Kichinosuke Kobayashi

Antifungal prophylaxis with micafungin in neutropenic patients with hematological malignancies.

The aim of the study was to assess the antifungal prophylactic efficacy, safety, and tolerability of micafungin, 150 mg daily, and to evaluate the usefulness of monitoring 1,3-β-d-glucan (BG) in neutropenic patients undergoing chemotherapy for hematological malignancies. This investigation was a retrospective, non-randomized study. A group of patients who did not receive systemic antifungal prophylaxis was compared to another group of patients who received micafungin 150 mg daily. All patients admitted with hematological malignancy and undergoing chemotherapy or stem cell transplant were included. The plasma BG level was measured once weekly. The clinical endpoint was the diagnosis of invasive fungal infection (IFI). Antifungal prophylaxis led to a significant decrease in the occurrence of IFI (from 12.3% to 1.5%, p = 0.001). Few severe adverse effects clearly attributable to micafungin were seen. Sensitivity, specificity, positive predictive value, negative predictive value, and efficiency of BG values >8.9 pg/mL for diagnosis of IFI were 0.90, 0.99, 0.82, 0.99, and 0.99, respectively. Micafungin, 150 mg daily, is an effective and safe drug for antifungal prophylaxis, and monitoring of BG antigenemia is a useful tool for diagnosis of IFI in neutropenic patients with hematological malignancies.

Minimal-change nephrotic syndrome preceding Hodgkin lymphoma by 5 years with expression of tumor necrosis factor α in Hodgkin-Reed-Sternberg cells ☆

A 76-year-old man developed minimal-change nephrotic syndrome (NS). After treatment with prednisolone failed to induce sustained remission, cyclosporin was added. The NS improved, and prednisolone and cyclosporin doses were gradually decreased. However, he had repeated relapses of the syndrome, and at each relapse, the drug doses were increased. After 5 years, the patient developed left inguinal lymphadenopathy. The histological diagnosis was mixed cellularity classical Hodgkin lymphoma. He received 6 courses of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), and mixed cellularity classical Hodgkin lymphoma and NS both showed complete response. Although the association between Hodgkin lymphoma and minimal-change NS is well known, the pathogenesis is unknown. To the best of our knowledge, this is the first case report of minimal-change NS associated with Hodgkin lymphoma in which Hodgkin-Reed-Sternberg cells were immunostained for tumor necrosis factor-alpha (TNF-alpha) clearly demonstrating that Hodgkin-Reed-Sternberg produced TNF-alpha and in which the plasma level of TNF-alpha normalized after improvement of Hodgkin lymphoma by chemotherapy. The production of TNF-alpha by Hodgkin-Reed-Sternberg cells might play a key role as a potential mediator of minimal-change NS.

VIPoma with expression of both VIP and VPAC1 receptors in a patient with WDHA syndrome

We report a case of VIPoma in a 72-year-old female patient who presented with excessive diarrhea, severe hypokalemia, and acidemia. She had been referred to our hospital three times because of severe diarrhea. No primary tumor site was found by conventional techniques, including contrast-enhanced CT and MRI, angiography, endoscopy, and positron emission tomography (PET), but a tumor was subsequently found in the head of the pancreas by octreotide scanning. Her diarrhea diminished dramatically after octreotide treatment, while her diarrhea has ceased without the therapy of octreotide at the first admission in the course of 2 years of her disease. Immunohistochemial analysis of the excised tumor tissue revealed the expression of both vasoactive intestinal peptide (VIP) and VIP and pituitary adenylate cyclase-activating peptide 1 (VPAC1) receptors. This is the first case report of a VIPoma that immunostains for VIP and VPAC1 receptors and indicates that abundant VIP produced by VIPoma might inhibit its growth and reduce VIP secretion via the VPAC1 receptor in vivo.

Primary effusion lymphoma of T-cell origin with t(7;8)(q32;q13) in an HIV-negative patient with HCV-related liver cirrhosis and hepatocellular carcinoma positive for HHV6 and HHV8

Dear Editor, A 67-year-old man with chronic hepatitis C since 1981 was found to have a few mass lesions that were detected in an abdominal echogram performed in 2006. Hepatitis C virus (HCV) viremia was confirmed by a quantitative assay of viral load of 7.8 log IU/mL in the plasma (Cobas TaqMan HCV, Roche, Branchburg, NJ). Computed tomography (CT) detected one mass in S6 and another mass in S8 in his liver. On the basis of angiographic findings and liver biopsy, he was diagnosed with HCV-associated liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Lipiodol-transcatheter arterial embolization and percutaneous ethanol injection therapy were administered for the lesions, and HCC relapse was not detected. The patient was admitted in 2008 because of an enlarging abdomen and early satiety. CT scan showed massive fluid accumulation within the peritoneal cavity but there were no new HCC lesions (Fig. 1a). A gallium-67 scintigram revealed abnormal accumulation of the isotope in the abdominal cavity. The results of serological tests for human immunodeficiency virus (HIV), Epstein–Barr virus, and human T-lymphotropic virus 1 were negative. DNA of human herpesvirus (HHV) 6 (>2.0×10 copies/10 cells) and HHV8 DNA (>2.0× 10 copies/10 cells) were detected in peripheral blood leukocytes. The smear preparations showed noncohesive large lymphoma cells with abundant cytoplasm and prominent nucleoli (Fig. 1b). Most lymphoma cells were positive for CD45RO (Clone UCHL 1, DAKO, Carpinteria, CA; Fig. 1c) and negative for CD79a and CD20. The nucleoli of lymphoma cells were positive for latent HHV6 (2002, Thermo Fisher Scientific, Wattham, MA; Fig. 1d) and HHV8 (LN53, Diagnostic BioSystems, Pleasanton, CA; Fig. 1e) infections. Southern blotting revealed a clonal rearrangement of the T cell receptor Jγ chain gene. No clonal rearrangement of the immunoglobulin heavy chain gene was found by Southern blotting. Cytogenetic analysis of GTG banding was performed, where the specimen was cultured at 37°C for 24 h in an RPMI 1640 medium containing 10% fetal calf serum and antibiotics. After adding 0.04 μg/mL colcemide for 16 h, the cell suspension was exposed to 75 mM KCL and fixed with a mixture of methanol and acetic acid (3:1). Spreads of chromosomes were made by dropping the cell suspension onto glass slides S. Nakayama-Ichiyama (*) : T. Yokote :K. Kobayashi : Y. Hirata :N. Hiraoka :K. Iwaki :A. Takayama : T. Akioka : S. Oka : T. Miyoshi : T. Hanafusa Department of Internal Medicine (I), Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-0801, Japan e-mail: in1304@poh.osaka-med.ac.jp

Primary cutaneous diffuse large B-cell lymphoma, leg type, with features simulating POEMS syndrome.

A 91‐year‐old woman presented with a rapidly proliferative cutaneous lesion on the left lower limb, which was identified as a primary cutaneous diffuse large B‐cell lymphoma (PCLBCL), leg type, on biopsy. The patient also showed complications of hepatomegaly, endocrinopathy, edema, skin change, and polyneuropathy without monoclonal plasma cell proliferative disorder, and was therefore diagnosed with POEMS‐like syndrome owing to the lack of monoclonal plasma cell proliferative disorder. Levels of serum vascular endothelial growth factor (VEGF) and interleukin‐6 (IL‐6) were high with the lymphoma cells immunostained positively for VEGF and IL‐6. To the best of our knowledge, this is the first case report of PCLBCL, leg type, with POEMS‐like syndrome. The findings in this case suggest that the symptoms of POEMS‐like syndrome might be caused by the cytokines produced by the lymphoma cells. Furthermore, a wider range of diagnostic criteria associated with the result of abnormal secretion of cytokine may have to be considered for the diagnosis and evaluation of patients with possible POEMS syndrome, as against the present criteria specifying monoclonal plasma cell proliferative disorder as the essential criterion.

Inappropriate antidiuretic hormone production in diffuse large B-cell lymphoma

An 84-year-old woman presented with a 2-month history of a left cervical tumour, which was increasing in size. Clinical examination was otherwise normal. A diagnosis of diffuse large B-cell lymphoma was made by biopsy of a left cervical lymph node (left; haematoxylin and eosin). Clinical stage was II A, and the International Prognostic Index was lowintermediate. Twenty-six days after presentation, she received multi-agent chemotherapy with R-CHOP (rituximab, doxorubicin, vincristine, cyclophosphamide and prednisolone). On day 28, she showed severe reduction of consciousness, assessed at E3, V3, and M5 on the Glasgow Coma Scale. She was clinically normovolaemic with no signs of fluid retention. Thyroid and adrenal function were normal and she had no recent history of use of diuretic agents. Investigation showed serum sodium decreased to 111 mmol/l, chloride of 78 mmol/l and effective osmolality at 231 mOsm/kg (normal range: 276–292 mOsm/ kgÆH2O). Urinary investigation showed increased sodium 53 mmol/l, chloride 43 mmol/l and osmolality 338 mOsm/ kgÆH2O during hypotonicity with normal dietary salt intake. Serum antidiuretic hormone (ADH) was 4Æ2 pg/ml (normal range: 1Æ3–4Æ1 pg/ml). Immunohistochemistry of the original lymph node biopsy specimen showed lymphoma cells to be positive for ADH (right; rabbit anti-vasopressin; Fitzgerald Industries International, MA, USA). The inappropriate elevation of ADH in this patient is likely to have been the result of tumour lysis following chemotherapy. The patient was treated with 1000 ml/d of intravenous 0Æ9% saline, and further fluid was restricted. By day 39, serum sodium had increased to 142 mmol/l and serum chloride to 98 mmol/l. Given that the response to the first course of chemotherapy had been favourable and because it was considered that the syndrome of inappropriate secretion of ADH (SIADH) was likely to have been the result of tumour lysis rather than a complication of vincristine therapy, treatment with R-CHOP was continued with no adverse effects. This case demonstrates that in haematological malignancies with SIADH, immunohistochemical staining of the tumour can distinguish the production of ADH by malignant cells from that by cells of other origin and thus has a role in determining further therapy.

A paraneoplastic neuromyelitis optica spectrum disorder associated with a mature B-cell neoplasm.

Neuromyelitis optica (NMO) is an idiopathic inflammatory emyelinating disease of the central nervous system that primarly affects the optic nerves and the spinal cord. Optic neuritis nd myelitis can occur in discrete episodes separated by years 1]. Although it has long been considered a subtype of muliple sclerosis (MS), new pathological and serological findings ave clearly defined NMO as a distinct disease because of the iscovery of NMO immunoglobulin G (NMO-IgG), which is a ighly disease-specific autoantibody often called anti-aquaporin(AQP4) antibody ([AQP4-Ab]) found in NMO and NMO spectrum isorders, but absent in the classical form of MS [1]. A 57-year-old woman was admitted to our hospital because he developed progressive paresthesia in the chest and weakness n the lower limbs. She was afebrile, conscious, and there was o lymphadenopathy. Ophthalmological examination was normal. eurological examination on admission revealed flaccid parapareis with hyperreflexia in both lower limbs, bilateral extensor lantar responses, and a sensory level to pinprick at T1–T4 level. agnetic resonance imaging (MRI) of the spinal cord revealed a T2yperintense lesion extending from C5 to T4 (Fig. 1A). Brain MRI howed T2-hyperintense lesions mostly in periventricular white atter, but also in corona radiata. On gadolinium enhancement, he T1-weighted spin-echo sequence, which is a sensitive investiation for detecting acute optic neuritis, was normal. Whole-body omputed tomography revealed no evidence of lymphadenopathy. gallium-67 scintigram revealed no abnormal accumulation. The esults of blood analysis were as follows: white blood cell count, 5.32 × 109/L (48% neutrophils, 8% lymphocytes, and 39.5% abnoral small cleaved lymphoid cells with inconspicuous nucleoli); emoglobin, 125 g/L; platelet count, 219 × 109/L; lactate dehydroenase, 209 U/L (normal: 130–250 U/L); and C-reactive protein, .01 mg/dL (normal: <0.25 mg/dL). Serum NMO-IgG measured sing an AQP4 autoantibody ELISA kit (RSR Limited, Cardiff, UK) AQP4-Ab) was 3.8 U/mL (normal: <1.0 U/mL) [2]. A bone marow aspirate showed a diffuse abnormal lymphoid infiltration of 2.6%, with the same morphology as in peripheral blood (Fig. 2A). low cytometry CD45 gating for immunophenotyping displayed he following results: positive for CD10, CD19, CD20, and cytolasmic bcl-2; negative for CD3, CD4, and CD5; and lambda light hain restriction. Immunohistochemical analysis of the abnoral cells showed that the cells were positive for CD10 (56C6, ovocastra, Newcastle Upon Tyne, England; Fig. 2B), CD20 (SL26, yowa Medex, Tokyo, Japan; Fig. 2C), and bcl-2 (HM57, DAKO, arpinteria, CA; Fig. 2D). The abnormal cells were negative for QP4 (Sigma–Aldrich, St. Louis, MO, USA). Fluorescence in situ ybridization analysis of fusion signal of IgH/bcl-2 genes was postive. Southern blot analysis showed clonal rearrangement of the mmunoglobulin heavy chain gene. Cerebrospinal fluid (CSF) examnation showed pleocytosis (44 cells/mm3; normal: <5 cells/mm3), and thoracic spinal cord at the time of presentation (A) and after a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP therapy) (B). The scans show that the T2-hyperintense lesion and severe cord edema observed in the initial scan improved after therapy. These radiological changes correlated with clinical improvement of the patient.

Two case reports of non-secretary-Ig types of lymphoplasmacytic lymphoma (LPL)

Dear Editor, We encountered two patients with non-secretary-immunoglobulin (Ig) types of lymphoplasmacytic lymphoma (LPL) without paraprotein excretion and having genomic anomaly including t(9;14) involving Pax-5. In the first case, a 71-year-old woman presented at our hospital on March 31, 2008 with a month-long history of progressive fatigue and a right cervical tumor that was increasing in size. Laboratory data revealed a hemoglobin count of 8.8 g/dL, total protein 7.2 g/dL, immunoglobulin G (IgG) 877 mg/dL (normal, 840-1,615 mg/dL), IgA 162 mg/dL (normal, 67.0-346 mg/dL), IgM 133 mg/dL (normal 23.0-218 mg/dL). A computed tomography (CT) scan revealed a swollen right cervical lymph node measuring 3.2 cm×2.7 cm. Immunofixation did not reveal any monoclonal bands in the serum. Immunoelectrophoresis did not detect the presence of Bence Jones proteins in the urine. No osteolytic changes were present. A diagnostic biopsy of the bone marrow showed infiltration of abnormal cells admixed with variable numbers of plasma cells and plasmacytoid lymphocytes (Fig. 1). Flow cytometry of the marrow showed abnormal cells expressing CD19, CD20, CD22, IgM, and cytoplasmic IgM kappa light chain. Cytogenetics of the marrow (Giemsa-banding) revealed 46 XX normal female karyotype in the 20 cells that were analyzed. Fluorescence in situ hybridization (FISH) revealed Pax-5 split signal (448/1,000 cells; Fig. 2). The patient was diagnosed as clinical stage IVB of LPL, and the patient underwent induction therapy with Rituximab, Cytoxan, Hydroxydaunorubicin (Adriamycin), Oncovin (Vincristine), Prednisone/Prednisolone (R-CHOP). A restaging study following five cycles of the therapy revealed complete response. In the second case, a 60-year-old man presented at our hospital on March 31, 2007. The patient had experienced a 4.5-kg weight loss in 1 month together with night sweats. A physical examination at the time of presentation revealed right cervical lymphadenopathy with the largest node measuring 2.0×1.6×1.2 cm, and splenomegaly, which was palpable 2 cm inferior to the left costal margin. Laboratory data revealed a hemoglobin count of 13.7 g/ dL, total protein 6.4 g/dL, albumin 4.2 g/dL, IgG 811 mg/ dL, IgA 153 mg/dL, IgM 109 mg/dL. Immunofixation did not reveal any monoclonal bands in the serum. Immunoelectrophoresis did not detect the presence of Bence Jones proteins in the urine. A CT scan showed a swollen right cervical lymph node measuring 10×15×35 mm. No osteolytic changes were noted. A biopsy of the right cervical lymph node revealed diffuse involvement of plasma cytoid lymphocytes (Fig. 3a). Flow cytometry of the marrow showed a clonal population of B-cells expressing CD19, CD20, CD22, and cytoplasmic kappa light chain. Cytogenetics of the marrow (Giemsa banding) revealed 51, XY, +X, +3, +der(7)inv(7)(p13q32)del(7) (q32), +9, t(9;14)(p13;q32), +18, add(19)(p13), t(19;22) (q13.1;q11.1) (19/20 cells). Immunohistochemistry showed K. Kobayashi (*) : T. Yokote :Y. Hirata : S. Nakayama : N. Hiraoka :A. Takayama :K. Iwaki : T. Akioka : T. Hanafusa Department of Internal Medicine (I), Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-0801, Japan e-mail: in1268@poh.osaka-med.ac.jp

Syndrome of inappropriate antidiuretic hormone associated with chemotherapy-induced tumor lysis in a patient with peripheral T-cell lymphoma unspecified

A 74-year-old woman presenting with a 2-month history of bilateral cervical tumors, progressively increasing in size, was admitted to our hospital on 11 September 2006. Blood examination showed the following: white blood cells, 3.176 10/L; hemoglobin, 12.8 g/dL; platelets, 1796 10/L; lactate dehydrogenase (LDH ), 359 IU/L; serum C-reactive protein (CRP), 2.39 mg/dL; blood urea nitrogen (BUN), 8 mg/mL; creatinine, 0.71 mg/dL; serum sodium, 137 mmol/L; serum potassium, 5.0 mmol/L; and serum chloride, 103 mmol/L. Biopsy of the right cervical lymph node revealed disruption of the normal lymph node architecture by a diffuse infiltrate of medium to large sized atypical lymphoid cells with irregular pleomorphic nuclei, often prominent nucleoli and readily appreciated mitotic figures (Figure 1). These cells expressed CD3 and CD45RO but not CD79a and TdT. Southern blot analysis revealed rearrangement of T-cell receptor Cb1 gene; cytogenetic analysis showed normal karyotype (46XX). Thereafter, the patient was diagnosed with peripheral T-cell lymphoma unspecified (PTCL-U). Computed tomography (CT) scan of the chest showed bilateral mediastinal and hilar lymphadenopathy, and abdominal CT revealed inguinal lymphadenopathy. There were no signs of hepatomegaly or splenomegaly. Bone marrow biopsy showed no infiltration of the lymphoma cells. The disease was clinically staged III B, and the Prognostic Index for PTCL-U was Group 3. Multi-agent chemotherapy with CHOP [doxorubicin (50 mg/m, Day 1), vincristine (1.4 mg/m, Day 1), cyclophosphamide (750 mg/m, Day 1), and prednisolone (100 mg/body, Days 1–5)] was started; after six cycles, the rate of complete response to chemotherapy was assessed. Four months after the end of CHOP chemotherapy, the patient was readmitted because of fever and cervical lymphadenopathy. Blood examination showed the following: white blood cells, 1.166 10/L; hemoglobin, 9.1 g/dL; platelets, 676 10/L; LDH, 659 IU/L; serum CRP, 5.37 mg/ dL; BUN, 14 mg/mL; creatinine, 0.55 mg/dL; serum sodium, 141 mmol/L; serum potassium, 4.3 mmol/L; and serum chloride, 100 mmol/L. Chest CT revealed bilateral axillary, mediastinal, and hilar lymphadenopathy. Abdominal CT revealed inguinal, periaortic, and mesenteric lymphadenopathy and splenomegaly; however, there was no sign of hepatomegaly. Bone marrow biopsy revealed extensive infiltration by neoplastic CD3 positive T lymphoma cells, which comprised nearly 80% of the marrow cellularity. On 14 June 2007, the patient received multi-agent chemotherapy with ESHAP [VP-16 (40 mg/m, days 1–4), methylprednisolone (500 mg/kg body weight intravenously, Days 1–5), Ara-C (2 g/m intravenously, Day 5), and cisplatin (25 mg/m, 24-h intravenous infusion for 4 days)]. On 22 June, the patient developed nausea, headache, and general

Endophthalmitis Due to Trichosporon beigelii in Acute Leukemia

We describe 2 patients with hematologic malignancy who developed endophthalmitis due to Trichosporon beigelii during the course of treatment with multiagent chemotherapy. Blood cultures revealed T beigelii for both patients. Although one of the patients was treated with fluconazole (FLCZ) and 5-fluorocytosine, the trichosporonous endophthalmitis was resistant to both drugs. This patient subsequently received amphotericin B (AMPH-B) therapy, and the eyes were treated with vitrectomy. The second patient also received AMPH-B for FLCZ-resistant trichosporonous chorioretinitis. In both patients, systemic treatment with AMPH-B successfully resolved the trichosporonous endophthalmitis that was resistant to multiple antifungal drugs. Endophthalmitis due to trichosporonosis is difficult to treat. The administration of AMPH-B is likely to be more effective in treating endophthalmitis due to trichosporonosis when the disease is at an early stage.