Masaki Toshima

Rituximab plus 70% cyclophosphamide, doxorubicin, vincristine and prednisone for Japanese patients with diffuse large B-cell lymphoma aged 70 years and older

Abstract In the rituximab era, several large studies have suggested that full-dose rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) might be the best treatment for patients with diffuse large B-cell lymphoma (DLBCL) aged 60 years and older. However, it remains unclear whether this is also the case for those aged 70 years and older. Previously untreated patients with DLBCL aged 70 years and older (elderly) were treated with R-70%CHOP, and patients younger than 70 years (younger) were treated with full-dose R-CHOP every 3 weeks, for a total of 6–8 cycles. Complete remission (CR) rates in elderly versus younger patients were 75 vs. 78% (p = 0.7), respectively. The 3-year overall survival, event-free survival and progression-free survival of elderly versus younger patients were 58 vs. 78% (p < 0.05), 45 vs. 70% (p < 0.05) and 64 vs. 72% (p = 0.43), respectively. Severe adverse events were more frequent in the elderly, even with the dose reduction in that age group. Three-year PFS with R-70%CHOP for patients aged 70 years and older was not significantly worse than that with full-dose R-CHOP for younger patients, suggesting that R-70% CHOP might be a reasonable choice for patients with DLBCL aged 70 years and older, especially for those with comorbidities.

Massive Immune Hemolysis After Non-myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation with Minor ABO-incompatibility

A 35-year-old male, blood group B, Rh(D)+ type, received an allogeneic peripheral blood stem cell (PBSC) transplant after a non-myeloablative regimen of fludarabine and cyclophosphamide for resistant γ δ cutaneous T-cell lymphoma (CTCL). The donor was his HLA-identical brother, blood group O, Rh(D)+ type. Graft-versus-host disease (GVHD) prophylaxis was performed with cyclosporine alone. On day +8, massive immune hemolysis occurred, followed by acute renal failure. Hemodialysis was performed eight times until recovery of renal function on day +24. The risk of delayed immune hemolysis after non-myeloablative allogeneic PBSC transplantation with minor ABO-incompatibility must be considered.

OCULOMOTOR NERVE INVASION OF ACUTE MYELOGENOUS LEUKEMIA DEMONSTRATED BY MAGNETIC RESONANCE IMAGING

A 53-year-old male was diagnosed as having acute myelogenous leukemia (M2, FAB). He complained of double vision and right blepharoptosis after receiving remission induction chemotherapy. Magnetic resonance imaging (MRI) showed enlargement of the bilateral oculomotor nerves. Intrathecal injections of methotrexate and cytosine arabinoside were partially effective and repeated MRI showed shrinkage of the enlarged oculomotor nerves, after therapy. This case shows the importance of MRI in the early diagnosis of CNS leukemia.

Membranous nephropathy in an HIV-positive patient complicated with hepatitis B virus infection

In ordinary settings, human immunodeficiency virus (HIV)-associated nephropathy should be considered when HIV infection is associated with heavy proteinuria. On the other hand, hepatitis B virus (HBV) may also play a role in the development of glomerular injury among patients with HIV infection, since HIV and HBV infections commonly occur together due to shared modes of transmission. We present here a case of nephrotic syndrome in an HIV-positive patient complicated with HBV infection. A renal biopsy revealed sparse granular deposits of immunoglobulin G in the subepithelial region, consistent with membranous nephropathy (MN) stage I. Moreover, immunostaining exhibited weak anti-hepatitis B core activity within glomeruli. These results led us to consider that HBV-associated MN might play a role in the development of nephrotic syndrome. Although anti-viral treatment for patients with HBV-associated MN has been suggested to be clinically effective, the use of two anti-HIV agents (tenofovir and emtricitabine), both of which have anti-HBV activities, was not effective for the patient’s nephrotic syndrome, despite obtaining a decrease in the serum HBV-DNA levels. A lack of prospective data suggests that many decisions on the treatment of glomerulopathies with HIV infections are potentially empirical. Obviously, further studies and accumulated clinical experience are required to better determine the pathogenesis and management of HBV-associated MN among patients with HIV infections.

Correlation between flow cytometric identification of CD33-positive cells and morphological evaluation of myeloblasts in bone marrow of patients with acute myeloblastic leukemia

Abstract Determination of the percentage of myeloblasts in bone marrow is important for the evaluation of acute myeloblastic leukemia (AML) and related disorders. Using flow cytometry with a CD45-blast gate (FCM/CD45), 226 bone marrow aspiration samples serially collected from 71 patients with de novo AML were analyzed. Bone marrow smears were evaluated independently by pathologists who did not know the corresponding flow cytometric data in advance. Patients received remission induction followed by consolidation. The CD33+ cell percentages evaluated by FCM/CD45 were strongly correlated to the myeloblast percentages determined by microscopic examination (r=0·8360, p<0·001). When only samples containing leukemic cells demonstrated by chromosomal or fluorescence in situ hybridization (FISH) analysis after induction were evaluated, positive correlations were found between CD33+ cell percentages determined by FCM/CD45 and myeloblast percentages determined by morphology (r=0·672, p<0·001). The identification of CD33+ cells by FCM/CD45 is useful for the evaluation of bone marrow myeloblasts in AML.

Prediction of response to imatinib in patients with chronic myelogenous leukemia by flow cytometric analysis of bone marrow blastic cell phenotypes.

Chronic myelogeneous leukemia (CML) is characterised by a specific translocation t(9; 22)(q34; q11), the Philadelphia (Ph) chromosome, giving rise to the novel BCR/ABL fusion gene [1]. The deregulated tyrosine kinase activity of the protein encoded by the fusion gene has been shown to be both necessary and sufficient for the initiation and maintenance of CML [1]. High response rates and favourable toxicities of imatinib in patients with newly diagnosed CML in chronic phase have been reported [2]. Imatinib induces a complete cytogenetic response (CCyR), i.e. disappearance of the Ph chromosome, in most patients with CML in chronic phase after one year of treatment with the drug [3–5]. However, some patients with CML in chronic phase who received treatment with imatinib show residual Ph chromosome after one year of treatment, and event-free survival in such patients was worse than that in patients showing a CCyR [3–5]. We analysed phenotypes of the cells in the blast region of bone marrow in CML by flow cytometry (FCM) and determined whether the phenotypes of the cells predict response to imatinib. During the period from January 2005 to April 2007, 32 patients in Jichi University Hospital were diagnosed as having CML in chronic phase. The diagnosis of CML in chronic phase was based on peripheral blood pictures, bone marrow pictures and existence of the Ph chromosome in bone marrow. Three-colour FCM combined with two-colour FCM was performed to evaluate phenotypes of the cells in the blast region of bone marrow before the beginning of imatinib therapy. Bone marrow mononuclear cells were stained with fluorescein isothiocyanateconjugated monoclonal antibody and/or phycoerythrin-conjugated monoclonal antibody and peridinin chlorophyll protein-conjugated CD45 [6,7]. Monoclonal antibodies used in this study were as follows: CD5, CD7, CD2, CD19, CD20, CD10, CD13, CD14, CD15, CD33, CD34, CD117, CD41, CD11b, CD11c, CD36, CD25, CD56, CD45 and HLA-DR. A gate was set for identifying immature cells characterised by intermediate CD45 expression and low side scatter properties [6,7]. Phenotypes of the cells in the blast region were analysed using a flow cytometer (FACSCalibur; BD Biosciences, San Jose, CA). Karyotypic analysis of bone marrow cells was performed using a standard Giemsa-banding method, and approximately 20 metaphases were analysed. BCR-ABL transcripts in bone marrow cells were measured using a real-time quantitative polymerase chain reaction assay (SRL Inc., Tokyo) [8]. All patients received treatment with imatinib only after the diagnosis of CML in chronic phase. To compare phenotypes of the cells in the blast region of bone marrow, bone marrow cells from patients with

Cutaneous invasive aspergillosis in a patient with glioblastoma receiving long-term temozolomide and corticosteroid therapy

Glioblastoma is an aggressive brain tumor that requires multidisciplinary treatment including adjuvant radiotherapy, chemotherapy, and adjunct corticosteroids. Temozolomide is a commonly used chemotherapy drug and frequently causes lymphocytopenia. We describe the case of a 67-year-old woman with cutaneous invasive aspergillosis who had received long-term temozolomide and corticosteroid therapy for glioblastoma. She presented with multiple indurations, erythema, and purpura, some of which produced purulent discharge, in the anterior abdomen. Extensive intra- or inter-muscular abscesses of the right anterior abdominal wall were also observed. Her absolute lymphocyte counts were 156/μL on admission. Cultures obtained from the wound yielded Aspergillus fumigatus. She was diagnosed with secondary cutaneous invasive aspergillosis, which likely resulted from hematogenous dissemination. Although rare, this case illustrates that temozolomide-induced lymphocytopenia, especially in cases of concomitant corticosteroid use, can be associated with severe invasive aspergillosis.

Usefulness of 18F-Fluorodeoxyglucose-position emission tomography with computed tomography and gallium-67 scintigraphy for detection of Kaposi sarcoma lesions in a 40-year-old Japanese man with AIDS

A 40-year-old Japanese man with acquired immunodeficiency syndrome was diagnosed with Kaposi sarcoma (KS) on the basis of the results of skin lesion biopsies. In addition, 18F-fluorodeoxyglucose-position emission tomography–computed tomography revealed abnormal fluorodeoxyglucose uptake in KS lesions, whereas gallium-67 scintigraphy did not show uptake of gallium. These findings indicate that combining these imaging modalities can help distinguish KS from other malignancies and opportunistic infections.

Non-surgical management of post-cesarean uterine infection with marked myometrial gas formation

Gas in an infected organ generally indicates a severe infection, often requiring surgery; however, data are lacking as to post‐cesarean gas‐forming uterine infection. A 27‐year‐old Japanese primigravida underwent a difficult cesarean section, after which a high fever continued. Computed tomography (CT) revealed marked gas in the uterine anterior myometrium. Diagnosing this condition as post‐cesarean uterine scar infection, we recommended surgical intervention, that is, hysterectomy or at least drainage; however, the patient refused it. Considering the patients desire and lack of organ‐failure signs, we employed intensive antibiotic treatment for 6 weeks. Serial CT indicated a gradual decrement in the gas amount and she recovered completely after 8 weeks. This case suggests that surgical procedure may not always be necessary for post‐cesarean gas‐forming uterine infection and CT may be useful to detect/follow this condition.

Maintenance and preemptive therapy with ganciclovir for cytomegalovirus colitis with extremely high antigenemia in adult T-cell leukemia

Patients with adult T-cell leukemia (ATL) are susceptible to opportunistic infections. The major cause of death in ATL patients is cytomegalovirus (CMV) pneumonia [1]. However, the onset of CMV infection in a very early phase of ATL is uncommon [2]. In addition, there are no detailed descriptions concerning the effect of oral ganciclovir (GCV) in ATL. Herein, we report a case with ATL who demonstrated CMV colitis on the second day of prednisolone administration. A 48-year-old female was admitted because of fever, erythema, and fatigue. Her white blood cell (WBC) count was 18,400/mm (atypical lymphocytes including flower cells: 48.5%). The left and right cervical, axillary, and right inguinal lymph nodes were swollen. Erythema of the face, limbs, and neck was observed. Histopathologic findings of biopsy specimens from erythema sites demonstrated the possibility of ATL cells having invaded the skin. The lactate dehydrogenase (LDH) score was 505 U/L (more than twice the normal upper limit) and human T lymphotrophic virus type 1 provirus was detected on Southern blot analysis. Therefore, we diagnosed this case as acutetype ATL. The compensated calcium level was normal (9.6 mg/dL), and there were no other sites of involvement such as the liver, spleen, and cerebrospinal fluid. She was started on prednisolone for ATL. On the day following the start of administration, diarrhea and abdominal pain developed. We started chemotherapy primarily according to the LSG 15 protocol [3], because it was possible at that time that her diarrhea was caused by ATL cell invasion of the colon. However, an abdominal computed tomography scan showed ascites and mucosal thickening of the colon, which indicated colitis. Histopathologic findings of biopsy specimens from edematous lesions of the rectum detected by proctoscopy demonstrated intranuclear CMV inclusion bodies in endothelial cells but not the invasion of ATL cells. In addition, there were 3411 and 3258 CMV antigenpositive leukocytes each per 15 9 10 WBCs, and other pathogens which can induce diarrhea were not detected. No other manifestations induced by CMV infection such as CMV pneumonia and retinitis appeared. Therefore, the diagnosis of CMV colitis was confirmed. She received intravenous GCV. Diarrhea improved and the score of CMV antigenemia gradually declined (Fig. 1). After the diarrhea had fully resolved and informed consent was given, we continued maintenance therapy with oral GCV until CMV antigenemia became negative. Thereafter, we chose preemptive therapy involving oral GCV along with the monitoring of CMV antigenemia. This patient received allogeneic bone marrow transplantation (BMT) four months after the diagnosis of CMV colitis. We continued the same preemptive therapy until BMT. CMV infection never recurred before BMT. In addition, chemotherapy was effective. After chemotherapy, atypical lymphocytes in the peripheral blood disappeared, and the score of the soluble interleukin-2 receptor was reduced (Fig. 1). Swollen lymph nodes regressed. In addition, the level of LDH was reduced, but just less than half of the erythematous area S. Nagai M. Toshima K. Sato M. Mori T. Nagai K. Muroi K. Ozawa Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 3290498, Japan