adriamycin (ADM) of related to dose and frequency of administration. Posttreatment with IL-1 failed to protect. Neutrophil and platelet counts after the administration of ADM (16 mg/kg) did not differ between the group with and that without IL-1 pretreatment, whereas lipid peroxide levels in the heart were reduced in the group pretreated with IL-1. It appears that the chemoprotection mechanism of IL-1 lies in the prevention of cardiotoxicity due to ADM-induced free radicals.